Datasets:

rachel6603

/

zero_shot_1_PubMed

like 0

The pentose phosphate pathway in skeletal muscle under patho-physiological conditions. A combined histochemical and biochemical study. Over the last 30 years, research into the neuromuscular apparatus, has expanded greatly. Multidisciplinary investigations have rapidly advanced our understanding both of diseases and of the basic neuromuscular mechanisms. The mode of pathological reaction of the neuromuscular apparatus is now quite well understood. The most notable aspect of the reaction of the injured neuromuscular apparatus is the remarkably stereotyped character of the resulting pathological changes as demonstrated by a wide variety of harmful causes, producing surprisingly similar effects. The findings of our combined histochemical and biochemical investigations presented in this monograph, are in complete harmony with the stereotyped character of the pathological changes. For example, it is particularly striking that many affected muscle fibres of patients with muscular dystrophies, congenital myopathies, inflammatory myopathies, metabolic myopathies, endocrine myopathies, or with diseases of the lower motor neuron, display an enhanced activity of both oxidative enzymes of the pentose phosphate pathway. Likewise, we found that experimental animals with disordered skeletal muscles, provoked by different types of agents or treatments, reveal the same marked rise in activity of GPDH and PGDH in the muscle fibres, with a positive correlation between the activity of both enzymes. Other findings of our investigations point to a positive correlation between the activity of GPDH and PGDH on the one hand and that of the non-oxidative enzymes of the pentose phosphate pathway, the enzymes TA, TK, RPI and RPE on the other hand. The rise in activity of PGDH and, in particular, of GPDH is regulated by two different mechanisms. The first represents a rapid control mechanism based on the stimulation of both oxidative enzymes of the pentose phosphate pathway by NADP+ and on their inhibition by NADPH. The other mechanism represents a long-term effect directed at the synthesis of the enzymes. It is this type of mechanism which is responsible for the rise in activity of GPDH and PGDH we observed. The findings obtained with the applied enzyme histochemical techniques clearly demonstrated that the rise in activity of both enzymes is not homogeneously distributed in the disordered skeletal muscles of man and experimental animals. For that reason, in order to obtain reliable quantitative information about enzyme activities in the muscle fibres themselves, the application of biochemical assays on a micro-scale was indispensable. The biochemical assay of enzyme activities was performed on histologically and histochemically selected dissected muscle specimens.(ABSTRACT TRUNCATED AT 400 WORDS)

A New Race of Verticillium dahliae Causing Leaf Mottle of Sunflower in Europe. Sunflower (Helianthus annuus L.) plants with symptoms of interveinal chlorosis were observed in the summer of 2013 in one field in Cadiz (Spain) where the performance of 30 hybrids was assessed. Symptoms affected 80% of the hybrids with incidence as high as 90%. Chlorosis and yellowing near the leaf margin were visible at floral initiation, and they progressed from the lower to upper leaves. Mottled leaves were observed near the top of the plants. On severely affected leaves, chlorotic patches enlarged, coalesced, and large areas of the leaves became necrotic and dried. Cross sections of the lower stem showed a brown discoloration of the vascular system. The fungus that was consistently isolated from stem and petiole tissues of sunflower plants was morphologically identified as Verticillium dahliae Kleb. (Vd) (5) and molecularly confirmed by PCR amplification of the 526-bp band (4). The race of the isolates was determined in a greenhouse experiment at 18 to 28°C from February to April 2014. Isolates 1-13 and 2-13 of Vd, obtained from two of the hybrids in 2013, one of them being Transol, were independently inoculated to 1-month-old plants of each of three sunflower genotypes: the susceptible hybrid Transol and the inbred lines HA89 (carrying the V1 gene for resistance to Vd) (2) and HAR5 (resistant to other diseases but with unknown reaction to Vd). Plants were inoculated by immersing roots in a suspension of 106 conidia per ml for 30 min. Inoculated plants were individually transplanted to 1-liter pots filled with sand/silt. Roots of the control treatments were immersed in water. Six replications (pots) were established for each isolate × genotype combination, according to a complete randomized 3 × 3 factorial design. Five weeks after inoculation, symptoms developed in 100% of the plants in the three sunflower genotypes. Severity of symptoms (SS) in each plant was assessed as percentage of foliar tissue affected. Significantly higher SS occurred on inoculated plants as compared to non-inoculated plants, which did not develop symptoms. Mean disease severity on inoculated plants was 80% (averaged across isolates and genotypes). A significant effect of genotypes was obtained. Mean SS averaged across isolates were 98, 73, and 69% for HAR5, HA89, and Transol, respectively. When stem tissues from the three sunflower genotypes were sampled and incubated on potato dextrose agar at 25°C, the mycelial growth of Vd was confirmed for the inoculated plants but not for the control plants. Isolates of Vd infecting the resistant inbred line HA89 have only been identified in Argentina (1) and the United States (3). To our knowledge, this is the first report of a race overcoming the V1 gene in HA89 in Europe. This poses a risk to commercial sunflower breeding programs in European countries. References: (1) A. B. Bertero de Romano and A. Vázquez. Page 177 in: Proc. 10th Int. Sunf. Conf., Surfers Paradise, Australia, 1982. (2) G. N. Fick and D. E. Zimmer. Crop Sci. 14:895, 1974. (3) T. Gulya. Helia 30:115, 2007. (4) J. Mercado-Blanco et al. Plant Dis. 87:1487, 2003. (5) W. E. Sackston. Plant Dis. Rep. 41:885, 1957.

Hyperacetylation of core histones does not cause unfolding of nucleosomes. Neutron scatter data accords with disc shape of the nucleosome. Recent studies report that the frictional resistance of partially acetylated core particles increases when the number of acetyl groups/particle exceeds 10 (Bode, J., Gomez-Lira, M. M. & Schröter, H. (1983) Eur. J. Biochem. 130, 437-445). This was attributed to an opening of the core particle though other explanations, e.g. unwinding of the DNA ends were also suggested. Another possible explanation is that release of the core histone N-terminal domains by acetylation increased the frictional resistance of the particle. Neutron scatter studies have been performed on core particles acetylated to different levels up to 2.4 acetates/H4 molecule. Up to this level of acetylation the neutron scatter data show no evidence for unfolding of the core particle. The fundamental scatter functions for the envelope shape and internal structure are identical to those obtained previously for bulk core particles. The structure that gave the best fit to these fundamental scatter functions was a flat disc of diameter 11-11.5 nm and of thickness 5.5-6 nm with 1.7 +/- 0.2 turns of DNA coiled with a pitch of 3.0 nm around a core of the histone octamer. The data analysis emphasizes the changes in pair distance distribution functions at relatively low contrasts, particularly when the protein is contrast matched and DNA dominates the scatter. Under these conditions there is no evidence for the unwinding of long DNA ends in the hyperacetylated core particles. The distance distribution functions go to zero between 11.5 and 12 nm which gives the maximum chord length in a particle of dimension, 11 nm X 5.5 nm. The distance distribution function for the histone octamer contains 85% of the vectors within the 7.0-nm diameter of the histone core. 15% of the histone vectors lie between 7.0 and 12.0 nm, and these are attributed to the N-terminal domains of the core histones which extend out from the central histone core. Histone vectors extending beyond 7.0 nm are necessary to account for the measured radius of gyration of the histone core of 3.3 nm. A similar value of 3.2 nm is calculated for the recent ellipsoidal shape of 11.0 X 6.5 X 6.5 nm from the crystal structure of the octamer. However, the nucleosome model based on this structure is globular, roughly 11 nm in diameter, which does not accord with the flat disc shape core particle obtained from detailed neutron scatter data nor with the cross-section radii of gyration of the histone and DNA found previously for extended chromatin in solution.

Intravascular brachytherapy using 90Sr for saphenous vein grafts having diameters ranging from 2.0-5.0 mm. Symptomatic coronary artery disease is routinely treated with angioplasty and stenting. Unfortunately, treatment failure in the form of in-stent restenosis (ISR) occurs relatively frequently. Intravascular brachytherapy (IVBT) is a safe and effective method proven to markedly reduce the rate of ISR in native coronary arteries. The commercially available devices for IVBT are not FDA-approved for treatment of saphenous vein grafts (SVG). This article presents calculated dosimetry for treatment of a wide range of SVG, in addition to further evaluating the dose homogeneity for native coronary arteries. AAPM Task Group 43 and 60 formalisms permitted dose calculations for a wide range of vessel internal diameters (phi) in both native coronary arteries and SVG. Doses were analytically calculated for the Novoste Beta-Cath 5.0 French (F) treatment devices (30, 40, and 60 mm sourcetrains) when employed for the treatment of native vessels with 2.7 <or= phi <or= 4.0 mm and for SVG with 2.0 <or= phi <or= 5.0 mm. This latter range of phi was segmented into 7 bins to facilitate rapid clinical implementation with minimal errors. Calculations of dose and dose rate for the 3.5 F devices were also performed. Dose inhomogeneity in the form of dose maxima and minima were calculated for the 3.5 and 5.0 F catheters, with the 30, 40, and 60 mm sourcetrains, and for 2.0 <or= phi <or= 5.0 mm. The calculated doses rates for the 30 mm device were in agreement (typically +/- 0.3%) with measured dose rates. Reference dose calculations performed for SVG with 2.0 <or= phi <or= 5.0 mm were in alignment with those used for the more narrow range of native coronary arteries currently approved for IVBT. Errors associated with using a phi binning technique for simplifying clinical implementation did not exceed 15%, and were typically under 9%. The degree of dose inhomogeneity at a depth of 0.5 mm increased as phi increased, catheter size decreased, and sourcetrain length decreased, and was -42% and +101% relative to the prescribed dose for the 40 mm 5.0 F system with phi = 4.0 mm. Use of 7 phi bins facilitates rapid clinical implementation of IVBT in the typical cardiac catheterization laboratory. While calculation of reference dose for treatment of large vessels is possible with established formalisms, the degree of dose inhomogeneity in light of current clinical results suggests further research is needed.

Effect of gestational age and hypoxia on activity of ribonucleic acid polymerase in fetal guinea pig brain. The aim of this study was to determine the effect of gestational age and hypoxia on the activity of ribonucleic acid polymerase in fetal guinea pig brain. Fetal cerebral cortical neuronal nuclei were isolated at 40, 50, and 60 days (term) of gestation to determine the effect of gestational age on the activity of ribonucleic acid polymerase I, II, and III. Pregnant guinea pigs at 60 days' gestation were randomly assigned to a normoxic or hypoxic group to determine the effect of hypoxia on ribonucleic acid polymerase activity. The fetal neuronal nuclei were pooled from 6 pregnant animals in each group. In the normoxic group the pregnant guinea pigs were exposed to room air before delivery. In the hypoxic group delivery occurred after the pregnant guinea pig had been exposed to 7% oxygen for 60 minutes. The fetuses were delivered by cesarean, and the fetal cerebral cortical neuronal nuclei were isolated immediately. Ribonucleic acid polymerase activity was determined with nuclei suspended in a buffer containing adenosine triphosphate, guanosine triphosphate, cytidine triphosphate, and tritiated uridine triphosphate. Dactinomycin (actinomycin D) and polydeoxyadenylic-thymidylic acid were used to determine the activity of bound and free ribonucleic acid polymerase. alpha-Amanitin was used to determine the activity of ribonucleic acid polymerase II. The activity of total (bound and free) ribonucleic acid polymerase I and III increased from 85.4 +/- 9.4 fmol of tritiated uridine triphosphate incorporated per milligram of protein per hour at 40 days' gestation to 233.3 +/- 82.1 fmol at 50 days and to 343.4 +/- 231.6 fmol at 60 days (P =.02). Total ribonucleic acid polymerase II activity increased from 19.9 +/- 6.0 fmol of tritiated uridine triphosphate incorporated per milligram of protein per hour at 40 days to 123.8 +/- 53.0 fmol at 50 days and to 200.9 +/- 77.8 fmol at 60 days (P <.01). In the term fetal guinea pig brain the activity of bound ribonucleic acid polymerase I and III decreased from 116.8 +/- 107.2 fmol of tritiated uridine triphosphate incorporated per milligram of protein per hour under normoxic conditions to 92.8 +/- 76.0 fmol in hypoxic fetal brain, a decrease of 20.5%. Free ribonucleic acid polymerase I and III activity decreased from 199.2 +/- 115.2 fmol of tritiated uridine triphosphate incorporated per milligram of protein per hour in normoxic fetal brain to 132.0 +/- 66.4 fmol in hypoxic fetal brain, a decrease of 33.8%. Free ribonucleic acid polymerase II activity decreased from 62.4 +/- 70.4 fmol of tritiated uridine triphosphate incorporated per milligram of protein per hour in normoxic fetuses to 13.6 +/- 9.6 fmol in hypoxic fetal brain, a decrease of 78.2%. In contrast, however, in term fetal guinea pig brain, bound ribonucleic acid polymerase II activity increased from 8.0 +/- 10.4 fmol of tritiated uridine triphosphate incorporated per milligram of protein per hour under normoxic conditions to 35.2 +/- 8.8 fmol in hypoxic fetal brain, an increase of 340% (P <.01). The activity of ribonucleic acid polymerases I, II, and III increases throughout the latter half of gestation, from 40 to 60 days, in the fetal guinea pig brain. Hypoxia in utero is associated with a decrease in ribonucleic acid polymerase I and III activity. Although hypoxia is associated with a decrease in free ribonucleic acid polymerase II activity, we observed a marked increase in bound ribonucleic acid polymerase II activity, which may represent a hypoxia-induced alteration of gene expression.

A single-center, randomized, double-blind, three-way crossover study examining postchallenge glucose responses to human insulin 70/30 and insulin lispro fixed mixtures 75/25 and 50/50 in patients with type 2 diabetes mellitus. The aim of this study was to test the ability of human insulin 70/30, insulin lispro mixture 75/25 (75% neutral protamine lispro [NPL], 25% insulin lispro), and insulin lispro mixture 50/50 (50% NPL, 50% insulin lispro) to control postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus (DM). This single-center, randomized, double-blind, 3-way crossover study was conducted at the Diabetes and Glandular Disease Research Center, San Antonio, Texas. We measured serum glucose responses after a standardized breakfast test meal (500 kcal; 50% carbohydrate, 34% fat, 16% protein) in patients with type 2 DM receiving a single preprandial dose of human insulin 70/30, insulin lispro 75/25, or insulin lispro 50/50 by SC injection. All patients previously used insulin for at least 1 month prior to the study. The glucose responses were compared with those of healthy, untreated subjects administered the identical meal. A total of 33 patients were enrolled (23 with type 2 DM and 10 healthy controls). The baseline characteristics of the patients were as follows: sex ratio (M:F), 17:6; mean (SD) age, 61.3 (10.0) years; mean (SD) body weight, 98.5 (13.2) kg; mean (SD) body mass index, 33.0 (3.8) kg/m(2); mean (SD) glycosylated hemoglobin, 8.1% (1.6%); mean (SD) fasting serum glucose (FSG), 158.7 (27.6) mg/dL; and 56.5% white, 8.7% black, and 34.8% Hispanic. The mean (SD) doses (U/d) of the fixed-mixture preparations were similar: human insulin 70/30, 44.1 (18.2); insulin lispro 75/25, 44.1 (18.2); and insulin lispro 50/50, 43.8 (17.8). FSG levels obtained before the test meal were not significantly different between treatments. Compared with those in healthy subjects, incremental glucose AUC values for the 4 hours after the meal (AUCglucose 0-4) for patients with type 2 DM were 6.4-fold higher with human insulin 70/30, 4.6-fold higher with insulin lispro 75/25, and 3.0-fold higher with insulin lispro 50/50. Each insulin regimen produced AUC(glucose) 0-4 and 2-hour PPG values significantly different from all other regimens (all, P < 0.05). Mean (SD) 2-hour PPG values (mg/dL) were lower with mixtures containing insulin lispro than with human insulin 70/30 and decreased as the proportion of insulin lispro within the fixed mixtures increased: human insulin 70/30, 212.6 (47.0); insulin lispro 75/25, 198.0 (67.5); and insulin lispro 50/50, 158.8 (52.3). In this small study in patients with type 2 DM and healthy controls, preprandial administration of a fixed mixture containing rapid-acting or regular insulin and intermediate-acting components was associated with attenuation of the rise in PPG in patients with type 2 DM administered a test meal. Mixtures containing insulin lispro were associated with greater decreases in PPG concentrations compared with human insulin 70/30. Furthermore, greater amounts of rapid-acting insulin contained within the mixture were associated with better PPG control.

Proton magnetic resonance spectroscopy in the evaluation of infiltration zone of cerebral alveolar echinococcosis. Cerebral alveolar echinococcosis (CAE) grows infiltratively like a malignant tumor, causing great harm to the human body. It is possible to display mass lesions of CAE using various imaging systems, but regarding the infiltrating proliferation active regions, it is difficult to evaluate its actual range using conventional magnetic resonance imaging (cMRI). This research focused on proton magnetic resonance spectroscopy ((1)HMRS) techniques to find the mass and infiltration zone of CAE. We explored the marginal zone (MZ) of CAE nearly close to the actual infiltrating scope, to provide reliable images for clinical purposes, to overcome shortcomings of cMRI, to formulate beneficial clinical surgical plans and assess prognosis. Between September 2005 and May 2011, 15 patients who were suffering from CAE (36 effective lesions altogether) were examined by (1)HMRS at the first affiliated hospital of Xinjiang Medical University. Multi-voxel (1)HMRS was acquired with a 1.5T MRI scanner. Concentrations and the ratios of the metabolites of CAE were calculated. Furthermore, changes in the concentrations of the metabolites containing N-acetyl-aspartic-acid (NAA), choline (Cho), creatine (Cr), lipids and lactate (Lip + Lac) and the ratios of Cho/Cr, NAA/Cr, (Lip + Lac) /Cr were compared in the substantial region, 0 - 10 mm MZ, and 11 - 20 mm MZ of the infiltration zone, as well as the corresponding contralateral part of the normal brain parenchyma area (control group). In this study, the ratios of Cho/Cr in the substantial region, 0 - 10 mm MZ of infiltration zone and the control group were 1.78 ± 0.70, 1.90 ± 0.54, and 0.78 ± 0.15, respectively; the ratios of NAA/Cr were 1.60 ± 0.20, 1.80 ± 0.42, 2.24 ± 0.86, respectively; the ratios of (Lip + Lac)/Cr were 25.69 ± 13.84, 25.18 ± 16.03, and 0.61 ± 0.15, respectively. From the control group, 11 - 20 mm MZ to 0 - 10 mm MZ and the substantial region of CAE, the concentrations of the metabolites showed that NAA and Cho decreased gradually and markedly. But (Lip + Lac) increased gradually and markedly. The ratios of Cho/Cr and NAA/Cr, (Lip + Lac)/Cr were statistically significant (P < 0.0083) between the substantial region and the control group, as well as between the 0 - 10 mm MZ and the control group. The ratios of Cho/Cr and NAA/Cr, (Lip + Lac)/Cr displayed no statistically significant differences (P > 0.0083) between the substantial region and the 0 - 10 mm MZ. There was a pathological spectrum surrounding the infiltration zone of CAE. Multi-voxel 1HMRS has great clinical value for discerning the main lesion and the infiltration zone of CAE.

Early bone formation adjacent to oxidized and machined implant surfaces: a histologic study. Various designs of dental implants representing different geometries and surface technologies are commercially available for patient treatment. However, data with regard to the biologic events that occur immediately after implant placement, regardless of the surface characteristic, are scarce. It has become a common procedure to perform immediate/early prosthetic loading rather than delayed loading. The goal of this study was to observe the early biologic events of peri-implant healing to understand the role of surface modifications in relation to the early phases of bone integration. The secondary goal was to observe the possible differences in the healing pattern at two oral implant surfaces differing in morphology and roughness (Ra, with Ra values ranging from 0.5 μm (machined surface; MS) to 1.5 μm (oxidized surface; OS). A total of 36 implants were placed in six foxhound dogs, equally divided between machined and oxidized surfaces. Three implants were positioned per hemimandible following a randomization scheme. Each animal was euthanized at a specific time point for histologic observation and histomorphometry: immediately after implant insertion and after 24 hours, 7 days, 15 days, 30 days, and 90 days. The study demonstrated an extremely low bone-implant contact (BIC) for both OS and MS implant surfaces during the first 15 days after implant placement (ranging from 12.9% to 26.9% independent of the implant surface). Increased BIC values were observed only in the 30- and 90-day specimens. The presence and the degradation of residual bone particles acted as centers for new bone formation, with osteoblasts lining osteoid tissue and subsequently woven bone independent of the implant surface characteristics. The bone-forming activity appeared strongly reduced after 30 days of healing and seemed to be complete only in the 90-day specimens, where abundant lamellar bone was evident. There is a continuing effort to develop improved titanium surfaces to achieve more rapid osseointegration and improve BIC, with the ultimate goal of applying occlusal load as early as possible. Since immediate or early implant loading is applied during and not after the first 15 days, the findings in the present study of an extremely low BIC and limited mineralized bone formation for both implant surfaces during the first 15 days after implant placement suggest that the surface roughness may not be a key factor for successful osseointegration of immediately or early loaded implants. Within the limits of this study, it can be stated that osseointegration follows a similar healing pattern with machined and oxidized implant surfaces.

Xylanase increased the ileal digestibility of nonstarch polysaccharides and concentration of low molecular weight nondigestible carbohydrates in pigs fed high levels of wheat distillers dried grains with solubles. The objective was to study the effect of a commercially available xylanase (CAX), an experimental xylanase (EX), and EX in combination with protease (EXP) on the degradation of nondigestible carbohydrates (NDC) and apparent ileal digestibility (AID) of nutrients in wheat distillers dried grains with solubles (wDDGS). The control and 3 enzyme diets contained 96% wDDGS supplemented with vitamins, minerals, L-lysine, and chromic oxide as a digestibility marker in addition to enzyme premix. Eight ileal cannulated pigs were fed 4 experimental diets containing 96% wDDGS-a control diet or 1 of 3 diets with CAX, EX, or EXP-in a double 4 × 4 Latin square design. The experimental period lasted 7 d; adaptation lasted 4 d, and the ileal digesta were collected for 8 h on d 5 and 7, when spot samples of feces were also collected. Digesta samples were analyzed for NDC, total and soluble nonstarch polysaccharides (NSP), low molecular weight (LMW) NDC, OM, CP, fat, starch, and marker. Compared with the control diet, addition of CAX, EX, and EXP increased the AID of arabinoxylan by 32 (P < 0.001), 28 (P = 0.001), and 24% (P = 0.004), respectively. In addition, EXP increased the AID of noncellulosic polysaccharide glucose by 21% compared with the control (P = 0.005). Compared with the control, addition of EX, EXP, and CAX decreased the concentration of soluble arabinoxylan in ileal digesta by 40 (P < 0.0001), 40 (P < 0.0001), and 21% (P = 0.022), respectively. Furthermore, addition of CAX, EXP, and EX increased the concentration of LMW arabinoxylan in ileal digesta by 40 (P = 0.0001), 36 (P = 0.0006), and 24% (P = 0.023), respectively, compared with the control. Addition of EX and EXP decreased the concentration of soluble NSP of ileal digesta by 25 (P = 0.001) and 26% (P < 0.001), respectively, compared with the control diet. Addition of CAX (P < 0.0001) and EXP (P = 0.013) increased the arabinose-to-xylose ratio in the insoluble arabinoxylan fraction in ileal digesta compared with the control diet, and CAX increased the uronic acid-to-xylose ratio of the ileal insoluble NSP fraction (P < 0.0001) compared with the control diet. Enzyme addition did not affect AID of OM, CP, starch, and fat (P > 0.3). In conclusion, addition of xylanases to wDDGS diets increased the ileal digestibility of NSP and generated LMW NDC components in the small intestine of pigs but did not affect ileal digestibility of nutrients in the current study.

Prediction of foot clearance parameters as a precursor to forecasting the risk of tripping and falling. Tripping and falling is a serious health problem for older citizens due to the high medical costs incurred and the high mortality rates precipitated mostly by hip fractures that do not heal well. Current falls prevention technology encompasses a broad range of interventions; both passive (e.g., safer environments, hip protectors) and active (e.g., sensor-based fall detectors) which attempt to reduce the effects of tripping and falling. However the majority of these interventions minimizes the impact of falls and do not directly reduce the risk of falling. This paper investigates the prediction of gait parameters related to foot-to-ground clearance height during the leg swing phase which have been physically associated with tripping and falling risk in the elderly. The objective is to predict parameters of foot trajectory several walking cycles in advance so that anticipated low foot clearance could be addressed early with more volitional countermeasures, e.g., slowing down or stopping. In this primer study, foot kinematics was recorded with a highly accurate motion capture system for 10 healthy adults (25-32 years) and 11 older adults (65-82 years) with a history of falls who each performed treadmill walking for at least 10 min. Vertical foot displacement during the swing phase has three characteristic inflection points and we used these peak values and their normalized time as the target prediction values. These target variables were paired with features extracted from the corresponding foot acceleration signal (obtained through double differentiation). A generalized regression neural network (GRNN) was used to independently predict the gait variables over a prediction horizon (number of gait cycles ahead) of 1-10 gait cycles. It was found that the GRNN attained 0.32-1.10 cm prediction errors in the peak variables and 2-8% errors in the prediction of normalized peak times, with slightly better accuracies in the healthy group compared to elderly fallers. Prediction accuracy decreased linearly (best fit) at a slow rate with increasing prediction horizon ranging from 0.03 to 0.11 cm per step for peak displacement variables and 0.34 × 10(-3) - 1.81 × 10(-3)% per step for normalized peak time variables. Further time series analysis of the target gait variable revealed high autocorrelations in the faller group indicating the presence of cyclic patterns in elderly walking strategies compared to almost random walking patterns in the healthy group. The results are promising because the technique can be extended to portable sensor-based devices which measure foot accelerations to predict the onset of risky foot clearance, thus leading to a more effective falls prevention technology.

Anemia Screening in Naval Aviation: Is Hemoglobin a Better Indicator Than Hematocrit as the Primary Index? Because of the rigorous mental and physical health requirements for Naval Aviation, all applicants and designated personnel must meet physical standards, including initial and periodic screening for anemia. Most standards, including for accession to the U.S. Navy, use hemoglobin as the standard marker to screen for anemia. Moreover, previous literature generally supports the assertion that hemoglobin is more reliable and accurate than hematocrit. However, the U.S. Navy Aeromedical Reference and Waiver Guide uses a hematocrit standard for anemia screening. The purpose of this study was to determine whether hemoglobin or hematocrit correlates better with clinical anemia and evaluate which index is a more accurate indicator for anemia screening in Naval Aviation personnel. This is a retrospective cross-sectional study of Naval Aviation applicants (N = 95) who were evaluated by the Human Performance and Aeromedical Qualifications department at Naval Aerospace Medical Institute Clinic in Pensacola, Florida, from January 1, 2015 to September 30, 2018. Data were collected from electronic medical records in a de-identified manner that included demographics, class designations, labs results, diagnoses, and final disposition. Logistic regression was used to analyze whether hemoglobin (using the U.S. Navy standard of 13.5 g/dL for men and 12.0 g/dL for women) or hematocrit (using the Naval Aviation standard of 40% for men and 37% for women) predicted the diagnosis of anemia for subjects having at least one lab sample (1-sample) and for those having three samples (3-samples). Sensitivity and specificity values were calculated for hemoglobin and hematocrit as tools to predict a diagnosis of anemia using the same standards in the 1-sample and 3-sample groups. Data were collected for 95 subjects, 53 of whom had three sets of paired hemoglobin/hematocrit values. Using logistic regression, hemoglobin was found to be a statistically significant predictor of anemia for both the 1-sample group (odds ratio 3.4, confidence interval [1.130-10.196], P < 0.05) and the 3-sample group (odds ratio 10.5, confidence interval [1.776-62.580], P < 0.01). Hematocrit was not a significant predictor in either group. Hemoglobin was 80% sensitive and 52.3% specific for a diagnosis of anemia in the 1-sample group and 91.3% sensitive and 50.0% specific in the 3-samples group. Hematocrit was 86.7% sensitive and 35.4% specific for a diagnosis of anemia in the 1-sample group and 91.3% sensitive and 23.3% specific in the 3-samples group. This study found that hemoglobin correlates better with the diagnosis of anemia than hematocrit. When three samples are analyzed, hemoglobin is equally sensitive and more specific than hematocrit. Based on these results and the U.S. Navy accession standards using hemoglobin as the standard index for anemia, the U.S. Navy Aeromedical Reference and Waiver Guide should consider using hemoglobin instead of hematocrit to screen for anemia. Future research should focus on prospective research to determine whether hemoglobin or hematocrit is a better indicator of anemia in screening military personnel.

Using the ACGME Milestones for Resident Self-Evaluation and Faculty Engagement. Since July 2014 General Surgery residency programs have been required to use the Accreditation Council for Graduate Medical Education milestones twice annually to assess the progress of their trainees. We felt this change was a great opportunity to use this new evaluation tool for resident self-assessment and to furthermore engage the faculty in the educational efforts of the program. We piloted the milestones with postgraduate year (PGY) II and IV residents during the 2013/2014 academic year to get faculty and residents acquainted with the instrument. In July 2014, we implemented the same protocol for all residents. Residents meet with their advisers quarterly. Two of these meetings are used for milestones assessment. The residents perform an independent self-evaluation and the adviser grades them independently. They discuss the evaluations focusing mainly on areas of greatest disagreement. The faculty member then presents the resident to the clinical competency committee (CCC) and the committee decides on the final scores and submits them to the Accreditation Council for Graduate Medical Education website. We stored all records anonymously in a MySQL database. We used Anova with Tukey post hoc analysis to evaluate differences between groups. We used intraclass correlation coefficients and Krippendorff's α to assess interrater reliability. We analyzed evaluations for 44 residents. We created scale scores across all Likert items for each evaluation. We compared score differences by PGY level and raters (self, adviser, and CCC). We found highly significant increases of scores between most PGY levels (p < 0.05). There were no significant score differences per PGY level between the raters. The interrater reliability for the total score and 6 competency domains was very high (ICC: 0.87-0.98 and α: 0.84-0.97). Even though this milestone evaluation process added additional work for residents and faculty we had very good participation (93.9% by residents and 92.9% by faculty) and feedback was generally positive. Even though implementation of the milestones has added additional work for general surgery residency programs, it has also opened opportunities to furthermore engage the residents in reflection and self-evaluation and to create additional venues for faculty to get involved with the educational process within the residency program. Using the adviser as the initial rater seems to correlate closely with the final CCC assessment. Self-evaluation by the resident is a requirement by the RRC and the milestones seem to be a good instrument to use for this purpose. Our early assessment suggests the milestones provide a useful instrument to track trainee progression through their residency.

Allo- and autotransplantation of mature teeth in monkeys: a sequential time-related histoquantitative study of periodontal and pulpal healing. Root resorption is known to be the most relevant complication determining the long-term prognosis of allotransplanted teeth, and it is initiated during the first few postoperative months. The aim of the present study was to quantitatively assess the dynamics of the periodontal ligament (PDL) and pulpal healing reactions during the first 8 weeks after allotransplantation of mature teeth. The material comprised 112 maxillary central and mandibular lateral incisors of 28 mature green Vervet monkeys, immunogenetically untested, and only matched according to the size of the grafts. Donors and recipients exchanged simultaneously both maxillary incisors and one mandibular incisor, whereas the contralateral mandibular incisors were autotransplanted as controls. At random, every second maxillary allograft was endodontically treated preoperatively. Histoquantitative analysis of the PDL and pulpal healing reactions was carried out after 1, 2, 4 and 8 weeks on serial cross-sections of the grafts in 6, 6, 6 and 8 monkeys, respectively. Necrosis zones in the PDL were prominent in both auto- and allografts after 1 week. Inflammation in the PDL dominated healing in all types of grafts 1 week after transplantation, whereas it subsided significantly after 2 weeks in autografts compared to allografts (P = 0.005). Inflammatory resorption (IR) became prominent after 4 weeks in autografts and this remained stationary. In contrast, IR initiated significantly earlier in allografts compared to autografts after 2 weeks (P = 0.007), and this type of resorption was further increasing in allografts after 4 and 8 weeks. Endodontic treatment, however, reduced IR nearly totally in the allografts with time. Replacement resorption (RR) was nearly absent in autografts. In contrast, allografts showed increasing appearance of RR with time, initiating at 4 weeks. By removing IR from the allografts by endodontic treatment, RR was unmasked significantly at 4 weeks (P = 0.02) and dominated most of the periodontal ligament (70%) after 8 weeks (P = 0.0004). Within the 8 postoperative weeks autografts showed healing with increasing amount of normal PDL reaching significantly higher levels compared to allografts already after 2 weeks (P = 0.02), with increasing differences thereafter. In most allografts, the normal PDL occupied less than 10% of the entire root surface and was located in the supra-alveolar cervical region. Downgrowth of periodontal pocket epithelium was absent or found very infrequently in all groups irrespective of type, time and treatment. In conclusion, the healing of allo- and autotransplanted mature teeth differed significantly on several aspects during the first 8 postoperative weeks. The recorded differences included a higher amount of inflammation in the PDL of allografts after 2 weeks, inflammatory resorption from the second week, and replacement resorption dominating in the eighth week, indicated that an immunologic stimulus for root resorption existed in the allogenic PDL apart from the pulp. Furthermore, specific healing reactions was found in the cervical region with almost identical gingival healing in auto- and allografts.

Sterically congested uranyl complexes with seven-coordination of the UO2 unit: the peculiar ligation mode of nitrate in [UO2(NO3)2(Rbtp)] complexes. Addition of 1 or 2 molar equiv of Rbtp [Rbtp = 2,6-bis(5,6-dialkyl-1,2,4-triazin-3-yl)pyridine; R = Me, Pr ( n )] to UO 2(OTf) 2 in anhydrous acetonitrile gave the neutral compounds [UO 2(OTf) 2(Rbtp)] [R = Me ( 1), ( n )Pr ( 2)] and the cationic complexes [UO 2(Rbtp) 2][OTf] 2 [R = Me ( 3), Pr ( n ) ( 4)], respectively. No equilibrium between the mono and bis(Rbtp) complexes or between [UO 2(Rbtp) 2][OTf] 2 and free Rbtp in acetonitrile was detected by NMR spectroscopy. The crystal structures of 1 and 3 resemble those of their terpyridine analogues, and 3 is another example of a uranyl complex with the uranium atom in the unusual rhombohedral environment. In the presence of 1 molar equiv of Rbtp in acetonitrile, UO 2(NO 3) 2 was in equilibrium with [UO 2(NO 3) 2(Rbtp)] and the formation of the bis adduct was not observed, even with an excess of Rbtp. The X-ray crystal structures of [UO 2(NO 3) 2(Rbtp)] [R = Me ( 5), Pr ( n ) ( 6)] reveal a particular coordination geometry with seven coordinating atoms around the UO 2 fragment. The large steric crowding in the equatorial girdle forces the bidentate nitrate ligands to be almost perpendicular to the mean equatorial plane, inducing bending of the UO 2 fragment. The dinuclear oxo compound [U(CyMe 4btbp) 2(mu-O)UO 2(NO 3) 3][OTf] ( 7), which was obtained fortuitously from a 1:2:1 mixture of U(OTf) 4, CyMe 4btbp, and UO 2(NO 3) 2 [CyMe 4btbp = 6,6'-bis-(3,3,6,6-tetramethyl-cyclohexane-1,2,4-triazin-3-yl)-2,2'-bipyridine] is a very rare example of a mixed valence complex involving covalently bound U (IV) and U (VI) ions; its crystal structure also exhibits a seven coordinate uranyl moiety, with one bidentate nitrate group almost parallel to the UO 2 fragment. The distinct structural features of [UO 2(kappa (2)-NO 3) 2(Mebtp)], with its high coordination number and a noticeable bending of the UO 2 fragment, and of [UO 2(kappa (2)-NO 3)(kappa (1)-NO 3)(terpy)], which displays a classical geometry, were analyzed by Density Functional Theory, considering the bonding energy components and the molecular orbitals involved in the interaction between the uranyl, nitrate, and Mebtp or terpy moieties. The unusual geometry of the Mebtp derivative with the seven coordinating atoms around the UO 2 fragment was found very stable. In both the Mebtp and terpy complexes, the origin of the interaction appears to be primarily steric (Pauli repulsion and electrostatic); this term represents 62-63% of the total bonding energy while the orbital term contributes to about 37-38%.

The opportunities and challenges of personalized genome-based molecular therapies for cancer: targets, technologies, and molecular chaperones. There are now unprecedented opportunities for the development of improved drugs for cancer treatment. Following on from the Human Genome Project, the Cancer Genome Project and related activities will define most of the genes in the majority of common human cancers over the next 5 years. This will provide the opportunity to develop a range of drugs targeted to the precise molecular abnormalities that drive various human cancers and opens up the possibility of personalized therapies targeted to the molecular pathology and genomics of individual patients and their malignancies. The new molecular therapies should be more effective and have less-severe side effects than cytotoxic agents. To develop the new generation of molecular cancer therapeutics as rapidly as possible, it is essential to harness the power of a range of new technologies. These include: genomic and proteomic methodologies (particularly gene expression microarrays); robotic high-throughput screening of diverse compound collections, together with in silico and fragment-based screening techniques; new structural biology methods for rational drug design (especially high-throughput X-ray crystallography and nuclear magnetic resonance); and advanced chemical technologies, including combinatorial and parallel synthesis. Two major challenges to cancer drug discovery are: (1) the ability to convert potent and selective lead compounds with activity by the desired mechanism on tumor cells in culture into agents with robust, drug-like properties, particularly in terms of pharmacokinetic and metabolic properties; and (2) the development of validated pharmacodynamic endpoints and molecular markers of drug response, ideally using noninvasive imaging technologies. The use of various new technologies will be exemplified. A major conceptual and practical issue facing the development and use of the new molecular cancer therapeutics is whether a single drug that targets one of a series of key molecular abnormalities in a particular cancer (e.g. BRAF) will be sufficient on its own to deliver clinical benefit ("house of cards" and tumor addiction models). The alternative scenario is that it will require either a combination of agents or a class of drug that has downstream effects on a range of oncogenic targets. Inhibitors of the heat-shock protein (HSP) 90 molecular chaperone are of particular interest in the latter regard, because they offer the potential of inhibiting multiple oncogenic pathways and simultaneous blockade of all six "hallmark traits" of cancer through direct interaction with a single molecular drug target. The first-in-class HSP90 inhibitor 17AAG exhibited good activity in animal models and is now showing evidence of molecular and clinical activity in ongoing clinical trials. Novel HSP90 inhibitors are also being sought. The development of HSP90 inhibitors is used to exemplify the application of new technologies in drug discovery against a novel molecular target, and in particular the need for innovative pharmacodynamic endpoints is emphasized as an essential component of hypothesis-testing clinical trials.

Factors affecting the longevity of a short-term velocity store for predictive oculomotor tracking. Fast (up to 30 degrees /s) anticipatory smooth pursuit eye movements can be built up with repeated transient motion stimuli. It is thought that such stimuli charge a putative internal store of velocity information that can then drive anticipatory movements in the absence of a target. The aim of this study was to investigate the longevity of this store. Previous experiments with single ramp stimuli (Wells and Barnes 1998) suggested that the store lasts for only a few seconds before decaying to a baseline level. In the current study we investigate the possibility that the store was not maximally charged by single stimuli, precipitating its decay. The magnitude of the anticipatory response was indexed by smooth eye velocity 100 ms after target onset ( V(100)). In experiment 1 the build-up of the anticipatory response was examined by presenting sets of stimuli (comprising from one to five ramps) within a tracking phase and leaving a dark period (the 'gap') of 9.6 s between successive tracking phases. Each ramp was preceded by an audio warning cue and was accompanied throughout its 480 ms duration by an audio tone. Audio cues continued during the gap to reinforce timing information. V(100) for the first and last ramps of each set increased as the number of ramps was increased from one to three but reached an asymptotic level thereafter, suggesting that the velocity store is maximally charged after three presentations. In experiment 2 the store was maximally charged by presenting five ramps in each tracking phase and its decay was examined by leaving gaps of either 7.2 s or 14.4 s between successive tracking phases. V(100) was not diminished after either gap interval. In experiment 3 the velocity store was less well consolidated during tracking phases comprising two ramps. V(100) for the first response after the gap was unaffected by the 7.2 s gap interval but was significantly reduced when the gap interval was 14.4 s. The interval between the warning cue and ramp onset strongly influenced the magnitude of the anticipatory response, the optimum level being elicited by a cue time of 600 ms. In conclusion, this study has shown that the internal velocity store can be sustained for periods as long as 14.4 s provided that it is initially charged to a sufficiently high level and that accurate external timing cues are provided. Furthermore, we provide evidence to suggest that this process may be controlled by a two-part sample and hold mechanism.

Binding of indocyanine green in polycaprolactone fibers using blend electrospinning for in vivo laser-assisted vascular anastomosis. The clinical application of laser-assisted vascular anastomosis is afflicted by unreliable and low bonding strengths as well as tedious handling during microvascular surgery. The challenge to be met arises from the flow-off of the chromophore during soldering that changes the absorption and stains the surrounding tissue, leading to an uncontrollable thermal damage zone. In this study, we investigated the feasibility to produce an indocyanine green (ICG)-loaded patch by electrospinning and tested its applicability to both in vitro and in vivo microvascular laser soldering. A blend of polycaprolactone and ICG was electrospun to produce a pliable patch. Prior to soldering, the patch was soaked in 40% wt. bovine serum albumin solution. The solder patch was wrapped in vitro around blood vessel stumps of rabbit aortas. An intraluminal balloon catheter enabled an easy alignment and held the setup in place. The soldering energy was delivered via a diffusor fiber from the vessel lumen using a diode laser at 810 nm. During the procedure, the surface temperature was observed with an infrared camera. Afterward, samples were embedded in methylmethacrylate and epon to study thermal damage. The quality of the fusion was assessed by measuring the tensile strength. After in vitro tests with rabbit aortas, eight large white pigs were subjected to an acute in vivo experiment, and the artery of the latissimus dorsi flap was anastomosed to the distal femoral artery. The ICG-loaded patch, produced by electrospinning, has a thickness of 279 ± 62 μm, a fiber diameter of 1.20 ± 0.19 μm, and an attenuation coefficient of 1,119 ± 183 cm-1 at a wavelength of 790 nm. The patch was pliable and easy to handle during surgery. No leakage of the chromophore was observed. Thermal damage was restricted to the Tunica adventitia and Tunica media and the area of the vessel wall that was covered with the patch. Six pigs were successfully treated, without any bleeding and with a continuous blood flow. The in vivo flap model yielded a similar tensile strength compared to in vitro laser-assisted vascular anastomoses (138 ± 52 vs. 117 ± 30 mN/mm2 ). Our study demonstrated the applicability of the ICG-loaded patch for laser-assisted vascular anastomosis. By using electrospinning, ICG could be bound to polymer fibers, avoiding its flow-off and the staining of the surrounding tissue. This patch demonstrated several advantages over liquid solder as it was easier to apply, ensured a high and reliable bonding strength while maintaining a constant concentration of ICG concentration during the surgery. Lasers Surg. Med. 49:928-939, 2017. © 2017 Wiley Periodicals, Inc.

Ovarian follicular dynamics in ewes during the transition from anoestrus to the breeding season. Daily transrectal ovarian ultrasonography was performed in ten ewes for 5 consecutive days, once in early July, once in late July (anoestrus) and then continuously until from mid-August until ewes had completed one ovulatory cycle. During anoestrus the size range and numbers of ovarian antral follicles were similar to those seen during the breeding season. However, numbers of small antral follicles (2-3 mm in diameter) decreased during late anoestrus, and maximum follicle diameter increased just before the short period of progesterone secretion preceding the first observed ovulation. The ovarian antral follicles that ovulated first and second in the breeding season grew from 2 mm in diameter to 5.7 +/- 0.3 mm and 6.2 +/- 0.3 mm diameter over 4.7 +/- 0.3 days and 4.6 +/- 0.3 days, respectively, and the interovulatory interval was 16.6 +/- 0.2 days. During the first ovulatory cycle, follicles emerged to grow from the 2 mm size class on 11 of the 17 days, but peaks of emergence were seen on days 2 and 11. The first observed ovulation was preceded by a transient increase in serum concentrations of progesterone (6 days duration), with a peak concentration of 1.30 +/- 0.22 nmol l-1. With ultrasonography, no evidence of ovulation was seen before the increase in progesterone secretion and no luteal structures was detected during the small increase in progesterone secretion; however, luteal structures are normally detected by ultrasonography only from 3 to 5 days after ovulation. An LH surge similar to a preovulatory LH surge preceded the first increase in progesterone secretion in five ewes. Oestrus occurred consistently with ovulation only at the second observed ovulation of the breeding season, after a normal luteal phase. LH pulse frequency and mean and basal serum concentrations of LH all increased in late anoestrus, but no major trends in serum concentrations of FSH and oestradiol were seen during this period. It was concluded that at the end of anoestrus there is not major change in ovarian antral follicle dynamics. At this time, increased LH secretion was seen as was a reduction in numbers of small antral follicles and a greater maximum diameter of follicles. A surge release of LH resulted in a short-lived secretion of progesterone, the source of which was unclear; this was followed by the first observed ovulation and the first ovulatory cycle of the breeding season. Oestrus occurred consistently only at the second observed ovulation of the season and the peak concentration of progesterone at each period of progesterone secretion increased to at least the second ovulatory cycle.

Stereoisomers of N-substituted soft anticholinergics and their zwitterionic metabolite based on glycopyrrolate--syntheses and pharmacological evaluations. In this study, isomers of two N-substituted soft anticholinergics based on glycopyrrolate, SGM (PcPOAGP_NA.Me) and SGE (PcPOAGP_NA.Et) [3'-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1'-methyl-1'-alkoxycarbonylpyrrolidinium bromide] and their zwitterionic metabolite, SGa (PcPOAGP_NA.H) [3'-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1'-methyl-1'-carboxymethylpyrrolidinium inner salt] were synthesized and their pharmacological activities were evaluated in vitro and in vivo. The isomers of SGM and SGE were synthesized with both optically pure methyl-cyclopentylmandelate and 3-hydroxy-N-methylpyrrolidine. Trans-esterification followed by quarternization with alkyl bromoacetate gave four isomers of SGM or SGE with the nitrogen chiral center unresolved (2R3'S-SGM, 2R3'R-SGM, 2S3'S-SGM, 2S3'R-SGM or 2R3'S-SGE, 2R3'R-SGE, 2S3'S-SGE, 2S3'R-SGE). The hydrolysis of these four isomers followed by HPLC separation resulted in eight fully resolved isomers of SGa (2R3'R1'R, 2R3'S1'R, 2R3'R1'S, 2R3'S1'S, 2S3'R1'R, 2S3'S1'R, 2S3'R1'S, and 2S3'S1'S). Pharmacological activities were assessed by using in vitro receptor-binding assay and guinea pig ileum pA2-assay, and by evaluating the in vivo rabbit mydriatic effects. Results were compared to those obtained with conventional anticholinergic agents, such as glycopyrrolate, N-meythylscopolamine, and tropicamide, as well as those obtained with previously prepared racemic mixtures and 2R isomers. Receptor binding pKi values at cloned human muscarinic receptors (M1-M4 subtypes) were in the 6.0-9.5 range for the newly synthesized SGM and SGE isomers, and in the 5.0-8.6 range for the SGa isomers. In all cases, 2R isomers were significantly more active than 2S isomers (27 to 447 times for SGM isomers, and 6 to 4467 times for SGa isomers). Among the four SGM isomers with unresolved 1' (N) chiral center, the 3'R isomers were more active than the corresponding 3'S isomers (1.5-12.9 times), whereas, among the SGa isomers, the 3'S isomers were not always more active than the corresponding 3'R isomers indicating that activity determined based on configuration at chiral center 3' is significantly affected by the configuration of the other two chiral centers, 2 and 1'. Among the completely resolved eight SGa isomers (all three chiral centers resolved), 1'S isomers were always more active than the corresponding 1'R isomers (1.8-22.4 times). Results also indicate that some isomers showed good M3/M2 muscarinic-receptor subtype-selectivity (about 3-5 times), and 2R and 3'S were the determining configurations for this property. Guinea pig ileum assays and rabbit mydriasis tests on SGa isomers further confirmed the stereospecificity. In rabbit eyes, some 2R-SGa isomers showed mydriatic potencies similar to glycopyrrolate and exceeded tropicamide, but their mydriatic effects lasted considerably shorter, and they did not induce dilation of the pupil in the contralateral, water-treated eye. These results indicate that these compounds are locally active, but safe and have a low potential to cause systemic side effects. The pharmacological potency of the eight SGa isomers was estimated as 2R3'S1'S approximately equal to 2R3'R1'S approximately equal to 2R3'S1'R > 2R3'R1'R > 2S3'R1'S > 2S3'S1'S approximately equal to 2S3'R1'R > 2S3'S1'R (p < 0.05). The stereospecificity and M3/M2 muscarinic-receptor subtype-selectivity of soft anticholinergics, SGM, SGE, and SGa have been demonstrated. In agreement with previous results, the potential for their effective and safe use has been confirmed.

Why did drug spending increase during the 1990s? A decomposition based on Swedish data. To decompose drug spending in Sweden between the years 1990 and 2000. This paper updates a previous study, which looked at the period 1990-1995, by providing an additional 5 years of data (1995-2000) and extending the previous analysis in a number of ways. The paper builds on the earlier work that showed that changes in drug spending could be decomposed into three components: price, quantity and a residual. The size of the residual is a measure of the impact of changes in drug treatment patterns on drug spending. The data set used in this paper was collected from Apoteket AB (The National Corporation of Swedish Pharmacies) and was based on comprehensive information (inpatients as well as outpatients) on drug deliveries from wholesalers to pharmacies. Data were obtained for aggregate drug spending (from 1990-2000) and for spending according to anatomical therapeutic chemical (ATC) classification system group. Real drug spending increased by 119% during the study period. The residual rose by 67% indicating the switch from cheaper to more innovative and expensive drug therapies was a major cost driver. Real drug spending would have increased by about 31% if there had been no changes in treatment patterns. The second driver of drug spending was the quantity of drugs consumed, which increased by 41%. The main reason for the larger quantity sold appears to be increases in the intensity of medication in terms of defined daily doses per patient, rather than a larger number of patients starting drug treatment. Real prices decreased during the 10-year study period. We found large differences between ATC groups in terms of spending growth. The ATC groups that have contributed the most to the increase in spending are: drugs that affect the CNS (N), the alimentary tract and metabolism (A) and the cardiovascular system (C), which are also the three largest groups in terms of sales. For all three groups, it was the residual that mainly drove costs. This study indicates very clearly that the main driving force behind the increase in drug costs in Sweden between 1990 and 2000 was the change in drug therapy from old to new and more innovative and expensive drug therapies. This shows the importance of carrying out economic evaluations of new more costly drugs in order to make an assessment of the social benefits of a switch from a cheaper to a more expensive drug.

Type I collagen biomarkers in the diagnosis of bone metastases in breast cancer, lung cancer, urinary bladder cancer and prostate cancer. Comparison to CEA, CA 15-3, PSA and bone scintigraphy. In this study we evaluated the clinical usefulness of serum pro-I collagen peptide (PICP) and I collagen telopeptide (ICTP) as indicators of early bone metastases in patients with breast (BC), lung (LC), urinary bladder (UBC) and prostate cancer (PC). 305 patients were examined. 145 had histologically confirmed BC (92 with bone metastases), 20 UBC (6 with bone metastases), 11 LC (3 with bone metastases) and 129 PC (68 with bone metastases). In BC patients we compared the PICP and ICTP levels with those of CA 15-3, CEA and bone scintigraphy. Patients with LC and UBC had PICP and ICTP measurements, PC patients had serum PICP, prostate specific antigen (PSA) measurements and bone scans. 104 healthy individuals served as controls. ICTP and CA 15-3 levels were significantly higher in patients with BC and bone metastases in comparison to patients without metastases (p <0.05), while PICP and CEA were only marginally higher. Significant correlation was observed between existence of bone metastases and ICTP levels (p <0.05). The sensitivity of PICP, ICTP, CEA and CA 15-3 was 28.1, 48.6, 42, and 78%, respectively and specificity was 83.9, 94, 65 and 86%, respectively. ICTP and CA 15-3 were the most reliable markers for early diagnosis of bone metastases in BC. PICP alone or with ICTP were not sensitive enough. Only CA 15-3 showed sensitivity 78% and specificity 86%. When combined CA 15-3, ICTP and CEA the sensitivity and specificity increased to 82% and 96%, respectively. Furthermore, PICP and PSA levels were significantly higher in patients with PC and bone metastases in comparison to patients with benign prostate hyperplasia (BPH) (p <0.0001) or in patients with PC without bone metastases (p <0.0005 for PICP and p <0.0001 for PSA). The co-evaluation of PICP and PSA improved the sensitivity (78%), specificity (96%), accuracy (97%) and positive predictive value (97%). In LC patients, ICTP levels differed significantly between patients with and without bone metastases (p=0.025). In UBC patients, PICP levels differed significantly between patients with and without bone metastases (p=0.017). ICTP and CA 15-3 are the most reliable markers for early diagnosis of bone metastases in BC patients. PICP could be useful for diagnosing early bone metastases of PC and combined with PSA and bone scan can be an additional tool in the follow-up of PC patients. For LC patients, ICTP showed a significant difference in the discrimination of patients with and without bone metastases. In UBC patients, PICP showed a significant difference in the discrimination of patients with and without bone metastases.

Effects of competition on great and blue tit reproduction: intensity and importance in relation to habitat quality. 1. In studies on the effect of competition in plant communities two terms are used to describe its effects: the absolute reduction in growth of an individual as a consequence of the presence of another one is called intensity, while the relative impact of competition on an individual as a proportion of the impact of the whole environment is called importance. One school of thought is that the role of competition remains constant across productivity gradients, while the other is that it decreases with increasing severity. J.B. Grace (1991. A clarification of the debate between grime and tilman. Functional Ecology, 5, 583-587.) suggested that the apparent contradiction might be solved if we acknowledge that the two schools are discussing different aspects of competition: the intensity of competition might remain constant while its importance declines with increasing severity. 2. There are no studies that compare intensity and importance of competition in bird populations between areas that differ in quality or productivity and hence it is not possible to make predictions how intensity or importance of competition would vary between them. 3. I compared variation in intensity and importance of competition of three demographic variables between five plots that differ strongly in quality for great Parus major L. and blue tit Cyanistes caeruleus (L.). 4. Both intensity and importance of competition are larger in great than in blue tit populations meaning that the effect of competition on demographic variables is stronger in great than in blue tits and that the contribution of competition to variation in these variables is relatively higher in great than in blue tits. 5. Intensity of competition is higher in low quality than in high quality plots for both species, a result not expected from studies in plant communities. 6. Importance of competition varies strongly between plots. It is larger in oak-dominated plots than in mixed deciduous plots. 7. In birds breeding density increases with habitat quality but is limited by territorial behaviour. As a result competition for food is reduced in high quality habitats resulting in a reduction of competition intensity in high quality sites in which birds breed at high densities. 8. It can be predicted that in studies of territorial species density dependent effects on reproduction are more likely to be detected in low quality sites explaining in part differences in results between studies.

Serum LD1 isoenzyme and blood lymphocyte subsets as prognostic indicators for severe acute respiratory syndrome. The pathophysiology of severe acute respiratory syndrome (SARS) is at present poorly understood, but advanced age and serum total lactate dehydrogenase (LD) activity >300 U L(-1) have been associated with adverse clinical outcomes. Blood leucocytes and lymphocyte subsets were reported to decrease, respectively, in 47% and up to 100% of 38 patients in Beijing. However, their prognostic implications have not been thoroughly investigated. To investigate serum total LD, LD isoenzymes, and other parameters including blood lymphocyte subsets as prognostic indicators in SARS patients for adverse clinical outcomes in terms of admission to intensive care unit (ICU) and death. Retrospective analysis. A total of 109 patients with a clinical diagnosis of SARS according to the modified World Health Organization case definition of SARS were recruited from two major acute hospitals in Hong Kong. They were either involved in the initial outbreak of SARS, or cases from the community outbreak of Amoy Gardens between 10 March and 5 May 2003. The clinical diagnosis was subsequently confirmed by serological test and/or molecular analysis. Serum total LD and LD isoenzyme activities, complete blood picture with total leucocyte count and differential counts, absolute counts of CD3+, CD4+, CD8+, natural killer cells and B lymphocytes were measured daily upon admission. Receiver operating characteristic curve analysis was used to determine and compare different cut-offs for various biochemical and immunological parameters at peak serum total LD concentration in predicting adverse clinical outcomes. Of a total of 109 patients, 41 were admitted to ICU and 42 died. Of 42 fatal patients, 24 died in ICU and 18 died in general medical wards. Age was found to be an independent prognostic indicator for death with an area under curve (AUC) of 0.96 [95% confidence interval (CI) = 0.90-0.99] but not for admission to ICU [AUC = 0.61 (CI = 0.51-0.70)]. Whilst serum total LD could only achieve AUC of 0.68 (CI = 0.59-0.77) for predicting death, LD1 isoenzyme was found to be the best biochemical prognostic indicator with AUC of 0.84 (CI = 0.75-0.90), sensitivity of 62% (CI = 46-76%), specificity of 93% (CI = 83-98%) at cut-off activity of > or =80 U L(-1). CD3+, CD4+, CD8+ and natural killer cell counts were promising immunological prognostic indicators for predicting admission to ICU with AUC of 0.94 (CI = 0.86-0.98), 0.91 (CI = 0.81-0.96), 0.93 (CI = 0.85-0.98), and 0.87 (CI = 0.76-0.94), respectively. Apart from age, serum LD1 activity was the best prognostic indicator for predicting death in patients with SARS compared with serum total LD activity, haemoglobin concentration, leucocyte and lymphocyte counts. Its release could possibly be from blood erythrocytes and body tissues other than the myocardium. Blood CD3+, CD4+, CD8+ and natural killer cell counts were found to be good prognostic indicators for predicting admission to ICU in patients with SARS compared with age, leucocyte count and LD isoenzymes. The suppressed CD3+, CD4+, CD8+, and natural killer cell counts were also implicated in the pathophysiology of SARS. Patients with increased serum LD1 should be closely monitored to ensure prompt management, and preparation for admission to ICU could be planned ahead for patients with suppressed lymphocyte subsets.

Endothelial nitric oxide synthase and calcium production in arterial geometries: an integrated fluid mechanics/cell model. It is well known that atherosclerosis occurs at very specific locations throughout the human vasculature, such as arterial bifurcations and bends, all of which are subjected to low wall shear stress. A key player in the pathology of atherosclerosis is the endothelium, controlling the passage of material to and from the artery wall. Endothelial dysfunction refers to the condition where the normal regulation of processes by the endothelium is diminished. In this paper, the blood flow and transport of the low diffusion coefficient species adenosine triphosphate (ATP) are investigated in a variety of arterial geometries: a bifurcation with varying inner angle, and an artery bend. A mathematical model of endothelial calcium and endothelial nitric oxide synthase cellular dynamics is used to investigate spatial variations in the physiology of the endothelium. This model allows assessment of regions of the artery wall deficient in nitric oxide (NO). The models here aim to determine whether 3D flow fields are important in determining ATP concentration and endothelial function. For ATP transport, the effects of a coronary and carotid wave form on mass transport is investigated for low Womersley number. For the carotid, the Womersley number is then increased to determine whether this is an important factor. The results show that regions of low wall shear stress correspond with regions of impaired endothetial nitric oxide synthase signaling, therefore reduced availability of NO. However, experimental work is required to determine if this level is significant. The results also suggest that bifurcation angle is an important factor and acute angle bifurcations are more susceptible to disease than large angle bifurcations. It has been evidenced that complex 3D flow fields play an important role in determining signaling within endothelial cells. Furthermore, the distribution of ATP in blood is highly dependent on secondary flow features. The models here use ATP concentration simulated under steady conditions. This has been evidenced to reproduce essential features of time-averaged ATP concentration over a cardiac cycle for small Womersley numbers. However, when the Womersley number is increased, some differences are observed. Transient variations are overall insignificant, suggesting that spatial variation is more important than temporal. It has been determined that acute angle bifurcations are potentially more susceptible to atherogenesis and steady-state ATP transport reproduces essential features of time-averaged pulsatile transport for small Womersley number. Larger Womersley numbers appear to be an important factor in time-dependent mass transfer.

Stereological and biochemical analysis of muscular and connective tissue components in the penile corpus cavernosum adjacent to the fibrous plaque of Peyronie's disease. To investigate the structural organization of the connective tissue in the corpus cavernosum (CC) adjacent to the fibrous plaque in Peyronie's disease (PD) using stereological and biochemical techniques, as most studies on PD have focused on the analysis of the fibrous plaque that forms in the tunica albuginea (TA). Because this fibrotic reaction is mediated by various inflammatory soluble factors, adjacent connective tissues might also be affected and this secondary effect might explain, for example, the erectile dysfunction that occurs in PD. During surgery biopsies were taken from the CC adjacent to the fibrous plaque and from the plaque itself in seven patients with PD (mean age 48.3 years). All the patients had normal erections. Control samples were similarly located samples from 'normal' penises obtained during autopsy of five men (mean age 52.3 years). Tissue samples were stained with Weigert's stain (elastic fibres), Van Gieson's stain (connective tissue), and Sirius red (collagen). Stereological analysis was done using a 42-point grid to determine volumetric densities (Vv). Total collagen content was estimated as micrograms of hydroxyproline per milligram dry CC. The Vv of elastic fibres was significantly reduced in PD by 17.3% compared with controls, at a mean (sd) of 19.49 (3.27)% vs 23.56 (1.87)% (P < 0.05). While in PD the Vv of smooth muscle at 34.46 (2.06)% and connective tissue at 35.39 (6.15)% were not significantly different from those of controls at 38.38 (3.17)% and 38.02 (5.03)%, respectively. The Vv of elastic fibres in the fibrous plaque was decreased by 38.3% compared with the normal TA, at 20.25 (5.49)% vs 32.81 (4.75)% (P < 0.02). The mean (sd) collagen concentration in the CC from controls was 77.94 (24.26) microg/mg and in the patients with PD was 66.57 (19.39) microg/mg, which did not differ significantly. Sirius red-stained sections under polarized light showed that, in the normal CC, collagen-associated colours were homogeneously distributed. However, in the PD samples, stained collagen had a disrupted orientation and had a more heterogeneous birefringence, implying looser collagen bundles. The quantitative analyses indicated that collagen in the CC close to the fibrous plaque was not affected, although its organization was noticeably altered. The CC elastic fibres were reduced though, and there was a similar change in the fibrous plaque of the TA. These results suggest that, although occurring primarily in the TA, the PD fibrous plaque may induce changes in the adjacent CC.

Co-operation between the AKT and ERK signaling pathways may support growth of deep endometriosis in a fibrotic microenvironment in vitro. How can deep endometriotic stromal cells proliferate and persist in a fibrotic environment? The serine/threonine kinase AKT and extracellular regulated kinase (ERK) signaling pathways may co-operate to support growth of deep endometriotic lesions by enhancing endometriotic stromal cell proliferation and survival in a fibrotic microenvironment in vitro. Endometriosis, particularly deep infiltrating endometriosis, is characterized histologically by dense fibrous tissue that is primarily composed of type I collagen. This tissue may cause pelvic pain and infertility, which are major clinical issues associated with endometriosis. Proliferation of normal fibroblasts is tightly regulated, and fibrillar, polymerized type I collagen inhibits normal fibroblast proliferation. However, no studies to date have investigated how deep endometriotic stromal cells can proliferate and persist in a fibrotic environment. Endometrial and/or endometriotic tissues from 104 patients (61 with and 43 without endometriosis) of reproductive age with normal menstrual cycles were analyzed. A total of 25 nude mice received a single injection of endometrial fragments from a total of five samples. We evaluated cell proliferation, caspase 3/7 activity, and the AKT and ERK signaling pathways in endometrial and endometriotic stromal cells on three-dimensional (3D) polymerized collagen matrices in vitro. In addition, to determine whether aberrant activation of the AKT and ERK pathways is involved during progression of fibrosis in endometriosis in vivo, we evaluated the expression of phosphorylated AKT and ERK1/2 in endometriotic implants in a nude mouse model of endometriosis. Finally, we evaluated the effects of MK2206 (an AKT inhibitor) and U0126 (a MEK inhibitor) on cell proliferation, caspase 3/7 activity, and phosphorylation of AKT and ERK1/2 of endometriotic stromal cells on 3D polymerized collagen matrices. Proliferation of endometriotic stromal cells was significantly less inhibited than that of endometrial stromal cells (P < 0.05) on 3D polymerized collagen. Levels of phosphorylated AKT, phosphorylated p70S6K and phosphorylated ERK1/2 were significantly higher in endometriotic stromal cells than in endometrial stromal cells at 24 h (P < 0.05) and at 72 h (P < 0.05) on 3D polymerized collagen. Phosphorylated AKT expression was significantly increased on Days 21 and 28 compared with those on Days 3 and 7 (all P < 0.05) in endometriotic implants during progression of fibrosis in a nude mouse model of endometriosis. Inhibition of AKT or ERK1/2 with MK2206 or U0126, respectively, did not significantly increase caspase 3/7 activity in endometriotic stromal cells on either two-dimensional or 3D collagen matrices. Western blot analysis showed that MK2206 alone decreased levels of phosphorylated AKT; however, it increased levels of phosphorylated ERK in endometriotic cells compared with vehicle-treated cells (both P < 0.05). In addition, U0126 treatment decreased levels of phosphorylated ERK; however, it resulted in increased levels of phosphorylated AKT in endometriotic stromal cells compared with vehicle-treated cells (both P < 0.05). Endometriosis involves a number of processes, such as invasion, metastasis, angiogenesis, and apoptosis resistance, and a variety of signaling pathways may be involved in promoting development and progression of the disease. In addition, further animal experiments are required to determine whether the AKT and ERK signaling pathways co-operate to support growth of endometriotic lesions in a fibrotic microenvironment in vivo. Co-targeting the AKT and ERK pathways may be an effective therapeutic strategy for endometriosis treatment. This study was supported in part by Karl Storz Endoscopy & GmbH (Tuttlingen, Germany). No competing interests are declared.

[Pertussis: a reemerging infection?]. To analyze the incidence of pertussis in the Czech Republic, influencing factors and, in particular, the effect of vaccination on pertussis morbidity, clinical seriousness of the disease and circulation of Bordetella pertussis in the population. To study the causes of defective diagnosis and reporting and to propose remedial measures. Data on pertussis morbidity were obtained from the archives of the National Institute of Public Health and the public health information systems ISPO and EPIDAT. Mortality data were taken from the above sources and literature. The case definition was used as specified in the Methodical Guidance for Pertussis Surveillance and the EC Directive. Laboratory diagnosis was based on culture and serology. An at least fourfold increase in the serum antibody titer found within an experiment was considered as a positive result. Pertussis together with diphteria and measles used to be among the most dangerous infections in childhood. The oldest mortality data date back to 1890 when 62 deaths per 100,000 population were reported. In 1951, the death rate still reached 3.6/100,000. The pertussis morbidity peaked in 1955 with 540 cases per 100,000 population. Vaccination against pertussis since the early 1950's led to a rapid reduction of morbidity in children. Nevertheless, higher pertussis morbidity rates were observed at 2-4-year intervals (in the so- called epidemic years). The lowest morbidity rates were reported during the 1980's. However, a stable upward trend has been observed over the following years. In 2006, a neonate died from pertussis. The age specific morbidity rates in 1980 through 2000 were highest in children under one year of age. This fact together with the regularly increased morbidity rates observed at 2-3-year intervals indicate that Bordetella pertussis still circulates in the population. While in the 1980's, the cases of pertussis were reported almost exclusively in children under one year of age, in the 1990's, they became more common also among children 1-4 years of age and started to be prevalent in children 10-14 years of age since 2001. A high immunisation coverage (97%) with five doses of high quality whole-cell vaccine of Czech origin introduced into practice in 1958 played a crucial role in the reduction of pertussis morbidity from more than 500/100,000 in the mid-1950's to less than 0.5/100,000 in the 1980's. Nevertheless, this strategy did not lead to elimination of the causative agent in the population. It is evident that the current immunization scheme with the use of the available vaccines cannot solve the epidemiological situation. Since the efficacy of the currently available acellular pertussis vaccines is, at the best, the same as that of the whole-cell vaccines, any improvement of the current status cannot be expected. Only effective active surveillance, the use of new more immunogenic pertussis vaccines and revaccination of older age groups can result in desirable outcomes.

Basic scientific considerations in total disc arthroplasty. Total disc arthroplasty serves as the next frontier in the surgical management of intervertebral discogenic pathology. As we move from an era of interbody spinal arthrodesis to one in which segmental motion is preserved, this promising new technology offers increasing clinical and research challenges in the areas of spinal kinematics, histologic osseointegration at the prosthetic-bone interface and the effects of particulate wear debris. The primary focus of this paper is to provide a methodologic basis to investigate the spinal kinematics, histologic osseointegration and particulate wear debris after total disc arthroplasty by using in vitro and in vivo models. Part I: Using an in vitro cadaveric model, multidirectional flexibility testing evaluated the functional unit kinematics under the following L4-L5 reconstruction conditions: 1) intact spine, 2) Charite disc prosthesis, 3) BAK cages, 4) BAK cages+ISOLA pedicle screw or rod fixation (anteroposterior). Part II: A total of 27 mature baboons (n=27, Papio cynocephalus) underwent L5-L6 total disk replacement procedures to investigate the biomechanical, histochemical and biologic ingrowth characteristics of two different lumbar disc prostheses (AcroFlex and Charite) for total disc arthroplasty. Functional spinal unit fusion status was assessed by using radiographic analysis, biomechanical testing, undecalcified histopathologic and histomorphometric analyses. Part III: Using a total of 50 New Zealand white rabbits, this investigation served to quantify the neural and systemic tissue histopathologic response, after epidural application of four different types of spinal instrumentation particulate wear debris: 1) sham (control) (n=10), 2) stainless steel 316LVM (n=10), 3) titanium alloy Ti-6AL-4V (n=10), 4) cobalt chrome alloy (n=10) and 5) ultrahigh molecular weight polyethylene (UHMWPE) (n=10). In vitro multidirectional flexibility testing demonstrates the operative and adjacent level motion-preserving properties of total disc arthroplasty versus interbody arthrodesis cages and pedicle screw spinal instrumentation. To this end, disc replacement preserves the normal centrode or locus of intervertebral rotation at the operative and adjacent intervertebral spinal levels compared with conventional stabilization implants. On the basis of nonhuman primate modeling in the current studies, porous titanium interface surfaces afforded the greatest percentage of trabecular ingrowth at the prosthesis-end plate interface. In vivo segmental motion under multidirectional testing was preserved with the Charite device and slightly diminished with the AcroFlex implants. The porous ingrowth coverage at the bone-metal interface was more favorable for total disk replacement (range, 40% to 50%) compared with that reported for cementless total joint components in the appendicular skeleton (range, 10% to 30%). Direct epidural application of spinal instrumentation particulate wear debris elicits a chronic histiocytic reaction localized primarily within the epidural fibrous layers. Moreover, particles have the capacity to diffuse intrathecally, eliciting a macrophage and cytokine response within the epidural tissues, cerebrospinal fluid and spinal cord itself. Overall, on the basis of the postoperative time periods evaluated, no evidence was observed of an acute neural or systemic histopathologic response to the materials included in the current project. The implementation of dynamic spinal stabilization systems for fusionless correction of spinal deformity, dynamic posterior stabilization and total disc arthroplasty necessitates improved understanding with regard to spinal kinematics, patterns and mechanisms of histologic osseointegration and the neurohistopathologic response to particulate wear debris. Collectively, the current studies provide a methodologic basis to comprehensively evaluate these three areas.

Monitoring of ovarian activity by daily measurement of urinary excretion rates of oestrone glucuronide and pregnanediol glucuronide using the Ovarian Monitor, Part III: variability of normal menstrual cycle profiles. What are the characteristics of, and how variable are, individual normal menstrual cycle profiles of excretion rates for the urinary metabolites oestrone glucuronide (E1G) and pregnanediol glucuronide (PdG)? There is a continuum of menstrual cycle profiles that differ from standard textbook profiles but which can be understood simply in terms of growth, atresia and ovulation of ovarian follicles. Point-of-care assays with the Ovarian Monitor pre-coated assay tubes, using urine samples diluted to a constant volume per unit time, give laboratory accurate clinical data for individual menstrual cycles. Lay operators can perform the point-of-care assay system at home to achieve reliable and reproducible results, which can be used for natural family planning. This prospective study involved 62 women, with normal menstrual cycles, recruited from three centres: Palmerston North, New Zealand, Sydney, Australia and Santiago, Chile. The study lasted 3 years. Women collected daily urine samples and determined their E1G and PdG rates with a pre-coated enzyme assay system known as the Ovarian Monitor. For two cycles, the assays were repeated in a study centre and the results were averaged to give 113 individual menstrual cycles for analysis. The cycles were displayed individually in a proprietary database program. The individual normal hormonal profiles were more complex than the classic composite curves for 40% of the cycles. Of 113 ostensibly normal cycles, only 91 were potentially fertile and 22 had some luteal phase defect. The oestrone glucuronide and PdG excretion rates were reliable and informative in the non-invasive elucidation of ovulation and ovarian function for both simple and complex profiles. Daily monitoring revealed the variability of normal menstrual cycle profiles. The LH peaks were variable and ambiguous markers for ovulation. The study consisted of cycles only from women with regular cycles of 20-40 days duration. All the women were intending to avoid a pregnancy during the study thus the limits of the fertile window were not tested. The principles established in this study should apply to cycles of any length. All peaks in oestrone glucuronide excretion should be tested by concurrent measurements of PdG, which gives a positive indication of the fate of the follicle it represents. The Ovarian Monitor provides a useful addition for practitioners of natural family planning. Financial support for this study was obtained from the UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction (HRP). D.G.C. is currently employed by and holds stock in Manawatu Diagnostics Ltd, a company in the development phase of a potentially competing product. The remaining authors have nothing to declare.

Novel Use of Portable Audiometry to Track Hearing Fluctuations in Menière's Disease: A Pilot Study. Menière's Disease (MD) is a disorder of the inner ear consisting of episodic attacks of vertigo associated with aural fullness, tinnitus, and fluctuating hearing loss. Hearing levels in MD can often fluctuate over time, and may eventually decline permanently in a step-wise fashion. There are no current studies examining daily hearing fluctuations for prolonged periods in patients with MD. Portable audiometry has the potential to allow the patient to monitor their hearing on a daily basis without attending a center for formal audiology. The objective of this pilot study was to assess feasibility of using iPad-based audiometry on a daily basis to capture hearing fluctuations in a small sample of adult patients with active MD. We recruited five patients with active MD as defined by current diagnostic criteria (International Classification of Vestibular Disease 2015). "Active" MD was defined as the patient having had at least one typical Menière's episode within the last 4 weeks. Patients were trained on how to use the portable audiometer and asked to perform at least daily audiograms for 3 months. Patients were asked to manually track vertigo attacks in a diary. Qualitative feedback was obtained from each patient at each monthly visit. For each patient, individual pure tone thresholds at each frequency and pure-tone averages (PTA) were analyzed for maximum and minimum values and interquartile ranges. There were four women and one man, with an average age of 49.8 years. Duration of MD ranged from 4 months to 5 years. None of the patients experienced any technical difficulties performing the testing at home. The average duration of each test was 4.2 minutes, with the longest test taking 19.2 minutes. Patients completed between 45 and 102 tests, with an average of 72. The interquartile range for the PTA ranged from 2.5 to 25 dB for affected ears, and 0 to 6.25 dB for unaffected ears with maximums ranging from 5 to 35 dB in affected ears, and 0 to 10 dB in unaffected ears. Daily portable audiometry is feasible in patients with MD. Future studies are planned to further analyze hearing fluctuations in MD with respect to frequencies affected, relationship to vertigo attacks, and response to treatments. Understanding hearing fluctuations in MD may aid refinement of diagnostic criteria and improve prognostication for long-term hearing loss, with a goal of informing treatments that might improve final hearing outcome.

[Mortality of psychiatric inpatients in France during World War II: a demographic study]. In France, World War II lasted from 1939 to 1945. Under-nourishment was a national problem, and was more severe in mental hospitals. The mortality of psychiatric inpatients in France during World War II has long been a controversial issue in the country. Some authors wrote of the "soft extermination" of 40 000 mental patients, although this has been proven false. The historical study published in 2007 by Isabelle von Bueltzingsloewen provides in-depth description and analysis of starvation due to food restrictions in French mental hospitals. Although the French official statistic services published detailed data, no demographic study has been published so far. Such studies have been conducted in Norway and in Finland. "The influence of a period of under-nourishment upon mortality in mental hospitals can rarely be seen with a clarity equal to that in this work. The strict rationing was the same for everybody, but, extra muros, there was private initiative and ingenuity to help in alleviating the distress. Naturally, patients in institution had no ability to act on their own. The immense increase during the period of war from 1941 to 1945 appeared both as an increase in the exact death-risk and as an increase in the disproportion with normal mortality. The men reacted more strongly than women; which is readily comprehensible on physiological grounds, as the rations were virtually the same for all." Excess mortality continued after the war. Even though under-nourishment had ceased, death rates from tuberculosis remained high the following year. Both papers state that the poor hygiene and bad living conditions existing in mental hospitals before the war worsened the effects of food restrictions. DEMOGRAPHIC DATA: French data were published by the General Statistics of France (SGF) that became the National Institute of Statistics and Economic Studies (Insee) in 1946. A series of datasets were published each year according to sex, diagnosis and type of psychiatric institution. In 1943, the outdated diagnostic classification was replaced by a more modern one, with reference to ICD. The same year, the age groups also changed (instead of 35-44, it became 30-39). Publication of data by type of institution was discontinued in 1943; from 1945 to 1948, the only available data concerned patients in hospital on 31st December, by age, sex and diagnosis. General population data were published by the National Institute of Demographic Studies (INED). The data referring to civilian population during the war are provided by the Human Mortality Database. This study covers number of people in hospital, mortality rates by sex, age, diagnosis and type of institution, and standardised mortality ratios. These refer to the civilian population which is more relevant since mental patients would not have been allowed to join the armed forces, even if they had not been in hospital. Finally, mortality trends in mental hospitals are compared with those in "hospices for old, disabled or incurable people", in order to ascertain whether all vulnerable populations in institutions suffered to the same extent. The results show that the number of inpatients in 1945 was about half the total recorded in 1940, due to fewer admissions and to a large increase in the number of deaths. However, the number of discharges increased in 1940, even though the number of admissions had begun to slow down: many patients were sent to places offering better food and hygiene. The number of deaths began to rise as from 1939. Mortality rates were high in 1940 and especially in 1941, when almost one man in three and more than one woman in five died. Global rates did not change in 1942. In December that year, a government order stated that mental patients should receive more food. Mortality rates went down in 1943 and 1944, but rates did not return to the prewar values until 1946. In 1939, mortality rates are high but only among patients of 70 years of age or more. In 1940, they were highest above 55; in 1941, rates between ages 15 and 54 were double those of the preceding year. Thus, even though excess mortality affected all ages, its strongest effects were felt from the older patients to the younger ones from 1939 to 1941. Trends according to diagnosis are difficult to interpret because of the change of classification in 1943. The patients suffered greatest hardship in public hospitals, which had no budget of their own and were run by the departments and lowest in private hospitals contributing to the public service, most of which were congregational and received religious funding. In 1941, standardised mortality ratios were more than three times higher than they were before the war. Comparison with people living in hospices shows that during the war mortality rates were 50% higher in these institutions, while they almost tripled in mental hospitals. The number of people who died of starvation and infectious diseases in mental hospitals from 1939 to 1945 can be estimated at about 45,500. However, mental patients were made specially vulnerable by circumstances that existed before the war in mental hospitals, in terms of food, hygiene and staffing, as suggested by an official document quoted in the paper.

[Treatment of renal colic with double-J stent during pregnancy: a report of 25 cases]. There is no consensus on the treatment of renal colic, a hazardous condition for both pregnant women and their fetus during pregnancy. The present study was to evaluate the therapeutic safety and efficacy of double-J stent. Twenty-five pregnant women were admitted into our hospital for renal colic between January 2008 and June 2009. The mean age was (28.3 ± 4.9) years old. And the mean gestational week was (20.1 ± 6.9) weeks. The diagnostic and therapeutic procedures were as follows: (1) Upon admission, routine urine and blood tests, chemistry panel and ultrasonography were performed. (2) Analgesics or antispasticity drugs were dispended to the patients, such as progesterone. (3) Magnesium sulfate was used for anti-inflammation. (4) If renal colic was not relieved, a double-J stent was inserted into the ureter via cystoscopy. At pre-, intra- and post-operation, an obstetrician monitored the fetal heart and uterine contraction. (5) Ultrasonography was conducted to check the location of double-J stent. (6) After delivery, the women underwent ESWL (extracorporeal shock wave lithotripsy) and then the double-J stent was extracted. Five (20%, 5/25) patients had a positive previous history: three for renal calculus (n = 3), solitary kidney (n = 1) and reimplantation of ureter (n = 1). Only one patient run a high fever of 40°C. Most patients (84%) had a positive percussion over renal regions. Only 6 patients (24%, 6/25) were found to have a great quantity of red blood cells in urine. Half of the patients showed 10 - 20 white blood cells (WBC) per high power field in urine. Fifteen patients (60%, 15/25) had an elevated count of WBC in routine blood test. Only one patient was with elevated serum creatinine because of her solitary kidney. The calcium level decreased in 8 patients (32%, 8/25). All patients suffered hydronephrosis while 18 patients (72%, 18/25) were not found with calculus in ureters or kidneys. Pain of six patients (24%, 6/25) was relieved after the dosing of analgesics. Eighteen patients (72%, 18/25) underwent double-J stent insertion and 1 patient (4%, 1/25) received percutaneous renal puncture. Then pain was relieved and hydronephrosis vanished. After delivery, calculi were treated properly and then the double-J stent were extracted. Iconography showed no residual calculi. For pregnant women with renal colic, retrograde intra-ureteral cannula of double-J stent is both safe and effective. It should be recommended for all renal colic women during pregnancy with or without calculus after the ineffective dosing of analgesics.

Dilated cardiomyopathy in childhood: prognostic features and outcome. The natural history of dilated cardiomyopathy in children is difficult to predict due to the heterogeneous character of the disease. The outcome in infants and children is highly variable from complete recovery to death. In this study, 40 children diagnosed with dilated cardiomyopathy between 1995 and 2004 in our paediatric cardiology unit were reviewed with respect to clinical course and outcome, retrospectively. The medical history of these patients with dilated cardiomyopathy was reviewed to determine age, gender, family history, preceding viral illness, duration of symptoms before the diagnosis, symptoms and signs at presentation, treatment and outcome. The diagnosis was made on the basis of cardiomegaly and evidence of poor left ventricular function by echocardiography. Median age at diagnosis was 14 months, ranging from 2 months to 8 years. At presentation, 28 patients (70%) were under and twelve (30%) were above the age of two years. Twenty-eight (70%) patients had signs of congestive heart failure. Mean duration of follow-up was 40 +/- 24 months (ranging from 6 months to 9 years), 21 patients (52.5%) recovered, 17 patients (42.5%) had residual disease and two (5%) died. The cause of death in both patients was progressive cardiac failure. Sixteen of 28 patients (57%) who were below the age of two years and five of 12 patients (42%) who were above the age of two years at presentation recovered. The rate of recovery was significantly different between the two age groups (p < 0.05). Seventeen of 21 (81%) patients with a history of recent viral illness at presentation recovered. The mean duration of the disease among those who recovered was 11 +/- 8.3 months. Five of 19 (26%) patients without recent viral illness recovered. The mean duration of the disease in this group was 22 +/- 12 months. There was a significant difference between the two groups with respect to recovery and recovery time (p < 0.05). During the first 6 months after diagnosis, there was a significant difference between the patients who recovered and the patients who had residual disease with respect to improvement in the left ventricular FS (22 +/- 3.5%, 15.2 +/- 2.8%, respectively) (p < 0.05). In conclusion, in this study, the rate of recovery and survival is higher than in previous studies. A good outcome is related to age at presentation (< or = two years old), a history of viral disease within three months of presentation and improvement in ventricular function during the first 6 months after diagnosis. Intractable heart failure has an adverse effect on the outcome.

Inhibition of phosphoenolpyruvate carboxykinase, glyceroneogenesis and fatty acid synthesis in rat adipose tissue by quinolinate and 3-mercaptopicolinate. To study the interrelationships of phosphoenolpyruvate carboxykinase and glyceroneogenesis in adipose tissue, investigations with two effectors of the hepatic carboxykinase, Fe2+ and Mn2+, and two inhibitors of the enzyme and of gluconeogenesis in liver, quinolinic acid and 3-mercaptopicolinic acid, were carried out. Incubating adipose tissue cytosol with 30 microM Fe2+ or 100 microM Mn2+ prior to assaying for phosphoenolpyruvate carboxykinase activity doubled the enzyme activity. Inhibition of the enzyme by quinolinate alone was minimal. Adding 30 microM Fe2+ to the cytosol decreased the K0.5 (concentration that gives 50% inhibition) for quinolinate to 0.4 mM and the K0.5 for mercaptopicolinate from 200 to 14 microM. Activating the enzyme with 100 microM Mn2+ did not lower the K0.5 values and adding 500 microM Mn2+ to the cytosol completely interfered with the enhancement of inhibition induced by Fe2+. Each inhibitor interfered with 14C incorporation into glyceride glycerol from labeled pyruvate, alanine and lactate in suspensions of adipocytes. Adding 1 mM Mn2+ to the adipocyte suspension almost completely prevented the inhibition of pyruvate and alanine incorporation into glyceride glycerol, but adding the Mn2+ or 250 microM Fe2+ to the adipocytes in the absence of inhibitors did not enhance glyceride glycerol formation. Adding 250 microM Fe2+ to the adipocytes did not enhance inhibition of lipid synthesis by mercaptopicolinate or quinolinate. Mercaptopicolinate did not inhibit glyceride glycerol, fatty acid, total lipid or CO2 production from glucose. The lack of activation of glyceride glycerol synthesis by added Fe2+ or Mn2+, the lack of enhancement of pyridine carboxylate inhibition by Fe2+ and the interference with inhibition by Mn2+ are compatible with the idea that a transition metal ion similar to Fe2+, if not Fe2+ itself, is available to, or loosely bound to, the adipose tissue carboxykinase in vivo. Taken together with the results of previous work which showed ferroactivator (a cytosol protein necessary for Fe2+ activation of the carboxykinase) to be present in adipose tissue, the present results indicate that the control of the adipose tissue carboxykinase may be similar to the enzyme in liver. Fatty acid synthesis was also diminished by the inhibitors, albeit to a lesser extent than was glyceride glycerol formation. It is hypothesized that this was secondary to decreased esterification caused by the lack of glycerol 3-phosphate from inhibition of the carboxykinase. Decreased esterification would lead to a build-up of fatty acyl CoA which inhibits fatty acid synthesis.

Vena cava diameter measurement for estimation of dry weight in haemodialysis patients. A correct estimation of volume status and so-called dry weight in dialysis patients remains a difficult clinical problem. Clinical status and chest X-ray are not sensitive enough, while invasively measured central venous pressures are not routinely available. Recently, the sonographic determination of the diameter and collapse of the inferior vena cava (IVC) has been proposed as a noninvasive method for estimating intravascular volume. We tried to evaluate the clinical relevance of this method in dialysis patients by comparing it with central venous pressures (CVP) and atrial natriuretic peptide (ANP). To establish a normal range and to control for confounding variables, we examined a large number of healthy controls. Furthermore, the influence of tricuspid insufficiency was examined echocardiographically. Measurements of the IVC diameters were well reproducible, with a coefficient of variation for interobserver error of 2.2%, and a coefficient of variation of 1.4% for intraobserver error. The collapse index was less well reproducible and therefore not used for further analysis. In 86 normal controls (age 18 to 76 years), IVC diameters showed a wide variation, and they were not correlated to age, height, weight, or body surface area. However, there was a significant correlation of IVCex to heart rate (r = 0.63, P < 0.001). Therefore, we calculated percentiles of the heart rate-IVCex relation in normals, and compared the results in patients to these. In 10 overhydrated haemodialysis patients, CVP was closely correlated to IVCex (r = 0.72, P < 0.001), but there was a wide interindividual variation of the slope of this relation. An IVCex above the 95th percentile of normal was a good predictor of an elevated CVP (i.e. > 12 cmH2O). In another 39 stable, chronic haemodialysis patients, there was a significant correlation of the intradialytic decrease of ANP and IVCex (r = 0.69, P < 0.001). However, this correlation existed only in patients without tricuspid insufficiency. In summary, sonography of the inferior vena cava is a valuable tool for estimating dry weight in dialysis patients, provided that some caveats are kept in mind: (i) there is a wide variation of IVC diameters in normals, and single measurements are not helpful in individual patients; (ii) there is a significant, inverse correlation between IVC diameters and heart rate, and the precision of intravascular volume assessment is enhanced by interpreting heart rate corrected diameters; (iii) the presence of tricuspid insufficiency leads to unreliable results, as it influences IVC diameters per se. Intravascular volume changes are reflected by IVC measurements, as shown by the correlation to other indices of intravascular volume, such as CVP and alpha-hANP. IVC sonography is noninvasive and easily available; serial measurements allow an estimation of changes of intravascular volume in patients without cardiac filling impairment. However, unlike with body impedance, interstitial volume is not reflected by IVC diameters.

Acetaldehyde: déjà vu du jour. The possibility that acetaldehyde is responsible for some of the central nervous system effects of ethanol has been a popular hypothesis for many years. This review examines the evidence of a role for acetaldehyde in the actions of ethanol in the brain. The literature review was confined primarily to effects of acetaldehyde in the central nervous system in the realization that a great deal of information is also available on the actions of acetaldehyde in the periphery. The emphasis is on more recent findings, with only occasional references to older work. There are studies implicating acetaldehyde in nearly every central nervous system effect of ethanol that has been studied. With a few exceptions, the evidence for most of these effects is conflicting. For many years the dogma was that the brain did not metabolize ethanol. Any effects of acetaldehyde were therefore held to be due to acetaldehyde diffusing in from the blood. Recently, however, it has been established that ethanol is metabolized to acetaldehyde (primarily by catalase) and then to acetate (by aldehyde dehydrogenase) in the brain. These findings remove the problem that acetaldehyde does not penetrate the brain very well but leave questions as to what it does there. Almost invariably, the concentrations of acetaldehyde in the brain, under normal conditions of ethanol intoxication, are in the low micromolar range. Inhibition of aldehyde dehydrogenase will lead to increases of both peripheral and central acetaldehyde and usually to increases in the effects of ethanol or to behaviorally aversive effects. Stimulation of catalase should lead to increased levels of acetaldehyde in the brain, but this has not been directly demonstrated. Inhibition of catalase should lead to decreased acetaldehyde concentrations in vivo, but, again, this has not been directly demonstrated. Various effects of the direct application of acetaldehyde to the brain have been noted, but in most studies the concentration of acetaldehyde resulting from such manipulations has not been determined, and it is probably higher than that occurring during ethanol intoxication. These experiments tell us what acetaldehyde is capable of doing, not what it does after administration of ethanol. Still, this is a first step. Acetaldehyde is a product of ethanol metabolism in the brain. It clearly has central nervous system effects in its own right. The jury is still out as to whether it has effects under normal conditions of ethanol intoxication. This will remain the case until direct measurement of acetaldehyde concentrations in the brain is routinely accomplished under conditions in which behavioral effects of ethanol are also measured.

Non-invasive ventilation during exercise training for people with chronic obstructive pulmonary disease. Exercise training as a component of pulmonary rehabilitation improves health-related quality of life (HRQL) and exercise capacity in people with chronic obstructive pulmonary disease (COPD). However, some individuals may have difficulty performing exercise at an adequate intensity. Non-invasive ventilation (NIV) during exercise improves exercise capacity and dyspnoea during a single exercise session. Consequently, NIV during exercise training may allow individuals to exercise at a higher intensity, which could lead to greater improvement in exercise capacity, HRQL and physical activity. To determine whether NIV during exercise training (as part of pulmonary rehabilitation) affects exercise capacity, HRQL and physical activity in people with COPD compared with exercise training alone or exercise training with sham NIV. We searched the following databases between January 1987 and November 2013 inclusive: The Cochrane Airways Group specialised register of trials, AMED, CENTRAL, CINAHL, EMBASE, LILACS, MEDLINE, PEDro, PsycINFO and PubMed. Randomised controlled trials that compared NIV during exercise training versus exercise training alone or exercise training with sham NIV in people with COPD were considered for inclusion in this review. Two review authors independently selected trials for inclusion in the review, extracted data and assessed risk of bias. Primary outcomes were exercise capacity, HRQL and physical activity; secondary outcomes were training intensity, physiological changes related to exercise training, dyspnoea, dropouts, adverse events and cost. Six studies involving 126 participants who completed the study protocols were included. Most studies recruited participants with severe to very severe COPD (mean forced expiratory volume in one second (FEV1) ranged from 26% to 48% predicted). There was an increase in percentage change peak and endurance exercise capacity with NIV during training (mean difference in peak exercise capacity 17%, 95% confidence interval (CI) 7% to 27%, 60 participants, low-quality evidence; mean difference in endurance exercise capacity 59%, 95% CI 4% to 114%, 48 participants, low-quality evidence). However, there was no clear evidence of a difference between interventions for all other measures of exercise capacity. The results for HRQL assessed using the St George's Respiratory Questionnaire do not rule out an effect of NIV (total score mean 2.5 points, 95% CI -2.3 to 7.2, 48 participants, moderate-quality evidence). Physical activity was not assessed in any study. There was an increase in training intensity with NIV during training of 13% (95% CI 1% to 27%, 67 participants, moderate-quality evidence), and isoload lactate was lower with NIV (mean difference -0.97 mmol/L, 95% CI -1.58mmol/L to -0.36 mmol/L, 37 participants, moderate-quality evidence). The effect of NIV on dyspnoea or the number of dropouts between interventions was uncertain, although again results were imprecise. No adverse events and no information regarding cost were reported. Only one study blinded participants, whereas three studies used blinded assessors. Adequate allocation concealment was reported in four studies. The small number of included studies with small numbers of participants, as well as the high risk of bias within some of the included studies, limited our ability to draw strong evidence-based conclusions. Although NIV during lower limb exercise training may allow people with COPD to exercise at a higher training intensity and to achieve a greater physiological training effect compared with exercise training alone or exercise training with sham NIV, the effect on exercise capacity is unclear. Some evidence suggests that NIV during exercise training improves the percentage change in peak and endurance exercise capacity; however, these findings are not consistent across other measures of exercise capacity. There is no clear evidence that HRQL is better or worse with NIV during training. It is currently unknown whether the demonstrated benefits of NIV during exercise training are clinically worthwhile or cost-effective.

Differential effects of GH stimulation on fasting and prandial metabolism and plasma IGFs and IGF-binding proteins in lean and obese sheep. The effect of body condition per se on plasma IGFs and IGF-binding proteins (IGFBPs) and the whole-body metabolic responses to recombinant DNA-derived bovine GH (rbGH) in both the fed and the fasted state were determined in lean and dietary obese sheep (n = 6/group). Sheep at zero-energy balance and equilibrium body weight were injected s.c. for 12 days with 100 micrograms/kg rbGH immediately before their morning feeding. Before GH treatment, fasting plasma concentrations of insulin (17.0 +/- 1.9 vs 7.5 +/- 0.7 microU/ml), IGF-I (345 +/- 25 vs 248 +/- 10 ng/ml), glucose (52.6 +/- 1.1 vs 48.3 +/- 0.7 mg/dl), and free fatty acid (FFA) (355 +/- 45 vs 229 +/- 24 nmol/ml) were greater (P < 0.05) and those of GH (1.1 +/- 0.2 vs 2.6 +/- 0.3 ng/ml) were lower (P < 0.05) in obese than in lean sheep. Fasting concentrations of IGF-II and glucagon were not affected (P > 0.05) by obesity. GH concentrations were increased equivalently by 6-9 ng/ml in lean and obese sheep during GH treatment. GH caused an immediate and a marked fivefold increase in the fasting insulin level in obese sheep but only minimally affected insulin concentration in lean sheep. The increment in fasting glucose during GH treatment was greater (P < 0.05) in obese (8-12 mg/dl) than in lean (2-5 mg/dl) sheep. Frequent measurements in the first 8 h after feeding and injection of excipient (day 0) or the first (day 1) sixth (day 6) and twelfth (day 12) daily injection of GH showed that prandial metabolism in both groups of sheep was affected minimally by GH. However, GH treatment on day 1 (not days 6 or 12) acutely attenuated the feeding-induced suppression of plasma FFA in both groups of sheep and this effect was significantly greater in obese than in lean sheep. Although obese sheep were hyposomatotropic, the basal and GH-induced increases in plasma IGF-I concentrations were greater (P < 0.05) in obese than in lean sheep. Plasma IGF-II was unaffected by obesity and was not increased by GH stimulation. Western ligand blotting showed that IGFBP-3 accounted for approximately 50-60% of the plasma IGF-I binding capacity in sheep respectively both before and during GH treatment. Basal plasma levels of IGFBP-2 were lower (P < 0.05) and those of IGFBP-3 greater (P < 0.05) in obese compared with lean sheep. GH increased the level of IGFBP-3 equally in lean and obese sheep, but suppressed the expression of IGFBP-2 more (P < 0.05) in lean than in obese sheep. We concluded that the diabetogenic-like actions of GH in sheep were exaggerated markedly by obesity, and were expressed more during the fasted than the fed states. The effects of GH stimulation on the endocrine pancreas may be selective for beta-cells and preferentially enhanced by obesity. GH regulation of IGF-I and the IGFBPs differs in lean and obese sheep.

The Outcome of Cardiac Dysfunction in Critically Ill Trauma Patients: Myocardial Contusion Complicated by Refractory Hypotension. This work attempted to define the care and course of those most severely affected patients in the setting of blunt chest trauma, who had hypotension refractory to routine fluid resuscitation. Twenty-three critically ill blunt trauma ICU patients were resuscitated and enrolled with ongoing hypotension required placement of a pulmonary artery catheter. The REF(®)Explorer (Baxter, Edwards, Anaheim, CA) catheter was placed in the right heart measuring pressure, volume and oxygen utilization information, as well as recording Injury Severity Score, EKG, CXR, CPK/MB and echocardiography over the initial 72-h time period. There were an approximately 2,300 Level I trauma patients admitted annually over a 4-year period with an overall mortality rate of 4.3% (100) patients with 3.4% (79) patients "ruling in" with elevated cardiac enzymes, associated with an increased mortality rate of 6.7% (p < 0.05). The 23 patients were male (17, 74%), mean age 41.2 years, with no past medical history (19, 83%), in a motor vehicle accident (21, 91%), with pulmonary injury (9, 39%), undergoing celiotomy in (10, 44%). They presented with moderate to severe trauma acuity defined as mean GCS of 8.6, TS of 11.3, and ISS of 34 with an increased mean hospital stay of 15 days versus 6 days in the ICU; and a 26 days versus 10 days overall stay for those with myocardial contusion (p < 0.05). Analysis of diagnostic variables found an abnormal EKG in (21, 91%), CXR in (20, 87%) and echocardiogram in (8, 37%). The total CPK was found to be elevated, mean 2,219 (204-8,278 U/l), while the MB fraction was normal 2.3 ± 1.3%. Invasive cardiac monitoring found an increase in CO of 1.6 l/min from 5.9 to 7.8 l/min during the first 24 h of recovery. Survival was worsened with increased ISS (29 vs. 43) p < 0.02, but improved with longer ICU (17 vs. 8) p < 0.03 and hospital (39 vs. 7) p < 0.05 stay in days. The analysis of commonly used diagnostic modalities - EKG, CXR, ECHO, or CO, did not correlate with survival, but the total CPK was increased in survivors (2,715 vs. 1,432 U/l) p < 0.009. There is worsened morbidity with a 2-fold increase in ICU LOS and hospital stay, and a 1.5-fold increase in mortality in the severe myocardial contusion group. The diagnostic dilemma posed by lack of definitive testing continues unresolved after analysis of routinemodalities - EKG, CXR, ECHO, CPK or CO - failing to yield a "best test".

[Bipolar electrocoagulation in patients with persistent hemorrhage secondary to second degree postradiation proctopathy]. Our objective was to evaluate response to bipolar electrocoagulation (BICAP) in patients with persistent rectorragia (PR) secondary to PRP (post-radiation proctitis) degree II (telangiectasias). We had 64 cases prospective and conducted study cohort of 257 patients, with cervicouterine cancer, radiated, PRP degree II, and PR. We conducted prospective, cross-sectional and descriptive study. Patients were divided in three groups: (group 1), with hemodynamical instability; (group 2) with chronic anemia, and (group 3), without data of chronic anemia (Table 1). Clinical evaluation was carried out before and after the intervention (BICAP). BICAP of radial way at level of telangiectasias was applied, of sigmoides up to 2 cm of anal margin. Three sessions were average. A total of 55 patients had PR radiation dose average, with 49.85 Gy. Time average of appearance of rectorragia was 9 months. GROUP 1: A total of 21 patients, age 51.2 years average). Previous to BICAP, week by frequency of rectorragia was 2.23 (average). With hemoglobin (Hb) and hematocrit (Ht) of 7.1 g (average) and 24.4%, respectively (average). A total of 18 patients (85.7%) required hemotransfusion. Average hospital stay was 1.3 days. Cardiac frequency, arterial, blood and hemoglobin pressure, and hematocrit obtained later improvement to intervention with BICAP was statistically significant (p > 0.0001). Patients did not require additional blood transfusions. GROUP 2: A total of 18 patients with age average 56 years (average). Previous to BICAP they had weekly rectorragia of 2.16 (average). Hb was 11.4 g and Ht of 35.5% (average). Subsequent to BICAP, 100% patients had controlled hemostasis. The improvement observed with regard to cardiac frequency and blood pressure after application of BICAP did not have statistical significance despite the fact that it was demonstrated to laboratory parameters as well as diminution of weekly episodes of rectorragia if they were statistically significant (p > 0.0001). No blood transfusion was required. GROUP 3: There were 16 patients with average of 57.1 years of age (average). Previous to BICAP they had weekly 1 rectorragia of 2.06, Hb of 13.5 g and Ht of 41.2% (average). Subsequent to BICAP, there was 100% controlled haemostasis. In this group, diminution of weekly episodes of rectorragia, cardiac frequency, and blood pressure did not have statistically significant changes; nevertheless, hemoglobin and hematocrit had a statistically significant increase (p > 0.0001). No blood transfusion was required. Electrocoagulation (BICAP) is effective in hemostasis of bleeding telangiectasias, stabilizing to the patient, and diminishing recurrence, hospital stay, and blood requirements.

Resistance and resilience of traditionally managed West African Dwarf goats from the savanna zone of northern Nigeria to naturally acquired trypanosome and gastrointestinal nematode infections. A survey was conducted of gastrointestinal nematode infections and trypanosomosis in Nigerian West African Dwarf (WAD) goats from the savanna region of the country. Animals were screened at two markets, Gboko and Akpagher, from the beginning of April until the end of September, coinciding with the end of the dry season and the first 5 months of the wet season. Of 1054 goats that were examined, 80.5% carried gastrointestinal (GI) nematodes belonging to the genera Haemonchus (61.0%), Oesophagostomum (21.0%) and Trichostrongylus (17.9%). Faecal egg counts (FEC) increased very slowly but significantly from April to maximum levels in September, and varied marginally between the two market sources. The majority of goats (68.8 and 70.1% at the two markets) had low FEC not exceeding 50 eggs/g (epg). FEC did not differ significantly between the sexes or between age classes. Packed cell volume (PCV) also declined significantly with month of the study, but was affected by host sex (a significant month x sex interaction) being generally higher in male animals throughout the period. There was a highly significant negative correlation between log₁₀(FEC+1) and PCV, when all other factors had been taken into account. Body condition scores (BCS) also declined with month of the study, but there was a marked difference between the two sexes, with male animals generally showing a greater stability of BCS across the months compared with females. Trypanosome infections were found in only 4% of the goats and only during the rainy season. Most infections (92.86%) were caused by Trypanosoma brucei alone although T. vivax and T. congolense were occasionally detected. Overall, the majority of goats sampled each month maintained generally good body condition (BCS 3.0-5.0), normal or slightly reduced PCV, even when concurrently infected with trypanosomes and GI nematodes. However, four concurrently infected goats showed signs of overt anaemia during periods of peak infection, during the late rainy season, with marked reductions in PCV (< 15%). Two of the infected goats were also in poor body condition with BCS of < 2.0. There was no evidence of additive or synergistic pathogenic effects of the two parasites. These results are discussed in the context of the unexpectedly strong resistance and resilience of the savanna WAD ecotype to its native strains of GI nematode and trypanosome parasites.

Effects of tibolone and conventional hormone replacement therapies on arterial and hepatic cholesterol accumulation and on circulating endothelin-1, vascular cell adhesion molecule-1, and E-selectin in surgically menopausal monkeys. Menopause and aging are associated with a marked increase in the incidence of coronary heart disease as well as reductions in circulating estrogen, progestogen, and androgen levels. The synthetic compound tibolone and its metabolites have estrogenic, progestogenic, and androgenic characteristics. In the present study, we compared the effects of tibolone, estrogen replacement therapy, and estrogen plus progestogen replacement therapy on arterial and hepatic lipid accumulation and on circulating soluble adhesion molecule and endothelin-1 concentrations in surgically postmenopausal cynomolgus monkeys. Animals were fed an atherogenic diet for 2 years while receiving either no hormone treatment (control, n = 31) or the following treatments at doses designed to mimic the human dose on a daily caloric intake basis: tibolone at 2.5 mg/day (HiTib, n = 31), tibolone at 0.625 mg/day (LoTib, n = 29), conjugated equine estrogens (CEE) alone at 0.625 mg/day (CEE, n = 29), or CEE plus continuous medroxyprogesterone acetate (MPA) at 2.5 mg MPA/day (CEE + MPA, n = 30). Relative to the control group, iliac artery total cholesterol content was not different in the HiTib, LoTib, and CEE + MPA groups but was significantly lower in the group receiving CEE only (P < 0.05). In contrast, hepatic free cholesterol content was reduced in all treatment groups [HiTib (P < 0.01), LoTib (P < 0.05), CEE (P < 0.01), and CEE + MPA (P < 0.05)], whereas hepatic total and esterified cholesterol content were reduced in the HiTib, CEE, and CEE + MPA groups (all P < 0.05). HiTib and CEE groups had lower hepatic triglyceride levels per milligram of protein (P < 0.05). Iliac arterial cholesterol content was highly correlated with hepatic cholesterol content and with previously published histomorphometrically determined coronary artery atherosclerosis, supporting the use of the iliac artery as a surrogate for the coronary artery in the monkey. Circulating levels of soluble vascular cell adhesion molecule-1 were significantly reduced in the HiTib (P < 0.02) and CEE (P < 0.05) groups, whereas soluble E-selectin was reduced in the CEE group only (P < 0.01). Plasma endothelin-1 was significantly reduced in the LoTib (P < 0.05), CEE (P < 0.01), and CEE + MPA (P < 0.01) groups. These results suggest that while tibolone caused marked depression of high-density lipoprotein cholesterol and a resultant twofold increase in the total plasma cholesterol/high-density lipoprotein cholesterol ratio, those effects did not result in exacerbation of iliac artery atherosclerosis, perhaps because of beneficial effects on vascular biology or hepatic metabolism.

Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure. Acute liver failure (ALF) carries a high mortality in children. N-acetylcysteine (NAC), an antioxidant agent that replenishes mitochondrial and cytosolic glutathione stores, has been used in the treatment of late acetaminophen-induced ALF and non-acetaminophen-induced ALF. In our unit, NAC was introduced as additional treatment for non-acetaminophen-induced ALF in 1995. The aim of this study was to evaluate the safety and efficacy of NAC in children with ALF not caused by acetaminophen poisoning. A retrospective review of medical records of 170 children presenting with nonacetaminophen-induced ALF between 1989 and 2004 was undertaken. ALF was defined as either international normalized ratio of prothrombin time (INR) > 2 and abnormal liver function or INR >1.5 with encephalopathy and abnormal liver function. Children were divided into the following groups: Group 1 (1989-1994), standard care (n = 59; 34 [58%] male; median age 2.03 yr, range 0.003-15.8 yr); and Group 2 (1995-2004), standard care and NAC administration (n = 111; 57 [51%] male; median age 3.51 yr, range 0.005-17.4 yr). NAC was administered as a continuous infusion (100 mg/kg/24 hours) until INR < 1.4, death, or liver transplantation (LT). The median duration of NAC administration in Group 2 was 5 (range, 1-77) days. Complications were noted in 8 (10.8%) children: rash in 3, arrhythmia in 3, and dizziness and peripheral edema in 1. One child had an allergic reaction (bronchospasm) and NAC was stopped. A total of 41 (71%) children in Group 1 vs. 85 (77%) in Group 2 required admission to intensive care, P = not significant (ns). The length of intensive care stay was 6 (range, 1-58) days in Group 1 vs. 5 (range, 1-68) days in Group 2, P = ns and length of hospital stay was 25 (range, 1-264) days vs. 19 (range, 1-201) days, P = 0.05. The 10-yr actuarial survival was 50% in Group 1 compared to 75% in Group 2, P = 0.009. Survival with native liver occurred in 13 (22%) in Group 1 vs. 48 (43%) in Group 2, P = 0.005; 15 (25%) in Group 1 died without transplant vs. 21 (19%) in Group 2, P = ns; and LT was performed in 32 (54%) vs. 42 (38%), P = ns. Death after transplantation occurred in 15 (39%) in Group 1 vs. 8 (16%) in Group 2, P = 0.02. In conclusion, NAC is safe in non-acetaminophen-induced ALF. In this retrospective study NAC was associated with a shorter length of hospital stay, higher incidence of native liver recovery without transplantation, and better survival after transplantation.

Differential activation of MAPK and ICE/Ced-3 protease in chemical-induced apoptosis. The role of oxidative stress in the regulation of mitogen-activated protein kinases (MAPKs) leading to gene expression and survival or activation of caspases leading to apoptosis. Chemical-induced oxidative stress to a cell can signal many cellular responses which include proliferation, differentiation, hemeostasis, apoptosis or necrosis. To better understand the underlying molecular mechanisms after exposure to chemicals, we investigated the signal transduction pathways, in particular the mitogen-activated protein kinase (MAPK) pathway and the ICE/Ced-3 protease (caspase) pathway, activated by different agents. Butylated hydroxyanisol (BHA) and its metabolite, t-butyl-hydroquinone (tBHQ), both are well known phenolic antioxidants used in food preservatives, strongly activated c-Jun N-terminal kinase 1 (JNK1) and/or extracellular signal-regulated protein kinase 2 (ERK2) in a dose- and time-dependent fashion. Pretreatment with free radical scavengers N-acetyl-L-cysteine (NAC), glutathione (GSH), or vitamin E, inhibited ERK2 activation and, to a much lesser extent, JNK 1 activation by BHA and tBHQ, implicating the role of oxidative stress. Under conditions where JNK1 and ERK2 were activated, BHA also activated transcription factors nuclear factor kappa B (NF-kappaB), activated-protein-1 (AP-1), and anti-oxidant response element (ARE), leading to induction of genes such as c-jun, and c-fos. At relatively high concentrations, BHA and tBHQ stimulated proteolytic activity of ICE/Ced3 cysteine proteases, and caused apoptosis, which was blocked by pretreatment with NAC. Further increase in concentrations lead to rapid cell death predominantly occurred via necrosis. Some naturally occurring phytochemicals, such as phenylethyl isothiocyanate (PEITC), green tea polyphenols (GTP), and sulfarophane, which have been shown to be potent inducers of Phase II enzymes, also differentially regulated the activities of JNK, ERK, or CPP-32, in a time- and dose-dependent manner. Our data, together with the work of others, enable us to propose a model in which low concentrations of these chemicals (e.g., BHA, PEITC) activate MAPKs leading to induction of gene expression (e.g., c-jun, c-fos, GSI) which may protect the cells against toxic insults and enhance cell survival. At relatively high concentrations, these agents activated both MAPKS, and the ICE/Ced-3 caspase pathway, leading to apoptosis. The exact mechanisms by which MAPK and caspases are activated by these agents are currently unknown, but may involve oxidative modification of glutathione (GSH) and/or protein thiols, and/or generation of secondary messengers, ceramide and calcium, which further activate downstream events. Taken together, our results suggest that chemicals including phenolic antioxidants activate MAPK pathways which may lead to the induction of genes producing protection and survival mechanisms, as well as the ICE/Ced-3 protease pathway, leading to apoptosis. The balancing amongst these pathways may dictate the fate of the cells upon exposure to chemicals.

Early, but not advanced, glomerulopathy is reversed by pancreatic islet transplants in experimental diabetic rats: correlation with glomerular extracellular matrix mRNA levels. In this study, we investigated 1) whether long-term restoration of euglycemia by means of pancreatic islet transplants is capable of preventing and/or reversing renal functional and structural alterations in an experimental model of insulin-deficient diabetes, and 2) whether changes in extracellular matrix (ECM) and cell turnover at the glomerular level and biochemical abnormalities associated with hyperglycemia correlate with the renal outcome after transplantation. Male Lewis rats, rendered diabetic by intravenous injection of streptozotocin, underwent homologous islet transplantation via the portal vein at 2 weeks (study A), at 4 months (study B), and at 8 months (study C) after the induction of diabetes and killed 12 months after transplantation in study A and 4 months after transplantation in studies B and C. Age-matched nondiabetic and untreated diabetic rats were used as control animals and were studied at 4, 8, and 12 months. In the untreated diabetic animals, metabolic derangement was associated with increased erythrocyte polyol and fructose levels, tail-tendon content of advanced glycation end products (AGEs), total proteinuria, albuminuria, kidney weight, and mean glomerular volume as well as with marked glomerular and extraglomerular lesions. Glomerular gene expression for the ECM components fibronectin and collagen IV and for TGF-beta was also increased, whereas glomerular cell proliferation was unaffected by diabetes. In study A, changes in renal function and structure observed in diabetic rats at 12 months were completely prevented by successful islet transplants. In study B, all functional and structural abnormalities detected in diabetic rats at 4 months of disease duration were virtually reversed by 4 months of euglycemia in transplanted animals, whereas they progressed further in untreated diabetic rats. In study C, the course of functional and structural changes observed in untreated diabetic rats was not reversed by islet transplantation. Likewise, tissue AGE accumulation and particularly upregulation of glomerular ECM and transforming growth factor (TGF)-beta gene expression, which are believed to play a role in the pathogenesis of altered renal function and structure in diabetes, were normalized in transplanted rats from study A and study B, but not in those from study C. These experiments show that restoration of euglycemia by islet transplants is capable of preventing experimental diabetic glomerulopathy and reversing early changes in renal function and structure induced by diabetes. In a later phase of the disease, when glomerular matrix gene expression becomes independent of hyperglycemia, possibly because of the persistent increase in tissue AGE accumulation, metabolic control is not capable of reversing renal abnormalities.

Optimal myocardial protection during crystalloid cardioplegia. Interrelationship between volume and duration of infusion. There is often a large difference between volumes of crystalloid cardioplegic solution used clinically (2 to 4 ml/gm myocardium) and experimentally (in rat heart preparations, volumes of 30 ml/gm or more are used). In an attempt to reconcile these differences and define the minimum volume and/or duration of infusion of the St. Thomas' Hospital cardioplegic solution consistent with maximal myocardial protection, we have used the isolated working rat heart to characterize the relationships between myocardial protection and (1) the duration of cardioplegic infusion and (2) the volume of cardioplegic infusion. Hearts (n = 6 per group, weighing 0.90 +/- 0.06 gm) were subjected to 0, 5, 10, 15, 30, 45, 60, 120, 180, 240, or 300 seconds of cardioplegic infusion (mean infusion volumes = 0, 1.3 +/- 0.1, 2.0 +/- 0.1, 2.8 +/- 0.2, 5.0 +/- 0.1, 8.3 +/- 0.2, 10.5 +/- 0.8, 21.8 +/- 2.1, 22.7 +/- 1.3, 32.3 +/- 2.1, and 39.1 +/- 1.8 ml per heart, respectively) before 30 minutes of normothermic ischemia. They recovered 3.9% +/- 2.3%, 9.7% +/- 5.0%, 22.8% +/- 5.8%, 34.6% +/- 4.6%, 54.7% +/- 6.6%, 64.0% +/- 5.0%, 67.4% +/- 4.0%, 56.6% +/- 11.1%, 60.0% +/- 5.8%, 51.6% +/- 7.0%, and 68.0% +/- 7.8% of their preischemic cardiac output on reperfusion. Creatine kinase leakage, tissue adenosine triphosphate and creatine phosphate content, and other indices of cardiac function supported this observation. To assess volume of infusion rather than duration, we infused hearts (n = 6 per group) with 1.0, 1.5, or 2.0 ml of cardioplegic solution over 120 seconds. Although recovery of cardiac output with 2.0 ml (56.2% +/- 6.8%) was not significantly different from that (56.6% +/- 11.1%) observed with large volumes of solution (21.9 +/- 2.1 ml), infusion of 1.5 and 1.0 ml resulted in poor recovery of cardiac output (40.1% +/- 4.6% and 21.8% +/- 3.9%, respectively). To assess duration (with low volumes) rather than volume of infusion, we infused hearts (n = 6 per group) with 2.0 ml of cardioplegic solution over 10, 30, 60, or 120 seconds. Maximal protection was observed with 30, 60, and 120 seconds of infusion (recovery of cardiac output = 56.7% +/- 5.9%, 45.1% +/- 7.9%, and 56.2% +/- 6.8%, respectively). Our results suggest that, for maximum myocardial protection, the St. Thomas' Hospital solution should be infused at a rate of not less than 2.0 ml/gm wet weight of heart and that the duration of infusion should be not less than 30 seconds.

Reversible ischemia in severe stress technetium 99m-labeled sestamibi perfusion defects assessed from gated single-photon emission computed tomographic polar map Fourier analysis. Detection of reversible ischemia and regional viability by inference from the presence of preserved resting myocardial thickening on dynamic electrocardiographic-gated tomographic (GSPECT) images obtained after stress injection could potentially obviate the need for a separate resting injection. This would decrease the cost, effort, duration, and radiation exposure of diagnostic myocardial perfusion imaging. The aim of this study was to determine whether functional images derived from GSPECT stress myocardial perfusion images, which represent indices of regional wall thickening, could predict the pattern of reversibility of perfusion defects in myocardial segments with severe perfusion defects on stress 99mTc-labeled sestamibi (99mTc-sestamibi) images. Reversible ischemia in myocardial segments with severe hypoperfusion (< or = 50% of normal activity) on stress 99mTc-sestamibi images was assessed with GSPECT indexes of myocardial thickening, as reflected by an increase in regional count density during systole. GSPECT bullseye plots were generated for each of eight frames acquired after stress 99mTc-sestamibi injection in 44 patients with coronary artery disease and at least one severe perfusion defect on summed (ungated) SPECT images. With first harmonic Fourier amplitude (AMP) and AMP/perfusion ratio (APR) images, regional myocardial systolic thickening was assessed according to a nine-segment model as absent, markedly reduced, mildly reduced, or normal thickening. These data were compared on a regional basis with defect reversibility determined with resting sestamibi images. Of 124 severe stress defects, 32 showed absent, 53 minimal, 35 partial, and four complete reversibility on resting images. AMP and APR scores had 75% and 82% agreement on the presence or absence of reversibility on resting images, respectively (both p < or = 0.00005), and both had significant agreement (p = 0.0072 and p < or = 0.00005, respectively) with resting reversibility grades by kappa analysis. AMP correctly identified 83% of the defects that were reversible on resting images, whereas the APR identified 96% (p = 0.0014 for sensitivity of APR vs AMP). On analysis of the triad of segment scores, the AMP slightly underestimated the degree of resting reversibility (p = 0.0002), whereas APR images indicated more reversibility than did resting images (p < or = 0.00005). AMP and APR indicated a greater degree of reversibility than did resting images in at least one myocardial segment in 13 (30%) and 27 (61%) of the 44 patients, respectively. The presence and degree of reversible ischemia in severe stress sestamibi perfusion defects seen on resting images can be detected reliably by the pattern of regional myocardial thickening demonstrated by Fourier analysis of GSPECT polar maps. When indexed for degree of perfusion, the APR images predict a greater degree of reversibility than do resting images.

Effect of in vitro and in vivo 25-hydroxyvitamin D treatment on macrophages, T cells, and layer chickens during a coccidia challenge. This article describes the in vitro and in vivo effects of a 25-hydroxycholecalciferol (25[OH]D) treatment in layer hens during a mixed coccidia challenge. HD11 cells (chicken macrophage cell line) were treated in vitro with a coccidia antigen or in a medium supplemented with either 1,25-dihydroxycholecalciferol (1,25[OH]2D) or 25(OH)D. HD11 cells treated in vitro with 200 nM of 1,25(OH)2D had increased nitrite production (P < 0.01) compared with HD11 cells treated with 0 or 200 nM of 25(OH)D. Treating HD11 cells with 25(OH)D decreased IL-10 mRNA by 1.7-fold, but 1,25(OH)2D treatment increased the amount of IL-10 mRNA by 2.7-fold (P < 0.01) compared with the group treated with 0 nM of 25(OH)D. Post-coccidial antigen stimulation, 25(OH)D or 1,25(OH)2D treatment decreased (P < 0.01) 1α-hydroxylase mRNA amounts in HD11 cells. Stimulating primary T cells in vitro with Concanavalin A (Con-A) decreased (P = 0.020) the 1α-hydroxylase mRNA amounts by 3-fold. ConA-B1-VICK cells (chicken T cell line) stimulated with 100 nM 1,25(OH)2D or with supernatants from HD11 cells treated with 25(OH)D plus lipopolysaccharide (LPS) had 1.3-fold less (P < 0.01) interferon (IFN)-γ mRNA compared with the group treated with 25(OH)D. Layer birds were fed a basal diet supplemented with 25(OH)D at 6.25, 25, 50, or 100 μg/kg, and at 21 d of age orally challenged with 1 × 10(5) live coccidia oocysts. Compared with birds fed similar levels of 25(OH)D and unchallenged with the coccidia oocyst, birds challenged with the coccidia oocyst had 15% reduced BW gain in the groups supplemented with either 6.25, 25, or 50 μg/kg of 25(OH)D, but only a 4% reduced BW gain in birds fed 100 μg/kg of 25(OH)D (P < 0.01). Birds fed 100 μg/kg 25(OH)D had decreased (P = 0.012) CD8+ cell percentages in cecal tonsils in both coccidial oocyst challenged and unchallenged birds, compared with birds fed 6.25 μg/kg 25(OH) and unchallenged with coccidial oocysts. At 15 d post-coccidia challenge, birds fed 100 μg/kg 25(OH)D and challenged with coccidial oocysts had 17% more CD4+CD25+ cells (P = 0.018) in the cecal tonsil compared with the birds fed 100 μg/kg 25(OH)D and unchallenged with coccidial oocysts. At d 6 post-coccidia challenge, birds fed 100 μg/kg 25(OH)D had a 3.5-fold increase (P < 0.01) in IL-10 mRNA amounts in the cecal tonsils compared with birds fed 6.25 μg/kg 25(OH)D. In conclusion, supplementing birds with 100 μg/kg 25(OH)D could be a nutritional strategy to reduce the production losses post-coccidia challenge.

[Effects of calorie restriction on SIRT1 expression in liver of nonalcoholic fatty liver disease: experiment with rats]. To investigate the molecular mechanisms of calorie restriction (CR) in treatment of nonalcoholic fatty liver disease (NAFLD). 25 male Wistar rats were randomly divided into 2 groups: normal control group (NC, n = 7) fed with regular diet and high fat diet-NAFLD model group (HFM, n = 18) fed with high-fat diet. Two months later, the rats in Group HFM were further divided into 2 subgroups: continuous high-fat feeding group (HF, n = 9) and normal diet feeding with 60% calorie restriction group (CR, n = 9). The rats were sacrificed after 1 month calorie restriction. By the end of experiment, body weight (BW), visceral fat mass (VF), fasting plasma glucose (FPG), fasting serum insulin (FINS), blood lipids (BL), including total cholesterol (TC) and triglyceride (TG), and hepatoultrastructure changes were examined to evaluate the effect of different feeding protocols on the experimental animals. The mRNA expression of the longevity gene SIRT1 in the liver was detected by RT-PCR. Western blot analysis was performed to determine the expression of SIRT1 protein in each group. Electron microscopy showed that the rats in group HF displayed obviously abnormal hepatoultrastructure, and the ultramicropathology changes of liver cell were improved obviously in Group CR. The VF, FINS, FPG, TC, and TG of the Group HF were 15.1 g +/- 4.1 g, 29.22 mU/L +/- 7.28 mU/L, 6.2 mmol/L +/- 1.46 mmol/L, 2.61 mmol/L +/- 0.29 mmol/L, and 1.35 mmol/L +/- 0.21 mmol/L respectively, all significantly higher than those in Group NC (9.0 g +/- 0.4 g, 13.09 mU/L +/- 1.18 mU/L, 4.4 mmol/L +/- 0.57 mmol/L, 1.41 mmol/L +/- 0.28 mmol/L, and 0.67 mmol/L +/- 0.10 mmol/L respectively, all P < 0.01). The mRNA expression of SIRT1 in the liver of Group HF was significantly lower than that of Group NC (P < 0.05), and the mRNA expression of SIRT1 in the liver of Group CR was significantly higher than those of Group HF and Group NC (both P < 0.01). The protein expression of SIRT1 of Group HF was significantly lower than that of Group NC (P < 0.01), and that of Group CR was significantly higher than that of Group HF, however, still significantly lower than that of Group NC (both P < 0.01). The BW and VF, FINS, FPG, TC, and TG of Group CR were all significantly lower than those of Group HF (all P < 0.01). CR can reverse NAFLD significantly. The increased expression of SIRT1 in liver induced by CR may be an important molecular mechanism involved in the improvement of NAFLD by CR.

"A psychometric investigation of gender differences and common processes across borderline and antisocial personality disorders": Correction to Chun et al. (2017). Reports an error in "A psychometric investigation of gender differences and common processes across borderline and antisocial personality disorders" by Seokjoon Chun, Alexa Harris, Margely Carrion, Elizabeth Rojas, Stephen Stark, Carl Lejuez, William V. Lechner and Marina A. Bornovalova (Journal of Abnormal Psychology, 2017[Jan], Vol 126[1], 76-88). In the article, there were two errors in the article's supplemental material. The supplemental material stated, "In each case, if the relaxed model fit significantly better than the baseline model (i.e., ΔX²> 3.84, Δdf =2), then the item under investigation was flagged as noninvariant; otherwise the item was marked as invariant." The value for ΔX² should have been 5.99. The supplemental material also stated, "If there was no decrement in fit as a function of constraining a given item, the item in question was flagged as noninvariant." It should have stated that these items were flagged as invariant. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2016-53090-001.) The comorbidity between borderline personality disorder (BPD) and antisocial personality disorder (ASPD) is well-established, and the 2 disorders share many similarities. However, there are also differences across disorders: most notably, BPD is diagnosed more frequently in women and ASPD in men. We investigated if (a) comorbidity between BPD and ASPD is attributable to 2 discrete disorders or the expression of common underlying processes, and (b) if the model of comorbidity is true across sex. Using a clinical sample of 1,400 drug users in residential substance abuse treatment, we tested 3 competing models to explore whether the comorbidity of ASPD and BPD should be represented by a single common factor, 2 correlated factors, or a bifactor structure involving a general and disorder-specific factors. Next, we tested whether our resulting model was meaningful by examining its relationship with criterion variables previously reported to be associated with BPD and ASPD. The bifactor model provided the best fit and was invariant across sex. Overall, the general factor of the bifactor model significantly accounted for a large percentage of the variance in criterion variables, whereas the BPD and AAB specific factors added little to the models. The association of the general and specific factor with all criterion variables was equal for men and women. Our results suggest common underlying vulnerability accounts for both the comorbidity between BPD and AAB (across sex), and this common vulnerability drives the association with other psychopathology and maladaptive behavior. This in turn has implications for diagnostic classification systems and treatment. (PsycINFO Database Record

Charcot arthropathy of the foot and ankle associated with rheumatoid arthritis. Diabetic peripheral neuropathy is now well recognized as the most common cause of Charcot arthropathy of the foot and ankle, but it may be associated with other peripheral neuropathies. While not well known, it is well documented that rheumatoid arthritis is correlated with peripheral neuropathy. However, despite rheumatoid neuropathy, Charcot arthropathy has never been associated with rheumatoid arthritis. We report a series of Charcot arthropathy patients with concomitant rheumatoid arthritis. The medical records of patients treated between 1986 and 2009 with Charcot arthropathy and rheumatoid arthritis were reviewed. Recorded data included neuropathy risk factors, medications, history of ulcerations, ambulatory status, shoe wear, and treatment course. Radiographs of Charcot joints were categorized according to the Brodsky anatomic classification. Patient care was based on published treatment algorithms, emphasizing accommodative, nonoperative treatment with selective surgical interventions. Surgery was indicated for recalcitrant, nonhealing lesions of the soft tissue and/or unbraceable, nonplantigrade feet. A successful outcome was considered an ambulatory patient without amputation and a closed skin envelope at last follow-up. Four men and 16 women met the diagnostic criteria, resulting in 33 feet in the series. Average age was 61 years, and average follow-up was 4.3 years. In addition to rheumatoid arthritis, 4 patients (7 feet) had hypothyroidism, 4 patients (6 feet) had diabetes, 1 patient (2 feet) had megaloblastic anemia and diabetes, and 1 patient (1 foot) had hypothyroidism and diabetes; however, 17 feet (52%) had no known sources for neuropathy. Charcot involvement was type 1-midfoot in 21 feet (64%), type 2-hindfoot in 7 (21%), type 3a-ankle in 4 (12%), and type 3b-calcaneus in 1 (3%). Twenty-three feet (70%) were treated with conservative modalities. Ten feet (30%) required 15 surgeries, of which an exostectomy was the most common procedure. Of the 33 feet, 3 had persistent ulcerations and 1 underwent major amputation, representing 4 failures. Raising awareness within the orthopaedic community, we report a Charcot arthropathy population with a concomitant rheumatoid arthritis diagnosis, emphasizing a relationship between the 2 diseases. Through a conservative treatment regimen combined with selective surgical interventions, satisfactory outcomes were achieved in 88% of the rheumatoid Charcot feet. While several patients had additional neuropathy sources which could cause Charcot arthropathy (eg, diabetes), the majority of feet had no etiologies accounting for neuropathy or neuroarthropathy except rheumatoid arthritis. Further study is required to expand on this relationship between the 2 diseases. Level IV, retrospective case series.

Different preconditioning stimuli invoke disparate electromechanical and energetic responses to global ischemia in rat hearts. One hypothesized mechanism of the cardioprotection provided by preconditioning is decreased utilization of ATP during ischemia. Although ATP levels in preconditioned heart during ischemia have been previously studied, contractile activity during ischemia has not been investigated. Contractile activity accounts for significant ATP consumption during ischemia. We hypothesized that preconditioning stimuli may conserve energy during the ischemic period by decreasing myocardial contractile energy expenditure prior to asystolic cardiac arrest. We studied three preconditioning stimuli: (i) four cycles of 5-min periods of ischemia (4 x 5' CI), (ii) 2 min of alpha 1-adrenergic stimulation (phenylephrine; PE), and (iii) 2 min of P1-purinergic stimulation (adenosine). The effects of these stimuli on myocardial ATP, ventricular contractility, and the time to cessation of electromechanical function (asystole) during the sustained ischemic period were then examined. Preconditioning stimuli (4 x 5' CI, phenylephrine, and adenosine) improved postischemic functional recovery compared with nonpreconditioned controls. Myocardial ATP contents at the end of 20 min of global ischemia were higher for adenosine-treated (9.0 +/- 1.5 mumol/g dry weight; p < 0.05) and PE-treated (9.9 +/- 1.9 mumol/g dryweight; p < 0.05) hearts than for controls (6.6 +/- 1.2 mumol/g dry weight). The CI hearts began with lower myocardial ATP levels (9.9 +/- 1.2 mumol/g dry weight; p < 0.05) than other groups prior to the sustained ischemic period (control 13.4 +/- 1.0 mumol/g dry weight). As a result of a lower rate of ATP depletion, ATP levels in the CI group were similar to the untreated control after 20 min of sustained ischemia (5.5 +/- 0.7 mumol/g dry weight). Preconditioning with 4 x 5' CI or adenosine (but not PE) led to earlier ventricular arrest. Only adenosine-treated hearts demonstrated a more rapid decline in ventricular contractility during sustained ischemia than did nonpreconditioned control hearts. We conclude that while the final recovery of ventricular contractility after asystolic arrest and reperfusion is improved by preconditioning with different stimuli (4 x 5' CI, adenosine, or PE), each stimulus conferred a characteristic electromechanical and energy conservation strategy during sustained ischemia. Adenosine conserved myocardial ATP content and reduced total cardiac work (developed pressure and heart beats). CI conserved myocardial ATP and minimized the number of ischemic cardiac beats. PE preserved myocardial ATP during ischemia without changing contractile behavior. Thus, energy conservation strategies during ischemia could contribute to the protection afforded by preconditioning stimuli, but the mechanisms appear to differ among stimuli.

Outcome of juvenile headache in outpatients attending 23 Italian headache clinics. Italian Collaborative Study Group on Juvenile Headache (Società Italiana Neuropsichiatria Infantile [SINPI]). A multicenter 3-year follow-up study was carried out on young patients with headache referred to tertiary headache centers or pediatric clinics. Three years after the first examination in 1993, 442 (of an original sample of 719) young outpatients with headache (226 females and 216 males) were re-examined. The diagnostic criteria of the International Headache Society (IHS) and those modified for migraine without aura by Winner et al were applied at both the baseline evaluation and the 3-year re-examination. At the follow-up, 290 children still had headache, 101 were in clinical remission, and 51 had dropped out. Using the current diagnostic criteria, only 46.2% of patients having migraine without aura, 50% of those having migraine with aura, and 35.3% of those suffering from migraine disorders which do not fulfill IHS criteria for migraine received the same diagnosis at the time of follow-up. The percentage of patients receiving a diagnosis of migraine without aura rose significantly when new modified criteria were used (60.5%), whereas a drop in the frequency of migraine disorders not fulfilling IHS criteria was observed at follow-up, both in patients with the diagnosis of migraine without aura at the first examination (4.6%) and in patients with migraine not always fulfilling IHS criteria at the first examination (6.2%). Among all patients who received this latter diagnosis at the first examination, it was possible to make a diagnosis of migraine with aura at the follow-up in 8.8% of cases and that of migraine without aura in 26.5%. No significant variations in the frequency of either episodic tension-type headache or chronic tension-type headache were found, with the exception of a slight decrease in the percentage of tension-type headache which did not fulfill IHS criteria, but the difference between the first examination and the follow-up values does not reach the level of statistical significance (5% versus 12%). As far as the evolution of migraine is concerned, 17.4% of patients with migraine were headache-free at the 3-year follow-up. In tension-type headache, the percentage of patients who were headache-free was particularly high in those with the episodic form (32.9%) and in those suffering from tension-type headache not fulfilling IHS criteria (29.1%). The majority of patients who had been diagnosed as having unclassifiable headache at the first examination received a correct diagnosis at the follow-up with the exception of one patient. As observed in adult patients, variations in the headache characteristics were also observed in children and adolescents (that is, migraine with aura can change to migraine without aura, or the latter can transform into episodic tension-type headache or chronic tension-type headache can change into the episodic form). This follow-up study was aimed at reaching a better understanding of headache disturbances in children and adolescents, examining, in particular, variations of headache with time in this stage of life.

Association of Adipose Tissue Fatty Acids With Cardiovascular and All-Cause Mortality in Elderly Men. The major polyunsaturated fatty acids in adipose tissue objectively reflect long-term dietary intake, and may provide more reliable information than would self-reported intake. Whether adipose tissue fatty acids predict cardiovascular and all-cause mortality needs investigation. To investigate associations between adipose tissue fatty acids and cardiovascular and overall mortality in a cohort of elderly men. We hypothesized that polyunsaturated fatty acids reflecting dietary intake, are inversely associated with cardiovascular and all-cause mortality. In the Swedish cohort study Uppsala Longitudinal Cohort of Adult Men, buttock fatty acid composition was analyzed by gas-liquid chromatography in 1992 to 1993 and 2008. The study participants were followed during 11 311 person-years, between 1991 and 2011 (median follow-up, 14.8 years). In this community-based study that took place from 1970 to 1973, all men born in 1920 to 1924 in Uppsala, Sweden, were invited and 2322 (82%) were included (at age 50 years). At the reinvestigation at age 71 years, 1221 (73%) of the 1681 invited men participated. Adipose tissue biopsy specimens were taken in a subsample of 853 men. There was no loss to follow-up. Adipose tissue proportions of 4 polyunsaturated fatty acids that were considered to mainly reflect dietary intake (linoleic acid, 18:2n-6; α-linolenic acid, 18:3n-3; eicosapentaenoic acid, 20:5n-3; and docosahexaenoic acid, 22:6n-3) comprised primary analyses, and all other available fatty acids were secondary analyses. Hazard ratios (HRs) for cardiovascular and all-cause mortality using Cox proportional hazards regression analyses, performed in 2015. Among the 853 Swedish men, there were 605 deaths, of which 251 were cardiovascular deaths. After adjusting for risk factors, none of the 4 primary fatty acids were associated with cardiovascular mortality (HR, 0.92-1.05 for each standard deviation increase; P ≥ .27). Linoleic acid was inversely associated with all-cause mortality (HR, 0.90; 95% CI, 0.82-0.98; P = .02) and directly associated with intake (P < .001). In secondary analyses, palmitoleic acid, 16:1n-7 (HR, 1.11; 95% CI, 1.02-1.21; P = .02) was associated with higher all-cause mortality, whereas heptadecanoic acid, 17:0, tended to be associated with lower all-cause mortality (HR, 0.89; 95% CI, 0.79-1.00; P = .05). Arachidonic:linoleic acid ratio was associated with both cardiovascular (HR, 1.15; 95% CI, 1.05-1.31; P = .04) and all-cause (HR, 1.13; 95% CI, 1.04-1.23; P = .005) mortality. Adipose tissue linoleic acid was inversely associated with all-cause mortality in elderly men, although not significantly with cardiovascular mortality.

41.8 degrees C whole body hyperthermia as an adjunct to chemotherapy induces prolonged T cell activation in patients with various malignant diseases. Whole body hyperthermia (WBH) has been used as an adjunct to radio-/chemotherapy in patients with various malignant diseases. Although clear evidence is still missing, it has been hypothesized that an activation of the immune system might contribute to the therapeutic effect of WBH. To examine whether a treatment with 60-minute 41.8 degrees C WBH as an adjunct to chemotherapy (WBH-CT) induces an activation of T cells, blood samples were collected at numerous time points before and up to 48 h post-treatment. The aim of this study was to examine the effect of WBH-CT on the expression of a broad range of activation markers on peripheral blood lymphocytes (PBL), on serum cytokines and intracellular cytokine levels in T cells, and the capacity of these cells to proliferate. Immediately after 41.8 degrees C WBH-CT treatment, a drastic increase in peripheral natural killer (NK) cells ( P<0.05) and CD56+ cytotoxic T lymphocytes (CTL; P<0.01) in the patients' peripheral blood was observed. At 5 h post-treatment, the percentages of both effector cell types had returned to baseline levels. This transient phenomenon was accompanied by a short period of reduced T cell activity, indicated by diminished serum levels of soluble interleukin-2 receptors (sIL-2R) at 3 h post-WBH-CT ( P<0.05) and decreased lymphocytic proliferation at the same point in time. This first phase was followed by a marked but short-lived increase in the patients' serum levels of interleukin-6 (IL-6; P<0.01) during the first 5 h following treatment, with a subsequent decrease to baseline levels at 24 h and significantly increased serum levels of tumor necrosis factor-alpha (TNF-alpha) at 0 h ( P<0.01), 3 h ( P<0.05), 5 h ( P<0.05) and 24 h ( P<0.01) post-WBH-CT. The third phase of the immunological consequences of WBH-CT consisted of an increase in the percentage of peripheral cytotoxic T lymphocytes (CTL) expressing CD56, reaching a maximum at 48 h post-WBH ( P<0.01). Furthermore, the percentage of CD4+ T cells expressing the T cell activation marker CD69 increased nearly two-fold over time, reaching its maximum at 48 h ( P<0.05). As an additional marker for T cell activation, serum levels of sIL-2R increased markedly ( P<0.01), reaching maximum levels at the same point in time. Elevated intracellular concentrations of interferon-gamma (IFN-gamma) and/or TNF-alpha in CD8+ T cells were found in 4 out of 5 patients at 24 h post-WBH-CT. Since similar changes were not observed in patients receiving chemotherapy alone, this is the first study to provide evidence for prolonged WBH-CT-induced activation of human T cells.

Biological and remote sensing perspectives of pigmentation in coral reef organisms. Coral reef communities face unprecedented pressures on local, regional and global scales as a consequence of climate change and anthropogenic disturbance. Optical remote sensing, from satellites or aircraft, is possibly the only means of measuring the effects of such stresses at appropriately large spatial scales (many thousands of square kilometres). To map key variables such as coral community structure, percentages of living coral or percentages of dead coral, a remote sensing instrument must be able to distinguish the reflectance spectra (i.e. "spectral signature", reflected light as a function of wavelength) of each category. For biotic classes, reflectance is a complex function of pigmentation, structure and morphology. Studies of coral "colour" fall into two disparate but potentially complementary types. Firstly, biological studies tend to investigate the structure and significance of pigmentation in reef organisms. These studies often lack details that would be useful from a remote sensing perspective such as intraspecific variation in pigment concentration or the contribution of fluorescence to reflectance. Secondly, remote sensing studies take empirical measurements of spectra and seek wavelengths that discriminate benthic categories. Benthic categories used in remote sensing sometimes consist of species groupings that are biologically or spectrally inappropriate (e.g. merging of algal phyla with distinct pigments). Here, we attempt to bridge the gap between biological and remote sensing perspectives of pigmentation in reef taxa. The aim is to assess the extent to which spectral discrimination can be given a biological foundation, to reduce the ad hoc nature of discriminatory criteria, and to understand the fundamental (biological) limitations in the spectral separability of biotic classes. Sources of pigmentation in reef biota are reviewed together with remote sensing studies where spectral discrimination has been effectively demonstrated between benthic categories. The basis of reflectance is considered as the sum of pigmented components, such as zooxanthellae, host tissues and skeletons of corals. Problems in the empirical in situ measurement of reflectance are identified, such as the differing types of reflectance which can be measured, the interaction of the light field with morphology, and depth-dependent variability of measured reflectance due to fluorescence. The latter is estimated in some cases to introduce an error of up to 20% when depth differs by 8 m. Spectral features useful in discriminating reef benthos are identified and related to pigmentation. The slope in the reflectance spectra between 650 and 690 nm is dependent on chlorophyll-a concentration and can be used to discriminate bare sand with no algal component from chlorophyll-a containing benthos (algae, corals). The slope in reflectance at various locations between 500 and 560 nm can be useful in discriminating bleached and unbleached corals, possibly due to reduced peridinin concentration. Rhodophyta may be discernible by the presence of a dip in reflectance at 570 nm, due to a phycoerythrin absorption peak. However, the utility of some discriminatory criteria in deeper waters is mitigated by the relatively poor transmission of light through water at longer wavelengths (especially > 600 nm). Contrary to suggested categorizations of fluorescent pigments in coral host tissues, it is shown that these pigments form an almost continuous distribution with respect to their excitation and emission peaks. Remote sensing by induced fluorescence is a promising approach, but further details about the variation and distribution of these pigments are required. It is hoped that this review will promote cross-disciplinary collaboration between pigment biologists and the reef remote sensing community. Where possible, the discriminative criteria adopted in remote sensing should be related to biological phenomena, thus lending an intuitive, process-orientated basis for interpreting spectral data. Similarly, remote sensing may provide a novel scaling perspective to biological studies of pigmentation in reef organisms.

Ethanol decreases natural killer cell activation but only minimally affects anatomical distribution after administration of polyinosinic:polycytidylic acid: role in resistance to B16F10 melanoma. Natural killer (NK) cells are critical in resistance to B16F10 lung metastases in B6C3F1 mice. Activation of NK cells by polyinosinic:polycytidylic acid (poly I:C; 0.1 mg, intraperitoneally) increases resistance to B16F10 cells. This effect is reduced after administration of ethanol (EtOH; 6 g/kg by oral gavage). The present study was conducted to determine whether decreased resistance is due to alteration of the distribution and/or the activation of NK cells. These parameters were measured in the spleen, lungs, and peripheral blood 4 and 12 hr after EtOH and poly I:C administration. For assessing the time after poly I:C administration during which NK cells are important in resistance to B16F10 cells, anti-NK1.1 antibody was used to deplete NK cells in vivo 48 hr before and 0, 6, 12, and 24 hr after intravenous injection of B16F10 tumor cells. Depletion of NK cells at any time up to 12 hr after B16F10 administration significantly increased the number of tumor nodules in the lungs, but depletion at 24 hr had a smaller effect. Flow cytometry revealed that there was a small but significant increase in the percentage of NK cells in the lungs at 12 hr, which was not changed by EtOH. Corresponding NK cell lytic function in the lungs was increased significantly at both 4 and 12 hr by poly I:C. However, the increase was not significantly different from the naive control value at 4 hr in mice treated with poly I:C plus EtOH, indicating that EtOH decreased activation of NK cells in the lungs at 4 hr. In the spleen, no treatment significantly altered the percentage of NK cells at 4 or 12 hr. However, poly I:C significantly enhanced lytic function, and this enhancement was suppressed by EtOH (by approximately 50%). In the blood, the only significant change in NK cell percentage or lytic activity was an increase in the percentage of NK cells at 12 hr, which was equivalent in the poly I:C and the poly I:C plus EtOH groups. These results demonstrate that EtOH partially abrogates the poly I:C-induced enhancement of resistance to B16F10 cells and that decreased activation of NK cells in the lungs at a critical time early in the response to poly I:C may contribute to this effect. Other parameters could also contribute, but there was little support for an important role for changes in NK cell distribution.

The efficacy of the new SCD response compression system in the prevention of venous stasis. The current commercially available sequential intermittent pneumatic compression device used for the prevention of deep venous thrombosis has a constant cycle of 11 seconds' compression and 60 seconds' deflation. This deflation period ensures that the veins are filled before the subsequent cycle begins. It has been suggested that in some positions (eg, semirecumbent or sitting) and with different patients (eg, those with venous reflux), refilling of the veins may occur much earlier than 60 seconds, and thus a more frequent cycle may be more effective in expelling blood proximally. The aim of the study was to test the effectiveness of a new sequential compression system (the SCD Response Compression System), which has the ability to detect the change in the venous volume and to respond by initiating the subsequent cycle when the veins are substantially full. In an open controlled trial at an academic vascular laboratory, the SCD Response Compression System was tested against the existing SCD Sequel Compression System in 12 healthy volunteers who were in supine, semirecumbent, and sitting positions. The refilling time sensed by the device was compared with that determined from recordings of femoral vein flow velocity by the use of duplex ultrasound scan. The total volume of blood expelled per hour during compression was compared with that produced by the existing SCD system in the same volunteers and positions. The refilling time determined automatically by the SCD Response Compression System varied from 24 to 60 seconds in the subjects tested, demonstrating individual patient variation. The refilling time (mean +/- SD) in the sitting position was 40.6 +/- 10. 0 seconds, which was significantly longer (P <.001) than that measured in the supine and semirecumbent positions, 33.8 +/- 4.1 and 35.6 +/- 4.9 seconds, respectively. There was a linear relationship between the duplex scan-derived refill time (mean of 6 readings per leg) and the SCD Response device-derived refill time (r = 0.85, P <. 001). The total volume of blood (mean +/- SD) expelled per hour by the existing SCD Sequel device in the supine, semirecumbent, and sitting positions was 2.23 +/- 0.90 L/h, 2.47 +/- 0.86 L/h, and 3.28 +/- 1.24 L/h, respectively. The SCD Response device increased the volume expelled to 3.92 +/- 1.60 L/h or a 76% increase (P =.001) in the supine position, to 3.93 +/- 1.55 L/h or a 59% increase (P =. 001) in the semirecumbent position, and to 3.97 +/- 1.42 L/h or a 21% increase (P =.026) in the sitting position. By achieving more appropriately timed compression cycles over time, the new SCD Response System is effective in preventing venous stasis by means of a new method that improves on the clinically documented effectiveness of the existing SCD system. Further studies testing its potential for improved efficacy in preventing deep venous thrombosis are justified.

Chronology of early Archaean granite-greenstone evolution in the Barberton Mountain Land, South Africa, based on precise dating by single zircon evaporation. We report precise 207Pb/206Pb single zircon evaporation ages for low-grade felsic metavolcanic rocks within the Onverwacht and Fig Tree Groups of the Barberton Greenstone Belt (BGB), South Africa, and from granitoid plutons bordering the belt. Dacitic tuffs of the Hooggenoeg Formation in the upper part of the Onverwacht Group yield ages between 3445 +/- 3 and 3416 +/- 5 Ma and contain older crustal components represented by a 3504 +/- 4 Ma old zircon xenocryst. Fig Tree dacitic tuffs and agglomerates have euhedral zircons between 3259 +/- 5 and 3225 +/- 3 Ma in age which we interpret to reflect the time of crystallization. A surprisingly complex xenocryst population in one sample documents ages from 3323 +/- 4 to 3522 +/- 4 Ma. We suspect that these xenocrysts were inherited, during the passage of the felsic melts to the surface, from various sources such as greenstones and granitoid rocks now exposed in the form of tonalite-trondhjemite plutons along the southern and western margins of the BGB, and units predating any of the exposed greenstone or intrusive rocks. Several of the granitoids along the southern margin of the belt have zircon populations with ages between 3490 and 3440 Ma. coeval with or slightly older than Onverwacht felsic volcanism, while the Kaap Valley pluton along the northwestern margin of the belt is coeval with Fig Tree dacitic volcanism. These results emphasize the comagmatic relationships between greenstone felsic volcanic units and the surrounding plutonic suites. Some of the volcanic plutonic units contain zircon xenocrysts older than any exposed rocks. These indicate the existence of still older units, possibly stratigraphically lower and older portions of the greenstone sequence itself, older granitoid intrusive rocks, or bodies of older, unrelated crustal material. Our data show that the Onverwacht and Fig Tree felsic units have distinctly different ages and therefore do not represent a single, tectonically repeated unit as proposed by others. Unlike the late Archaean Abitibi greenstone belt in Canada, which formed over about 30 Ma. exposed rocks in the BGB formed over a period of at least 220 Ma. The complex zircon populations encountered in this study imply that conventional multigrain zircon dating may not accurately identify the time of felsic volcanic activity in ancient greenstones. A surprising similarity in rock types, tectonic evolution, and ages of the BGB in the Kaapvaal craton of southern Africa and greenstones in the Pilbara Block of Western Australia suggests that these two terrains may have been part of a larger crustal unit in early Archaean times.

Syntheses, structures, and magnetic properties of diphenoxo-bridged Cu(II)Ln(III) and Ni(II)(low-spin)Ln(III) compounds derived from a compartmental ligand (Ln = Ce-Yb). Syntheses, characterization, and magnetic properties of a series of diphenoxo-bridged discrete dinuclear M(II)Ln(III) complexes (M = Cu or Ni, Ln = Ce-Yb) derived from the compartmental Schiff base ligand, H(2)L, obtained on condensation of 3-ethoxysalicylaldehyde with trans-1,2-diaminocyclohexane, are described. Single crystal X-ray structures of eight Cu(II)Ln(III) compounds (Ln = Ce (1), Pr (2), Nd (3), Sm (4), Tb (7), Ho (9), Er (10), and Yb (12)) and three Ni(II)Ln(III) (Ln = Ce (13), Sm (16), and Gd (18)) compounds have been determined. Considering the previously reported structure of the Cu(II)Gd(III) (6) compound (Eur. J. Inorg. Chem. 2005, 1500), a total of twelve structures are discussed/compared in this study. Four types of composition are observed in the Cu(II)Ln(III) complexes: [Cu(II)LLn(III) (NO(3))(3)(H(2)O)] (1-3: Ln = Ce-Nd), [Cu(II)LSm(III)(NO(3))(3)]·CH(3)COCH(3) (4), [Cu(II)(H(2)O)LLn(III)(NO(3))(3)] (5: Ln = Eu; 6: Ln = Gd), and [Cu(II)LLn(III)(NO(3))(3)] (4A: Ln = Sm; 7-12: Ln = Tb-Yb). On the other hand, the Ni(II)Ln(III) complexes are characterized to have two types of composition: [Ni(II)LLn(III)(H(2)O)(NO(3))(3)] (13-15: Ln = Ce-Nd) and [Ni(II)LLn(III)(NO(3))(3)]·0.5CH(3)COCH(3) (16-24: Ln = Sm-Yb). Among twelve X-ray structures, seven belong to three different isomorphous sets (Cu(II)Ce(III) (1), Cu(II)Pr(III) (2), Cu(II)Nd(III) (3), and Ni(II)Ce(III) (13); Cu(II)Tb(III) (7), Cu(II)Ho(III) (9), Cu(II)Er(III) (10), and Cu(II)Yb(III) (12); Ni(II)Sm(III) (16) and Ni(II)Gd(III) (18)), whereas space group/unit cell parameters of two others (Cu(II)Sm(III) (4) and Cu(II)Gd(III) (6)) are of different types. The lanthanide(III) centers in Cu(II)Ce(III) (1), Cu(II)Pr(III) (2), Cu(II)Nd(III) (3), and Ni(II)Ce(III) (13) complexes are eleven-coordinated, while the lanthanide(III) centers in other compounds are ten-coordinated. As evidenced from the dihedral angle (δ) between the CuO(phenoxo)(2) and LnO(phenoxo)(2) planes, variation in the extent of planarity of the bridging moiety in the Cu(II)Ln(III) compounds takes place; the ranges of δ values are 0.8-6.2° in the 4f(1-7) analogues and 17.6-19.1° in the 4f(8-13) analogues. The Cu(II)Gd(III) (6) compound exhibits ferromagnetic interaction (Eur. J. Inorg. Chem. 2005, 1500). The nature of the magnetic exchange interaction in the Cu(II)Ln(III) complexes has been understood by utilizing the empirical approach; the Ni(II)Ln(III) complexes have been used as references. The metal centers in the Eu(III) complex are uncorrelated, while other 4f(1-6) analogues (Ce(III), Pr(III), Nd(III), and Sm(III)) exhibit antiferromagnetic interaction. Among the higher analogues (4f(7-13)), only Yb(III) exhibits antiferromagnetic interaction, while interaction in other analogues (Gd(III), Tb(III), Dy(III), Ho(III), Er(III), and Tm(III)) is ferromagnetic. An important aspect of the present study is the measurement of the magnetic susceptibility of the unblocked samples as well as on blocking the samples with grease to avoid powder reorientation, if any. Comparison of the two sets of data reveals significant difference in some cases.

Ability of King's College Criteria and Model for End-Stage Liver Disease Scores to Predict Mortality of Patients With Acute Liver Failure: A Meta-analysis. Several prognostic factors are used to identify patients with acute liver failure (ALF) who require emergency liver transplantation. We performed a meta-analysis to determine the accuracy of King's College criteria (KCC) versus the model for end-stage liver disease (MELD) scores in predicting hospital mortality among patients with ALF. We performed a systematic search of the literature for articles published from 2001 through 2015 that compared the accuracy of the KCC with MELD scores in predicting hospital mortality in patients with ALF. We identified 23 studies (comprising 2153 patients) and assessed the quality of data, and then performed a meta-analysis of pooled sensitivity and specificity values, diagnostic odds ratios (DORs), and summary receiver operating characteristic curves. Subgroups analyzed included study quality, era, location (Europe vs non-Europe), and size; ALF etiology (acetaminophen-associated ALF [AALF] vs nonassociated [NAALF]); and whether or not the study included patients who underwent liver transplantation and if the study center was also a transplant center. The DOR for the KCC was 5.3 (95% confidence interval [CI], 3.7-7.6; 57% heterogeneity) and the DOR for MELD score was 7.0 (95% CI, 5.1-9.7; 48% heterogeneity), so the MELD score and KCC are comparable in overall accuracy. The summary area under the receiver operating characteristic curve values was 0.76 for the KCC and 0.78 for MELD scores. The KCC identified patients with AALF who died with 58% sensitivity (95% CI, 51%-65%) and 89% specificity (95% CI, 85%-93%), whereas MELD scores identified patients with AALF who died with 80% sensitivity (95% CI, 74%-86%) and 53% specificity (95% CI, 47%-59%). The KCC predicted hospital mortality in patients with NAALF with 58% sensitivity (95% CI, 54%-63%) and 74% specificity (95% CI, 69%-78%), whereas MELD scores predicted hospital mortality in patients with NAALF with 76% sensitivity (95% CI, 72%-80%) and 73% specificity (95% CI, 69%-78%). In patients with AALF, the KCC's DOR was 10.4 (95% CI, 4.9-22.1) and the MELD score's DOR was 6.6 (95% CI, 2.1-20.2). In patients with NAALF, the KCC's DOR was 4.16 (95% CI, 2.34-7.40) and the MELD score's DOR was 8.42 (95% CI, 5.98-11.88). Based on a meta-analysis of studies, the KCC more accurately predicts hospital mortality among patients with AALF, whereas MELD scores more accurately predict mortality among patients with NAALF. However, there is significant heterogeneity among studies and neither system is optimal for all patients. Given the importance of specificity in decision making for listing for emergency liver transplantation, MELD scores should not replace the KCC in predicting hospital mortality of patients with AALF, but could have a role for NAALF.

Acute titration and chronic follow-up with captopril in hypertension. A one-year safety profile on combination therapy with captopril and a diuretic. The present study examines acute titration with captopril and chronic follow-up data on captopril and a diuretic in patients with all forms of hypertension. Captopril was initiated in those patients in whom previous antihypertensive agents either failed to control high blood pressure or produced adverse reactions. Acute titration was done in 88 patients in whom average diastolic blood pressure was equal to or more than 95 mm Hg. Initial titration dosage was decided on the basis of initial blood pressure recordings. During initial titration, 5 patients received 12.5 mg, 51 received 25 mg, 28 received 50 mg, and the remaining 4 received 100 mg of captopril. Post-captopril blood pressure data were normalized by using pre-captopril data as 100% for each patient. The blood pressure-lowering effect of captopril on both systolic and diastolic blood pressure in all 88 patients was statistically significant (p less than 0.05), within forty-five minutes of captopril administration irrespective of the doses. No adverse reactions were seen during the acute titration. After the initial titration, in all 88 patients a diuretic was added to obtain a synergistic effect. Eleven patients were dropped from the study, for they could not follow the requirements of the protocol. In 77 patients the data for a one-year safety profile with captopril and diuretic were available. There were no overall significant statistical changes in serial white blood cell count, serum potassium, and serum creatinine values in those 77 patients. In 31 patients the initial and maintenance dosage of captopril and the diuretic remained unaltered for one year. Post-captopril blood pressure and heart rate data were normalized, pre-captopril data being considered as 100% in those 31 patients. The blood pressure data following captopril and a diuretic therapy compared with the pre-captopril data were statistically significant (p less than 0.05) throughout the study period. However, no significant changes in heart rates were observed during the study period. In all other patients, diuretic therapy was continued throughout the study period. In 6 severely hypertensive patients, an additional beta-blocker was needed for further control of high blood pressure. In 3 severe hypertensives with renal failure, besides a diuretic and a beta-blocker, minoxidil was needed to normalize their high blood pressure. In 4 of 77 patients, verapamil was used for treatment of either vasospastic angina or paroxsysmal supraventricular arrhythmia.(ABSTRACT TRUNCATED AT 400 WORDS)

Electronic Health Interventions for Preventing and Treating Negative Psychological Sequelae Resulting From Pediatric Medical Conditions: Systematic Review. Pediatric medical conditions have the potential to result in challenging psychological symptoms (eg, anxiety, depression, and posttraumatic stress symptoms [PTSS]) and impaired health-related quality of life in youth. Thus, effective and accessible interventions are needed to prevent and treat psychological sequelae associated with pediatric medical conditions. Electronic health (eHealth) interventions may help to meet this need, with the capacity to reach more children and families than in-person interventions. Many of these interventions are in their infancy, and we do not yet know what key components contribute to successful eHealth interventions. The primary objective of this study was to conduct a systematic review to summarize current evidence on the efficacy of eHealth interventions designed to prevent or treat psychological sequelae in youth with medical conditions. MEDLINE (PubMed) and PsycINFO databases were searched for studies published between January 1, 1998, and March 1, 2019, using predefined search terms. A total of 2 authors independently reviewed titles and abstracts of search results to determine which studies were eligible for full-text review. Reference lists of studies meeting eligibility criteria were reviewed. If the title of a reference suggested that it might be relevant for this review, the full manuscript was reviewed for inclusion. Inclusion criteria required that eligible studies (1) had conducted empirical research on the efficacy of a Web-based intervention for youth with a medical condition, (2) had included a randomized trial as part of the study method, (3) had assessed the outcomes of psychological sequelae (ie, PTSS, anxiety, depression, internalizing symptoms, or quality of life) in youth (aged 0-18 years), their caregivers, or both, (4) had included assessments at 2 or more time points, and (5) were available in English language. A total of 1512 studies were reviewed for inclusion based on their title and abstracts; 39 articles qualified for full-text review. Moreover, 22 studies met inclusion criteria for the systematic review. Of the 22 included studies, 13 reported results indicating that eHealth interventions significantly improved at least one component of psychological sequelae in participants. Common characteristics among interventions that showed an effect included content on problem solving, education, communication, and behavior management. Studies most commonly reported on child and caregiver depression, followed by child PTSS and caregiver anxiety. Previous research is mixed but suggests that eHealth interventions may be helpful in alleviating or preventing problematic psychological sequelae in youth with medical conditions and their caregivers. Additional research is needed to advance understanding of the most powerful intervention components and to determine when and how to best disseminate eHealth interventions, with the goal of extending the current reach of psychological interventions.

Structure/Property Relations in "Giant" Semiconductor Nanocrystals: Opportunities in Photonics and Electronics. Semiconductor nanocrystals exhibit size-tunable absorption and emission ranging from the ultraviolet (UV) to the near-infrared (NIR) spectral range, high absorption coefficient, and high photoluminescence quantum yield. Effective surface passivation of these so-called quantum dots (QDs) may be achieved by growing a shell of another semiconductor material. The resulting core/shell QDs can be considered as a model system to study and optimize structure/property relations. A special case consists in growing thick shells (1.5 up to few tens of nanometers) to produce "giant" QDs (g-QDs). Tailoring the chemical composition and structure of CdSe/CdS and PbS/CdS g-QDs is a promising approach to widen the spectral separation of absorption and emission spectra (i.e., the Stokes shift), improve the isolation of photogenerated carriers from surface defects and enhance charge carrier lifetime and mobility. However, most stable systems are limited by a thick CdS shell, which strongly absorbs radiation below 500 nm, covering the UV and part of the visible range. Modification of the interfacial region between the core and shell of g-QDs or tuning their doping with narrow band gap semiconductors are effective approaches to circumvent this challenge. In addition, the synthesis of g-QDs composed of environmentally friendly elements (e.g., CuInSe2/CuInS2) represents an alternative to extend their absorption into the NIR range. Additionally, the band gap and band alignment of g-QDs can be engineered by proper selection of the constituents according to their band edge positions and by tuning their stoichiometry during wet chemical synthesis. In most cases, the quasi-type II localization regime of electrons and holes is achieved. In this type of g-QDs, electrons can leak into the shell region, while the holes remain confined within the core region. This electron-hole spatial distribution is advantageous for optoelectronic devices, resulting in efficient electron-hole separation while maintaining good stability. This Account provides an overview of emerging engineering strategies that can be adopted to optimize structure/property relations in colloidal g-QDs for efficient photon management or charge separation/transfer. In particular, we focus on our recent contributions to this rapidly expanding field of research. We summarize the design and synthesis of a variety of colloidal g-QDs with the aim of tuning the optical properties, such as absorption/emission in a wide region of the solar spectrum, which allows enlargement of their Stokes shift. We also describe the band alignment within these systems, charge carrier dynamics, and charge transfer from g-QDs into semiconducting oxides. We show how these tailored g-QDs may be used as active components in luminescent solar concentrators, photoelectrochemical cells for hydrogen generation, QD-sensitized solar cells and optical nanothermometers. In each case, we aim at providing insights on structure/property relationships and on how to optimize them toward improving device performance. Finally, we describe perspectives for future work, sketching new directions and opportunities in this field of research at the intersection between chemistry, physics, materials science and engineering.

Influence of molecular geometry, exchange-correlation functional, and solvent effects in the modeling of vertical excitation energies in phthalocyanines using time-dependent density functional theory (TDDFT) and polarized continuum model TDDFT methods: can modern computational chemistry methods explain experimental controversies? A time-dependent density functional theory (TDDFT) approach coupled with 14 different exchange-correlation functionals was used for the prediction of vertical excitation energies in zinc phthalocyanine (PcZn). In general, the TDDFT approach provides a more accurate description of both visible and ultraviolet regions of the UV-vis and magnetic circular dichroism (MCD) spectra of PcZn in comparison to the more popular semiempirical ZINDO/S and PM3 methods. It was found that the calculated vertical excitation energies of PcZn correlate with the amount of Hartree-Fock exchange involved in the exchange-correlation functional. The correlation was explained on the basis of the calculated difference in energy between occupied and unoccupied molecular orbitals. The influence of PcZn geometry, optimized using different exchange-correlation functionals, on the calculated vertical excitation energies in PcZn was found to be relatively small. The influence of solvents on the calculated vertical excitation energies in PcZn was considered for the first time using a polarized continuum model TDDFT (PCM-TDDFT) method and was found to be relatively small in excellent agreement with the experimental data. For all tested TDDFT and PCM-TDDFT cases, an assignment of the Q-band as an almost pure a1u (HOMO)-->eg (LUMO) transition, initially suggested by Gouterman, was confirmed. Pure exchange-correlation functionals indicate the presence of six 1Eu states in the B-band region of the UV-vis spectrum of PcZn, while hybrid exchange-correlation functionals predict only five 1Eu states for the same energy envelope. The first two symmetry-forbidden n-->pi* transitions were predicted in the Q0-2 region and in the low-energy tail of the B-band, while the first two symmetry-allowed n-->pi* transitions were found within the B-band energy envelope when pure exchange-correlation functionals were used for TDDFT calculations. The presence of a symmetry-forbidden but vibronically allowed n-->pi* transition in the Q0-2 spectral envelope explains the long-time controversy between the experimentally observed low-intensity transition in the Q0-2 region and previous semiempirical and TDDFT calculations, which were unable to predict any electronic transitions in this area. To prove the conceptual possibility of the presence of several degenerate 1Eu states in the B-band region of PcZn, room-temperature UV-vis and MCD spectra of zinc tetra-tert-butylphthalocyanine (PctZn) in non-coordinating solvents were recorded and analyzed using band deconvolution analysis. It was found that the B-band region of the UV-vis and MCD spectra of PctZn can be easily deconvoluted using six MCD Faraday A-terms and two MCD Faraday B-terms with energies close to those predicted by TDDFT calculations for 1Eu and 1A2u excited states, respectively. Such a good agreement between theory and experiment clearly indicates the possibility of employing a TDDFT approach for the accurate prediction of vertical excitation energies in phthalocyanines within a large energy range.

Effects of preconceptional irradiation on mortality and cancer incidence in the offspring of patients given injections of Thorotrast. Findings from a British case-control study suggest that a preconceptional paternal external radiation dose of more than 100 mSv (10 rem) is significantly related to risk for leukemia and non-Hodgkin's lymphoma in offspring. The suggestion, however, has not been supported by experimental or other epidemiologic studies. The purpose of this study was to investigate if preconceptional irradiation of males and females from internally deposited radionuclides affects mortality and risk of developing cancer in their offspring. The offspring of 260 females (n = 143) and 320 males (n = 226) who lived longer than 1 year after receiving Thorotrast (a compound no longer in use) for cerebral arteriography were studied for mortality rate and the risk for developing cancer. Thorotrast was used as a contrast medium containing a 20% colloidal solution of thorium dioxide-Th 232, an alpha particle-emitting radionuclide, which is retained lifelong in nearly all organs. The offspring of the exposed patients were identified by manual linkage with the municipal population registers and followed-up for vital status by computerized linkage with the Danish National Central Population Registry and for incidence of cancer by computerized linkage with the Danish National Cancer Registry. The standardized mortality/morbidity ratios (SMRs) for death and for site-specific incidence of cancer in the offspring were calculated as ratios of the observed rates in the study population to the expected rates in the general population. After a median follow-up of 40 years, four cases of cancer (breast [one], uterine cervix [one], melanoma of skin [one], and retinoblastoma [one]) versus 2.9 cases expected, developed among 143 children born to mothers who received injections of Thorotrast (SMR = 1.4; 95% confidence interval [CI] = 0.4-3.5), while six cases of cancer (one case each of cancer of lung, testis, thyroid, and Hodgkin's lymphoma and two cases of melanoma of skin), versus 4.5 expected, occurred among 226 children of exposed fathers (SMR = 1.3; 95% CI = 0.5-2.9). No case of leukemia or non-Hodgkin's lymphoma occurred in any of the offspring studied. Mortality was lower than expected both for children of exposed mothers (SMR = 0.7; 95% CI = 0.3-1.5) and of exposed fathers (SMR = 0.5; 95% CI = 0.2-1.0). This study does not support the previously proposed association between parental exposure to radiation and the risk of childhood leukemia and lymphoma. Furthermore, since mortality from all causes was not increased in any offspring, our results do not support the belief that preconceptional parental low-dose exposure to alpha radiation increases the incidence of cancer or mortality in the offspring.

Trauma and identity through two generations of the Holocaust. In summary, these four second generation women were/are in search of an equilibrium which includes integrating approach-avoidance feelings about their upbringing. They have struggled in various ways, through their own personal styles, with issues of enmeshment with their parents' ordeals, and this has helped to shape their identities. The approach-avoidance dilemma around the suffering of their parents involves finding a way to separate from, yet to include in the meaning of their lives, the suffering of their parents. In these women, empathy preserves the "good" aspect of the parent and in the end allows for separateness to be achieved. An evolution of their approach to the Holocaust occurs throughout their lives and is enhanced by their having children. Creativity and knowledge play an important role in the expression of tormented feelings in both second and third generations. The issues grappled with by the second generation reverberate in their children. This is a group of resolute, serious people who believe in the preciousness of life. They are also thoughtful, empathic youngsters, aware of social and political inequities. These third-generation members feel somewhat burdened by the legacy of the Holocaust, inasmuch as they feel obligated to stand up for Jewish identity and be successful in their own lives. Placing the suffering in a larger group context helps the second generation confront the suffering of their parents. This diminishes individual liability so that the suffering does not have to be taken on personally. The cause goes beyond the self and the family. When, as in Sylvia's case, this outlook is not achieved, the struggle against family enmeshment continues. Seeing the suffering in a group context creates a different set of responsibilities, that of allegiance and closeness to the group. It promotes a need to find meaning in the suffering, a need to cope with the sense of identification with group loss. This urge for empathy is accompanied by its opposite, a wish to dissociate, and the need consequently to negotiate boundaries. The struggle for integration of various feelings becomes a part of their identity in both generations. This paper points to the possibility that, as the Holocaust becomes part of a story, a myth, it becomes a guide (albeit perhaps of a demanding one) by which to live life rather than simply a recall of death. The work of memory has been completed, at times embellished. It also includes, however, a continuous wake up call to vulnerability, a sense of burden, a "chronic" sense of the seriousness and preciousness of life. This paper therefore reflects the fact that suffering can be channeled into identity formation, integrated into an articulation of the meaning of life and a philosophy of life. As the third generation's identity becomes intimately intertwined with its origins, a feeling of continuity is developed which provides a sense of affirmation of the group and of the self. It does, however, also include an awareness of the suffering of that group and in the world at large.

Effect of a practice-based strategy on test ordering performance of primary care physicians: a randomized trial. Numbers of diagnostic tests ordered by primary care physicians are growing and many of these tests seem to be unnecessary according to established, evidence-based guidelines. An innovative strategy that focused on clinical problems and associated tests was developed. To determine the effects of a multifaceted strategy aimed at improving the performance of primary care physicians' test ordering. Multicenter, randomized controlled trial with a balanced, incomplete block design and randomization at group level. Thirteen groups of primary care physicians underwent the strategy for 3 clinical problems (arm A; cardiovascular topics, upper and lower abdominal complaints), while 13 other groups underwent the strategy for 3 other clinical problems (arm B; chronic obstructive pulmonary disease and asthma, general complaints, degenerative joint complaints). Each arm acted as a control for the other. Primary care physician groups in 5 regions in the Netherlands with diagnostic centers recruited from May to September 1998. Twenty-six primary care physician groups, including 174 primary care physicians. During the 6 months of intervention, physicians discussed 3 consecutive, personal feedback reports in 3 small group meetings, related them to 3 evidence-based clinical guidelines, and made plans for change. According to existing national, evidence-based guidelines, a decrease in the total numbers of tests ordered per clinical problem, and of some defined inappropriate tests, is considered a quality improvement. For clinical problems allocated to arm A, the mean total number of requested tests per 6 months per physician was reduced from baseline to follow-up by 12% among physicians in the arm A intervention, but was unchanged in the arm B control, with a mean reduction of 67 more tests per physician per 6 months in arm A than in arm B (P =.01). For clinical problems allocated to arm B, the mean total number of requested tests per 6 months per physician was reduced from baseline to follow-up by 8% among physicians in the arm B intervention, and by 3% in the arm A control, with a mean reduction of 28 more tests per physician per 6 months in arm B than in arm A (P =.22). Physicians in arm A had a significant reduction in mean total number of inappropriate tests ordered for problems allocated to arm A, whereas the reduction in inappropriate test ordered physicians in arm B for problems allocated to arm B was not statistically significant. In this study, a practice-based, multifaceted strategy using guidelines, feedback, and social interaction resulted in modest improvements in test ordering by primary care physicians.

The influence of religious moral beliefs on adolescents' mental stability. The aim of this paper is to determine the influence of religious moral beliefs on the stability of adolescents' mental health. The sample consists of 240 mentally and physically healthy male and female adolescents attending a high school, who are divided into groups equalized by gender (male and female), age (younger 15, older 18 years); school achievement (very good, average student); behaviour (excellent, average); family structure (complete family with satisfactory family relations), and level of exposure to psycho-social stress (they were not exposed to specific traumatizing events). Subjects were assessed with regard to the level of belief in some basic ethical principles that arise from religious moral values. The score of religious moral belief index was used to compare two groups of subjects. For sample selection the measuring instruments were used to assess the religious, moral and social profile of subject. For the assessment of personality structure a standardized test battery (Freiburg's Personality Questionnaire/ Das Freiburger Personlichkeitsinventar - FPI, Profile Index of Emotions - PIE, Life Style Questionnaire - OM) was used to assess personality profile, emotional profile and subject's defence orientation. The score of the moral belief index was negatively correlated to neuroticism and depressiveness (Pearson's r=-0.242, P<0.001; r=-0.311, P<0.001, respectively). Spontaneous and reactive aggressiveness and irritability were negatively correlated with the score of moral belief index (Pearson's r=-0.197, P=0.002; r=-0.147, P=0.023; r=-0.350, P<0.001, respectively). Emotional instability is negatively associated with the moral belief index of the investigated adolescents (Pearson's r=-0.324, P<0.001). The moral belief index was highly negatively correlated with repression (r=-0.206, P=0.001), regression (r=-0.325, P<0.001), compensation (r=-0.186, P=0.004), transfer (r=-0.290, P<0.001) and defensive orientation (r=-0.129, P=0.046). Verified intellectualisation and reactive formation are in positive correlation with the moral belief index among our investigated adolescents (Pearson's r=0.168, P=0.009; r=0.356; P<0.001, respectively). A higher index of religious moral beliefs in adolescents enables better control of impulses, providing better mental health stability. It enables neurotic conflicts typical for adolescence to be more easily overcome. It also causes healthier reactions to external stimuli. A higher index of religious moral beliefs of young people provides a healthier and more efficient mechanism of anger control and aggression control. It enables transformation of that psychical energy into neutral energy which supports the growth and development of personality, which is expressed through socially acceptable behaviour. In this way, it helps growth, development and socialization of the personality, leading to the improvement in mental health.

The changing impact of HIV/AIDS on Kenyatta National Hospital, Nairobi from 1988/89 through 1992 to 1997. Consequences of the growing HIV/AIDS epidemic for health services in sub-Saharan Africa remain poorly defined. Longitudinal data from the same centre are scarce. We aimed to describe the impact of a rapidly rising HIV/AIDS disease burden on an urban hospital over the last decade. Cross-sectional observational study in 1997, compared to similar data from 1988/89 and 1992. The study was carried out in the Kenyatta National Hospital, Nairobi, Kenya. Consecutive adult medical patients were enrolled on admission and then followed up until death or discharge. The main outcome measures were clinical stage, HIV status, bacteraemia, length of stay, bed occupancy, final diagnosis and outcome of hospital admission. In 1997, 518 patients, 493 with HIV serology, were enrolled: HIV prevalence was 40.0%, bed occupancy 190%, the mean length of stay 9.5 days (SD 12) and overall mortality 18.5%. The mean number of HIV-positive admissions per day steadily rose from 4.3 [95% confidence interval (CI), 0.6] patients in 1988/89, through 9.6 (95% CI, 1.4) in 1992, to 13.1 (95% CI, 2.8) or 13.9 adjusted for those enrolled without HIV serology in 1997. In contrast the mean number admitted with clinical AIDS, 1.7 in 1988/89 and 3.3 in 1992, fell to 2.6 cases per day in 1997. With HIV-negative admissions increasing by 37% and bed occupancy nearly doubling in 1997, HIV prevalence appeared to be stabilizing (19 then 39 and 40% respectively). Over time fewer HIV-infected patients were bacteraemic (26, 24 and 14%; P < 0.01); had clinical AIDS (39, 34 and 24% respectively; P < 0.01); or died (36, 35 and 22.6%; P < 0.02). HIV-negative mortality, 14% in 1988/89, rose to 23% in 1992 but fell to 15% in 1997. The mean length of hospital stay (9.5-10 days) did not differ according to HIV status nor did it change across the decade. The HIV/AIDS disease burden in Kenyatta National Hospital medical wards has risen inexorably over the last decade. Most recently, the number of HIV-uninfected patients has also risen, leading to bed occupancy figures of 190%. Despite overcrowding and irrespective of HIV status, in-patient mortality has fallen. Time trends suggest fewer clinical AIDS patients are presenting for hospital care, implying a rising community burden of chronic HIV/AIDS disease. Although widely predicted, it is not inevitable that medical services in urban African hospitals dealing with large volumes of HIV/AIDS disease, will collapse or become overwhelmed with chronic, end-stage disease and death.

Fluconazole susceptibility and strain variation of Candida albicans isolates from HIV-infected patients with oropharyngeal candidosis. Over a 16 month period we conducted a prospective study in a cohort of 45 HIV-positive patients to detect the development of resistance to fluconazole and to analyse the epidemiology of oropharyngeal candidosis (OPC). Each episode was treated with fluconazole 100 mg/day po for 10 days. All yeast isolates were tested for their in-vitro susceptibility to fluconazole. Multiple strains of Candida albicans simultaneously isolated from a given patient were typed by electrophoretic karyotyping. Overall, 106 episodes of OPC were diagnosed among the 45 patients: 18/45 patients (40%) had only one episode, 11/45 (24%) had two episodes, and the remaining 16/45 (36%) had three or more episodes (range 3-7). Cure (complete resolution of signs and symptoms and negative post-treatment cultures) and improvement (complete resolution of signs and symptoms but positive post-treatment cultures) were observed in 30/106 (28%) and 69/106 (65%) episodes of OPC, respectively. Failure (absence of improvement or exacerbation of signs and symptoms) was observed in seven episodes (7%) from four patients. In two of these four patients a significant and progressive increase in fluconazole MICs was observed: from 0.25 to 16 mg/L in one patient, and from < or = 0.125 to 32 mg/L in the second one. Tests on multiple colonies from individual isolation plates showed that it was not unusual to obtain different fluconazole MICs, indicating that, in order to avoid misleading results, one should perform in-vitro susceptibility testing by using a multiple colony inoculum rather than an inoculum made from a single colony. A total of 213 strains of C. albicans isolated from seven patients who suffered from four or more episodes of OPC through the course of the study were typed by electrophoretic karyotyping. Five individuals (71%) were infected with yeasts with only one DNA type, while the other two patients showed the presence of two or three different DNA types. The simultaneous presence of multiple types was found only in one of the seven subjects. Our data confirm the efficacy of fluconazole 100 mg/day for the treatment of OPC in HIV patients. Isolation of fluconazole-resistant strains of C. albicans with this regimen is rare. The vast majority of HIV patients are infected with a unique strain of C. albicans throughout each episode of infection. A minority of patients, however, can harbour strains of C. albicans with variable patterns of fluconazole susceptibility simultaneously.

[Study on the application of classification tree model in screening the risk factors of ischemic stroke]. To construct a prediction model for the risk of ischemic stroke (IS) by classification tree model, and evaluate its application value. By cluster sampling, 858 IS patients with perfect clinical data from January to December 2017 in the Affiliated Hospital of Guilin Medical College (IS group) were enrolled, and 844 health checkups matched with the gender and age of IS patients in the same period were enrolled as controls (healthy control group). The metabolic characteristics of the two groups were compared and analyzed. The classification tree model was used to construct the prediction model of the risk of IS, and the gain diagram, index chart, risk value of misclassification probability and receiver operating characteristic curve (ROC) were used to evaluate the application value of the model. Compared with the healthy control group, body mass index (BMI), fasting blood glucose (FPG), triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) in IS group were significantly increased [BMI (kg/m2): 25.34±3.70 vs. 24.24±3.10, FPG (mmol/L): 6.79±2.89 vs. 5.73±1.17, TG (mmol/L): 1.62±1.06 vs. 1.44±1.06, TC (mmol/L): 4.70±2.73 vs. 4.35±0.79, LDL-C (mmol/L): 3.18±0.94 vs. 2.73±0.73, all P < 0.01], high density lipoprotein cholesterol (HDL-C) was significantly decreased (mmol/L: 1.12±0.33 vs. 1.35±0.36, P < 0.01), and the proportion of hypertension, smoking and drinking were significantly increased (69.0% vs. 41.9%, 23.1% vs. 16.8%, 19.2% vs. 13.4%, all P < 0.01). By assigning values to each factor [IS: No = 0,Yes = 1; BMI: < 24.0 kg/m2 = 0, ≥ 24.0 kg/m2 = 1; FPG: < 7.0 mmol/L = 0, ≥ 7.0 mmol/L = 1; TG: < 2.26 mmol/L = 0, ≥ 2.26 mmol/L = 1; TC: < 6.22 mmol/L = 0, ≥ 6.22 mmol/L = 1; LDL-C: < 4.14 mmol/L = 0, ≥ 4.14 mmol/L = 1; HDL-C: < 1.04 mmol/L = 0, ≥ 1.04 mmol/L = 1; hypertension: No = 0,Yes = 1; smoking: No = 0,Yes = 1; drinking: No = 0,Yes = 1], a classification tree model was established to analyze the risk factors of IS. The classification tree model consisted of 4 layers and 17 nodes: the first layer was hypertension, the second layer was FPG and HDL-C, the third layer was HDL-C and FPG, and the fourth layer was LDL-C and smoking. There were five explanatory variables screened out in the model, including hypertension, FPG, HDL-C, LDL-C and smoking. The first layer of the tree showed that the incidence of IS in hypertensive population (62.6%) was significantly higher than that in non-hypertensive population (35.2%). The second layer of the tree showed that the incidence of IS in people with hypertension with HDL-C ≥ 1.04 mmol/L (53.6%) was lower than that in people with HDL-C < 1.04 mmol/L (78.5%). However, in the population without hypertension, the probability of IS occurrence in the population with FPG ≥ 7.0 mmol/L (71.1%) was significantly higher than that in the population with FPG < 7.0 mmol/L (28.3%). The third layer of the tree showed that the IS incidence of HDL-C ≥ 1.04 mmol/L (21.8%) was lower than that of HDL-C < 1.04 mmol/L (48.7%) in the population without hypertension and FPG < 7.0 mmol/L. However, in the population with hypertension and HDL-C ≥ 1.04 mmol/L, the probability of IS occurrence in the population with FPG ≥ 7.0 mmol/L (78.6%) was significantly higher than that in the population with FPG < 7.0 mmol/L (46.7%). The fourth layer of the tree showed that the IS incidence of people with LDL-C ≥ 4.14 mmol/L (53.8%) was higher than that of people with LDL-C < 4.14 mmol/L (19.0%) in the population without hypertension, FPG < 7.0 mmol/L and HDL-C ≥ 1.04 mmol/L. In the population without hypertension, the incidence of IS in smokers (76.9%) was higher than that in non-smokers (39.1%) of people with FPG < 7.0 mmol/L and HDL-C < 1.04 mmol/L. In the population with hypertension, the probability of IS occurrence in the population with LDL-C ≥ 4.14 mmol/L (72.5%) was higher than that in the population with LDL-C < 4.14 mmol/L (44.4 %) of people with HDL-C ≥ 1.04 mmol/L and FPG < 7.0 mmol/L. The gain diagram of IS classification tree model shown that the gain value increased rapidly from 0% to 100% and then tended to be stable. The index chart shown that the index value kept stable in the moving direction from above 100% and then dropped rapidly to 100%, indicating the model was very well. The risk value of misclassification probability of the classification tree model was 0.291, and the correct rate of risk factor for IS patients was 70.90%. The area under ROC curve (AUC) was 78.0% [95% confidence interval (95%CI) = 75.9%-79.9%, P < 0.001], the sensitivity was 62.5% (95%CI = 59.1%-65.7%) and the specificity was 79.4% (95%CI = 76.5%-82.1%). Classification tree model can properly predict the risk factor of IS, and the most important risk factors are hypertension, hyperglycemia, high LDL-C and smoking.

Response of unmyelinated (C) polymodal nociceptors to thermal stimuli applied to monkey's face. 1. The response of C polymodal nociceptors to thermal and mechanical stimuli applied to the monkey's face was recorded extracellulary in the trigeminal ganglion in rhesus monkeys anesthetized with sodium pentobarbital. Conduction velocities, determined from electrical stimulation of receptive fields (RFs), were in the range for unmyelinated C fibers (mean=0.82 m/s, n=20; SD=+/-0.17). With two exceptions cutaneous RFs were single spots (median=2 mm2; n=37) and usually were identical for thermal and mechanical stimuli. The median force threshold for the sample of units was 1.2 g (von Frey technique; n = 39; range = 0.07-8.5 g). 2. Discharges to thermal stimuli were investigated with a feedback-controlled contact thermode which permitted temperature changes less than or equal 12.0 degrees C/s. Thermal thresholds ranged from 38 degree to 49 degree C (median=46 degrees C; n=37), and maximum discharge frequencies were obtained in the noxious heat range (45-55 degrees C). For a graded series of 5 s duration stimuli from an adapting temperature of 35 degrees C, the number of impulses increased as a monotonic function of stimulus intensity over the range from threshold temperature to 50-53 degrees C. Many stimulus-response functions were positively accelerated, and linear regression analyses showed that most units examined were best fit by nonlinear functions. 3. The typical pattern of activity to 5 s duration temperature shifts into the noxious heat range was a short accelerating burst of impulses followed by deceleration to a lower rate of discharge prior to termination of the stimulus. The temporal profile of the discharge of impulses was virtually identical at different adapting temperatures. In units tested with 30 s duration stimuli at 2-6 degrees C above threshold, the mean frequency of discharge during the final 25 s was 1.46 impulses/s (n=6; SD=+/-0.89). 4. Application of noxious heat stimuli a few degrees above threshold temperature typically sensitized or enhanced the response of the unit to subsequent application of heat stimuli. The signs of sensitization consisted of a decrease in threshold temperature, increased frequency of discharge, decreased latency to the first impulse, and afterdischarges. Units failed to respond throughout the duration of 30 s stimuli if the final temperature exceeded 50 degrees C. Depressed responses were sometimes produced by application of intense (greater than or equal 55 degrees C) stimuli, presumably as a result of partial inactivation of the receptor. 5. In a correlative analysis, the latency and pattern of discharge in a sample of units were compared with escape responses in two monkeys to temperature shifts into the noxious heat range (49 and 51 degrees C). The analysis revealed that the discharge of C polymodal nociceptors alone cannot account for fast escape responses, but the discharge may contribute to escape responses which occur more than 3.5 s after the onset of stimulation.

Toxicity and efficacy of conventional amphotericin B deoxycholate versus escalating doses of amphotericin B deoxycholate---fat emulsion in HIV-infected patients with oral candidosis. BACKGROUND: Amphotericin B deoxycholate remains the treatment of choice for most systemic fungal infections; however, its clinical use can be limited by infusion-related side effects and nephrotoxicity. New formulations of amphotericin in lipid compounds have been shown to decrease toxicity. We previously showed that a lipid emulsion preparation of amphotericin B deoxycholate was better tolerated than the conventional preparation in dextrose. Therefore, we have now studied the clinical tolerance, renal toxicity and efficacy of higher doses of amphotericin B deoxycholate prepared and infused in a fat emulsion (Intralipid 20%). Thus, this report adds information to the previous publication. METHODS: Forty-two patients infected with HIV and suffering oral candidosis entered the study. The patients received either amphotericin B deoxycholate---glucose 1 mg/kg/day or amphotericin B deoxycholate---lipid emulsion 1 mg/kg/day for 4 days (randomized phase), or amphotericin B deoxycholate---lipid emulsion 2 mg/kg/day or 3 mg/kg/day (escalating-dose phase) for 5 days. Clinical (immediate) side effects and renal (creatinine) tolerance were assessed daily; efficacy against oral candidosis was measured by using a simple clinical score. Serum levels of amphotericin B were also measured. RESULTS: None of the patients receiving amphotericin B deoxycholate---lipid emulsion had treatment interrupted, as compared to four (36%) in the amphotericin B deoxycholate---glucose group (pless-than-or-equal0.01); chills during or after the infusions were significantly less frequent in the amphotericin B deoxycholate---lipid emulsion groups than in the amphotericin B deoxycholate-glucose group (p=0.03). The increase of creatininemia during treatment was significantly higher for patients receiving amphotericin B deoxycholate---glucose than for those receiving amphotericin B deoxycholate---lipid emulsion (p=0.001). The number of patients who had a creatininemia greater-than-or-equal18 mg/L during treatment was significantly higher in both the amphotericin B deoxycholate---glucose group (36%) and in the group receiving the highest dose of amphotericin B deoxycholate---lipid emulsion than in other groups (pless-than-or-equal0.06). The serum concentrations of amphotericin B were lower for the amphotericin B deoxycholate---lipid emulsion regimen than for the amphotericin B deoxycholate---glucose regimen at the same dose of 1 mg/kg/day, but increased with the dose. The change of the oral candidosis score was similar for the same dose of 1 mg/kg/day of amphotericin B deoxycholate infused in either glucose or lipid emulsion; higher doses of amphotericin B deoxycholate---lipid emulsion were more efficacious (p=0.009) and this efficacy seemed to increase with the dose (p=0.06). CONCLUSIONS: The clinical and renal tolerance of amphotericin B deoxycholate are improved when the drug is directly prepared and infused in lipid emulsion (Intrapid) and this preparation allows for greater dosage, up to 3 mg/kg/day, with resultant greater efficacy. This preparation is simple and cost-effective (approximately 7 US $ per 50 mg of amphotercin B) and could be clinically compared to other formulations of amphotericin B.

Effect of nitrate supply on the in-vivo synthesis and distribution of trifollin A, a Rhizobium trifolii-binding lectin, in Trifolium repens seedlings. In-vivo synthesis of the white-clover lectin, trifoliin A, was examined by the incorporation of labeled amino acids into protein during heterotrophic growth of intact Trifolium repens L. seedlings. Lectin synthesis was quantified by measuring the level of labeled protein immunoprecipitated from root exudate, from the hapten (2-deoxyglucose) eluate of the roots, and from root and shoot homogenates. The presence of labeled trifoliin A was confirmed by non-denaturing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, followed by fluorography and comparison with trifoliin A standards. In-vivo-labeled trifoliin A was detected in seedling root homogenate 2 h after the addition of labeled amino acids and on the root surface by 8 h. Incorporation of labeled amino acids into protein and trifoliin A was greatest with 2-d-old seedlings and was greater when the plants were grown continuously in the dark than when they were exposed to 14 h light daily. Significantly more labeled lectin accumulated on the root surface of seedlings grown with 1.5 mM KNO3 than of seedlings grown either without N or with 15.0 mM KNO3. The labeled lectin from the root surface in all nitrate treatments and from the rootexudate samples of seedlings grown N-free and with 1.5 mM KNO3 was fully able to bind to Rhizobium trifolii. In contrast, only 2% of the immunoprecipitable protein found in the root exudate of seedlings grown with 15.0 mM KNO3 was able to bind to the bacteria. Thus, excess nitrate does not repress the synthesis of trifoliin A in the root, but does affect the distribution and activity of this newly synthesized lectin in a way which reduces its ability to interact with R. trifolii. By using Western blot analysis, much more total trifoliin A is detected in the homogenates of shoots than roots. However, greater than 80% of the total labeled protein and 85-90% of the total labeled lectin were found in the root homogenates of 2-d-old dark-grown seedlings incubated for 5 h with labeled amino acids. In addition, Western blot analysis indicated that the shoot homogenate contained smaller-molecular-weight peptides which reacted with the specific anti-trifoliin A antibody. These studies indicate that stored trifoliin A in the seed is degraded in the shoots during seedling development, while newly synthesized trifoliin A in the roots is excreted to the root surface and external environment.

Remission of Graves' hyperthyroidism predicted by smooth decreases of thyroid-stimulating antibody and thyrotropin-binding inhibitor immunoglobulin during antithyroid drug treatment. It is important to know whether a patient with Graves' disease will get into remission or not during antithyroid drug (ATD) treatment. Thyrotropin (TSH) receptor antibodies (TRAb) cause Graves' disease. Thyroid-stimulating antibody (TSAb) and TSH-binding inhibitor immunoglobulin (TBII) have been measured as TRAb to diagnose Graves' disease and to follow Graves' patients. Smooth decreases of TSAb and TBII during ATD treatment predict the remission of Graves' hyperthyroidism. We followed serial changes of TSAb and TBII in 58 Graves' patients before, during, and after ATD treatment; TSAb was measured as a stimulator assay, using porcine thyroid cells, and TBII as a receptor assay. Patterns of TSAb and TBII changes during ATD treatment differ from one patient to another. TSAb and TBII activities decreased and disappeared in 52 (group A) but continued to be high in the other 6 (group B); 39 of the 52 group A patients achieved remission, but all of the 6 group B patients with persistently positive TSAb and TBII continued to have hyperthyroidism. No differences in the initial TSAb and TBII activities were noted between the 52 group A patients and the 6 group B patients. Of the 52 group A patients in whom TSAb and TBII had disappeared, 44 had smooth decreases of TSAb and TBII (group A1), and 8 had complex changes of TSAb and/or TBII (group A2); 36 of the 44 group A1 patients (82%) but only 3 of the 8 group A2 patients (37%) continued to be in remission more than 1 year after ATD discontinuation. The number of remission in group A1 was significantly larger than that in group A2. No differences in the initial TSAb and TBII activities were noted between group A1 and group A2. More than 80% of group A1 patients, who had smooth decreases of TSAb and TBII, continued to be in remission longer than 1 year. We demonstrated that smooth decreases of TSAb and TBII during ATD treatment predicted the remission of Graves' hyperthyroidism. The Graves' patients can be classified into A1, A2, and B groups according to the patterns of TSAb and TBII changes during ATD treatment. Group A1 patients, who had smooth decreases of TSAb and TBII, had higher rate of remission than the others. Smooth decreases of TSAb and TBII during the early phase of ATD treatment are a reliable predictor of the remission.

Synthesis and Investigation of the Role of Benzopyran Dihydropyrimidinone Hybrids in Cell Proliferation, Migration and Tumor Growth. Cancer is the second leading cause of mortality worldwide after heart diseases, and lung cancer is the topmost cause of all cancer-related deaths in both sexes. Dihydropyrimidinones (DHPMs) are medicinally important class of molecules with diverse pharmacological activities including anticancer activity. The present study focuses on the molecular hybridization of novel Benzopyran with Dihydropyrimidinone and evaluation of the resulting hybrids for cancer cell proliferation, migration and tumor growth. We have synthesized a focused library of dihydropyrimidinone benzopyran hybrids (compounds 1-11) by joining the aromatic as well as pyran portions of the benzopyran core with dihydropyrimidinone. All the synthesized hybrid molecules were evaluated for their cytotoxic activities against a panel of four human cancer cell lines of diverse tissue origin, viz: A549 (lung carcinoma), MCF7 (mammary gland adenocarcinoma), HCT-116 (colorectal carcinoma), and PANC-1 (pancreatic duct carcinoma) with the help of MTT cell viability assay. A structure-activity relationship was made on the basis of IC50 values of different hybrids. Effect on cell proliferation was examined through colony formation assay, reactive oxygen species generation and mitochondrial membrane potential studies. Wound healing assays and cell scattering assays were employed to check the effect on cell migration. Western blotting experiments were performed to find out the molecular mechanism of action and anti-tumor studies were carried out to evaluate the in vivo efficacy of the selected lead molecule. Two types of novel hybrids were synthesized efficiently from benzopyran aldehydes, ethylacetoacetate and urea under heteropolyacid catalysis. Compound 3 was found to be the most potent hybrid among the synthesized compounds with consistent cytotoxic activities against four human cancer cell lines (IC50 values: 0.139 - 2.32 μM). Compound 3 strongly inhibited proliferation abilities of A549 cells in colony formation assay. Compound 3 exerted oxidative stress-mediated mitochondrial dysfunction, in which mitochondrial reactive oxygen species (ROS) generation as a mechanism of its anti-proliferative effects was analysed. Further, the molecule abrogated migration and cell scattering properties of aggressive PANC-1 cells. Mechanistic studies revealed that compound 3 modulated NF-kB expression and its downstream oncogenic proteins involved in cancer cell proliferation and invasion. Finally, compound 3 confirmed its in vivo anti-tumor efficacy; there observed 41.87% tumor growth inhibition at a dose of 30 mg/kg/body weight against a mouse model of Ehrlich solid tumor. Our study unravels a potential anticancer lead (compound 3) from DHPMs that have opened up new research avenues for the development of promising anticancer therapeutic agents.

Waiting with and without recombination: the time to production of a double mutant. R.A. Fisher and H.J. Muller argued in the 1930s that a major evolutionary advantage of recombination is that it allows favorable mutations to be combined within an individual even when they first appear in different individuals. This effect is evaluated in a two-locus, two-allele model by calculating the average waiting time until a new genotypic combination first appears in a haploid population. Three approximations are developed and compared with Monte Carlo simulations of the Wright-Fisher process of random genetic drift in a finite population. First, a crude method, based on the deterministic accumulation of single mutants, produces a waiting time of 1/square root of N mu(2) with no recombination and [formula: see text] with recombination between the two loci, where mu is the mutation rate, N is the haploid population size, and R is the recombination rate. Second, the waiting time is calculated as the expected value of a heterogeneous geometric distribution obtained from a branching process approximation. This gives accurate estimates for small values of N mu large. The estimates for small values of N mu are considerably lower than the simulated values. Finally, diffusion analysis of the Wright-Fisher process provides accurate estimates for N mu small, and the time scales of the diffusion process show a difference between R = 0 and for R >> 0 of the same order of magnitude as seen in the deterministic analysis. In the absence of recombination, accurate approximations to the waiting time are obtained by using the branching process for high N mu and the diffusion approximation for low N mu. For low N mu the waiting time is well approximated by 1/the square root of 8N2 mu(3). With R >> 0, the following dependence on N mu is observed: For N mu > 1 the waiting time is virtually independent of recombination and is well described by the branching process approximation. For N mu approximately equal to 1 the waiting time is well described by a simplified diffusion approximation that assumes symmetry in the frequencies of single mutants. For N mu << 1 the waiting time is well described by the diffusion approximation allowing asymmetry in the frequencies of single mutants. Recombination lowers the waiting time until a new genotypic combination first appears, but the effect is small compared to that of the mutation rate and population size. For large N mu, recombination has a negligible effect, and its effect is strongest for small N mu, in which case the waiting time approaches a fixed fraction of the waiting time for R = 0. Free recombination lowers the waiting time to about 45% of the waiting time for absolute linkage for small N mu. Selection has little effect on the importance of recombination in general.

Bone morphogenetic proteins. Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor beta (TGFbeta) superfamily. The roles of BMPs in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. Signal transduction studies have revealed that Smad1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and related genes have shown that BMP signaling plays critical roles in heart, neural and cartilage development. BMPs also play an important role in postnatal bone formation. BMP activities are regulated at different molecular levels. Preclinical and clinical studies have shown that BMP-2 can be utilized in various therapeutic interventions such as bone defects, non-union fractures, spinal fusion, osteoporosis and root canal surgery. Tissue-specific knockout of a specific BMP ligand, a subtype of BMP receptors or a specific signaling molecule is required to further determine the specific role of a BMP ligand, receptor or signaling molecule in a particular tissue. BMPs are members of the TGFbeta superfamily. The activity of BMPs was first identified in the 1960s (Urist, M.R. (1965) "Bone formation by autoinduction", Science 150, 893-899), but the proteins responsible for bone induction remained unknown until the purification and sequence of bovine BMP-3 (osteogenin) and cloning of human BMP-2 and 4 in the late 1980s (Wozney, J.M. et al. (1988) "Novel regulators of bone formation: molecular clones and activities", Science 242, 1528-1534; Luyten, F.P. et al. (1989) "Purification and partial amino acid sequence of osteogenin, a protein initiating bone differentiation", J. Biol. Chem. 264, 13377-13380; Wozney, J.M. (1992) "The bone morphogenetic protein family and osteogenesis", Mol. Reprod. Dev. 32, 160-167). To date, around 20 BMP family members have been identified and characterized. BMPs signal through serine/threonine kinase receptors, composed of type I and II subtypes. Three type I receptors have been shown to bind BMP ligands, type IA and IB BMP receptors (BMPR-IA or ALK-3 and BMPR-IB or ALK-6) and type IA activin receptor (ActR-IA or ALK-2) (Koenig, B.B. et al. (1994) "Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells", Mol. Cell. Biol. 14, 5961-5974; ten Dijke, P. et al. (1994) "Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4", J. Biol. Chem. 269, 16985-16988; Macias-Silva, M. et al. (1998) "Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2", J. Biol. Chem. 273, 25628-25636). Three type II receptors for BMPs have also been identified and they are type II BMP receptor (BMPR-II) and type II and IIB activin receptors (ActR-II and ActR-IIB) (Yamashita, H. et al. (1995) "Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects", J. Cell. Biol. 130, 217-226; Rosenzweig, B.L. et al. (1995) "Cloning and characterization of a human type II receptor for bone morphogenetic proteins", Proc. Natl Acad. Sci. USA 92, 7632-7636; Kawabata, M. et al. (1995) "Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor", J. Biol. Chem. 270, 5625-5630). Whereas BMPR-IA, IB and II are specific to BMPs, ActR-IA, II and IIB are also signaling receptors for activins. These receptors are expressed differentially in various tissues. Type I and II BMP receptors are both indispensable for signal transduction. After ligand binding they form a heterotetrameric-activated receptor complex consisting of two pairs of a type I and II receptor complex (Moustakas, A. and C.H. Heldi (2002) "From mono- to oligo-Smads: the heart of the matter in TGFbeta signal transduction" Genes Dev. 16, 67-871). The type I BMP receptor substrates include a protein family, the Smad proteins, that play a central role in relaying the BMP signal from the receptor to target genes in the nucleus. Smad1, 5 and 8 are phosphorylated by BMP receptors in a ligand-dependent manner (Hoodless, P.A. et al. (1996) "MADR1, a MAD-related protein that functions in BMP2 signaling pathways", Cell 85, 489-500; Chen Y. et al. (1997) "Smad8 mediates the signaling of the receptor serine kinase", Proc. Natl Acad. Sci. USA 94, 12938-12943; Nishimura R. et al. (1998) "Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12", J. Biol. Chem. 273, 1872-1879). After release from the receptor, the phosphorylated Smad proteins associate with the related protein Smad4, which acts as a shared partner. This complex translocates into the nucleus and participates in gene transcription with other transcription factors (). A significant advancement about the understanding of in vivo functions of BMP ligands, receptors and signaling molecules has been achieved in recent years.

Regional intestinal absorption and biliary excretion of fluvastatin in the rat: possible involvement of mrp2. The first purpose of this study was to investigate the in vivo absorption, biliary secretion, and first-pass effect of fluvastatin following regional intestinal dosing in the rat. We also examined the membrane transport mechanisms and made in silico predictions of the relative importance of various intestinal regions to the human absorption of fluvastatin. Fluvastatin was administered intravenously (2, 10, and 20 micromol/kg) and into the duodenum (1.46, 2.92, 7.32, and 14.6 micromol/kg), jejunum (14.6 micromol/kg), ileum (1.46 and 14.6 mciromol/kg), and colon (1.46 and 14.6 micromol/kg) as a solution to conscious rats. In a separate group of rats, bile was collected after an i.v. dose of fluvastatin (2 micromol/kg). In the Caco-2 model the bidirectional transport of fluvastatin (16 microM) was investigated with and without various efflux inhibitors (verapamil, vinblastine, probenecid, and indomethacin, 160 microM). The human in vivo absorption of fluvastatin from an oral immediate release tablet and that from an oral extended release tablet (both 40 mg) were simulated in GastroPlus. Neither the dose nor the intestinal region influenced the bioavailability of fluvastatin significantly. The rate of absorption was, however, affected by both the dose and the site of administration; duodenum = jejunum > colon > ileum, and higher following the high dose. Increasing the i.v. dose from 2 to 20 micromol/kg decreased the clearance (26 +/- 3 to 12 +/- 1 mL/min/kg), the hepatic extraction (66 +/- 8 to 30 +/- 2%), and the volume of distribution (7.3 +/- 0.3 to 2.1 +/- 0.7 L/kg) for fluvastatin (p < 0.05). Neither bile cannulation nor bile sampling affected the pharmacokinetics. Fluvastatin was secreted into the bile, probably by active transport. The in vitro permeability for fluvastatin was high (>10 x 10(-6) cm/s). Indomethacin, but not the other inhibitors, affected the transport in both directions suggesting mrp2 to be involved. In silico, 93% of the dose was absorbed from the small intestine and 6% from the colon when given as an immediate release formulation. The corresponding values for an extended release formulation were 21% and 74%, respectively. In conclusion, fluvastatin exhibits dose-dependent pharmacokinetics in the rat. The rate of absorption (Cmax, Tmax, and Cmax/AUC(lqc)) from the intestinal tract is both region and dose-dependent in the rat. This may be due to the involvement of mrp2 in the intestine and/or in the liver. These absorption properties have to be considered in the development of an extended release formulation of fluvastatin.

Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in the human male. III. Effects of long term combined treatment with GnRH agonist and androgen. Chronic treatment with agonist analogs of GnRH results in reversible oligospermia in man, but leads to impotence and decreased libido due to a concomitant fall in serum testosterone (T) concentrations. We, therefore, assessed the effects of combined treatment with a potent GnRH agonist and T on gonadotropins and spermatogenesis in normal men, anticipating that addition of androgen would prevent agonist-induced changes in libido. Seven normal men were treated with 200 micrograms of the GnRH agonist D-(Nal2)6GnRH (GnRH-A), sc, daily for 16 weeks. In addition, 200 mg T enanthate were administered every 2 weeks for the entire 16-week treatment period. Basal LH, FSH, and T concentrations were measured every week during a 5-week control period, daily on treatment days 0, 1-10, 14, 18, 22, 26, and 28, every week thereafter until day 56, and every 2 weeks thereafter for the remainder of the treatment and recovery phases. Detailed analysis of LH and FSH over the 24-h period was performed by multiple blood sampling on days 0, 1, 10, 28, 56, 84, and 112. Semen analyses were performed every week during the control phase and every 2 weeks during the treatment and recovery phases. The mean sperm count declined by 83%, to a nadir of 16.6 +/- 6.2 (+/- SEM) million/ml. One subject had no significant decrease in sperm count. Azoospermia was not achieved in any subject. Basal serum LH concentrations, after an early phase of stimulation, declined to near baseline by day 14. However, basal, 24-h integrated serum LH concentrations, and 24-h urinary LH excretion were not significantly lowered by combined treatment. Bioassayable serum LH concentrations, however, declined significantly from 20.4 +/- 6.3 to 4.5 +/- 0.5 mIU/ml, and the bioassayable to immunoassayable LH ratio decreased from 2.1 +/- 1.0 to 0.7 +/- 0.1 after 16 weeks of GnRH-A treatment. Basal and 24-h integrated FSH concentrations, after an initial period of stimulation, declined progressively to baseline by days 5-6 and were significantly below baseline by day 112. Serum T concentrations did not fall into the hypogonadal (less than 250 ng/dl) range in any subject at any time during the treatment period. After discontinuation of treatment, LH, FSH, and sperm counts returned to normal in all subjects. Thus, single daily injection of GnRH-A and T failed to predictably induce azoospermia in normal men over the 16-week treatment period.(ABSTRACT TRUNCATED AT 400 WORDS)

Fluted Projectile Points: Their Age and Dispersion: Stratigraphically controlled radiocarbon dating provides new evidence on peopling of the New World. The stratigraphic record shows Clovis projectile points to be restricted to sediments between 11,000 and 11,500 years old. Underlying deposits dating back 11,600 to 13,000 years are without evidence of human occupation. In the High Plains, overlying deposits dating back 10,000 to 11,000 years contain Folsom and Hell Gap artifacts and are without mammoth remains. The glacial history of Alaska, Canada, and the Great Lakes region indicates that, for the first time in at least 15,000 years, an ice-free, trans-Canadian corridor opened up approximately 12,000 years ago. Since Clovis points are distributed from coast to coast south of the Valders ice border, the abrupt appearance of Clovis artifacts in the stratigraphic record of the High Plains some 700 years later suggests that Clovis progenitors passed through Canada during Two Creeks time. If eastern fluted points (for example, Enterline) are older than Clovis points, the difference may be on the order of only a hundred or so years, not thousands. The change from Clovis points to Folsom points in the High Plains may be related to a marked decline in the mammoth population after 11,000 years ago, but whether or not man was a prime factor in the extinction of Pleistocene megafauna is a moot question. On the basis of new data and critical geological evaluation of dates obtained by the radiocarbon method a hypothesis has been offered to explain (i) the abrupt appearance of Clovis points in the stratigraphic record of the United States around 11,500 years ago, and (ii) the lack of a cultural continuum in the United States leading to fluted projectile points. Llano hunters, like the game they pursued, may have persisted longer in some areas of the continent (for example, Bull Brook) than in others, but if a Clovis site can be found for which good stratigraphic evidence supports a date earlier than the Two Creeks interstade, then correlation of this event to the opening of the trans-Canadian ice-free corridor is incorrect (see 41a). Such a misinterpretation of timing would not affect the explanation for the lack of Clovis progenitors in the United States. We must continue to look for an indigenous cultural continuum leading to Clovis points, but if such cannot be demonstrated in the conterminous United States, then it would appear that fluted projectile points were developed elsewhere. Clovis progenitors might best be sought in northern Alaska or the Mackenzie Valley. The interpretations offered here are based on new data and critical geological evaluation of dates previously obtained by the radiocarbon method. How valid these interpretations are can be ascertained only through careful scrutiny of all man-mammoth associations found in the future, to assure precise relating of dates, fossils, and artifacts to the stratigraphic framework. We must pay closer attention to stratigraphic detail if we are to make the fullest use of radiocarbon dating.

Survey of endogenous virus and TVB* receptor status of commercial chicken stocks supplying specific-pathogen-free eggs. Endogenous avian leukosis virus (ALVE) and the ALVE receptor (TVB*S1) status of six commercial chicken lines supplying specific-pathogen-free eggs were analyzed. All commercial chicken lines are certified free of the avian leukosis virus (ALV) by screening for expression of the p27 protein using the standard enzyme-linked immunosorbent assay. The commercial chicken lines A, E, and F contained replication competent ALVE inserts. Line A was fixed for ALVE21, and lines E and F were segregating for ALVE10. In addition, ALVE1 was detected in all the chicken lines. Chicken lines B, D, and F were essentially fixed for the TVB*S1 allele that confers susceptibility to ALVE, whereas lines A, C, B, and E were resistant, containing either the TVB*S3 or TVB*R alleles. The results show that lines selected to be ALV p27 negative give rise to two different genotypes. One genotype lacks the TVB*S1 receptor for ALVE. Chicken lines with the TVB*S1 negative genotype can retain replication competent endogenous virus inserts such as ALVE2, 10, or 21 and still display the p27 negative phenotype. These replication competent ALVE viruses are phenotypically p27 negative in the absence of the TVB*S1 receptor because their chromosomal integration sites restrict transcription and subsequent production of the p27 protein and virus particles to levels below the detection limit. If the TVB*S1 receptor is present, the limited production of ALVE virus particles reinfects and integrates into more productive chromosomal locations in the cell. Increased production of infective virus particles and detectable levels of p27 follow this reinfection and integration into more active regions of the cells genome. The other genotype observed in the commercial lines retains the ALVE receptor (TVB*S1) but either lacks replication competent inserts or expresses the envelope encoded protein from defective inserts such as ALVE3 or ALVE6. In this phenotype, the env-coded glycoprotein encoded by the defective inserts binds to the TVB*S1 receptor and blocks the reinfection of the replication competent ALVE virus. This receptor interference stops reinfection and subsequent production of detectable virus particles and the p27 protein. Mixtures of different p27 negative phenotypes can result in the p27 positive phenotype and ALVE virus production. For example, mixtures of ALVE receptor positive (TVB*S1) but ALVE negative (p27 negative and envelope negative) chick embryo fibroblasts (CEFs) with fibroblasts that are receptor negative but ALVE positive could generate cells expressing high levels of p27 and ALVE virus. In this situation, the undetectable levels of ALVE virus from the receptor negative CEFs would infect and integrate into the receptor positive CEFs and produce detectable levels of ALVE virus. The implications of these findings for vaccine manufacturers and regulatory agencies are discussed.

[Computer-assisted total-knee arthroplasty. Comparison of two successive systems. Learning curve]. The increasing popularity of total-knee arthroplasty has led to many technical improvements both in the field of prosthesis design and implanted material and instrumentation. The recent advent of computer-assisted techniques is the fruit of a search for more precision for the bone cuts and better ligament balance. The purpose of the present study was to demonstrate how easy it is to use navigation systems by examining the difficulties encountered by one operator with navigation experience when the material was changed. The first 30 total-knee arthroplasties implanted with a new navigation system were investigated. Elements specifically related to navigation difficulties were studied. The series was composed of 16 women and 14 men, mean age 65.9 years at the time of surgery (range, 43 to 84). Mean BMI was 30.66 (range, 23.05 to 39.54). All patients were reviewed by the operator using a standard X-ray protocol. Mean follow-up was six months. The 30 arthroplasties were consecutive, with no exclusions excepting revision procedures. Primary or post-traumatic degeneration was the main reason for surgery. This series was compared with two prior series of 30 prostheses each, implanted with a different navigation system. The first 30 and last 30 implantations using the previous navigation system were thus compared in terms of operative time and precision (comparison of postoperative alignment and implant position). The study focused on difficulties encountered when using the new system, on intra- and postoperative complications and on assessment of implant position. All procedures were totally performed with the navigation system, no interruptions. Operative time was lengthened by an average of 18 min (range, 0 to 45 min). There were no complications specifically related to the navigation system. The position of the implants was assessed in the frontal and sagittal plane on the plain X-rays and with a goniometer. Computed tomography was used to assess femoral component rotation. The overall alignment of the lower limb was within the "ideal" range of +/-3 degrees in 97% (average 0.1 degrees varus). The position of the femoral implant and the tibial plate was correct in the frontal and sagittal planes and no internal rotation of the femoral piece was noted on the 27 ct scan studies (mean 1.9 degrees external rotation). Implant accuracy was equivalent to that observed in the series of the last 30 implants using the prior navigation system. The learning curve was shorter. This small series demonstrated the absence of major problems with the new navigation system. The length of the learning curve was acceptable. This study demonstrated that prior experience with navigation is beneficial because the learning curve with the new system was shorter and the accuracy of implantation was equivalent to that achieved with the prior system. Widespread use of computer-assisted surgery should enable continued improvement in ancillary systems in the upcoming years, particularly concerning rotatory position of the femoral implants, which is still a problem. Cost containment will also be a necessary goal.

Pulsed Radiofrequency on Dorsal Root Ganglion Relieved Neuropathic Pain Associated with Downregulation of the Spinal Interferon Regulatory Factor 8, Microglia, p38MAPK Expression in a CCI Rat Model. Interferon regulatory factor 8 (IRF8), which is induced by peripheral nerve injury (PNI), plays a key role in activating spinal microglia to release inflammatory cytokines in a p38-dependent way, thereafter results in formation of central sensitization. Pulsed radiofrequency (PRF) on dorsal root ganglion (DRG) alleviates neuropathic pain and inhibits the microglial activation in chronic constriction injury (CCI) rats. However, the consequences of PRF on spinal IRF8 of CCI rats remains unknown. We explore if PRF on DRG of rats with CCI could restrain IRF8, microglia, and p38 hyperactivity in the spinal cord to alleviate neuropathic pain. A randomized, controlled animal study. Department of Pain Management, Fujian Provincial Hospital, Fujian Key Laboratory of Geriatrics, Provincial Clinic College of Fujian Medical University. The changes in pain behaviors and the expressions of IRF8, Iba1 and p-p38 in the spinal cord of CCI rats which were administrated with antisense/ mismatch oligodeoxynucleotide of IRF8 were studied. Rats in CCI+AS ODN group, CCI+MM ODN group or CCI+NS group were intrathecally treated with antisense oligodeoxynucleotide of IRF8, mismatch oligodeoxynucleotide of IRF8 or same volume 0.9% NaCl once daily respectively, beginning from the day after nerve transection 12 hours and lasting for 7 days. The effects of PRF on L4-5 DRG of rats with CCI were investigated. PRF was applied adjacent to the L4-5 DRG at an intensity of 45 V for 6 minutes after CCI, whereas the control rats were treated without radiofrequency current. The withdrawal thresholds were studied and the spinal levels of IRF8, ionized calcium-binding adapter molecule 1 (Iba1, microglia characteristic marker) and p-p38 were calculated by ELISA, western blot, RT-PCR, and immunofluorescence. Intrathecal administration of antisense oligodeoxynucleotide of IRF8 led to the reversal of CCI-induced allodynia, lower activation of spinal microglia and p-p38. Withdrawal thresholds were partially recovered after a single PRF treatment for 14 days. CCI-induced IRF8 upregulation, microglia hyperactivity, and p38 phosphorylation in the spinal cord were reduced due to PRF treatment. However, PRF did not alter pain behaviors and pain signals in normal rats. In our study, one time point was selected just to assess the levels of microglia, and p-p38. The changes of IRF8, microglia, p-p38 in the ipsilateral DRG were not investigated. A more detailed study on how PRF on the DRG could further relieve NP is needed. Restraining IRF8, microglia and p38 hyperactivity in the spinal cord of CCI rats involved in the contribution to the long-lasting analgesia of PRF. Neuropathic pain, pulsed radiofrequency, dorsal root ganglion, microglia, p38MAPK, Interferon regulatory factor 8, chronic constriction injury of sciatic nerve.

Differences between "classical" risk factors for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and risk factors for nosocomial bloodstream infections caused by multiple clones of the staphylococcal cassette chromosome mec type IV MRSA strain. To identify risk factors associated with nosocomial bloodstream infections caused by multiple clones of the staphylococcal cassette chromosome mec (SCCmec) type IV strain of methicillin-resistant Staphylococcus aureus (MRSA). An unmatched case-control study (at a ratio of 1:2) performed during the period from October 2002 through September 2003. A 2,000-bed tertiary care teaching hospital affiliated with the University of São Paulo in São Paulo, Brazil. Case patients (n=30) were defined either as patients who had a bloodstream infection due to SCCmec type IV MRSA diagnosed at least 48 hours after hospital admission or as neonates with the infection who were born in the hospital. Control patients (n=60) were defined as patients with SCCmec type III MRSA infection diagnosed at least 48 hours after hospital admission. Genes encoding virulence factors were studied in the isolates recovered from case patients, and molecular typing of the SCCmec type IV MRSA isolates was also done by pulsed-field gel electrophoresis and multilocus sequence typing. In multivariate analysis, the following 3 variables were significantly associated with having a nosocomial bloodstream infection caused by SCCmec type IV strains of MRSA: an age of less than 1 year, less frequent use of a central venous catheter (odds ratio [OR], 0.07 [95% confidence interval {CI}, 0.02-0.28]; p= .025), and female sex. A second analysis was performed that excluded the case and control patients from the neonatal unit, and, in multivariate analysis, the following variables were significantly associated with having a nosocomial bloodstream infection caused by SCCmec type IV strains of MRSA: less frequent use of a central venous catheter (OR, 0.12 [95% CI, 0.03-0.55]; p= .007), lower Acute Physiology and Chronic Health Evaluation II score on admission (OR, 0.14 [95% CI, 0.03-0.61]; p= .009), less frequent surgery (OR, 0.21 [95% CI, 0.06-0.83]; p= .025), and female sex (OR, 5.70 [95% CI, 1.32-24.66]; p= .020). Of the 29 SCCmec type IV MRSA isolates recovered from case patients, none contained the Panton-Valentine leukocidin, gamma-hemolysin, enterotoxin B or C, or toxic shock syndrome toxin-1. All of the isolates contained genes for the LukE-LukD leukocidin and alpha-hemolysin. Genes for enterotoxin A were present in 1 isolate, and genes for beta-hemolysin were present in 3 isolates. "Classical" risk factors do not apply to patients infected with the SCCmec type IV strain of MRSA, which is an important cause of nosocomial bacteremia. This strain infects a patient population that is less ill and has had less frequent invasive procedures than a patient population infected with the multidrug-resistant strain of SCCmec type III MRSA. We found that virulence factors were rare and that Panton-Valentine leukocidin was absent. There were multiple clones of the SCCmec type IV strain in our hospital. Children under 1 year of age were at a higher risk. There was a predominant clone (sequence type 5) in this patient population.

Comparing strategies to synchronize estrus before fixed-time artificial insemination in primiparous 2-year-old beef cows. Two experiments evaluated controlled internal drug release (CIDR)-based protocols to synchronize estrus in primiparous 2-year-old beef cows. In each experiment, treatments were balanced according to body condition score and days postpartum. Experiment 1 compared the 14-day CIDR-PG (14-d) and 7-day CO-Synch + CIDR (7-d) protocols on the basis of estrous response, pregnancy rates after fixed-time artificial insemination (FTAI), and final pregnancy rate. Cows assigned to 14-d (n = 355) received a CIDR insert on Day 0 with removal on Day 14. Cows assigned to 7-d (n = 349) received gonadotropin releasing hormone (GnRH) and a CIDR insert on Day 23. On Day 30, CIDRs were removed from 7-d cows, and PGF2α was administered to all cows in each treatment. On Day 33, GnRH was administered concurrent with FTAI at 66 and 72 hours after PGF2α for 7-d and 14-d treated cows, respectively. Estrous response before FTAI was higher for 7-d compared with 14-d cows (74% vs. 43%, respectively; P < 0.0001); however, pregnancy rates resulting from FTAI were similar (14-d 63%; 7-d 64%; P = 0.52). Ovarian follicular dynamics and serum estradiol-17β concentrations were evaluated among a subset of cows assigned to each protocol. Dominant follicle diameter was smaller at PGF2α (P = 0.04) and FTAI (P = 0.002) among 14-d cows compared with 7-d cows; however, estradiol-17β at PGF2α (P = 0.06) and FTAI (P = 0.001) was greater for 14-d versus 7-d treated cows. Experiment 2 compared estrous response and pregnancy rates in 2-year-old beef cows after FTAI- or split-time artificial insemination (STAI) following synchronization of estrus with the 14-day protocol. Cows assigned to FTAI (n = 266) were inseminated at a fixed time concurrent with GnRH at 72 hours after PGF2α regardless of estrus expression, whereas cows assigned to STAI (n = 257) were inseminated based on estrus expression as determined by activation of an estrus detection aid. Cows assigned to STAI that exhibited estrus by 72 hours were inseminated; however, AI was delayed until 24 hours after GnRH (96 hours after PGF2α) for nonestrous cows. Total estrous response was increased for STAI- versus FTAI-treated cows (STAI 64%; FTAI 42%; P < 0.0001); pregnancy rates resulting from AI were similar (STAI 55%; FTAI 56%; P = 0.60). In summary, the 14-day CIDR-PG and 7-day CO-Synch + CIDR protocols can be used effectively to synchronize estrus before FTAI in primiparous 2-year-old beef cows. Although expression of estrus was increased using STAI in conjunction with the 14-day protocol, this approach did not increase pregnancy rates compared with FTAI.

Aductive laser iridoplasty and laser goniopuncture after non-perforating trabeculectomy. Successful non-perforating trabeculectomy (NPT) results in filtration of aqueous humor out of the anterior chamber and into a filtration bleb, without surgical excision of tissue from the anterior chamber angle, and without penetration into the anterior chamber. The complications of perforating trabeculectomy, due to early postoperative hypotony (shallow anterior chamber, hyphema, macular folds, suprachoroidal effusion, and ciliochoroidal hemorrhage) (3, 4, 5, 6, 7, 8, 9) are regarded by many surgeons as significant risks. Nonperforating surgery has been reported to reduce the incidence of early hypotony-related complications (10), because it has the advantage of creating gradual filtration of aqueous humor, through a thin trabeculodescemetic membrane (TDM), which markedly reduces postoperative complications seen after a conventional trabeculectomy (11), and also has been reported to provide better long-term intraocular pressure (IOP) control (12, 13). NPT is reported to be a procedure with a significant learning curve, sometimes necessitating conversion to perforating trabeculectomy, and requiring careful postoperative monitoring (14, 15, 16, 17). Zimmerman et al. reported filtration of aqueous humor under a filtering bleb, by resecting the roof of Schlemms canal and removing corneal stroma overlying the trabecular meshwork (18) Mermoud et al. reported filtration of aqueous humor under a filtering, bleb by unroofing Schlemms canal and removing corneal stroma overlying the trabecular meshwork as well Descemets membrane (19); he found that resistance across the TDM sometimes increased with time. When this resistance to aqueous humor outflow occurred, Mermoud found TDM resistance could be eliminated by performance of goniopuncture (ab interno Nd:YAG laser membranotomy via gonioprism), to enhance aqueous humor outflow into the filtration bleb. Failure to filter adequately through the TDM is a potential complication following NPT which can result in a rise in intraocular pressure (IOP). In this paper we examine the effectiveness of adjunctive Nd:YAG laser goniopuncture (YGP) in patients who underwent NPT, to reduce post-operative IOP rise, secondary to scarring at or poor aqueous outflow through the TDM. Iris prolapse (IP) is another potential complication following NPT which can result in a rise in IOP. In this paper we examine the effectiveness of adjunctive argon laser peripheral iridoplasty (ALPI) in patients who underwent NPT, to reduce post-operative IOP rise, secondary to IP obstructing outflow across the TDM. Nd:YAG laser goniopuncture consists of placing several laser shots on the undersurface of the trabeculodescemetic membrane. The result is a microperforation in this membrane, with flow of aqueous into the filtration bleb, which converts a non-perforating filtration procedure into a partial thickness filtration procedure. In this technique, several high power, multi-burst shots are applied, ab interno, by a Nd:YAG laser via a gonioprism, to the underside of the TDM, to facilitate aqueous outflow out from the anterior chamber. YGP can be effective when increased aqueous outflow is desired postoperatively. After this procedure, patent perforation in the TDM is usually observed gonioscopically, generally accompanied with reduction in IOP, and increase in bleb elevation (in height and in circumferential extent). Argon laser peripheral iridoplasty consists of placing several laser burns on the surface of the peripheral iris to contract the iris stroma, in a centripetal fashion, between the site of the burn and the anterior chamber angle. The result is iris stromal tissue contraction and compaction, movement of IP away from the angle and toward the pupil, which physically widens the angle and clears the synechial apposition of the peripheral iris against the TDM. In this technique, a series of low power, long duration, and large size burns is applied to the iris periphery to contract the iris stroma, to open the angle, and to clear IP causing synechial obstruction of the TDM after successful NPT. Used previously in acute angle closure glaucoma, ALPI may be effective in controlling IOP and clearing corneal edema when systemic and topical anti-glaucoma treatments fail to control high IOP, and when laser peripheral iridotomy (LPI) is not possible (e.g. in cases of severe corneal edema). Additionally, ALPI can be effective in permanently reopening the anterior chamber angle of iridectomized eyes with plateau iris syndrome; in this technique a full 360 degrees ring of spots is often applied, but a more limited area of treatment may also be effective. When a post-operative elevation in IOP was detected in a patients eye which had undergone NPT, careful indentation gonioscopy was performed to examine the TDM at the surgical site. If the peripheral iris was flat, the anterior chamber angle was open, and the TDM did not appear obstructed by IP, YGP was performed. First, the eyes were pre-treated with aproclonodine 1% and pilocarpine 2% (if needed to allow visualization of the TDM). Next, a Nd:YAG laser was set on triple burst mode and shots were applied to the underside of the TDM at the NPT site, using a Goldman 3-mirror lens in the following manner: Energy - 3-5 mJ; Mode - Triple burst. The power and amount of spots were titrated in order to achieve partial or microperforation of TDM at the NPT surgical site, thus resulting in restoration of aqueous outflow into the filtration bleb. When a post-operative elevation in IOP was detected in a patients eye which had undergone NPT and or YGP, careful indentation gonioscopy was performed to examine the TDM at the surgical site. If irreducible synechial IP were detected, which obstructed filtration through the TDM at the NPT surgical site, ALPI was performed. First, the eyes were pre-treated with aproclonodine 1% and pilocarpine 2%. Next, an argon laser was set on blue-green mode and shots were applied to the IP adherent to cornea or to the TDM at the NPT site, using a Goldman 3-mirror lens in the following manner: Spot Size - 500 mM; Duration - 0.5 s; Power - 200 to 400 mW. The power and amount of burns were titrated in order to achieve partial or complete centripetal retraction of the IP from the TDM at the NPT surgical site, causing a clearance of the obstruction to the TDM, thus resulting in restoration of aqueous outflow into the filtration bleb.

Oral progestogen combined with testosterone as a potential male contraceptive: additive effects between desogestrel and testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid metabolism. The effects of a synthetic oral progestogen, desogestrel (DSG), administered with low dose testosterone (T) were investigated to determine the optimal combination for suppression of gonadotropins and spermatogenesis to targets compatible with effective male contraception. Twenty-four healthy male volunteers (33.2 +/- 0.9 yr) were randomly assigned to 3 groups (n = 8) to receive: 1) 300 microg DSG orally daily and 100 mg T enanthate, i.m., weekly; 2) 300 microg DSG and 50 mg T enanthate; or 3) 150 microg DSG and 100 mg T enanthate for 24 weeks. To investigate the individual contribution to the combined action, DSG was administered alone for the first 3 weeks, and T enanthate was added on day 22. After 24-week treatment, sperm density in 78% (18 of 23) of the subjects became azoospermic, whereas 91.7% (22 of 24) and 95.8% (23 of 24) suppressed to less than 1 million/mL and less than 3 million/mL, respectively. The 300 microg DSG with 50 mg T enanthate combination induced azoospermia in 8 of 8 subjects, and the suppression of sperm density was significantly greater than that in the 300 microg DSG/100 mg T enanthate group, but was not different from that in the 150 microg DSG/100 mg T enanthate group. DSG (300 or 150 microg daily) alone in the first 3 weeks suppressed LH, FSH, and T to 60.6%, 48.0%, and 35.4%, respectively, of the baseline. Addition of T enanthate (50 and 100 mg weekly) raised plasma T to the physiological range and induced a further fall in LH and FSH to the limits of assay detection. There was no consistent difference in mean LH and FSH levels among the three groups during treatment or recovery, except that FSH remained detectable in a higher proportion of samples from the group receiving 300 microg DSG with 50 mg T enanthate. Total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol decreased by 9.3 +/- 1.7%, 10.3 +/- 2.6%, and 7.7 +/- 2.8%, respectively, during treatment with DSG alone with no difference between 300 and 150 microg. Addition of T enanthate (both 50 and 100 mg weekly) induced a further fall only in high density lipoprotein cholesterol to 22.6 +/- 3.7% from the baseline. In summary, the combined actions of oral DSG with low doses of T enanthate were highly effective in suppressing pituitary-testicular functions in adult men. The optimal regimen for inducing azoospermia was 300 microg DSG daily with 50 mg T enanthate weekly. Oral DSG exerted discernible effects on lipid metabolism. We conclude that the combination of oral progestogens with low dose T is a promising approach to achieve effective reversible male contraception.

[Chemotactic effects of burn rat serum on mesenchymal stem cells derived from different sources]. To isolate and culture mesenchymal stem cells ( MSC) from different sources and to investigate the chemotactic effects of burn rat serum on MSC derived from different sources. Seventy-two Wistar rats were randomly divided into burn( n = 36, with 30% TBSA full-thickness burns on the back) and sham burn (n = 36, without burns) groups. Bone marrow and peripheral blood of the rats in both groups were collected to isolate and culture MSC. Ratio of MSC, growth speed and cell morphology were observed with inverted microscope. Effects of different serum ( fetal bovine serum, normal rat serum and burn rat serum) on chemotaxis of MSC derived from different sources and their migration ability were subsequently examined with a transwell system. Results MSC were obtained from bone marrow of the rats in both groups. MSC were successfully obtained from bone marrow of all burn rats(100% , P <0.05) , but only from peripheral blood of 7 burn rat(58% ) , and no MSCs were obtained from peripheral blood of 12 rats in sham group( P <0.05). There was small amount of adherent cells 24 hrs after culture, and fusiform shaped adherent cells were sporadically observed in scattered distribution 2-3 days later with inverted microscope. There was no obvious difference in the cell morphology between the 2 groups. In the sham group, the number of MSC migrating to the lower surface of transwell after burn serum treatment [ (94 Il ) cells/ high power field] was significantly greater than that after the treatment with normal rat serum and fetal bovine serum [ (37 +/- 6) , (38 +/- 11) cells/high power field , P <0.01 ] , while no difference in migration ability was found after normal serum treatment compared with that after fetal bovine serum treatment ( P >0. 05). The migration rate of MSCs which were derived from bone marrow in sham group was obviously lower than those derived from bone marrow and peripheral blood from burn rats ( P <0. 05 or 0. 01). Though some difference of the migration ability existed between MSC derived from bone marrow and peripheral blood, there was no statistically significant difference ( P >0. 05). MSC can be isolated and cultured from bone marrow and peripheral blood of burn rat, but not from peripheral blood of normal rat. Burn rat serum has a stronger chemotactic effect on MSC. Moreover, the migration ability of MSC derived from burn rat is stronger than that of MSC derived from normal rat.

LIFE-HISTORY EVOLUTION IN GUPPIES (POECILIA RETICULATA): 1. PHENOTYPIC AND GENETIC CHANGES IN AN INTRODUCTION EXPERIMENT. Previous investigations (Reznick and Endler, 1982; Reznick, 1982a, 1982b) demonstrated that genetic differences in guppy life histories were associated with differences in predation. Guppies from localities with the pike cichlid Crenicichla alta and associated predators matured earlier, had greater reproductive efforts, and produced more and smaller offspring than did guppies from localities with only Rivulus harti as a potential predator. Crenicichla preys primarily on large, sexually mature size-classes of guppies, while Rivulus preys primarily on small, immature size-classes. These patterns of predation are hypothesized to alter mean age-specific survival. Theoretical treatments of such differences in survival predict the observed trends in age at maturity and reproductive effort. We are using introduction experiments to evaluate the role of predators in selecting for these life-history patterns. The experiment whose results are presented here was conducted in a tributary to the El Cedro River (Trinidad), where a waterfall was the upstream limit to the distribution of all fish except Rivulus. Guppies collected from the Crenicichla locality immediately below the waterfall (the downstream control) were introduced over the waterfall in 1981. This introduction released the guppies from Crenicichla predation, exposed them instead to Rivulus predation only, and also introduced them to a different environment, since the introduction site has greater canopy cover than the site of origin. Changes in guppy life-history patterns can be attributed to predation and/or the environment. Evidence from fish collected and preserved in the field demonstrated that, by mid-1983, guppies from the introduction site above the waterfall matured at larger sizes and produced fewer, larger offspring. There were no consistent differences in reproductive allotment (weight of offspring/total weight). With the exception of reproductive allotment, these patterns are identical to previous comparisons between Rivulus and Crenicichla localities. A laboratory genetics experiment demonstrated that males from the introduction site matured at a later age and at a larger size than did males from the control site downstream, as predicted from the "age-specific predation" hypothesis. No differences between localities were observed for female age and size at maturity or for reproductive effort. The trends for fecundity and offspring size were the reverse of those observed in the field. Because only the males changed in the predicted fashion, it is not possible either to reject or to accept the hypothesis of age-specific predation at this time. We discuss the possible causes for these patterns and the high degree of plasticity in the life history, as evidenced by the differences in fecundity and offspring size between the field and laboratory results.

[Comparative study of clinical efficacy between video-assisted anal fistula treatment and traditional fistula resection plus seton in treatment of complex anal fistula]. To explore the efficacy of video-assisted anal fistula treatment (VAAFT) in treatment of complex anal fistula. Clinical data of 87 patients with complex anal fistula undergoing operation at Department of General Surgery, the Second Affiliated Hospital of Suzhou University from September 2015 to December 2016 were collected to conduct a cohort study. The operative procedure depended on economic conditions and patient preference. Patients were divided into VAAFT group (42 cases) and traditional fistula resection plus seton (FRS) group (45 cases). The procedure of FRS was to completely remove the fistula along external wall, the inner opening and surrounding scar tissues, then, the inner opening was closed with absorbable suture. For deeper and more complex fistula, the above procedure should be combined with seton. Based on the concept of endoscopic minimally invasive surgery, VAAFT could deal with the fistula and inner opening under direct vision. The brief steps were as follows: insertion of the anal fistula scope through external opening into the fistula; continuous injection of glycine-mannitol solution to expand and clean the foul fistula; electrocoagulation of all lesions; clearance of burnt tissues from the lumen with endoscopic brush and forceps; injection of medical fibrin glue through the inner opening; closing the inner opening by suture. Intraoperative and postoperative indices were compared between two groups. VAAFT group included 33 males and 9 females with mean age of (37.4±13.5) years, mean BMI of (24.3±3.2) kg/m2, and mean disease course of (4.8±3.9) months. Of 42 cases, 5 had preoperative diabetes mellitus, 31 were high fistula and 11 were low fistula. FRS group included 32 males and 13 females with mean age of (42.1±15.6) years, mean BMI of (24.8±3.7) kg/m2, and mean disease course of (5.7±3.6) months. Of 45 cases, 4 had preoperative diabetes mellitus, 37 were high fistula and 8 were low fistula. There were no significant differences in baseline data between two groups(all P>0.05). Compared with FRS group, VAAFT group had significantly shorter operative time [(44.6±10.5) minutes vs. (57.4±12.3) minutes, t=5.203, P=0.000], lower incidence of postoperative bleeding (14.3% vs. 33.3%,χ²=4.304, P=0.038), less pain (Visual Analogue Scale,VAS) (2.9±1.8 vs. 7.3±1.2, t=13.500, P=0.000), faster pain relief [(1.0±0.8) days vs. (4.5±1.2) days, t=15.890, P=0.000] and shorter hospital stay [(4.1±3.5) days vs.(7.5±2.3) days, t=5.389, P=0.000]. However, there were no significant differences between two groups in urinary retention rate, first postoperative fecal time and postoperative infection rate(all P>0.05). All patients were followed up for more than 6 months, FRS group had significantly higher incidence of anal incontinence than VAAFT group (20.0% vs. 2.4%, Fisher P=0.015). However, no significant difference in recurrence rate was found between VAAFT and FRS group(7.1% vs. 15.6%, Fisher P=0.317). Compared to traditional FRS treatment, VAAFT possesses some advantages in less injury, less pain, faster recovery, and lower postoperative anal incontinence rate. Thus, VAAFT is a superior operative choice in treatment of patients with complex anal fistula.

A mouse model of angiotensin II slow pressor response: role of oxidative stress. ABSTRACT. The slow pressor response to prolonged infusions of angiotensin II (AngII) entails a delayed rise in BP. This study investigated the hypothesis that the response depends on the generation of oxidative stress. The BP and renal functional response of mice to graded doses (200, 400, and 1000 ng. kg(-1). min(-1)) of subcutaneously infused AngII was studied. The SBP of conscious mice increased by day 3 at AngII1000 but showed a delayed rise by days 9 to 13 (slow pressor response) at the lower rates of AngII infusion. By day 13, there was a graded increase in SBP with the rate of AngII infusion (Vehicle, -2.6 +/- 2.6%; AngII200, +14.1 +/- 5.0%; AngII400, +31.9 +/- 1.9%; AngII1000, +43.2 +/- 5.5%). The MAP measured under anesthesia rose significantly (P < 0.001) with AngII400 at 14 d (Vehicle, 85 +/- 2 mmHg; AngII400, 100 +/- 3 mmHg). When studied at day 6, the MAP of AngII400 rats was not elevated (88 +/- 2 mmHg; NS versus vehicle), yet the GFR was higher (1.05 +/- 0.05 versus 1.25 +/- 0.05 ml. min(-1). g(-1); P < 0.05) accompanied by an increase in the filtration fraction (FF) (28.8 +/- 1.2 versus 37.2 +/- 0.8%; P < 0.001). From day 6 through day 14, the MAP had increased (P < 0.01) in AngII400, accompanied by a significant reduction in GFR to 1.05 +/- 0.04 ml. min(-1). g(-1) (P < 0.01) and elevation of renal vascular resistance (RVR) (day 6 versus day 14, 15.3 +/- 0.6 versus 19.2 +/- 1.2 mmHg. ml(-1). min(-1). g(-1); P < 0.05). Renal excretion of 8-iso PGF(2alpha) was increased in AngII400 group at day 12 (2.52 +/- 0.35 versus 5.85 +/- 0.78 pg. day(-1); P < 0.01). The permeant superoxide dismutase mimetic tempol reduced the effects of AngII400 on the SBP (-1.7 +/- 5.8%; P < 0.01), the MAP (87 +/- 4 mmHg; P < 0.01), and the RVR (15.2 +/- 0.5 mmHg. ml(-1). min(-1). g(-1); P < 0.05) at day 14 and the renal 8-iso PGF(2alpha) excretion (3.53 +/- 0.71 pg. d(-1); P < 0.05) at day 12. It is concluded that the AngII infused mouse is a valid model for the slow pressor response. There is an early rise in GFR and FF, consistent with increased postglomerular vascular resistance and a late rise in RVR with a fall in GFR, consistent with increased preglomerular vascular resistance that is accompanied by a rise in BP. There is evidence of increased oxidative stress that is implicated in the increase in the BP and RVR in this model.

Bone marrow oedema and aseptic osteonecrosis in children and adolescents with acute lymphoblastic leukaemia or non-Hodgkin-lymphoma treated with hyperbaric-oxygen-therapy (HBO): an approach to cure? -- BME/AON and hyperbaric oxygen therapy as a treatment modality. There is a striking need for additional therapies of bone marrow oedema (BME) and aseptic osteonecrosis (AON) in paediatric oncology patients. Hyperbaric oxygenation (HBO) therapy used in the treatment of osteoradionecrosis is demonstrated effectiveness. Aim of this retrospective analysis was to investigate whether HBO-therapy might lead to subjective as well as objective effects in the treatment of BME and/or AON in paediatric oncology patients with acute lymphoblastic leukaemia (ALL) or Non-Hodgkin lymphoma (NHL). Between 11/1988 and 01/2001 27/291 (9.3 %) patients with ALL or NHL were diagnosed with a BME and/or AON in the Clinic for Paediatric Oncology, Haematology, and Immunology at University of Dusseldorf. 19/27 patients were submitted to HBO-therapy. Patients received average 45 HBO-treatments per patient (min. 13, max. 80 treatments). The affected regions were re-evaluated with MRI for radiological extent of lesions every 3 months. Pain in its intensity and localisation was serially recorded during HBO-therapy as key symptom in 11 of 19 patients. 27 patients (15 females, 12 males; mean age at diagnosis of malignancy 8.2 +/- 4.7 (SD) years, range 7 months to 16 years) presented with 138 lesions. 133/138 lesions were localised in the lower extremities. At diagnosis of BME and/or AON, 78/133 lesions were shown in females and 55/133 lesions in male. Girls < 10 years predominantly presented BME (33 BME vs. 6 AON), girls aged > 10 years predominantly offered AON (28 AON vs. 11 BME). BME was more often exhibited in boys < 10 years (34 BME vs. 10 AON) and rarely in boys > 10 years (4 BME vs. 6 AON). 11 patients treated with HBO-therapy were serially evaluated for pain intensity throughout their HBO-therapy courses by visual analogue scale (VAS) assessment. During the first 15 treatment courses the HBO-therapy a clear-cut reduction of pain was observed. The mean pain score before the first HBO-treatment unit was 2.4 +/- 2.7 (X +/- SD), decreased before the fifth to 1.6 +/- 1.7 and prior to the 35 (th) and 40 (th) HBO treatment to 0. Girls < 10 years treated with HBO showed an increase of BME (31 --> 46) and declining AON numbers (6 --> 2). Girls > 10 years with and without HBO-therapy showed decrease of BME lesions (7 --> 4 vs. 4 --> 0), whereas AON increased in the HBO-treated group (28 --> 29) as well as the non-treated group (0 --> 4). Males < 10 years showed an increase in BME lesion numbers despite HBO intervention (24 --> 26). The AON lesion numbers dropped in parallel (6 --> 3). Male patients not treated with HBO showed constant numbers of BME (11-->11) and a decreased numbers of AON (4 --> 2). All differences are statistically not significant. Children and adolescents diagnosed with ALL or NHL have a risk for accruement of BME and/or AON irrespective of the age, with an almost exclusive involvement of the lower extremities. Lesions of pedal bones and ankle joints predominantly affect children < 10 years. Lesions of knee and hip joints predominantly affect children > 10 years. In children < 10 years of age we demonstrate declining AON numbers and conversion of AON to BME thereby implicating possible beneficial effect of HBO in such patients. HBO failed to show beneficial effect on BME whether by preventing new lesions or by improving existent lesions in children > 10 years.

A New Formula for Predicting the Fraction of Delivered Oxygen During Low-Flow Oxygen Therapy. During O2 therapy at low flow in patients who breathe spontaneously, the fraction of delivered O2 (FDO2 ) is unknown. In recent years, FDO2 prediction formulas have been proposed. However, they do not take into account the effect of inspiratory flow (V̇I) on the FDO2 . The aim of this study was to validate a new FDO2 prediction formula, which takes into account the V̇I and compares it with other FDO2 prediction formulas. During a bench study, spontaneous breathing was generated with a mechanical test lung connected to a mechanical ventilator set to volume control mode. O2 flow from a wall-mounted tube was delivered through a heat-and-moisture exchanger filter. A flow sensor recorded each breath of the V̇I in ambient temperature and barometric pressure conditions. Three parameters [O2 flow at 2, 3, 4, 5, 6 L/min; minute ventilation at 5, 10, 15, 20 L/min; and ratio of the inspiratory time (TI) to the total breathing cycle time (Ttot) (TI/Ttot) of 0.33 (TI/Ttot value) and 0.50 (TI/Ttot value)] were modified to generate many ventilatory patterns. An O2 analyzer continuously examined the FDO2 . When the O2 flow and/or TI/Ttot increased, the FDO2 increased. When the minute ventilation increased, the FDO2 decreased. The results of the Bland-Altman method for the FDO2 , calculated by using our mathematical model and the measured FDO2 , showed that the mean ± SD bias value was equal to 1.49 ± 0.84%, and the limits of agreement ranged from -0.17% to 3.14%. The intraclass correlation coefficients were 0.991 for TI/Ttot = 0.33 and 0.994 for TI/Ttot = 0.50, and the coefficient of variation was 2.1% for TI/Ttot = 0.33 and 1.3% for TI/Ttot = 0.50. The results of the Bland-Altman method for the FDO2 calculated by using the Shapiro formula and the FDO2 measured on the bench indicated that the bias value was 0.075 ± 8.66% and the limits of agreement ranged from -16.89% to 17.04%. For the Vincent formula, the bias value was 3.08% ± 8.56% and the limits of agreement ranged from -13.69% to 19.84%. The V̇I has a major impact on FDO2 during O2 therapy at low flow. FDO2 comparisons between frequently used prediction formulas and FDO2 measured on the bench indicated greater differences. Uncritical use of these formulas should be used cautiously to predict FDO2 . In this study, our prediction formula indicated a good accuracy for predicting FDO2 during supplemental oxygenation through a heat-and-moisture exchanger in patients who breathe spontaneously.

Direct measurements of the ozone formation potential from livestock and poultry waste emissions. The global pattern of expanding urban centers and increasing agricultural intensity is leading to more frequent interactions between air pollution emissions from urban and agricultural sources. The confluence of these emissions that traditionally have been separated by hundreds of kilometers is creating new air quality challenges in numerous regions across the United States. An area of particular interest is California's San Joaquin Valley (SJV), which has an agricultural output higher than many countries, a rapidly expanding human population, and ozone concentrations that are already higher than many dense urban areas. New regulations in the SJV restrict emissions of reactive organic gases (ROGs) from animal sources in an attempt to meet Federal and State ozone standards designed to protect human health. The objective of this work is to directly measure the ozone formation potential (OFP) of agricultural animal plus waste sources in representative urban and rural atmospheres using a transportable "smog" chamber. Four animal types were examined: beef cattle, dairy cattle, swine, and poultry. Emissions from each animal plus waste type were captured in a 1 m(3) Teflon bag, mixed with representative background NO(x) and ROG concentrations, and then exposed to UV radiation so that ozone formation could be quantified. The emitted ROG composition was also measured so that the theoretical incremental reactivity could be calculated for a variety of atmospheres and directly compared with the measured OFP under the experimental conditions. The results demonstrate that OFP associated with waste ROG emissions from swine (0.39 +/- 0.04 g-O(3) per g-ROG), beef cattle (0.51 +/- 0.10 g-O(3) per g-ROG), and dairy cattle (0.42 +/- 0.07 g-O(3) per g-ROG) are lower than OFP associated with ROG emissions from gasoline powered light-duty vehicles (LDV) (0.69 +/- 0.05 g-O(3) per g-ROG). The OFP of ROG emitted from poultry waste (1.35 +/- 0.73 g-O(3) per g-ROG) is approximately double the LDV OFP. The measured composition of ROG emitted from animal plus waste sources is nine times less reactive than the current regulatory profiles that are based on dated measurements. The new animal waste ROG OFP measurements combined with adjusted animal waste ROG emissions inventory estimates predict that actual ozone production in the SJV from livestock and poultry (5.7 +/- 1.3 tons O(3) day(-1)) is 40 +/- 10% of the ozone produced by light duty gasoline vehicles (14.3 +/- 1.4 tons O(3) day(-1)) under constant NO(x) conditions.

Music perception with temporal cues in acoustic and electric hearing. The first specific aim of the present study is to compare the ability of normal-hearing and cochlear implant listeners to use temporal cues in three music perception tasks: tempo discrimination, rhythmic pattern identification, and melody identification. The second aim is to identify the relative contribution of temporal and spectral cues to melody recognition in acoustic and electric hearing. Both normal-hearing and cochlear implant listeners participated in the experiments. Tempo discrimination was measured in a two-interval forced-choice procedure in which subjects were asked to choose the faster tempo at four standard tempo conditions (60, 80, 100, and 120 beats per minute). For rhythmic pattern identification, seven different rhythmic patterns were created and subjects were asked to read and choose the musical notation displayed on the screen that corresponded to the rhythmic pattern presented. Melody identification was evaluated with two sets of 12 familiar melodies. One set contained both rhythm and melody information (rhythm condition), whereas the other set contained only melody information (no-rhythm condition). Melody stimuli were also processed to extract the slowly varying temporal envelope from 1, 2, 4, 8, 16, 32, and 64 frequency bands, to create cochlear implant simulations. Subjects listened to a melody and had to respond by choosing one of the 12 names corresponding to the melodies displayed on a computer screen. In tempo discrimination, the cochlear implant listeners performed similarly to the normal-hearing listeners with rate discrimination difference limens obtained at 4-6 beats per minute. In rhythmic pattern identification, the cochlear implant listeners performed 5-25 percentage points poorer than the normal-hearing listeners. The normal-hearing listeners achieved perfect scores in melody identification with and without the rhythmic cues. However, the cochlear implant listeners performed significantly poorer than the normal-hearing listeners in both rhythm and no-rhythm conditions. The simulation results from normal-hearing listeners showed a relatively high level of performance for all numbers of frequency bands in the rhythm condition but required as many as 32 bands in the no-rhythm condition. Cochlear-implant listeners performed normally in tempo discrimination, but significantly poorer than normal-hearing listeners in rhythmic pattern identification and melody recognition. While both temporal (rhythmic) and spectral (pitch) cues contribute to melody recognition, cochlear-implant listeners mostly relied on the rhythmic cues for melody recognition. Without the rhythmic cues, high spectral resolution with as many as 32 bands was needed for melody recognition for normal-hearing listeners. This result indicates that the present cochlear implants provide sufficient spectral cues to support speech recognition in quiet, but they are not adequate to support music perception. Increasing the number of functional channels and improved encoding of the fine structure information are necessary to improve music perception for cochlear implant listeners.

The social structure and strategies of delphinids: predictions based on an ecological framework. Dolphins live in complex social groupings with a wide variety of social strategies. In this chapter we investigate the role that differing habitats and ecological conditions have played in the evolution of delphinid social strategies. We propose a conceptual framework for understanding natural patterns of delphinid social structure in which the spatial and temporal predictability of resources influences the ranging patterns of individuals and communities. The framework predicts that when resources are spatially and temporally predictable, dolphins should remain resident in relatively small areas. Predictable resources are often found in complex inshore environments where dolphins may hide from predators or avoid areas with high predator density. Additionally, available food resources may limit group size. Thus, we predict that there are few benefits to forming large groups and potentially many benefits to being solitary or in small groups. Males may be able to sequester solitary females, controlling mating opportunities. Observations of inshore populations of bottlenose dolphins (Tursiops sp.) and island-associated spinner dolphins (Stenella longirostris) seem to fit this pattern well, along with forest-dwelling African antelope and primates such as vervets (Cercopithicus aethiops), baboons (Papio sp.), macaques (Macaca sp.) and chimpanzees (Pan troglodytes). In contrast, the framework predicts that when resources such as food are unpredictable, individuals must range further to find the necessary resources. Forming groups may be the only strategy available to avoid predation, especially in the open ocean. Larger home ranges are likely to support a greater number of individuals; however, prey is often sparsely distributed, which may act to reduce foraging competition. Cooperative foraging and herding of prey schools may be advantageous, potentially facilitating the formation of long-term bonds. Alternately, individuals may display many short-term affiliations. These large groups make it difficult for a male or a small group of males to sequester a female, and polygynandry is the most likely mating strategy. While it is difficult to study wide-ranging delphinids to examine these predictions, this ranging and behavioural pattern has been suggested for dusky dolphins (Lagenorhynchus obscurus), coastal bottlenose dolphins (Tursiops sp.) and mixed species of dolphins in the Eastern Tropical Pacific. These patterns also resemble the ranging and social strategies of open savannah African antelopes and desert-dwelling macropods. Resource availability exists in a range of complex distributions and we predict that delphinid ranging patterns will also vary. At intermediate-ranging patterns, the framework predicts that individuals should form mid-sized groups balancing intra-group competition with predation protection. Humpback dolphins (Sousa sp.) appear to fit this pattern, with some site fidelity over relatively large ranges. They display fluid associations with other individuals. Predation pressure is not sufficiently high to cause large groups to form, and individuals probably reduce predation pressure more by hiding whenever possible. This pattern is likely to prevent the formation of long-term complex bonds. In contrast, killer whales (Orcinus orca) also display intermediate-ranging patterns, but have extremely strong social bonds within familial groups. Cooperative and altruistic behaviour in killer whales facilitate the formation of life-long bonds, similar to those observations in sperm whales (Physeter macrocephalus) and elephants (Loxodonta africana). This conceptual framework remains largely untested, and for many species it is not currently possible to describe ranging behaviours, anti-predator tactics or social behaviour in sufficient detail for appropriate examination of these ideas. Few studies on dolphins have been conducted to explicitly test this type of framework; however, existing observations of delphinid social strategies and communities are used throughout this chapter to examine this framework. Additionally, we anticipate that the present framework may provide a starting point to test hypotheses regarding the evolution of social strategies of delphinids.

Radiofrequency ablation versus hepatic resection for the treatment of hepatocellular carcinomas 2 cm or smaller: a retrospective comparative study. To compare retrospectively the effects of percutaneous radiofrequency (RF) ablation with those of hepatic resection in the treatment of hepatocellular carcinoma (HCC) measuring 2 cm or smaller. This study was approved by the institutional ethics committee, and all patients provided written informed consent before treatment. From December 2003 to December 2008, 145 patients with a resectable HCC measuring 2 cm or smaller were studied. Sixty-six patients had a central HCC (located at least 3 cm from the liver capsule). As an initial treatment, 71 patients were treated with percutaneous RF ablation and 74 with surgical resection. Of the patients with central HCC, 37 underwent percutaneous RF ablation and 29 underwent surgical resection. Survival curves were constructed with the Kaplan-Meier method and compared by using the log-rank test. The relative prognostic significance of the variables for predicting overall survival rates was assessed with multivariate Cox proportional hazards regression analysis. Complications were observed clinically when patients were admitted and assessed by telephone interview after patients were discharged. One death was considered to be related to treatment after surgical resection. Major complications occurred significantly more often in the surgical resection group (38 of 74 patients) than in the RF ablation group (14 of 71 patients) (P = .009). The 1-, 3-, and 5-year overall survival rates were 98.5%, 87.7%, and 71.9%, respectively, with RF ablation and 90.5%, 70.9%, and 62.1% with surgical resection (P = .048). The corresponding recurrence-free survival rates were 76.4%, 65.2%, and 59.8% with RF ablation and 75.6%, 56.1%, and 51.3% with surgical resection (P = .548). At subgroup analysis of patients with central HCC, 1-, 3-, and 5-year overall survival rates were 96.6%, 93.0%, and 79.9% with RF ablation and 92.0%, 71.6%, and 61.5% with surgical resection (P = .020). The corresponding recurrence-free survival rates were 86.5%, 74.0%, and 67.0% with RF ablation and 68.0%, 40.0%, and 40.0% with surgical resection (P = .033). For patients with peripheral HCC, 1-, 3-, and 5-year overall survival rates were 97.3%, 83.3%, and 65.1% with RF ablation and 87.8%, 68.4%, and 62.9% with surgical resection (P = .464). The corresponding recurrence-free survival rates were 68.7%, 59.2%, and 54.9% with RF ablation and 82.9%, 66.6%, and 52.9% with surgical resection (P = .351). The efficacy and safety of percutaneous RF ablation were better than those of surgical resection in patients with HCC measuring 2 cm or smaller, especially those with central HCC.

Impact of suprarenal neck angulation on endovascular aneurysm repair outcomes. Hostile infrarenal proximal neck (β) anatomy of abdominal aortic aneurysm has been associated with increased risk of aneurysm-related complications after endovascular aneurysm repair (EVAR). However, there is a paucity of literature addressing the suprarenal angle (α). The aim of this study was to evaluate short- and long-term outcomes after EVAR in patients with severe suprarenal neck angulation (α >60 degrees). A retrospective review of the medical records of 561 patients who underwent EVAR between January 2005 and December 2017 was performed. The main exclusion criteria were preoperative aneurysm rupture and fenestrated or branched endograft placement. High-resolution computed tomography images of 452 patients were available. Patients were grouped into angulated (α >60 degrees) and nonangulated (α ≤60 degrees) groups. The primary end point was freedom from type IA endoleak. Secondary end points included 30-day mortality, long-term survival, primary clinical success, and freedom from aneurysm rupture and graft migration. Primary clinical success was defined according to Society for Vascular Surgery guidelines as clinical success without the need for an additional or secondary surgical or endovascular procedure. Of 452 patients, 45 (10%) were included in the angulated group (α >60 degrees). Median follow-up time was 34 months (interquartile range, 14-56 months). Compared with patients in the nonangulated group, those in the angulated group had larger neck diameter at the level of the renal arteries (mean [standard deviation], 25.6 [3.8] mm vs 24.6 [3.4] mm; P = .06) and increased β angle (mean [standard deviation], 50.5 [22.9] degrees vs 41.6 [23.9] degrees; P = .01). The 3-year freedom from type IA endoleak estimate was 80.2% for the angulated group compared with 97.8% for the nonangulated group (P < .001). The angulated group showed significantly higher 30-day mortality (11.1% vs 0.25%; P < .001).The 3-year results showed that patients in the nonangulated group had higher rates of primary clinical success (90.2% vs 67.1%; P < .001), freedom from rupture (99% vs 97.1%; P = .02), freedom from migration (100% vs 92.4%; P < .001), and long-term survival (91.6% vs 75.8%; P = .006) compared with those in the angulated group. After adjustment for age, sex, neck diameter, and β angle, severe suprarenal neck angulation was associated with higher odds of type IA endoleak (adjusted hazard ratio, 8.9; 95% confidence interval [CI], 2.9-27), loss of primary clinical success (adjusted hazard ratio, 4.8; 95% CI, 2.6-8.9), and 30-day mortality (adjusted odds ratio, 52.5; 95% CI, 5.3-514) compared with α ≤60 degrees (all P < .001). This is the first report to show a significant increase in operative mortality in patients undergoing EVAR with severely angulated suprarenal neck. Patients who survive the operation are at increased risk of secondary interventions. These findings suggest that EVAR should be used with caution in patients with severe α angulation and underpin the role of close follow-up in this particular population.