Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia.
Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders.


Carotenoid functions in photoprotection and cancer prevention.
Carotenoid pigments in in vitro and in vivo systems are able to quench excited species, such as singlet oxygen and free radicals. The U.S. Food and Drug Administration has approved beta-carotene for use in humans for prevention of the photosensitivity associated with the orphan disease, erythropoietic protoporphyria. Although the usual adult dose used is 180 mg/day, intake up to 300 mg/day is allowed. No serious toxicity to beta-carotene has been reported. Carotenoids have demonstrated some anticancer activity in certain animals. Clinical trials in populations at high risk for developing certain types of cancer are presently underway, using doses of beta-carotene ranging from 15 to 50 mg/day, or much lower doses than used for photosensitivity prevention. There is no way of predicting which dose will be effective in preventing cancer: The lower doses were chosen to avoid development of marked carotenodermia; they are sufficient to cause an increase in the serum carotenoid level but may, occasionally, in individuals, cause the development of some degree of carotenodermia. This article reviews development of the use of beta-carotene for preventing photosensitivity in humans, studies investigating the anticancer properties of the carotenoids, and studies aimed at understanding how the carotenoids exert their protective functions.


Low Transvalvular Flow Rate in Patients Undergoing Transcatheter Aortic Valve Implantation (TAVI) Is a Predictor of Mortality: The TFR-TAVI Study.
Transvalvular flow rate (TFR) represents a better reflection of transvalvular flow than the stroke volume index (SVi), and has recently emerged as a useful prognostic tool in patients undergoing surgical aortic valve replacement. There is a paucity of data investigating the role of TFR and its relationship with other clinical or echocardiographic factors in patients undergoing transcatheter aortic valve implantation (TAVI). This was a retrospective single-centre study of 629 consecutive patients who underwent TAVI between March 2009 and September 2020. Pre-TAVI low TFR was defined as <200 c/s. The primary study end point was all-cause mortality. Low TFR was observed in 41.8% (263/629) of included patients and was associated with increasing age, low body surface area, hypertension, diabetes, atrial fibrillation, left ventricular (LV) dysfunction, and significant mitral regurgitation. LV function status and severity of aortic valve disease were independent predictors of low TFR. Low TFR was significantly associated with long-term all-cause mortality even after adjustment for other risk factors (adjusted hazard ratio [aHR] 1.44; 95% confidence interval [CI] 1.02-2.03; p=0.038). When data were stratified according to SVi, low TFR was an independent predictor of long-term all-cause mortality in patients with normal SVi (aHR 1.98; 95% CI 1.06-3.69; p=0.032) but not in patients with low SVi (HR 1.23; 95% CI 0.71-2.11; p=0.46; p=0.016 for interaction). Low TFR is common in patients undergoing TAVI and is an independent predictor of all-cause mortality, particularly in patients with normal SVi.


Polymorphisms in the GluR2 gene are not associated with amyotrophic lateral sclerosis.
Excitotoxicity is thought to play a pathogenic role in amyotrophic lateral sclerosis (ALS). Excitotoxic motor neuron death is mediated through the Ca(2+)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type of glutamate receptors and Ca(2+) permeability is determined by the GluR2 subunit. We investigated whether polymorphisms or mutations in the GluR2 gene (GRIA2) predispose patients to ALS. Upon sequencing 24 patients and 24 controls no nonsynonymous coding variants were observed but 24 polymorphisms were identified, 9 of which were novel. In a screening set of 310 Belgian ALS cases and 794 healthy controls and a replication set of 3157 cases and 5397 controls from 6 additional populations no association with susceptibility, age at onset, or disease duration was observed. We conclude that polymorphisms in the GluR2 gene (GRIA2) are not a major contributory factor in the pathogenesis of ALS.


Endobronchial ultrasound-guided transbronchial biopsy and brushing: a comparative evaluation for the diagnosis of peripheral pulmonary lesions.
The diagnosis of peripheral pulmonary lesions (PPLs) often involves endobronchial ultrasound (EBUS)-guided transbronchial biopsy (TBB), washing and brushing. Certain echoic features of PPL have been associated with biopsy yield. This study compared yields of TBB and bronchial washing (TBBW) with those of TBBW plus bronchial brushing and analysed the associations between clinical and echoic features and yield. We performed a retrospective review of 271 patients undergoing TBB for PPL. TBBW was performed in 139 patients and 132 underwent TBBW plus brushing. The diagnostic yield of TBBW plus brushing was superior to that of TBBW (80.3 vs 66.2%, P < 0.01). In TBBW patients, lesions <3 cm (57.1 vs 73.7%, P < 0.05), EBUS probe adjacent to the lesion (47.6 vs 74.2%, P < 0.01), continuous margin (56.5 vs 75.7%, P < 0.01) and homogeneous echogenicity (51.0 vs 75.0%, P < 0.01) predicted lower yields, but adding bronchial brushing rendered the diagnostic yields similar, irrespective of EBUS echoic features, leaving lesion size of <3 cm (odds ratio 2.81; 95% confidence interval 1.08-7.31, P < 0.05) as the single independent predictor of lower yield by multivariate regression analysis. TBB plus brushing was not inferior to TBBW plus brushing (78.8 vs 80.3%, P = 0.88). Bronchial brushing boosted diagnostic yields, particularly for PPLs with echoic features previously associated with a reduced biopsy yield.


Multiparametric cell cycle analysis by automated microscopy.
Cell cycle analysis using flow cytometry (FC) to measure cellular DNA content is a common procedure in drug mechanism of action studies. Although this technique lends itself readily to cell lines that grow in suspension, adherent cell cultures must be resuspended in a cumbersome and potentially invasive procedure that normally involves trypsinization and mechanical agitation of monolayer cultures. High-content analysis (HCA), an automated microscopy-based technology, is well suited to analysis of monolayer cell cultures but provides intrinsically less accurate determination of cellular DNA content than does FC and thus is not the method of choice for cell cycle analysis. Using Cellomics's ArrayScan reader, the authors have developed a 4-color multiparametric HCA approach for cell cycle analysis of adherent cells based on detection of DNA content (4,6-diamidino-2-phenylindole [DAPI] fluorescence), together with the known cell cycle markers bromo-2-deoxyuridine (BrdU) incorporation, cyclin B1 expression, and histone H3 (Ser28) phosphorylation within a single cell population. Considering all 4 markers together, a reliable and accurate quantification of cell cycle phases was possible, as compared with flow cytometric analysis. Using this assay, specific cell cycle blocks induced by treatment with thymidine, paclitaxel, or nocodazole as test drugs were easily monitored in adherent cultures of U-2 OS osteosarcoma cells.


Generation of Islet-like Cell Aggregates from Human Adipose Tissue-derived Stem Cells by Lentiviral Overexpression of PDX-1.
Pancreatic duodenal homeobox1 (PDX-1) is a transcription factor that is important in regulating pancreas development and maintaining β-cell function. β-cell replacement is an effective approach for the treatment of type 1 diabetes. Human adipose-mesenchymal stem cells (hAMSCs) are the ideal population cells for differentiating into insulin-producing cells. To determine if islet-like cell aggregates production could be generated from hAMSCs by lentiviral overexpression of PDX-1. After isolation of hAMSCs, characteristics of these cells were identified by flow-cytometic analysis and multilineage differentiation studies. PDX-1 gene delivered into hAMSCs through lentiviral vector for differentiating hAMSCs into insulin-producing cells (IPCs) at the utilized protocol for 14 days. Characteristics of IPCs were evaluated by immunocytofluorescence, dithizone staining, and quantitative reverse transcription PCR. In response to high glucose medium, insulin release was detected by chemiluminescence enzyme immunoassay. The islet-like cell aggregates appeared about 10 days after introduction of PDX-1 into hAMSCs. PDX-1 induced its own expression (auto-induction), a number of islet-related genes such as Ngn3, Nkx2-2, and insulin. The insulin-positive cells were detected in the PDX-1 transduced cells. In response to glucose challenge test, secretion of insulin hormone in the medium with high glucose concentration significantly increased in the PDX-1-transduced cells related to medium with low glucose concentration. Introduction of lentiviral PDX-1 significantly induces hAMSCs to differentiate into islet-like cell aggregates, which may provide a source of adipose stem cells-derived insulin-producing cells for cell replacement therapy in type 1 diabetes.


[Drug treatment of hypertrophic cardiomyopathy].
Both, beta-receptor blocking agents and calcium-antagonists have been proven to be very effective in the treatment of idiopathic hypertrophic cardiomyopathy. In the vast majority of patients they lead to a significant reduction of the predominant clinical symptoms--angina and dyspnea--or even abolish them. Since beta-blockers primarily act on the contractile behaviour of the left ventricle they are especially suited in the obstructive form of the disease where they reduce outflow tract obstruction. In contrast, calcium-antagonists seem to mainly influence diastolic muscle mechanics by increasing diastolic distensibility, and thus may be indicated in the nonobstructive forms of hypertrophic cardiomyopathy. In cases with severe, life-threatening arrhythmias especially if associated with syncope, an antiarrhythmic therapy is mandatory.


A Comparison of Dynamics in Two Models for the Spread of a Vector-Borne Disease.
In 2007, bluetongue virus (BTV) was introduced to both Denmark (DK) and the United Kingdom (UK). For this reason, simulation models were built to predict scenarios for future incursions. The DK and UK models have a common description of within-herd dynamics, but differ greatly in their descriptions of between-herd spread, one using an explicit representation of vector dispersal, the other a transmission kernel. Here, we compare model predictions for the dynamics of bluetongue in the UK, based on the 2007 incursion and vaccination rollout in 2008. We demonstrate how an agent-based model shows greater sensitivity to the level of vaccine uptake and has lower variability compared with a kernel-based model. However, a model using a transmission kernel requires less detailed data and is often faster.


[Jejunal secretion of immunoglobulins and secretory component in three patients with primitive humoral immunoglobulin deficiency].
Jejunal secretion of albumin, immunoglobulins and secretory component was studied using the segmental perfusion technique with an occluding balloon, in two patients with common variable hypogammaglobulinemia and one patient with selective immunoglobulin A deficiency. Results were compared with those of twenty-two controls previously studied under the same conditions. In all three cases, jejunal secretion rate of immunoglobulin A was nil and secretion rates of albumin and immunoglobulin G were increased as compared to controls. Jejunal secretion rate of immunoglobulin M was increased in the patient with selective immunoglobulin A deficiency, normal in one case of common variable hypogammaglobulinemia and almost nil in the other case. Secretory component was secreted in the jejunal lumen mostly or exclusively under a free form depending on partial or total absence of immunoglobulin A and M. This study allowed to confirm in vivo that secretion of secretory component is independent of the presence of immunoglobulins. Intestinal perfusion might be a useful tool in the investigation of immunological diseases of the intestinal tract.


Happiness is pleasant, or is it? Implicit representations of affect valence are associated with contrahedonic motivation and mixed affect in daily life.
People typically want to feel good. At times, however, they seek to maintain or enhance negative affect or to dampen positive affect. The prevalence of such contrahedonic motivation has been related to simultaneous experiences of positive and negative (i.e., mixed) affect. We investigated the role that implicit mental representations of affect valence may play in this regard in a study with N = 400 participants aged 11-88 years. Results demonstrated the age-fairness and reliability of the affect-valence Implicit Association Test, a newly developed implicit measure of interindividual differences in mental representations of affect valence. The older participants were, the more distinctively they implicitly associated happiness with pleasantness and/or unhappiness with unpleasantness. Participants furthermore carried mobile phones as assessment instruments with them for 3 weeks while pursuing their daily routines. The phones prompted participants on average 54 times to report their momentary affective experience and affect-regulation motivation. Contrahedonic motivation and mixed affect were most prevalent among adolescents and least prevalent among older adults, and thus showed a similar pattern of age differences as the affect-valence Implicit Association Test. Furthermore, the more distinctive participants' implicit associations of happiness with pleasantness, and/or unhappiness with unpleasantness, the less likely participants were to report contrahedonic motivation and mixed affect in their daily lives. These findings contribute to a refined understanding of the mixed-affect perspective on contrahedonic motivation by demonstrating the respective role of implicit affect-valence representations.


Riboflavin Deficiency-Implications for General Human Health and Inborn Errors of Metabolism.
As an essential vitamin, the role of riboflavin in human diet and health is increasingly being highlighted. Insufficient dietary intake of riboflavin is often reported in nutritional surveys and population studies, even in non-developing countries with abundant sources of riboflavin-rich dietary products. A latent subclinical riboflavin deficiency can result in a significant clinical phenotype when combined with inborn genetic disturbances or environmental and physiological factors like infections, exercise, diet, aging and pregnancy. Riboflavin, and more importantly its derivatives, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), play a crucial role in essential cellular processes including mitochondrial energy metabolism, stress responses, vitamin and cofactor biogenesis, where they function as cofactors to ensure the catalytic activity and folding/stability of flavoenzymes. Numerous inborn errors of flavin metabolism and flavoenzyme function have been described, and supplementation with riboflavin has in many cases been shown to be lifesaving or to mitigate symptoms. This review discusses the environmental, physiological and genetic factors that affect cellular riboflavin status. We describe the crucial role of riboflavin for general human health, and the clear benefits of riboflavin treatment in patients with inborn errors of metabolism.


Mitotic activity index and CD25+ lymphocytes predict risk of stage progression in non-muscle invasive bladder cancer.
In urothelial cell type non-muscle invasive urinary bladder carcinoma, TNM stage and WHO grade are widely used to classify patients into low and high‑risk groups for prognostic and therapeutic decision-making. However, stage and grade reproducibility and prediction accuracy are wanting. This may lead to suboptimal treatment. We evaluated whether proliferation features, nuclear area of the epithelial cancer cells and the composition of stromal and tumor infiltrating lymphocytes have independent prognostic value. In 183 primary non-muscle invasive bladder cancer patients with long follow-up (median for stage progression cohort: 119 months, range 5-173; median for tumor recurrence cohort: 82, range 3-165) proliferation features Ki67, PPH3 and Mitotic Activity Index (MAI), Mean Nuclear Area (MNA), lymphocyte subsets (CD8+, CD4+, CD25+) and plasma cells (CD138+) were assessed on consecutive sections. Post-resection instillation treatments (none, mitomycin, BCG) were strictly standardized during the intake period. Risk of recurrence was associated with expression of Ki67 (≤ 39 vs. > 39) and Multifocality (p = 0.01). Patients with low Ki67 had a higher recurrence rate than those with high Ki67. Lymphocyte composition did not predict recurrence. Stage progression was strongly associated with high values for MAI (>15) and CD25+ (>0.2%). In a multivariate analysis the combination of MAI and CD25+ was the single most prognostic feature (p<0.001). Validation of these results in additional, independent studies is warranted.


Acute biological effects of simulating the whole-body radiation dose distribution from a solar particle event using a porcine model.
In a solar particle event (SPE), an unshielded astronaut would receive proton radiation with an energy profile that produces a highly inhomogeneous dose distribution (skin receiving a greater dose than internal organs). The novel concept of using megavoltage electron-beam radiation to more accurately reproduce both the total dose and the dose distribution of SPE protons and make meaningful RBE comparisons between protons and conventional radiation has been described previously. Here, Yucatan minipigs were used to determine the effects of a superficial, SPE-like proton dose distribution using megavoltage electrons. In these experiments, dose-dependent increases in skin pigmentation, ulceration, keratinocyte necrosis and pigment incontinence were observed. Five of 18 animals (one each exposed to 7.5 Gy and 12.5 Gy radiation and three exposed to 25 Gy radiation) developed symptomatic, radiation-associated pneumonopathy approximately 90 days postirradiation. The three animals from the highest dose group showed evidence of mycoplasmal pneumonia along with radiation pneumonitis. Moreover, delayed-type hypersensitivity was found to be altered, suggesting that superficial irradiation of the skin with ionizing radiation might cause immune dysfunction or dysregulation. In conclusion, using total doses, patterns of dose distribution, and dose rates that are compatible with potential astronaut exposure to SPE radiation, animals experienced significant toxicities that were qualitatively different from toxicities previously reported in pigs for homogeneously delivered radiation at similar doses.


Exercise-based cardiac rehabilitation for adults after heart valve surgery.
Exercise-based cardiac rehabilitation may benefit heart valve surgery patients. We conducted a systematic review to assess the evidence for the use of exercise-based intervention programmes following heart valve surgery. To assess the benefits and harms of exercise-based cardiac rehabilitation compared with no exercise training intervention, or treatment as usual, in adults following heart valve surgery. We considered programmes including exercise training with or without another intervention (such as a psycho-educational component). We searched: the Cochrane Central Register of Controlled Trials (CENTRAL); the Database of Abstracts of Reviews of Effects (DARE); MEDLINE (Ovid); EMBASE (Ovid); CINAHL (EBSCO); PsycINFO (Ovid); LILACS (Bireme); and Conference Proceedings Citation Index-S (CPCI-S) on Web of Science (Thomson Reuters) on 23 March 2015. We handsearched Web of Science, bibliographies of systematic reviews and trial registers (ClinicalTrials.gov, Controlled-trials.com, and The World Health Organization International Clinical Trials Registry Platform). We included randomised clinical trials that investigated exercise-based interventions compared with no exercise intervention control. The trial participants comprised adults aged 18 years or older who had undergone heart valve surgery for heart valve disease (from any cause) and received either heart valve replacement, or heart valve repair. Two authors independently extracted data. We assessed the risk of systematic errors ('bias') by evaluation of bias risk domains. Clinical and statistical heterogeneity were assessed. Meta-analyses were undertaken using both fixed-effect and random-effects models. We used the GRADE approach to assess the quality of evidence. We sought to assess the risk of random errors with trial sequential analysis. We included two trials from 1987 and 2004 with a total 148 participants who have had heart valve surgery. Both trials had a high risk of bias.There was insufficient evidence at 3 to 6 months follow-up to judge the effect of exercise-based cardiac rehabilitation compared to no exercise on mortality (RR 4.46 (95% confidence interval (CI) 0.22 to 90.78); participants = 104; studies = 1; quality of evidence: very low) and on serious adverse events (RR 1.15 (95% CI 0.37 to 3.62); participants = 148; studies = 2; quality of evidence: very low). Included trials did not report on health-related quality of life (HRQoL), and the secondary outcomes of New York Heart Association class, left ventricular ejection fraction and cost. We did find that, compared with control (no exercise), exercise-based rehabilitation may increase exercise capacity (SMD -0.47, 95% CI -0.81 to -0.13; participants = 140; studies = 2, quality of evidence: moderate). There was insufficient evidence at 12 months follow-up for the return to work outcome (RR 0.55 (95% CI 0.19 to 1.56); participants = 44; studies = 1; quality of evidence: low). Due to limited information, trial sequential analysis could not be performed as planned. Our findings suggest that exercise-based rehabilitation for adults after heart valve surgery, compared with no exercise, may improve exercise capacity. Due to a lack of evidence, we cannot evaluate the impact on other outcomes. Further high-quality randomised clinical trials are needed in order to assess the impact of exercise-based rehabilitation on patient-relevant outcomes, including mortality and quality of life.


Clinical evaluation of the effect of a hydrogen peroxide mouth rinse, sodium bicarbonate dentifrice, and mouth moisturizer on oral health.
The objective of this 60-day single-blind, parallel trial, using 150 subjects, was to evaluate the effect of a 20% sodium bicarbonate dentifrice, a 1.5% hydrogen peroxide solution and a mouth moisturizer on oral tissues and microflora. Subjects were randomly assigned to one of five groups. The treatments were: 1) Sage dentifrice (sodium bicarbonate). Toothette Plus containing baking soda saturated with the hydrogen peroxide solution and use of a mouth moisturizer, 2) Crest dentifrice, Toothette Plus containing baking soda saturated with the hydrogen peroxide solution and use of a mouth moisturizer, 3) Crest dentifrice, Toothette Plus containing baking soda with a control solution and no mouth moisturizer, 4) Crest dentifrice, Toothette (without baking soda), saturated with a control solution and no mouth moisturizer, and 5) Crest dentifrice, Toothette saturated with 1.5% flavored H2O2 and no mouth moisturizer. From a subgroup of 35 patients (seven from each group) buccal smears for exfoliative cytology were taken as were supragingival microbiological samples from the mesial aspect of first molars (pooled). Buccal smears were evaluated for signs of histopathological changes. Microbiological samples from supra- and subgingival plaque for P. gingivalis, P. intermedia, A. actinomycetemcomitans. A viscosus, F. nucleatum, F. sanguis and C. albicans were evaluated. Clinical parameters measured were a stain index (SI), the modified gingival index (MGI), and a plaque index (PI). There were no adverse changes in the oral microflora and no anaplastic or other pathological changes in any subjects. Clinical parameters showed a statistically significant reduction in the MGI ranging from 26.7-29.9% with no significant differences among the groups (p > 0.05). The PI showed small reductions in all groups except group 2, but the differences were not statistically significant from each other or baseline (p > 0.05). The SI revealed slight increases in all groups and no differences among the groups. It can be concluded that use of Sage dentifrice, Toothette Plus saturated with Perox-A-Mint and Sage Mouth Moisturizer are safe to oral tissues. Using these components did not result in clinically noticeable stain formation, promote plaque formation, or produce any significant adverse changes in the oral microflora.


Disruption of the ovarian follicle reservoir of prepubertal rats following prenatal exposure to a continuous 900-MHz electromagnetic field.
The effects on human health of electromagnetic field (EMF) have begun to be seriously questioned with the entry into daily life of devices establishing EMF, such as cell phones, wireless fidelity, and masts. Recent studies have reported that exposure to EMF, particularly during pregnancy, affects the developing embryo/fetus. The aim of this study was therefore to examine the effects of exposure to continuous 900-Megahertz (MHz) EMF applied in the prenatal period on ovarian follicle development and oocyte differentiation. Six pregnant Sprague Dawley rats were divided equally into a non-exposed control group (CNGr) and a group (EMFGr) exposed to continuous 900-MHz EMF for 1 h daily, at the same time every day, on days 13-21 of pregnancy. New groups were established from pups obtained from both groups after birth. One group consisting of female pups from CNGr rats was adopted as newborn CNGr (New-CNGr, n = 6), and another group consisting of female pups from EMFGr rats was adopted as newborn EMFGr (New-EMFGr, n = 6). No procedure was performed on New-CNGr or New-EMFGr rats. All rat pups were sacrificed on the postnatal 34th day, and their ovarian tissues were removed. Follicle count, histological injury scoring and morphological assessment with apoptotic index criteria were performed with sections obtained following routine histological tissue preparation. Follicle count results revealed a statistically significant decrease in primordial and tertiary follicle numbers in New-EMFGr compared to New-CNGr (p < 0.05), while atretic follicle numbers and apoptotic index levels increased significantly (p < 0.05). Histopathological examination revealed severe follicle degeneration, vasocongestion, a low level of increased stromal fibrotic tissue and cytoplasmic vacuolization in granulosa cell in New-EMFGr. Prenatal exposure to continuous 900-MHz EMF for 1 h each day from days 13-21 led to a decrease in ovarian follicle reservoirs in female rat pups at the beginning of the prepubertal period.


Late recovery after traumatic, anoxic, or hemorrhagic long-lasting vegetative state.
Late recovery of awareness in vegetative state (VS) is considered as an exceptional outcome, and has been reported prevalently after traumatic brain injury (TBI). The present prospective study aimed to verify frequency of late recovery (later than 1 year postonset in TBI and 3 months postonset in patients without TBI) of responsiveness and consciousness in traumatic and nontraumatic long-lasting (more than 6 months after onset) VS. Fifty inpatients with long-lasting VS (36% TBI, 36% hemorrhagic, and 28% anoxic) were enrolled and followed up for a mean of 25.7 months from onset (5 patients for more than 4 years). Level of responsiveness and functional disability were evaluated by means of validated scales (Coma Recovery Scale-Revised and Disability Rating Scale). At the end of the study, 21 patients (42%) had died, 17 patients (34%) were in VS, and 2 patients with TBI (4%) had recovered responsiveness within 12 months postonset. The remaining 10 (20%) patients with TBI and patients without TBI showed late recovery of responsiveness; 6 of them (12%) further progressed to consciousness. Late recovery was significantly associated with younger age and was relatively more frequent in TBI. Functional abilities were severely impaired in all patients. This clinical study demonstrates that late recovery of responsiveness and consciousness is not exceptional in patients with traumatic and nontraumatic VS, although with residual severe disability.


Induction of heat shock protein 70 in the rat brain following intracisternal infusion of autologous blood: evaluation of acute neuronal damage.
Investigation into a potential treatment for the acute period following onset of spontaneous subarachnoid hemorrhage (SAH) is hampered by the lack of a standardized experimental model. For that purpose the authors elaborated on a small-animal model in which computer-controlled intracisternal blood infusion is used and investigated whether this model can reliably reproduce acute neuronal injury after SAH. Whole autologous blood (blood-infused group) or isotonic saline (control group) was infused into the cisterna magna or olfactory cistern of rats. The infusions decreased exponentially during a 5-minute period. Throughout the infusion period, intracranial pressure (ICP) was monitored. Neuronal injury was quantified by observing tissue immunoreactivity to a 70-kD heat shock protein (HSP70) and comparing this with the tissue's reaction to hematoxylin and eosin staining. On Days 1, 3, and 5, the CA1, CA3, and dentate gyrus regions of the hippocampus were analyzed, respectively. During saline infusion ICP increased within seconds beyond 80 mm Hg and afterward decreased in accordance with the infusion rate. During the infusion of blood, the same initial pressure peak was found, but the ICP remained increased beyond this pressure level throughout the 5-minute infusion period. The HSP70 immunoreactivity in the saline-infused group was found only on Day 1 in the CA1 region and the dentate gyrus, but not in the CA3. After injection of whole blood, there was HSP70-positive staining in the CA1, CA3, and dentate gyrus regions throughout the observation period. The controlled cisternal infusion of blood caused neuronal injury that resembled that of previous experimental models that produce SAH by rupture of intracranial vessels with endovascular techniques. Unlike those experiments, the intracisternal infusion technique presented by the authors provides more standardized bleeding with regard to ICP, the volume of subarachnoid blood, and the extent of acute cellular injury.


[Candida esophagitis in an immunocompetent women. A case report].
Candida esophagitis (CE) is one of the invasive infections caused by Candida albicans (CA). Its prevalence diagnosed by upper endoscopy ranges between 0.77-2.4%. Its main cause is CA. CE more often affects immunocompromised people, however it may affect healthy people too. CE requires systemic antifungal therapy. We report a case of a CE in a healthy woman who presented good response to prescribed treatment. Omeprazole might be involved in the development of her CE.


How "healthy" should children be when selecting reference samples for spirometry?
How "healthy" do children need to be when selecting reference samples for spirometry? Anthropometry and spirometry were measured in an unselected, multi-ethnic population of school children aged 5-11 years in London, UK, with follow-up assessments 12 months later. Parents provided information on children's birth data and health status. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were adjusted for sex, age, height and ethnicity using the 2012 Global Lungs Initiative equations, and the effects of potential exclusion criteria on the z-score distributions were examined. After exclusions for current and chronic lung disease, acceptable data were available for 1901 children on 2767 occasions. Healthy children were defined as those without prior asthma or hospitalisation for respiratory problems, who were born at full-term with a birthweight ≥2.5 kg and who were asymptomatic at testing. Mean±sd z-scores for FEV1 and FVC approximated 0±1, indicating the 2012 Global Lungs Initiative equations were appropriate for this healthy population. However, if children born preterm or with low birthweight, children with prior asthma or children mildly symptomatic at testing were included in the reference, overall results were similar to those for healthy children, while increasing the sample size by 25%. With the exception of clear-cut factors, such as current and chronic respiratory disease, paediatric reference samples for spirometry can be relatively inclusive and hence more generalisable to the target population.


Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis.
Pain due to pancreatic cancer/PCa or chronic pancreatitis/CP, is notoriously resistant to the strongest pain medications. Here, we aimed at deciphering the specific molecular mediators of pain at surgical-stage pancreatic disease and to discover novel translational targets. We performed a systematic, quantitative analysis of the neurotransmitter/neuroenzmye profile within intrapancreatic nerves of CP and PCa patients. Ex vivo neuronal cultures treated with human pancreatic extracts, conditional genetically engineered knockout mouse models of PCa and CP, and the cerulein-induced CP model were employed to explore the therapeutic potential of the identified targets. We identified a unique enrichment of neuronal nitric-oxide-synthase (nNOS) in the pancreatic nerves of CP patients with increasing pain severity. Employment of ex vivo neuronal cultures treated with pancreatic tissue extracts of CP patients, and brain-derived-neurotrophic-factor-deficient (BDNF+/-) mice revealed neuronal enrichment of nNOS to be a consequence of BDNF loss in the progressively destroyed pancreatic tissue. Mechanistically, nNOS upregulation in sensory neurons was induced by tryptase secreted from perineural mast cells. In a head-to-head comparison of several genetically induced, painless mouse models of PCa (KPC, KC mice) or CP (Ptf1a-Cre;Atg5fl/fl) against the hypersecretion/cerulein-induced, painful CP mouse model, we show that a similar nNOS enrichment is present in the painful cerulein-CP model, but absent in painless genetic models. Consequently, mice afflicted with painful cerulein-induced CP could be significantly relieved upon treatment with the specific nNOS inhibitor NPLA. We propose nNOS inhibition as a novel strategy to treat the unbearable pain in CP. FUND: Deutsche Forschungsgemeinschaft/DFG (DE2428/3-1 and 3-2).


The effect of tailor-made information on vitamin D status of immigrant mothers in Norway: a cluster randomized controlled trial.
A high prevalence of vitamin D deficiency has been reported in non-Western immigrants in Norway. Our objective was to test whether written information about how to improve vitamin D status could improve the vitamin D status in immigrants mothers attending child health clinics. In this cluster randomized controlled trial in eight child health clinics in Oslo, mothers aged 18-43 years with Pakistani, Turkish, or Somali background were included when their infants were 6 weeks old. The public health nurses gave the intervention group a brochure with information on how to improve vitamin D status, written in their native language. They were compared with a control group receiving usual care, consisting of oral information only. The principal outcome measure was increase in serum 25-hydroxyvitamin D [s-25(OH) D] in mothers 7 weeks later. Forty-four mothers completed the study. Mean baseline s-25(OH) D was 29.1 (14.8) nmol l(-1) in the intervention and 19.4 (9.2) in the control group. There was no significant increase in s-25(OH) D from baseline to follow-up in the intervention [6.3 (95%CI: -1.9, 14.4) nmol l(-1) )] or in the control group [2.9 (95% CI [confidence interval]: -1.2, 7.0) nmol l(-1) ]. When adjusting for baseline s-25(OH) D concentration the mean difference in increase between the intervention and control group was 1.4 (95% CI: -18.7, 21.4) nmol l(-1) (P = 0.87). Adjustment for ethnicity, season and mother's educational background did not alter the results. In sum, providing immigrant mothers with written information about how to improve their vitamin D status did not have an effect on the mothers' vitamin D status.


Seroprevalence of transfusion transmitted infections in healthy blood donors: A 5-year Tertiary Care Hospital experience.
Transfusion transmitted infections (TTIs) can cause threat to bloody safety as blood transfusion is an important mode of transmission of TTI to the recipient, hence, to prevent transmission of these diseases, screening tests on blood bags is an important step for blood safety. This study was undertaken with the aim of determining the seroprevalence of TTI in healthy blood donors in a tertiary care blood bank. A retrospective study was carried out over a period of 5 years from January 2007 to December 2011. Serum samples were screened for hepatitis B surface antigen (HBsAg), antibodies to human immunodeficiency virus (HIV) Type 1 and 2, hepatitis c virus (HCV) and syphilis using enzyme-linked immunosorbent assays with the third generation kits and venereal disease research laboratory test, respectively. A total of 76,653 healthy donors were included out of which majority of donors were male (91.79%). The overall seroprevalence of HIV, HBsAg, HCV, and syphilis were 0.26%, 1.30%, 0.25%, and 0.28%, respectively. Methods to ensure a safety blood supply should be encouraged. For that, screening with a better selection of donors and use of sensitive screening tests including nucleic acid testing technology should be implemented.


Cancer control and the older person. Issues in treatment.
The Committee on Treatment acknowledged the paucity of information related to the management of cancer in older patients and identified short-term and long-term efforts to study these issues. Short-term efforts should focus on effects of cancer and cancer treatment on survival and quality of life, efficacy and toxicity of antineoplastic therapy, barriers to adequate treatment, alternative settings of cancer care, and special supportive care needs. Long-term efforts should focus on unique features of cancer in older patients, long-term effects of cancer and cancer treatment, and prevention and detection of new primary malignancies. The Committee recognized that our recent advances in cancer treatment including palliative surgery, limited surgery, radiosurgery, and antidotes to drug toxicity may improve the tolerance of antineoplastic therapy by older patients and be beneficial in terms of survival and quality of life.


Impact of three-dimensional chemoradiation on pelvic bone mineral density, low back pain, and disability in cervical cancer: a prospective study.
To prospectively analyze the effect of three-dimensional chemoradiation on the bone mineral density of pelvic bones and its association with low back pain and disability in patients with locally advanced cervical cancer. In biopsy proven locally advanced cervical cancer patients, bone mineral density and T scores for lumbar vertebrae 5, dorsal thoracic vertebrae 12, and T scores for the femoral neck were analyzed. Low back pain was scored using the visual analog scale while disability scoring was done using the Oswestry low back pain disability scale. Furthermore, a subgroup analysis for patients (classified according to menopausal status) was performed. In total, 106 patients were analyzed. A statistically significant decline in mean bone mineral density was observed at all three sites (vertebrae 5 and 12, and the femoral neck) post-chemoradiation therapy compared with pretreatment bone mineral density (0.671 vs 0.828, -2.083 vs -1.531, -2.503 vs -1.626; all p<0.001). Similarly, in subgroup analyses, at all three sites, pre-menopausal patients showed a statistically significant association (0.876 vs 0.697, -1.203 vs -0.2.761, -1.403 vs -2.232; all p<0.001) while a non-significant association was observed for post-menopausal patients at vertebrae 12 (-1.707 vs -1.719; p=0.09) with a statistically significant association at vertebrae 5 and the femoral neck (0.803 vs 0.656, -1.746 vs -2.648; p<0.01). Although statistically significant low back pain and disability scores were observed overall and irrespective of menopausal status, no correlation between bone mineral density and low back pain and disability was observed. Pelvic bone mineral density decreases significantly after chemoradiation, irrespective of menopausal status. However, no correlation with low back pain and disability was observed. Pelvic bone mineral density analysis should be considered before chemoradiation in cervical cancer.


An Approach of Anomaly Detection and Neural Network Classifiers to Measure Cellulolytic Activity.
A common method used for massive detection of cellulolytic microorganisms is based on the formation of halos on solid medium. However, this is a subjective method and real-time monitoring is not possible. The objective of this work was to develop a method of computational analysis of the visual patterns created by cellulolytic activity through artificial neural networks description. Our method learns by an adaptive prediction model and automatically determines when enzymatic activity on a chromogenic indicator such as the hydrolysis halo occurs. To achieve this goal, we generated a data library with absorbance readings and RGB values of enzymatic hydrolysis, obtained by spectrophotometry and a prototype camera-based equipment (Enzyme Vision), respectively. We used the first part of the library to generate a linear regression model, which was able to predict theoretical absorbances using the RGB color patterns, which agreed with values obtained by spectrophotometry. The second part was used to train, validate, and test the neural network model in order to predict cellulolytic activity based on color patterns. As a result of our model, we were able to establish six new descriptors useful for the prediction of the temporal changes in the enzymatic activity. Finally, our model was evaluated on one halo from cellulolytic microorganisms, achieving the regional classification of the generated halo in three of the six classes learned by our model. We assume that our approach can be a viable alternative for high throughput screening of enzymatic activity in real time.


Dependence of mammalian putrescine and spermidine transport on plasma-membrane potential: identification of an amiloride binding site on the putrescine carrier.
The mechanism of mammalian polyamine transport is poorly understood. We have investigated the role of plasma-membrane potential (DeltaPsipm) in putrescine and spermidine uptake in ZR-75-1 human breast cancer cells. The rate of [3H]putrescine and [3H]spermidine uptake was inversely correlated to extracellular [K+] ([K+]o) and to DeltaPsipm, as determined by the accumulation of [3H]tetraphenylphosphonium bromide (TPP). Inward transport was unaffected by a selective decrease in mitochondrial potential (DeltaPsimit) induced by valinomycin at low [K+]o, but was reduced by approximately 60% by the rheogenic protonophore carbonylcyanide m-chlorophenylhydrazone (CCCP), which rapidly (<=15 min) collapsed both DeltaPsipm and DeltaPsimit. Plasma-membrane depolarization by high [K+]o or CCCP did not enhance putrescine efflux in cells pre-loaded with [3H]putrescine, suggesting that decreased uptake caused by these agents did not result from a higher excretion rate. On the other hand, the electroneutral K+/H+ exchanger nigericin (10 microM) co-operatively depressed -3H-TPP, [3H]putrescine and [3H]spermidine uptake in the presence of ouabain. Suppression of putrescine uptake by nigericin+ouabain was Na+-dependent, suggesting that plasma-membrane repolarization by the electrogenic Na+ pump was required upon acidification induced by nigericin, due to the activation of the Na+/H+ antiporter. The sole addition of 5-N, N-hexamethylene amiloride, a potent inhibitor of the Na+/H+ antiporter, strongly inhibited putrescine uptake in a competitive fashion -Ki 4.0+/-0.9 (S.D.) microM-, while being a weaker antagonist of spermidine uptake. The potency of a series of amiloride analogues to inhibit putrescine uptake was clearly different from that of the Na+/H+ antiporter, and resembled that noted for Na+ co-transport proteins. These data demonstrate that putrescine and spermidine influx is mainly unidirectional and strictly depends on DeltaPsipm, but not DeltaPsimit. This report also provides first evidence for a high-affinity amiloride-binding site on the putrescine carrier, which provides new insight into the biochemical properties of this transporter.


Pharmacokinetics of metronidazole in pregnant patients with bacterial vaginosis.
The present study was undertaken to investigate the pharmacokinetics of metronidazole in pregnant patients with bacterial vaginosis. Twenty patients received metronidazole (Flagyl ®, Pfizer, 235 East 42nd Street, NY, NY 10017) oral dose 500 mg twice a day for 3 consecutive days. Pharmacokinetic analyses of metronidazole were performed after a single oral dose on the morning of day 4. Although absolute estimates of metronidazole total body exposure were highest in women during early term pregnancy, weight-corrected estimates of exposure maximum plasma drug concentration (C(max)) and the area under the plasma concentration-versus-time curve (AUC(0-12)), along with apparent oral clearance and distribution volume, were not significantly different between women at early, middle, and late stages of pregnancy and were in the range of reported values for nonpregnant patients receiving a similar dose. The pharmacokinetic profile of metronidazole did not change at the different time points assessed during pregnancy.


Crystal structure of thermostable aspartase from Bacillus sp. YM55-1: structure-based exploration of functional sites in the aspartase family.
The crystal structure of the thermostable aspartase from Bacillus sp. YM55-1 has been solved and refined for 2.5A resolution data with an R-factor of 22.1%. The present enzyme is a homotetramer with subunits composed of three domains. It exhibits no allosteric effects, in contrast to the Escherichia coli aspartase, which is activated by divalent metal cation and L-aspartate, but is four-times more active than the E.coli enzyme. The overall folding of the present enzyme subunit is similar to those of the E.coli aspartase and the E.coli fumarase C, both of which belong to the same superfamily as the present enzyme. A local structural comparison of these three enzymes revealed seven structurally different regions. Five of the regions were located around putative functional sites, suggesting the involvement of these regions into the functions characteristic of the enzymes. Of these regions, the region of Gln96-Gly100 is proposed as a part of the recognition site of the alpha-amino group in L-aspartate for aspartase and the hydroxyl group in L-malate for fumarase. The region of Gln315-Gly323 is a flexible loop with a well-conserved sequence that is suggested to be involved in the catalytic reaction. The region of Lys123-Lys128 corresponds to a part of the putative activator-binding site in the E.coli fumarase C. The region in the Bacillus aspartase, however, adopts a main-chain conformation that prevents the activator binding. The regions of Gly228-Glu241 and Val265-Asp272, which form a part of the active-site wall, are suggested to be involved in the allosteric activation of the E.coli aspartase by the binding of the metal ion and the activator. Moreover, an increase in the numbers of intersubunit hydrogen bonds and salt-bridges is observed in the Bacillus aspartase relative to those of the E.coli enzyme, implying a contribution to the thermostability of the present aspartase.


Ureteroscopic approach to upper-tract urothelial tumors.
Transitional-cell carcinoma (TCC) of the upper urinary tract has traditionally been managed by nephroureterectomy, whereas nephron-sparing surgery has been reserved for those few patients with solitary kidneys or bilateral lesions. However, with the introduction of improved diagnostic and therapeutic technology, including smaller ureteroscopes and working instruments, and the concomitant ease of surveillance, ureteroscopic treatment of upper-tract urothelial tumors has become a reasonable alternative to open operative intervention in patients requiring conservative management. Furthermore, as preoperative grading and staging have improved, ureteroscopic treatment of upper-tract urothelial tumors is assuming an increasingly important role in the management of some patients who might have otherwise been treated with a nephroureterectomy. The technique of ureteroscopic resection is described in detail.


Anaphylaxis: lessons from mouse models.
Studies with mouse models demonstrate 2 pathways of systemic anaphylaxis: a classic pathway mediated by IgE, FcepsilonRI, mast cells, histamine, and platelet-activating factor (PAF) and an alternative pathway mediated by IgG, FcgammaRIII, macrophages, and PAF. The former pathway requires much less antigen and antibody than the latter. This is modified, however, by IgG antibodies that prevent IgE-mediated anaphylaxis by intercepting antigen before it binds to mast cell-associated IgE. Consequently, IgG antibodies block systemic anaphylaxis induced by small quantities of antigen but mediate systemic anaphylaxis induced by larger quantities. The importance of the alternative pathway in human subjects is unknown, but human IgG, IgG receptors, macrophages, mediators, and mediator receptors have appropriate properties to support this pathway if sufficient IgG and antigen are present. The severity of systemic anaphylaxis is increased by nitric oxide produced by the enzyme endothelial nitric oxide synthase and by the cytokines IL-4 and IL-13 and decreased by endogenous beta-adrenergic stimulation and receptors that contain ITIM that bind tyrosine phosphatases. Anaphylaxis is also suppressed by other receptors and ion channels that function through distinct mechanisms. Unlike systemic anaphylaxis, intestinal anaphylaxis (allergic diarrhea) is almost totally IgE and mast cell dependent and is mediated predominantly by PAF and serotonin. Some potent food allergens, including peanuts and tree nuts, can directly enhance anaphylaxis by stimulating an anaphylactoid response through the innate immune system. Results of these studies suggest novel prophylactic agents, including nonstimulatory anti-IgE mAbs, IL-4 receptor antagonists, PAF antagonists, and agents that cross-link FcepsilonRI or FcgammaRIII to an ITIM-containing inhibitory receptor.


Esophageal stenosis associated with tumor regression in radiotherapy for esophageal cancer: frequency and prediction.
To determine clinical factors for predicting the frequency and severity of esophageal stenosis associated with tumor regression in radiotherapy for esophageal cancer. The study group consisted of 109 patients with esophageal cancer of T1-4 and Stage I-III who were treated with definitive radiotherapy and achieved a complete response of their primary lesion at Kyushu University Hospital between January 1998 and December 2007. Esophageal stenosis was evaluated using esophagographic images within 3 months after completion of radiotherapy. We investigated the correlation between esophageal stenosis after radiotherapy and each of the clinical factors with regard to tumors and therapy. For validation of the correlative factors for esophageal stenosis, an artificial neural network was used to predict the esophageal stenotic ratio. Esophageal stenosis tended to be more severe and more frequent in T3-4 cases than in T1-2 cases. Esophageal stenosis in cases with full circumference involvement tended to be more severe and more frequent than that in cases without full circumference involvement. Increases in wall thickness tended to be associated with increases in esophageal stenosis severity and frequency. In the multivariate analysis, T stage, extent of involved circumference, and wall thickness of the tumor region were significantly correlated to esophageal stenosis (p = 0.031, p < 0.0001, and p = 0.0011, respectively). The esophageal stenotic ratio predicted by the artificial neural network, which learned these three factors, was significantly correlated to the actual observed stenotic ratio, with a correlation coefficient of 0.864 (p < 0.001). Our study suggested that T stage, extent of involved circumference, and esophageal wall thickness of the tumor region were useful to predict the frequency and severity of esophageal stenosis associated with tumor regression in radiotherapy for esophageal cancer.


[Effect of NaCl stress on ion compartmentation, photosynthesis and growth of Salicornia bigelovii Torr].
Seedlings of Salicornia bigelovii Torr. were treated with different concentrations of NaCl (0, 100, 300, 600 mmol/L). Ion contents, Na(+) subcelluar localization, photosynthetic rate, ultrastructure of chloroplast and other parameters were measured. The data showed both fresh and dry weight of whole plant of Salicornia bigelovii Torr. under salinity were higher than the control. When NaCl concentration is about 300 mmol/L Salicornia bigelovii Torr. grow strongest. The contents of Na(+) and Cl(-) and c(Na)/c(K) in shoots increased with the salinity. Both Na(+) and Cl(-) were mainly transported to shoots. Ion X-ray microanalysis indicated Na(+) was mainly compartmentalized into vacuoles. Photosynthetic rate increased with the salinity under NaCl 100-300 mmol/L, but declined under NaCl 600 mmol/L. Ultrastructure of chloroplast was destroyed by NaCl 600 mmol/L.


Analysis of covariance with incomplete data via semiparametric model transformations.
We propose a method for fitting semiparametric models such as the proportional hazards (PH), additive risks (AR), and proportional odds (PO) models. Each of these semiparametric models implies that some transformation of the conditional cumulative hazard function (at each t) depends linearly on the covariates. The proposed method is based on nonparametric estimation of the conditional cumulative hazard function, forming a weighted average over a range of t-values, and subsequent use of least squares to estimate the parameters suggested by each model. An approximation to the optimal weight function is given. This allows semiparametric models to be fitted even in incomplete data cases where the partial likelihood fails (e.g., left censoring, right truncation). However, the main advantage of this method rests in the fact that neither the interpretation of the parameters nor the validity of the analysis depend on the appropriateness of the PH or any of the other semiparametric models. In fact, we propose an integrated method for data analysis where the role of the various semiparametric models is to suggest the best fitting transformation. A single continuous covariate and several categorical covariates (factors) are allowed. Simulation studies indicate that the test statistics and confidence intervals have good small-sample performance. A real data set is analyzed.


[The restoration of colonic continuity after Hartmann's operation].
The experience of restorational intervention with formation of duplicature (invagination) anastomosis after Hartmann's operation in 45 patients with complicated cancer recti and colonic cancer was summarized. Complications had occurred in 9.8% of observations, one patient died.


[Laboratory diagnosis of chronic forms of ophthalmic herpes].
The duration and pattern of the course of herpes virus infection of the eye and the method used were shown to influence the effectiveness of the laboratory diagnosis. In the first two weeks of the disease conjunctival scrappings should be examined by immunofluorescence and virus isolation by intracerebral inoculation of mice, at later periods by immunofluorescence of conjunctival scrappings or infected cell cultures. Isolated herpes uveitis should be diagnosed by demonstration of viremia. In surgical treatment of herpetic eye diseases virus should be demasked from the cornea by cocultivation of its fragments with human embryo fibroblast culture.


User satisfaction with train fares: A comparative analysis in five Australian cities.
In the public transport industry, travellers' perceived satisfaction is a key element in understanding their evaluation of, and loyalty to ridership. Despite its notable importance, studies of customer satisfaction are under-represented in the literature, and most previous studies are based on survey data collected from a single city only. This does not allow a comparison across different transport systems. To address this underrepresentation, this paper reports on a study of train passengers' satisfaction with the fare paid for their most recent home-based train trip in five Australian capital cities: Sydney, Melbourne, Brisbane, Adelaide, and Perth. Two data sources are used: a nation-wide survey, and objective information on the train fare structure in each of the targeted cities. In particular, satisfaction with train fares is modelled as a function of socio-economic factors and train trip characteristics, using a random parameters ordered Logit model that accounts for unobserved heterogeneity in the population. Results indicate that gender, city of origin, transport mode from home to the train station, eligibility for either student or senior concession fare, one-way cost, and waiting time as well as five diverse interaction variables between city of origin and socio-economic factors are the key determinants of passenger satisfaction with train fares. In particular, this study reveals that female respondents tend to be less satisfied with their train fare than their male counterparts. Interestingly, respondents who take the bus to the train station tend to feel more satisfied with their fare compared with the rest of the respondents. In addition, notable heterogeneity is detected across respondents' perceived satisfaction with train fare, specifically with regard to the one-way cost and the waiting time incurred. An intercity comparison reveals that a city's train fare structure also affects a traveller's perceived satisfaction with their train fare. The findings of this research are significant for both policy makers and transport operators, allowing them to understand traveller behaviours, and to subsequently formulate effective transit policies.


[Hyponatremia in the postoperative period after a neurosurgical tumor condition].
A four-year-old girl suffered difficult-to-diagnose hyponatremia resistant to treatment following surgery for a suprasellar tumor. The final diagnosis was diabetes insipidus evolving in three stages. Hyponatremia is a common problem following surgery to remove brain tumors. Early diagnosis and treatment of this electrolytic imbalance are essential for preventing serious neurological symptoms or death. The conditions most closely related to hyponatremia are inappropriate antidiuretic hormone secretion syndrome (IADHSS) and cerebral salt wasting syndrome (CSWS). The latter has become more common in recent years among patients undergoing brain surgery. Whereas IADHSS is treated by restricting fluids, CSWS requires administration of salt and volume fluid volume. We believe that for differential diagnosis of postoperative hyponatremia, a fluid restriction test takes priority over of fluid loading following neurosurgery. The course of hyponatremia must be carefully monitored and a complete endocrinological workup must be performed to detect the possible presence of hypophyseal deficiencies, particularly hypothyroidism and suprarenal insufficiency.


Plasma membrane-associate filament systems in cultured cells visualized by dry-cleaving.
Substrate-attached critical-point-dried cells cleave along the level of the substrate-adherent membrane if removed by means of adhesive tape. The remaining membrane fragments on grids can be visualized three-dimensionally by means of stereo transmission electron microscopy. Attachment of cells may be achieved by active spreading of the cell, or artificially by poly-L-lysine adherence of prefixed cells. In 11 different cell types a filamentous network appears to remain associated with the cytoplasmic face of the membrane. In one hepatoma cell type virtually no filamentous network could be detected. Two general network morphologies are described: the hepatocytic network and the lymphoid network. Since no correspondence could be found between cytoplasmic structure and the structure of the membrane-associated network, and since cells generally cleave along the level of this network, excluding cell organelles, we conclude that it comprises a distinct structural system, analogous to the membrane skeleton of the red cell membrane.


View-adaptation reveals coding of face pose along image, not object, axes.
High-level adaptation effects reveal important features of the neural coding of objects and faces. View-adaptation in particular is a highly useful means of characterizing how depth rotation of the face is represented and therefore, how view-invariant recognition of the face may be achieved. In the present study, we used view adaptation to determine the extent to which depth rotations of a face are represented in an image-based or object-based manner. Specifically, we dissociated object-based axes from image-based axes via a 90° planar rotation of the adapting face and observed that participants' responses pre- and post-adaptation are most consistent with an image-based representation of depth rotations of the face. We discuss our data in the context of previous results describing the impact of planar rotation on related aspects of face perception.


[Development and appraisement of functional molecular marker: intron sequence amplified polymorphism (ISAP)].
Molecular markers are playing an increasingly important role in map construction, QTL analysis, gene mapping and marker-assisted selection. Researchers hope the target gene and locus are as close as possible, one locus can present one gene, or linked with some important trait, then, individuals with useful trait can be selected through molecular markers selecting, and it's the functional molecular marker. PCR-based molecular markers such as RAPD, SSR, AFLP amplified non-coding regions, or the whole genome randomly, the locus is far away from the gene of targeted trait, this limit the ap-plication of these molecular markers. This study established a kind of functional molecular markers based on intron of gene sequence, trying to link loci with gene sequence to achieve the purpose of its function. It used the conservative consistent sequence of intron splicing sites as its core sequence of amplification. ISAP is a PCR-based marker system, it has two kinds of primers: forward primer and reverse primer, both primers are 18 bases. Any of the primers can be used to construct a primer combination with the other kind of primers. Seventeen primers, 9 forward and 8 reverse, were used to construct 72 primer combinations, 67 of them showed polymorphism in a G. hirsutum cv. CCRI36 x G. barbadense cv. H7124 F2 population and a total of 212 loci were obtained. Together with 164 SRAP loci, these 212 loci were used to construct a genetic linkage map. ISAP markers distributed evenly in the entire linkage group, part of the region had a high saturation, might be the coding sequence-rich region. Sequencing results of 20 fragments showed that 85% of the sequences announced homology with published EST sequence stored in the NCBI which indicated that they were amplified adjacent to expressed sequences. These results showed that ISAP marker system was simple, efficient, reliable, and had a relatively high polymorphism, furthermore, it directly targeted gene sequence, was a functional molecular marker system. ISAP was also used to amplify other plants and good results were achieved.


Expanding role for vitamin D in chronic kidney disease: importance of blood 25-OH-D levels and extra-renal 1alpha-hydroxylase in the classical and nonclassical actions of 1alpha,25-dihydroxyvitamin D(3).
Recent advances in the understanding of vitamin D have revolutionized our view of this old nutritional factor and suggested that it has much wider effects on the body than ever believed before. In addition to its well-known effects on calcium/phosphate homeostasis, vitamin D, through its hormonal form, 1alpha,25-dihydroxyvitamin D(3) or calcitriol, is a cell differentiating factor and anti-proliferative agent with actions on a variety of tissues around the body (e.g., skin, muscle, immune system). By influencing gene expression in multiple tissues, calcitriol influences many physiological processes besides calcium/phosphate homeostasis including muscle and keratinocyte differentiation, insulin secretion, blood pressure regulation, and the immune response. The incidence of various diseases including epithelial cancers, multiple sclerosis, muscle weakness as well as bone-related disorders has been correlated with vitamin D deficiency/insufficiency and has led to a re-evaluation of recommended daily intakes both in the normal subject and CKD patient. Critical developments have been the emergence of the value of blood 25-OH-D measurement as a tool in predicting vitamin D-related problems and this has in turn emphasized the importance of the extra-renal version of the 1alpha-hydroxylase, the enzyme responsible for the final step in vitamin D activation. The widespread expression of this extra-renal enzyme supports the view that it exists to boost intracellular concentrations of calcitriol within some target tissues in order to modulate a unique set of genes specifically in those tissues, a process which is therefore dependent upon circulating 25-OH-D. For CKD patients with their tendency to vitamin D substrate insufficiency coupled with their documented loss of the renal 1alpha-hydroxylase in late stages, this new information has profound implications. Physicians must start to manage the vitamin D insufficiency by vitamin D supplements throughout stages 1-5 whilst continuing to provide calcitriol replacement therapy, in the form of calcitriol or its analogs, in stages 3-5.


A century of controversy regarding the benefit or detriment of occlusal contacts on the mediotrusive side.
Many opinions have been presented in the literature during the past century regarding so-called mediotrusive/balancing/non-working side contacts. During the first half of this century, most authors advocated the advantage of these contacts (it was more or less the state of the art in prosthetic treatments), while during the last 50 years mediotrusive side contacts/interferences have mostly been regarded as a disturbing factor in the functioning of the mandible. Recently, it has been proposed that mediotrusive side contacts have a protective effect on the temporomandibular joint (TMJ). The aim of this study was to review opinions advocated during the twentieth century regarding the advantages and disadvantages of having contacts on the mediotrusive side during lateral excursions of the mandible. We conclude that, at present, there is no uniform body of scientific evidence supporting a balanced occlusion in favour of a mutually protective occlusion or vice versa. Longitudinal studies based on cohorts with different types of occlusal contacts, estimating the risk among these of developing signs and symptoms of temporomandibular disorders, are generally lacking and could provide valuable knowledge in this field.


Prevalence and factors associated with utilisation of postnatal care in Sierra Leone: a 2019 national survey.
Within Sub-Saharan Africa, some countries still report unacceptably high rates of maternal and perinatal morbidity and mortality, despite improvements in the utilisation of maternity care services. Postnatal care (PNC) is one of the recommended packages in the continuum of maternity care aimed at reducing maternal and neonatal mortality. This study aimed to determine the prevalence and factors associated with PNC utilisation in Sierra Leone. We used Sierra Leone Demographic and Health Survey (UDHS) 2019 data of 7326 women aged 15 to 49 years. We conducted multivariable logistic regression to determine the factors associated with PNC utilisation, using SPSS version 25. Out of 7326 women, 6625 (90.4, 95% CI: 89.9-91.2) had at least one PNC contact for their newborn, 6646 (90.7, 95% CI: 90.2-91.5) had a postnatal check after childbirth and 6274 (85.6, 95% CI: 85.0-86.6) had PNC for both their babies and themselves. Delivery by caesarean section (aOR 8.01, 95% CI: 3.37-19.07), having a visit by a health field worker (aOR 1.80, 95% CI: 1.46-2.20), having had eight or more ANC contacts (aOR 1.37, 95% CI: 1.08-1.73), having tertiary education (aOR 2.71, 95% CI: 1.32-5.56) and having no big problems seeking permission to access healthcare (aOR 1.51, 95% CI: 1.19-1.90) were associated with higher odds of PNC utilisation. On the other hand, being resident in the Northern (aOR 0.48, 95% CI: 0.29-0.78) and Northwestern regions (aOR 0.54, 95% CI: 0.36-0.80), belonging to a female headed household (aOR 0.69, 95% CI: 0.56-0.85) and being a working woman (aOR 0.66, 95% CI: 0.52-0.84) were associated with lower odds of utilizing PNC. Factors associated with utilisation of PNC services operate at individual, household, community and health system/policy levels. Some of them can be ameliorated by targeted government interventions to improve utilisation of PNC services.


Influence of polymer addition on the mechanical properties of a premixed calcium phosphate cement.
Premixed calcium phosphate cements can reduce handling complications that are associated with the mixing of cements in the operating room. However, to extend the clinical indication of ceramic cements their mechanical properties need to be further improved. The incorporation of a polymeric material with intrinsically high tensile properties could possibly assist in increasing the mechanical properties of calcium phosphate cement. In this study polymer microparticles made from poly(lactid-co-glycolide) plasticised with poly(ethylene glycol) 400 (PLGA/PEG microparticles) were added in amounts of up to 5 wt% to a premixed acidic calcium phosphate cement. The PLGA/PEG microparticles added undergo a shape transformation at 37 °C, which could give a better integration between polymer microparticles and ceramic cement compared with polymer microparticles lacking this property. The results showed that the incorporation of 1.25 wt% PLGA/PEG microparticles increased the compressive strength by approximately 20% up to 15.1 MPa while the diametral tensile strength was kept constant. The incorporation of PLGA/PEG microparticles increased the brushite to monetite ratio after setting compared with pure ceramic cements. In conclusion, small amounts of PLGA/PEG microparticles can be incorporated into premixed acidic calcium phosphate cement and increase their mechanical properties, which could lead to increased future applications.


Humpback whale song occurrence reflects ecosystem variability in feeding and migratory habitat of the northeast Pacific.
This study examines the occurrence of humpback whale (Megaptera novaeangliae) song in the northeast Pacific from three years of continuous recordings off central California (36.713°N, 122.186°W). Song is prevalent in this feeding and migratory habitat, spanning nine months of the year (September-May), peaking in winter (November-January), and reaching a maximum of 86% temporal coverage (during November 2017). From the rise of song in fall through the end of peak occurrence in winter, song length increases significantly from month to month. The seasonal peak in song coincides with the seasonal trough in day length and sighting-based evidence of whales leaving Monterey Bay, consistent with seasonal migration. During the seasonal song peak, diel variation shows maximum occurrence at night (69% of the time), decreasing during dawn and dusk (52%), and further decreasing with increasing solar elevation during the day, reaching a minimum near solar noon (30%). Song occurrence increased 44% and 55% between successive years. Sighting data within the acoustic detection range of the hydrophone indicate that variation in local population density was an unlikely cause of this large interannual variation. Hydrographic data and modeling of acoustic transmission indicate that changes in neither habitat occupancy nor acoustic transmission were probable causes. Conversely, the positive interannual trend in song paralleled major ecosystem variations, including similarly large positive trends in wind-driven upwelling, primary productivity, and krill abundance. Further, the lowest song occurrence during the first year coincided with anomalously warm ocean temperatures and an extremely toxic harmful algal bloom that affected whales and other marine mammals in the region. These major ecosystem variations may have influenced the health and behavior of humpback whales during the study period.


Integrating strategies for podiatric public health, clinical services, and education.
Changes in the health-care system will continue to modify the delivery of podiatric medical care and podiatric medical education. Podiatric medicine and its educational programs will need to focus on the management of care, special populations, and disease prevention. Future providers will need to participate as team members and respond to new patterns of care, including the special needs of the older population. This article explores methodologies for professional activities, administration, incentives for change, academic issues, innovation, implementation, outcome measures, and health policy development. Podiatric medicine must be prepared to establish standards, protocols, and guidelines to serve as the benchmark for foot health.


CT-guided percutaneous cordotomy for intractable pain in what is more than a disease: lung malignancies.
Lung cancer is the leading cause of cancer-related mortality worldwide. Pain is a common problem in these patients, yet inadequate or dissatisfactory management is prevalent. Between 1987 and 2012, 224 patients with intractable pain were treated with computerized tomography (CT)- guided cordotomy. Among them, 210 had intractable pain due to malignancies. The majority of the cases were diagnosed as pulmonary malignancies (108 patients). Sixty-seven were pulmonary carcinoma, 26 mesothelioma and 15 Pancoast tumors. After cordotomy, 98.13% of cancer patients reported initial pain relief. Minimum and maximum preoperative scores of the Karnofsky Performance Scale were 20 and 70, versus postoperative scores of 40 and 90 (p < 0.001). The median preoperative VAS score was 8 (6-9). On the first postoperative day, the score dropped sharply to 0 (0-8) (p < 0.001). In this selected series of 108 percutaneous cordotomy procedures, as well as in the total series of 224 patients, there was no mortality or major morbidity. CT-guided percutaneous cordotomy is an effective procedure that should be used in the treatment of cancer-related pain problems. We suggest that cordotomy should be preferred as soon as possible in patients who fail to respond to the classic analgesic therapy.


Evidence for calcium inactivation during hormone release in the rat neurohypophysis.
1. A study has been made of the relationship between 45Ca uptake into and hormone release from isolated rat neurohypophyses incubated in vitro. 2. Hormone secretion is triggered by high-K (56 mM) but long exposure to the stimulus does not generate a maintained release of hormone. 3. When hormone release began to wane, addition of Ba of La increased hormone output which suggests that the decline in output did not result from depletion of the neurosecretory granules at the nerve terminals. 4. 45Ca uptake is enhanced in the presence of high-K concentration, but the initial high rate declines during long exposure to the potassium stimulus with a time constant similar to that of the decline in hormone release. 5. After a period of incubation in a K-rich, calcium-free medium, addition of calcium to the medium induced hormone release. The magnitude of this release was dependent on the time of exposure to excess potassium. 6. After inactivation of secretion, mobilization of internal calcium by means of a calcium ionophore increased hormone release.


Single Low-Density Lipoprotein Apheresis Does Not Improve Vascular Endothelial Function in Chronically Treated Hypercholesterolemic Patients.
Objective. To investigate vascular endothelial function (VEF) responses to a single low-density lipoprotein (LDL) apheresis session in hypercholesterolemic patients undergoing chronic treatment. Methods. We measured brachial artery flow-mediated dilation (FMD), plasma lipids, vitamin E (α- and γ-tocopherol), markers of oxidative/nitrative stress (malondialdehyde (MDA) and nitro-γ-tocopherol (NGT)), and regulators of NO metabolism (arginine (ARG) and asymmetric dimethylarginine (ADMA)) prior to (Pre) and immediately following (Post) LDL apheresis and at 1, 3, 7, and 14 d Post in 5 hypercholesterolemic patients (52 ± 11 y). Results. Relative to Pre, total cholesterol (7.8 ± 1.5 mmol/L) and LDL-cholesterol (6.2 ± 1.2 mmol/L) were 61% and 70% lower (P < 0.01), respectively, at Post and returned to Pre levels at 14 d. Brachial FMD responses (6.9 ± 3.6%) and plasma MDA, ARG, and ADMA concentrations were unaffected by LDL apheresis. Plasma α-tocopherol, γ-tocopherol, and NGT concentrations were 52-69% lower at Post (P < 0.01), and α-tocopherol remained 36% lower at 1 d whereas NGT remained 41% lower at d 3. Conclusions. Acute cholesterol reduction by LDL apheresis does not alter VEF, oxidative stress, or NO homeostasis in patients treated chronically for hypercholesterolemia.


A dataset for the analysis of antibody response to glycan alpha-Gal in individuals with immune-mediated disorders.
Humans evolved by losing the capacity to synthesize the glycan Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal), which resulted in the development of a protective response mediated by anti-α-Gal IgM/IgG/IgA antibodies against pathogens containing this modification on membrane proteins. As an evolutionary trade-off, humans can develop the alpha-Gal syndrome (AGS), a recently diagnosed disease mediated by anti-α-Gal IgE antibodies and associated with allergic reactions to mammalian meat consumption and tick bites. However, the anti-α-Gal antibody response may be associated with other immune-mediated disorders such as those occurring in patients with COVID-19 and Guillain-Barré syndrome (GBS). Here, we provide a dataset (209 entries) on the IgE/IgM/IgG/IgA anti-α-Gal antibody response in healthy individuals and patients diagnosed with AGS, tick-borne allergies, GBS and COVID-19. The data allows correlative analyses of the anti-α-Gal antibody response with factors such as patient and clinical characteristics, record of tick bites, blood group, age and sex. These analyses could provide insights into the role of anti-α-Gal antibody response in disease symptomatology and possible protective mechanisms.


Gene expression changes in the ventral hippocampus and medial prefrontal cortex of adolescent alcohol-preferring (P) rats following binge-like alcohol drinking.
Binge drinking of alcohol during adolescence is a serious public health concern with long-term consequences, including decreased hippocampal and prefrontal cortex volume and deficits in memory. We used RNA sequencing to assess the effects of adolescent binge drinking on gene expression in these regions. Male adolescent alcohol-preferring (P) rats were exposed to repeated binge drinking (three 1-h sessions/day during the dark/cycle, 5 days/week for 3 weeks starting at 28 days of age; ethanol intakes of 2.5-3 g/kg/session). Ethanol significantly altered the expression of 416 of 11,727 genes expressed in the ventral hippocampus. Genes and pathways involved in neurogenesis, long-term potentiation, and axonal guidance were decreased, which could relate to the impaired memory function found in subjects with adolescent alcohol binge-like exposure. The decreased expression of myelin and cholesterol genes and apparent decrease in oligodendrocytes in P rats could result in decreased myelination. In the medial prefrontal cortex, 638 of 11,579 genes were altered; genes in cellular stress and inflammatory pathways were increased, as were genes involved in oxidative phosphorylation. Overall, the results of this study suggest that adolescent binge-like alcohol drinking may alter the development of the ventral hippocampus and medial prefrontal cortex and produce long-term consequences on learning and memory, and on control of impulsive behaviors.


The functional emergence of prefrontally-guided working memory systems in four- to eight-year-old children.
The neural processes that underlie the functional emergence of human cognitive functions, particularly those associated with the prefrontal cortex (PFC), are of growing interest to developmental psychologists and neuroscientists. Specifically, working memory functions have been correlated with PFC activity in nonhuman primates and adult humans but have not been extensively studied in children. We examined the developmental emergence of functions involved in working memory through the use of the Cambridge Neuropsychological Test Automated Battery (CANTAB), a computerized battery of nonverbal visually-presented neuropsychological tests designed to dissociate frontal from temporal lobe behavioral functions. Participants were normal children, aged 4-8 (n = 181) and a small group of young adults (n = 24) who completed measures of Spatial Memory Span, Spatial Working Memory, the Tower of London planning task, Visual Pattern and Spatial Recognition tasks, and a Set-Shifting task. Findings indicate a general age-related progression in ability levels on frontal lobe tasks, with 4-year-olds performing worse than 5- to 7-year-olds on all measures. Eight-year-olds are superior to younger children in their ability to solve complex problems but have not yet reached adult levels of performance on the most difficult items of the Tower of London and Spatial Working Memory tasks. We conclude that the development of working memory functions proceeds dimensionally, starting with refinement of basic perceptual and sensorimotor functions and culminating with the physiological maturation of widespread neural networks that integrate complex processing demands inherent to working memory tasks.


Major Differences in the Use of Protocols for Dispatcher-Assisted Cardiopulmonary Resuscitation Among ILCOR Member Countries.
Dispatcher-assisted cardiopulmonary resuscitation (DA-CPR) increases the rate of bystander cardiopulmonary resuscitation (CPR). DA-CPR is recommended by resuscitation councils globally and it has been shown that the general public expects to receive pre-arrival instructions while waiting for help. A scientific advisory from the American Heart Association identifies standardized and structured DA-CPR protocols as important to increase bystander CPR rates. This study aims to investigate whether different International Liaison Committee on Resuscitation (ILCOR) member countries use DA-CPR protocols and to compare protocol contents between countries. All resuscitation councils forming ILCOR were inquired by email to provide a copy of their DA-CPR protocol, and to state whether this protocol was used by all emergency dispatch centers in their country. The collected protocols were translated into English, and content was compared. A total of 60 countries were contacted (response rate: 83%). Of these, 46% stated to have a nationwide protocol, 30% reported to use local protocols, and 24% did not use a protocol. Overall, 54% provided a copy of their protocol. All translated protocols asked the rescuer to check for responsiveness and breathing, 35% to activate phone speaker function, half contained notes about agonal breathing and 59% included notes about integrating an automated external defibrillator. Almost one quarter of ILCOR member countries did not use a protocol for DA-CPR. Half of the protocols included notes about agonal breathing. Activation of phone speaker function and protocolled encouragements during CPR were rarely included.


A deep new look at color.
Bowers et al. counter deep neural networks (DNNs) as good models of human visual perception. From our color perspective we feel their view is based on three misconceptions: A misrepresentation of the state-of-the-art of color perception; the type of model required to move the field forward; and the attribution of shortcomings to DNN research that are already being resolved.


Developing a core outcome set for physical activity interventions in primary schools: a modified-Delphi study.
To develop a core outcome set (COS) for physical activity interventions in primary schools. Modified-Delphi study. The UK and international. 104 participants from four stakeholder groups (educators, public health professionals, health researchers, parents); 16 children (aged 8-9 years) from 1 London primary school. Physical activity interventions. Four-stage process: (1) outcomes extracted from relevant studies identified from an umbrella review and a focus group; (2) list of outcomes produced and domains established; (3) stakeholders completed a two-round Delphi survey by rating (Round 1) and re-rating (Round 2) each outcome on a nine-point Likert Scale from 'not important' to 'critical': a>70% participant threshold identified the outcomes rated 'critical' to measure, and outcomes important to children were identified through a workshop; and (4) a stakeholder meeting to achieve consensus of the outcomes to include in the COS. In total, 74 studies were extracted from 53 reviews. A list of 50 outcomes was produced and three domains were established: 'physical activity and health' (16 outcomes), 'social and emotional health' (22 outcomes) and 'educational performance' (12 outcomes). 104 participants completed survey Round 1; 65 participants completed both rounds. In total, 13 outcomes met the threshold; children identified 8 outcomes. Fourteen outcomes achieved consensus to produce the COS: five outcomes for physical activity and health (diet (varied and balanced), energy, fitness, intensity of physical activity, sleep (number of hours)); seven outcomes for social and emotional health (anxiety, depression, enjoyment, happiness, self-esteem, stress, well-being); and two outcomes for educational performance (concentration, focus). We have developed the first COS for physical activity interventions in primary schools in consultation with those interested in the development and application of an agreed standardised set of outcomes. Future studies including these outcomes will reduce heterogeneity across studies. Core Outcome Measures in Effectiveness Trials Initiative registration number 1322; Results.


Homozygous factor V splice site mutation associated with severe factor V deficiency.
We investigated a family whose proband has a severe bleeding disorder and factor V antigenic and functional levels of 8% and less than 1% of control values, respectively. Molecular analysis of the factor V gene revealed a novel homozygous mutation in the last nucleotide of exon 10. 1701G>T causes activation of a cryptic exonic splice site in exon 10, which encodes part of the factor V heavy chain (A2 domain). This leads to the deletion of 35 nucleotides and results in a frameshift with a premature stop codon at amino acid position 498. The G1701 and corresponding Gln509 are conserved in murine, bovine, and porcine factor V and in human factor VIII. Few factor V deficiency mutations have been identified as yet. Several are present in the heterozygous form in combination with factor V Leiden (Arg506Gln). This is the first reported homozygous splice site mutation in a patient with factor V deficiency.


Variation in Speech Intelligibility Ratings as a Function of Speech Rate Modification in Parkinson's Disease.
Purpose The aim of this study was to quantify changes in speech intelligibility in two cohorts of people with Parkinson's disease (PD; those with and without deep brain stimulation [DBS]) across a broad range of self-selected speech rate alterations in (a) read sentences and (b) extemporaneous speech (monologues). Method Four speaker groups participated in this study: younger and older controls, people with PD undergoing standard pharmaceutical treatment, and people with PD and DBS. Naïve listeners rated the intelligibility of read sentences and extemporaneous monologues, spoken by participants at seven self-selected speech rates from very slow to very fast. Intelligibility was modeled as a function of group, speech rate condition, and speech task. Results Overall, compared to habitual speech rate, slower speech rate conditions were not associated with changes in speech intelligibility, whereas faster-than-habitual conditions were associated in declines in intelligibility. Results were mediated by group and task effects, such that talkers with PD and DBS were more likely to see intelligibility benefits at slower self-selected speech rates and less likely to see detriments at faster rates, and these differences were amplified in monologues compared to sentences. Conclusion Findings suggest differences in the ways in which slower and faster speech rate adjustments impact speech intelligibility in people with PD with and without DBS, with the latter demonstrating greater magnitudes of change.


Biosensors and the clinical laboratory.
Aside from the economic factors that make biosensors attractive, on-board signal conditioning and signal processing improve the limits of detection and simplify use of the devices. The present discussion summarizes the breadth of biosensor design and application, and the requirements of clinical assay detection. Current sensor research is aimed toward extending the lower limits of detection for nonradioactive immunoassays. The clinical laboratory is in a state of change; operating and instrumentation costs will affect the delivery of diagnostics. Technology will assume a major role in reshaping the clinical laboratory. Biosensors promise to deliver the diagnostic tools for the evolution that is now in progress. The clinical laboratory will no doubt continue to perform chemical profiling and the more specialized tests. The successful implementation of solid-state sensor technology promises to simplify immunoassay procedures, as the autoanalyzer did some 20 years ago for the profiling of blood metabolites. It is likely that more tests will be performed in physicians' offices with the advent of highly automated and cost-effective biosensors. By the use of this technology, practitioners of critical care medicine will be able to assume greater responsibility for diagnostic testing.


Incidence and risk factors of stomal complications in patients undergoing cystectomy with ileal conduit urinary diversion for bladder cancer.
In this study we examined the incidence and associated factors of stomal complications in patients undergoing radical cystectomy with ileal conduit urinary diversion for bladder cancer. In addition, we evaluated the treatment and outcomes of surgical procedures in patients in whom stoma related complications developed. From 2001 to 2005 a total of 137 patients underwent ileal conduit diversion after cystectomy or exploration for bladder cancer, had complete clinical followup and were followed for at least 12 months after surgery. The incidence of stomal complications (including parastomal hernia, stomal stenosis and stomal prolapse) is reported with correlations made to age, race, gender, body mass index, smoking history, alcohol consumption, preoperative laboratory values (creatinine, hematocrit), operative estimated blood loss and surgical complications. In addition, management of stomal complications is reported. Of the 137 patients 21 stomal complications (15.3%) occurred in 20 patients (14.6%). The most common complication was parastomal hernia in 19 patients (13.9 %). Stomal stenosis developed in 1 patient (0.7%) and stomal prolapse developed in 1 patient with a parastomal hernia (0.7%). There were no significant differences in gender, age, race, preoperative laboratory values or history of abdominal/pelvic radiation therapy between patients with or without complications. However, patients in whom complications developed had a significantly higher mean body mass index compared to those without complications (30.8 vs 26.5 kg/m(2), respectively, p = 0.012). Operative outcomes, extent of disease and length of postoperative followup were also similar between patients with or without stomal complications. In addition, there were no significant differences in lifestyle factors (eg smoking, alcohol abuse) in patients in whom complications developed. Stomal complications associated with ileal conduit urinary diversion are not uncommon and occur in almost 15% of patients, with the most common problem being parastomal hernia. Evaluation of possible risk factors demonstrates that obesity may be a contributing factor in the development of stomal complications, particularly in the elderly. Furthermore, our experience suggests that subsequent repairs of parastomal hernias are only moderately successful.


Effect of intravenous infusion of insulin in diabetics with acute myocardial infarction.
Diabetes mellitus is associated with a high mortality after myocardial infarction. To see whether this may be decreased by improved diabetic control the effect of an insulin infusion regimen was studied in patients with acute myocardial infarction. From April 1982 to April 1983, 33 diabetics were admitted with acute myocardial infarction. Those being treated with diet alone or oral hypoglycaemic drugs continued with this unless control was poor, when they were changed to a "sliding scale" regimen of subcutaneous insulin injections thrice daily. Those already receiving insulin were maintained on thrice daily subcutaneous injections. From April 1983 to April 1984, 29 diabetics had acute myocardial infarction. Those receiving treatment with oral hypoglycaemic drugs or insulin were changed to continuous intravenous infusion of insulin, the aim being to maintain the blood glucose concentration at 4-7 mmol/I (72-126 mg/100 ml). Those being treated with diet alone continued with this if blood glucose concentrations were acceptable. Total mortality fell from 42% in the first year to 17% in the second (p less than 0.05). Over the same period mortality among non-diabetic patients with myocardial infarction did not change significantly. There was a significant fall in cardiac arrhythmias (expressed as the percentage of patients in whom arrhythmias were recorded) from 42% to 17% (p less than 0.05). The most significant fall in the incidence of complications occurred in those who had been receiving oral hypoglycaemic drugs on entry to the study (87% to 50%, p less than 0.05).


Prolonging life and delaying death: the role of physicians in the context of limited intensive care resources.
Critical care is in an emerging crisis of conflict between what individuals expect and the economic burden society and government are prepared to provide. The goal of critical care support is to prevent suffering and premature death by intensive therapy of reversible illnesses within a reasonable timeframe. Recently, it has become apparent that early support in an intensive care environment can improve patient outcomes. However, life support technology has advanced, allowing physicians to prolong life (and postpone death) in circumstances that were not possible in the recent past. This has been recognized by not only the medical community, but also by society at large. One corollary may be that expectations for recovery from critical illness have also become extremely high. In addition, greater numbers of patients are dying in intensive care units after having receiving prolonged durations of life-sustaining therapy. Herein lies the emerging crisis -- critical care therapy must be available in a timely fashion for those who require it urgently, yet its provision is largely dependent on a finite availability of both capital and human resources. Physicians are often placed in a troubling conflict of interest by pressures to use health resources prudently while also promoting the equitable and timely access to critical care therapy. In this commentary, these issues are broadly discussed from the perspective of the individual clinician as well as that of society as a whole. The intent is to generate dialogue on the dynamic between individual clinicians navigating the complexities of how and when to use critical care support in the context of end-of-life issues, the increasing demands placed on finite critical care capacity, and the reasonable expectations of society.