Sudden infant death in a tropical environment: Singapore's experience.
A total of 206 cases of sudden infant deaths examined at the Institute of Science and Forensic Medicine, Singapore, over a 5 year period (1989-93) were identified to assess the pattern of sudden death in this age group, which was subdivided into the neonatal and post-neonatal periods. A total of 34% (70) of infant deaths occurred in neonatal life and the remaining 66% (136) in the post-neonatal period; 90% of the neonatal deaths were natural, of which over half were due to congenital heart disease and complications of prematurity. Unnatural deaths in this period were uncommon, there being only seven such deaths. In the post-neonatal period, unnatural deaths constituted 25% of the total with trauma and aspiration heading the list. Natural deaths in the post-neonatal period are predominantly due to infections (34%) and a group of sudden natural deaths with minimal findings (31%). The latter group may arguably represent cases of Sudden Infant Death Syndrome (SIDS). The yearly incidence of this group in our study varied between 0.08 to 0.2 per 1000 live births, which is considerably lower than the incidence quoted for Western populations. The criteria for the classification and the impact of sudden infant deaths in Asian countries are discussed.


Meal time shift disturbs circadian rhythmicity along with metabolic and behavioral alterations in mice.
In modern society, growing numbers of people are engaged in various forms of shift works or trans-meridian travels. Such circadian misalignment is known to disturb endogenous diurnal rhythms, which may lead to harmful physiological consequences including metabolic syndrome, obesity, cancer, cardiovascular disorders, and gastric disorders as well as other physical and mental disorders. However, the precise mechanism(s) underlying these changes are yet unclear. The present work, therefore examined the effects of 6 h advance or delay of usual meal time on diurnal rhythmicities in home cage activity (HCA), body temperature (BT), blood metabolic markers, glucose homeostasis, and expression of genes that are involved in cholesterol homeostasis by feeding young adult male mice in a time-restrictive manner. Delay of meal time caused locomotive hyperactivity in a significant portion (42%) of subjects, while 6 h advance caused a torpor-like symptom during the late scotophase. Accordingly, daily rhythms of blood glucose and triglyceride were differentially affected by time-restrictive feeding regimen with concurrent metabolic alterations. Along with these physiological changes, time-restrictive feeding also influenced the circadian expression patterns of low density lipoprotein receptor (LDLR) as well as most LDLR regulatory factors. Strikingly, chronic advance of meal time induced insulin resistance, while chronic delay significantly elevated blood glucose levels. Taken together, our findings indicate that persistent shifts in usual meal time impact the diurnal rhythms of carbohydrate and lipid metabolisms in addition to HCA and BT, thereby posing critical implications for the health and diseases of shift workers.


[Biliary stent placement for postoperative benign bile duct stenosis: personal experience].
To describe the management and outcome after endoscopic treatment of 23 patients with post-operative benign bile duct stricture (BBDS) managed in Authors' Department from 1991 to 2000. The management of the postoperative bile duct strictures remains a challenge for even the most skilled biliary tract surgeon and endoscopist. The 1990s saw a dramatic increase in the incidence of bile duct strictures from the introduction and widespread use of laparoscopic cholecystectomy. The management of these injuries, short-term outcome and follow-up have been reported. Data were collected retrospectively on 23 patients treated in the Service of Diagnostic and Operative Endoscopy of the Operative Unit of General and Thoracic Surgery (Policlinico Paolo Giaccone, Palermo, Italy) with BBDS between 1991 and 2000. All patients underwent ERCP (endoscopic retrograde cholangiopancreatography). Follow-up and pharmacological therapy post-ERCP were conducted by scheduled medical audit. Of the 23 initial patients, 20 undergoing endoscopic stenting (3 with complete transaction were invited to surgery), 16 had completed treatment with symptoms resolution (mean follow-up of 70 months). One patient died of reason unrelated to biliary tract disease before the completion of treatment. Seven had not completed treatment. Of 16 patient who had completed treatment, 13 were considered to have a successful outcome without the need of follow-up invasive, diagnostic or therapeutic interventional procedures. Overall, a successful outcome, was obtained in 65% of patients, including those requiring a secondary procedure for recurrent strictures. Postoperative bile duct strictures remain a considerable surgical challenge. Management with endoscopic cholangiography to delineate the postoperative anatomy and to place biliary stents, to solve the symptoms, is associated with a successful outcome in up of 65% of patients, in well experienced team. Endoscopic treatment should be the initial management of choice for postoperative bile duct stenosis, as a real alternative to surgical reconstruction: because his failure will not compromised the following surgical treatment prior endoscopic treatment does not preclude surgery), whereas endoscopic treatment is impossible one a Roux-en-Y loop has been constructed


Expression of pS2 in prostate cancer correlates with grade and Chromogranin A expression but not with stage.
The biological potential of prostate cancer is extremely variable. Particular interest is focused on markers not expressed in normal prostatic tissues. pS2 protein expression has been demonstrated in a range of malignant tissues in an oestrogen-independent pathway. Recently, it has been demonstrated that pS2, in prostate cancer, is closely associated with neuro-endocrine differentiation. In the present study, we have analyzed, the potential of Neuro-endocrine and pS2 (TFF1) expression in human prostate cancer determined by immunohistochemistry, in primary adenocarcinoma of the prostate and attempted to correlate this with the clinico-pathologic features of the patient and neuroendocrine expression. Ninety-five malignant prostatic specimens from primary adenocarcinoma, obtained from either transurethral resection of prostate or radical retropubic prostatectomy, from 84 patients between January 1991 and December 1998 were evaluated by immuno-histochemical staining using selected neuroendocrine tumor markers i.e. chromogranin A (CgA) and estrogen inducible pS2 protein. The relationship between the expressions of pS2 was studied with CgA expression, clinical stage (TNM) and tumour grade (Gleason system). Fischer exact test was used for statistical analysis. The mean age of the patients was 70 + /- 9.2 years. The pS2 expression was seen in 10% of primary prostate cancers. Worsening histological grade was associated with greater expression of pS2 (p < 0.001). The expression of CgA was noted in 31% of malignant prostatic tissue. In pS2, positive cases 2/3rd of patients were also CgA +ve. However, there was no significant correlation between pS2 expression and the stage of disease. pS2 expression in prostate cancer significantly correlates with histological grade and the neuroendocrine differentiation, as demonstrated by Chromogranin A expression but not with the clinical stage of the disease. However, the overall expression was low consequently; no definitive conclusions can be drawn. We feel further work is required in a larger series, both in primary and metastatic cancer.


Strategies of professional phagocytes in vivo: unlike macrophages, neutrophils engulf only surface-associated microbes.
The early control of potentially invading microbes by our immune system primarily depends on its main professional phagocytes - macrophages and neutrophils. Although the different functions of these two cell types have been extensively studied, little is known about their respective contributions to the initial control of invading microorganisms before the onset of adaptive immune responses. The naturally translucent zebrafish larva has recently emerged as a powerful model vertebrate in which to visualise the dynamic interactions between leukocytes and microbes in vivo. Using high-resolution live imaging, we found that whereas macrophages efficiently engulf bacteria from blood or fluid-filled body cavities, neutrophils barely do so. By contrast, neutrophils very efficiently sweep up surface-associated, but not fluid-borne, bacteria. Thus the physical presentation of unopsonised microbes is a crucial determinant of neutrophil phagocytic ability. Neutrophils engulf microbes only as they move over them, in a 'vacuum-cleaner' type of behaviour. This context-dependent nature of phagocytosis by neutrophils should be of particular relevance to human infectious diseases, especially for the early phase of encounter with microbes new to the host.


Genetic Defects of the β-Cell That Cause Diabetes.
Individuals with higher-than-normal blood sugar levels used to be diagnosed as having either type 1 or type 2 diabetes. We now know that a wide range of different factors can cause diabetes, including single gene defects, which account for at least 1% of all diabetes cases and up to 4% of cases in the pediatric population. However, misdiagnosis remains common due to the considerable clinical overlap between the different diabetes forms. Monogenic diabetes onset can occur shortly after birth, as observed in neonatal diabetes mellitus, or any time later in life. The present chapter outlines the genes currently known to be involved in monogenic diabetes. Some of these genes are involved in β-cell development, with mutations often leading to a decreased β-cell number, while others play important roles in β-cell function and maintenance. Monogenic forms of autoimmune diabetes and epigenetic causes will also be discussed. A genetic diagnosis may influence treatment choice and prognosis determination and may also lead to family counseling. Genetic screening using next-generation sequencing is becoming more practical as it becomes increasingly accessible and less expensive.


[Role of the stress protein p8 in tumor progression and development of metastasis].
In spite of the great advances made on the knowledge of cancer etiology and the significant breakthroughs in terms of treatment, complete remission is obtained in only around half of cancer patients. In fact, therapies that appear successful for some cancers are totally unfruitful for others, and some cancer types still remain incurables. In order to develop new therapies suitable to these tenacious cancers, we need to renew our view on cancer and to revise some old paradigms and "false friends" that can hide unexpected new therapeutic targets. A good example of these paradigms is the role of the cell stress response in tumor progression. Indeed, a number of studies has been devoted to the pivotal tumor suppressor function of some players of this response, of which the p53 protein is the best example. Nevertheless, during tumor progression and metastasis, the cancer cell faces many stresses imposed by tumor microenvironment and its survival will be conditioned by an efficient cell stress response. This review is consecrated to the role played by a pivotal actor of the cell stress response, the p8 protein, during carcinogenesis. We will recapitulate the data available on its different cell functions and the assets p8 confer to the cancer cell in terms of growth, drugs resistance and metastasis formations.


Bactericidal effect of solar water disinfection under real sunlight conditions.
Batch solar disinfection (SODIS) inactivation kinetics are reported for suspensions in water of Campylobacter jejuni, Yersinia enterocolitica, enteropathogenic Escherichia coli, Staphylococcus epidermidis, and endospores of Bacillus subtilis, exposed to strong natural sunlight in Spain and Bolivia. The exposure time required for complete inactivation (at least 4-log-unit reduction and below the limit of detection, 17 CFU/ml) under conditions of strong natural sunlight (maximum global irradiance, approximately 1,050 W m(-2) +/- 10 W m(-2)) was as follows: C. jejuni, 20 min; S. epidermidis, 45 min; enteropathogenic E. coli, 90 min; Y. enterocolitica, 150 min. Following incomplete inactivation of B. subtilis endospores after the first day, reexposure of these samples on the following day found that 4% (standard error, 3%) of the endospores remained viable after a cumulative exposure time of 16 h of strong natural sunlight. SODIS is shown to be effective against the vegetative cells of a number of emerging waterborne pathogens; however, bacterial species which are spore forming may survive this intervention process.


Survival of Salmonella in bathrooms and toilets in domestic homes following salmonellosis.
The survival and environmental spread of Salmonella bacteria from domestic toilets was examined in homes, where a family member had recently suffered an attack of salmonellosis. In four out of six households tested, Salmonella bacteria persisted in the biofilm material found under the recess of the toilet bowl rim which was difficult to remove with household toilet cleaners. In two homes Salmonella bacteria became incorporated into the scaly biofilm adhering to the toilet bowl surface below the water line. Salmonella enteritidis persisted in one toilet for 4 weeks after the diarrhoea had stopped, despite the use of cleaning fluids. Salmonellas were not isolated from normally dry areas such as, the toilet seat, the flush handle and door handle. Toilet seeding experiments were set up with Salmonella enteritidis PT4 to mimic environmental conditions associated with acute diarrhoea. Flushing the toilet resulted in contamination of the toilet seat and the toilet seat lid. In one out of three seedings, Salmonella bacteria were also isolated from an air sample taken immediately after flushing, indicating that airborne spread of the organism could contaminate surfaces in the bathroom. In the seeded toilet Salmonella bacteria were isolated from the biofilm in the toilet bowl below the waterline for up to 50 d after seeding, and also on one occasion from the bowl water. The results suggest that during diarrhoeal illness, there is considerable risk of spread of Salmonella infection to other family members via the environment, including contaminated hands and surfaces in the toilet area.


A Differential Pressure Instrument with Wireless Telemetry for In-Situ Measurement of Fluid Flow across Sediment-Water Boundaries.
An instrument has been built to carry out continuous in-situ measurement of small differences in water pressure, conductivity and temperature, in natural surface water and groundwater systems. A low-cost data telemetry system provides data on shore in real time if desired. The immediate purpose of measurements by this device is to continuously infer fluxes of water across the sediment-water interface in a complex estuarine system; however, direct application to assessment of sediment-water fluxes in rivers, lakes, and other systems is also possible. Key objectives of the design include both low cost, and accuracy of the order of ±0.5 mm H(2)O in measured head difference between the instrument's two pressure ports. These objectives have been met, although a revision to the design of one component was found to be necessary. Deployments of up to nine months, and wireless range in excess of 300 m have been demonstrated.


Tolerance of hypothalamic beta-endorphin neurons to mu-opioid receptor activation after chronic morphine.
The mu-opioid receptor is an autoreceptor on hypothalamic beta-endorphin neurons that when activated inhibits cell firing via increasing an inwardly rectifying potassium conductance. The membrane hyperpolarization to DAMGO ([D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin) in beta-endorphin and other arcuate (ARC) neurons was investigated in hypothalamic slices from control and morphine-treated, ovariectomized guinea pigs. Chronic morphine treatment caused both a decreased potency (EC50 220 +/- 10 nM vs. 64 +/- 3 nM in controls) and a decreased efficacy (Vmax: -7.1 +/- 1.1 mV vs. -10.7 +/- 0.6 mV in controls) of DAMGO in a population of ARC neurons including beta-endorphin neurons. In another population of ARC neurons from morphine-treated animals, DAMGO was less potent (EC50: 110 +/- 4 nm) than in controls (EC50: 64 +/- 3nM), but there was not a significant change in the efficacy of DAMGO. Twenty percent of ARC neurons did not exhibit any signs of tolerance. The density of mu-opioid receptors labeled with the antagonist radioligand [3H]diprenorphine was found to be significantly decreased in the ARC and surrounding mediobasal hypothalamus after morphine treatment (Bmax: 217 +/- 9 vs. 276 +/- 16 fmol/mg protein in controls), which is consistent with the altered response in beta-endorphin neurons. In summary, chronic morphine treatment decreases mu-opioid receptor density and the functional coupling of mu-opioid receptors to K+ channels in ARC neurons. This expression of morphine tolerance by beta-endorphin (ARC) neurons may serve as a homeostatic mechanism to maintain opioid control of a variety of systems ranging from reproduction to motivation and reward.


The fine structure of dexamethasone-induced growth hormone cells in the anterior pituitary gland of the rat fetus.
The effect of synthetic glucocorticoid, dexamethasone (DEX), on the fine structure of the fetal growth hormone (GH) cell was examined in rats on Days 17-19 of gestation by the protein A-gold method of immuno-electron microscopy. GH cells appeared on Day 19 in the control fetuses. The DEX-induced GH cells of Day 17 fetuses displayed more immature features than those of Day 18, which closely resembled GH cells found in the control fetus on Day 19. Cytological changes which indicate increased secretory activity such as the development of the rough endoplasmic reticulum or enlargement of the Golgi complex, and an accumulation of secretory granules were evident only in the DEX-treated fetuses on Day 19. It is concluded that DEX not only accelerates the development of GH cells, as observed on Day 17 or 18, but also brings them to a functionally stimulated state by Day 19.


Genetics of Intraspecies Variation in Avoidance Behavior Induced by a Thermal Stimulus in Caenorhabditis elegans.
Individuals within a species vary in their responses to a wide range of stimuli, partly as a result of differences in their genetic makeup. Relatively little is known about the genetic and neuronal mechanisms contributing to diversity of behavior in natural populations. By studying intraspecies variation in innate avoidance behavior to thermal stimuli in the nematode Caenorhabditis elegans, we uncovered genetic principles of how different components of a behavioral response can be altered in nature to generate behavioral diversity. Using a thermal pulse assay, we uncovered heritable variation in responses to a transient temperature increase. Quantitative trait locus mapping revealed that separate components of this response were controlled by distinct genomic loci. The loci we identified contributed to variation in components of thermal pulse avoidance behavior in an additive fashion. Our results show that the escape behavior induced by thermal stimuli is composed of simpler behavioral components that are influenced by at least six distinct genetic loci. The loci that decouple components of the escape behavior reveal a genetic system that allows independent modification of behavioral parameters. Our work sets the foundation for future studies of evolution of innate behaviors at the molecular and neuronal level.


Critical limb ischemia: does long-term patency matter?
In critical limb ischemia (CLI), an underlying principle of treatment is that it takes more oxygenated blood to heal a wound than to maintain tissue integrity. Urgent restoration of perfusion to the ischemic territory, not long-term patency of the target vessel, is the primary treatment goal. However, in patients with CLI treated by surgical bypass, loss of graft patency is associated with poor outcomes. We decided to address the conventional wisdom that restenosis is not a major concern in CLI as long as tissue healing occurs in patients undergoing endovascular revascularization. We retrospectively reviewed the records of consecutive patients treated for CLI with infra-popliteal percutaneous revascularization from 2007 to 2009. Those with prior ipsilateral percutaneous revascularization for CLI formed the study population. Among 29 CLI patients treated for infra-popliteal revascularization, six patients had a history of prior successful ipsilateral revascularization for CLI. All six patients were free of rest pain and ulcers at the 60-day follow-up. The median time interval between the two percutaneous revascularization procedures was 21 months (quartile ranges: 25th = 4.5 months, 75th = 36 months). Five of the six patients had restenosis of a previous lesion, while the sixth patient had a de novo lesion causing recurrent CLI. In conclusion, we found that one in five patients receiving infra-popliteal angioplasty for CLI has had a similar percutaneous revascularization procedure in the past. Among these patients most cases were for restenosis rather than de novo lesions. Further research is needed to determine whether the incidence of recurrent CLI is due to de novo lesions or restenosis. Close clinical follow-up of these patients and maintaining long-term patency with endovascular techniques will likely reduce CLI recurrence.


Gliding motility leads to active cellular invasion by Cryptosporidium parvum sporozoites.
We examined gliding motility and cell invasion by an early-branching apicomplexan, Cryptosporidium parvum, which causes diarrheal disease in humans and animals. Real-time video microscopy demonstrated that C. parvum sporozoites undergo circular and helical gliding, two of the three stereotypical movements exhibited by Toxoplasma gondii tachyzoites. C. parvum sporozoites moved more rapidly than T. gondii sporozoites, which showed the same rates of motility as tachyzoites. Motility by C. parvum sporozoites was prevented by latrunculin B and cytochalasin D, drugs that depolymerize the parasite actin cytoskeleton, and by the myosin inhibitor 2,3-butanedione monoxime. Imaging of the initial events in cell entry by Cryptosporidium revealed that invasion occurs rapidly; however, the parasite does not enter deep into the cytosol but rather remains at the cell surface in a membrane-bound compartment. Invasion did not stimulate rearrangement of the host cell cytoskeleton and was inhibited by cytochalasin D, even in host cells that were resistant to the drug. Our studies demonstrate that C. parvum relies on a conserved actin-myosin motor for motility and active penetration of its host cell, thus establishing that this is a widely conserved feature of the Apicomplexa.


Moral Judgment and Empathic/Deontological Guilt.
People often make complicated decisions to help or to punish perfect strangers. Harming someone or breaking some moral imperative is usually linked to feeling guilt, and several researches suggested the existence of two different kinds of guilt: altruistic/empathic and deontological. Our study aimed to investigate the decision-making processes in moral and nonmoral judgments and assess how specific situations in which the subject is close to the victim or flanked by an authority can influence his decisions. We used three different moral conditions: Empathic Moral (the decision has made while physically close to the potential victims), Deontological Moral (the decision has made while flanked by an "authority"), and Standard Moral (without any influence); a fourth condition is represented by Nonmoral dilemmas (the subject must make a choice between two different things and this does not cause any harm or victims). Previously, a pilot study was carried out for validating the experimental stories to be used in the main study. We observed a higher number of utilitarian/positive responses when individuals had to respond to Empathic Moral condition, with respect to Deontological Moral and Nonmoral dilemmas. Moreover, looking at the time needed to read the dilemma, under empathic guilt condition, people tended to be slower in reading the dilemmas than in other conditions and this both in case of positive and negative responses. No significant differences in time needed to effectively respond emerged. These findings suggested that be physically close to potential victims or be flanked by an "authority" differentially influence the decision-making processes in moral judgment, inducing slower decisions and more utilitarian answers, particularly in the scenario of physical proximity.


Dynamics of resistance mutations to NS3 protease inhibitors in a cohort of Brazilian patients chronically infected with hepatitis C virus (genotype 1) treated with pegylated interferon and ribavirin: a prospective longitudinal study.
About sixty thousand new cases of Hepatitis C virus (HCV) infection are recorded in Brazil each year. These cases are currently treated with pegylated interferon (PEG-IFN) and ribavirin (RBV) with an overall success rate of 50%. New compounds for anti-HCV therapy targeted to the HCV NS3 protease are being developed and some already form the components of licensed therapies. Mapping NS3 protease resistance mutations to protease inhibitors or anti-viral drug candidates is important to direct anti-HCV drug treatment. Sequence analysis of the HCV NS3 protease was conducted in a group of 68 chronically infected patients harboring the HCV genotype 1. The patients were sampled before, during and after a course of PEG-IFN-RBV treatment. Resistance mutations to the protease inhibitors, Boceprevir and Telaprevir were identified in HCV isolated from three patients (4.4%); the viral sequences contained at least one of the following mutations: V36L, T54S and V55A. In one sustained virological responder, the T54S mutation appeared during the course of PEG-IFN and RBV therapy. In contrast, V36L and V55A mutations were identified in virus isolated from one relapsing patient before, during, and after treatment, whereas the T54S mutation was identified in virus isolated from one non-responding patient, before and during the treatment course. The incidence and persistence of protease resistance mutations occurring in HCV from chronically infected patients in Brazil should be considered when using protease inhibitors to treat HCV disease. In addition, patients treated with the current therapy (PEG-IFN and RBV) that are relapsing or are non-responders should be considered candidates for protease inhibitor therapy.


Perimenopausal mental disorders: epidemiology and phenomenology.
Perimenopause, the interval of irregular menstrual activity which directly precedes menopause, is characterized by widely fluctuating hormone levels amidst a large-scale decline in circulating estrogen. This phase in a woman's life is typically accompanied by physical discomforts including vasomotor symptoms, such as headaches, insomnia, and hot flushes, as well as genital atrophy. Not surprisingly, studies suggest a significant increase in mood lability for women during this time. While some evidence points toward an exacerbation of bipolar mood symptoms and an increase in schizophrenic psychosis during perimenopause, the majority of research conducted on perimenopausal mental disorders has focused on unipolar depression. Studies vary widely in methodology, definitions of menopausal status, and degrees of depression among subjects; however, the majority of findings indicate an increased susceptibility to depression during the perimenopausal transition. This greater susceptibility may be due to neuroendocrine effects of declining estrogen levels, the subjective experience of somatic symptoms resulting from this hormonal decline, and/or the more frequent occurrence of "exit" or "loss" events for women during this stage of life. At this time, more research is needed to address questions of prevalence, risk, and etiology for depression and other major mental disorders as related to the physiological and psychosocial changes associated with perimenopause.


Functional outcome of stroke inpatients according to human immunodeficiency virus status: A feasibility study.
Stroke in human immunodeficiency virus positive (HIV+) individuals is becoming an increasing concern. Being significantly younger than typical stroke patients, the impact of functional challenges on quality of life and burden on society becomes more eminent. This feasibility study aims to determine the requirements for a large descriptive cohort, to adequately describe the functional outcome of stroke patients with varying HIV status. All stroke patients meeting the inclusion criteria were recruited over a 6-month period at a South African inpatient rehabilitation centre. Data were collected on admission and discharge using outcome measures including the Barthel Index (BI), Berg Balance Scale (BBS) and the use of assistive devices used to describe independence with activities of daily living (ADL), mobility and safety post-stroke. Statistical analysis was performed using Stata version 14.2. The feasibility study identified appropriate procedures and barriers to a successful study in addition to describing preliminary data on participant demographics, relevant medical history and functional outcomes post-stroke. Limitations that affected feasibility included minimal recruitment sites, length of data collection period, timely communication of participant discharge plans and dates, and confirmation of participant HIV status. An appropriate comparison between sub-groups could not be made because of disproportionate group sizes, median age differences and no assessor blinding. To increase generalisability and the understanding of the unique HIV+ stroke profile, multiple recruitment sites, longer data collection periods, assessor blinding and age-matched groups with HIV status confirmation are recommended.


Monosodium Glutamate Dietary Consumption Decreases Pancreatic β-Cell Mass in Adult Wistar Rats.
The amount of dietary monosodium glutamate (MSG) is increasing worldwide, in parallel with the epidemics of metabolic syndrome. Parenteral administration of MSG to rodents induces obesity, hyperglycemia, hyperlipidemia, insulin resistance, and type 2 diabetes. However, the impact of dietary MSG is still being debated. We investigated the morphological and functional effects of prolonged MSG consumption on rat glucose metabolism and on pancreatic islet histology. Eighty adult male Wistar rats were randomly subdivided into 4 groups, and test rats in each group were supplemented with MSG for a different duration (1, 3, 6, or 9 months, n=20 for each group). All rats were fed ad libitum with a standard rat chow and water. Ten test rats in each group were provided MSG 2 mg/g body weight/day in drinking water and the 10 remaining rats in each group served as non-MSG treated controls. Oral glucose tolerance tests (OGTT) were performed and serum insulin measured at 9 months. Animals were sacrificed at 1, 3, 6, or 9 months to examine the histopathology of pancreatic islets. MSG-treated rats had significantly lower pancreatic β-cell mass at 1, 6 and 9 months of study. Islet hemorrhages increased with age in all groups and fibrosis was significantly more frequent in MSG-treated rats at 1 and 3 months. Serum insulin levels and glucose tolerance in MSG-treated and untreated rats were similar at all time points we investigated. Daily MSG dietary consumption was associated with reduced pancreatic β-cell mass and enhanced hemorrhages and fibrosis, but did not affect glucose homeostasis. We speculate that high dietary MSG intake may exert a negative effect on the pancreas and such effect might become functionally significant in the presence or susceptibility to diabetes or NaCl; future experiments will take these crucial cofactors into account.


In situ spectroscopic monitoring of CO2 reduction at copper oxide electrode.
Copper oxide modified electrodes were investigated as a function of applied electrode potential using in situ infrared spectroscopy and ex situ Raman and X-ray photoelectron spectroscopy. In deoxygenated KHCO3 electrolyte bicarbonate and carbonate species were found to adsorb to the electrode during reduction and the CuO was reduced to Cu(i) or Cu(0) species. Carbonate was incorporated into the structure and the CuO starting material was not regenerated on cycling to positive potentials. In contrast, in CO2 saturated KHCO3 solution, surface adsorption of bicarbonate and carbonate was not observed and adsorption of a carbonato-species was observed with in situ infrared spectroscopy. This species is believed to be activated, bent CO2. On cycling to negative potentials, larger reduction currents were observed in the presence of CO2; however, less of the charge could be attributed to the reduction of CuO. In the presence of CO2 CuO underwent reduction to Cu2O and potentially Cu, with no incorporation of carbonate. Under these conditions the CuO starting material could be regenerated by cycling to positive potentials.


Menstrual and reproductive factors in women, genetic variation in CYP17A1, and pancreatic cancer risk in the European prospective investigation into cancer and nutrition (EPIC) cohort.
Menstrual and reproductive factors and exogenous hormone use have been investigated as pancreatic cancer risk factors in case-control and cohort studies, but results have been inconsistent. We conducted a prospective examination of menstrual and reproductive factors, exogenous hormone use and pancreatic cancer risk (based on 304 cases) in 328,610 women from the EPIC cohort. Then, in a case-control study nested within the EPIC cohort, we examined 12 single nucleotide polymorphisms (SNPs) in CYP17A1 (an essential gene in sex steroid metabolism) for association with pancreatic cancer in women and men (324 cases and 353 controls). Of all factors analyzed, only younger age at menarche (<12 vs. 13 years) was moderately associated with an increased risk of pancreatic cancer in the full cohort; however, this result was marginally significant (HR = 1.44; 95% CI = 0.99-2.10). CYP17A1 rs619824 was associated with HRT use (p value = 0.037) in control women; however, none of the SNPs alone, in combination, or as haplotypes were associated with pancreatic cancer risk. In conclusion, with the possible exception of an early age of menarche, none of the menstrual and reproductive factors, and none of the 12 common genetic variants we evaluated at the CYP17A1 locus makes a substantial contribution to pancreatic cancer susceptibility in the EPIC cohort.


Identifying molecular tags selectively retained on the surface of brain endothelial cells to generate artificial targets for therapy delivery.
Current strategies to identify ligands for brain delivery select candidates based on preferential binding to cell-membrane components (CMC) on brain endothelial cells (EC). However, such strategies generate ligands with inherent brain specificity limitations, as the CMC (e.g., the transferrin receptor TfR1) are also significantly expressed on peripheral EC. Therefore, novel strategies are required to identify molecules allowing increased specificity of therapy brain delivery. Here, we demonstrate that, while individual CMC are shared between brain EC and peripheral EC, their endocytic internalization rate is markedly different. Such differential endocytic rate may be harnessed to identify molecular tags for brain targeting based on their selective retention on the surface of brain EC, thereby generating 'artificial' targets specifically on the brain vasculature. By quantifying the retention of labelled proteins on the cell membrane, we measured the general endocytic rate of primary brain EC to be less than half that of primary peripheral (liver and lung) EC. In addition, through bio-panning of phage-displayed peptide libraries, we unbiasedly probed the endocytic rate of individual CMC of liver, lung and brain endothelial cells. We identified phage-displayed peptides which bind to CMC common to all three endothelia phenotypes, but which are preferentially endocytosed into peripheral EC, resulting in selective retention on the surface of brain EC. Furthermore, we demonstrate that the synthesized free-form peptides are capable of generating artificial cell-surface targets for the intracellular delivery of model proteins into brain EC with increasing specificity over time. The developed identification paradigm, therefore, demonstrates that the lower endocytic rate of individual CMC on brain EC can be harnessed to identify peptides capable of generating 'artificial' targets for the selective delivery of proteins into the brain vasculature. In addition, our approach identifies brain-targeting peptides which would have been overlooked by conventional identification strategies, thereby increasing the repertoire of candidates to achieve specific therapy brain delivery.


Identifying Targets for Improving Mental Healthcare of Adolescents with Systemic Lupus Erythematosus: Perspectives from Pediatric Rheumatology Clinicians in the United States and Canada.
To identify targets for improving mental healthcare of adolescents with systemic lupus erythematosus (SLE) by assessing current practices and perceived barriers for mental health intervention by pediatric rheumatology clinicians. Members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) completed a Web-based survey assessing current mental health practices, beliefs, and barriers. We examined associations between provider characteristics and the frequency of barriers to mental health screening and treatment using multivariable linear regression. Of the 375 eligible CARRA members, 130 responded (35%) and 119 completed the survey. Fifty-two percent described identification of depression/anxiety in adolescents with SLE at their practice as inadequate, and 45% described treatment as inadequate. Seventy-seven percent stated that routine screening for depression/anxiety in pediatric rheumatology should be conducted, but only 2% routinely used a standardized instrument. Limited staff resources and time were the most frequent barriers to screening. Respondents with formal postgraduate mental health training, experience treating young adults, and practicing at sites with very accessible mental health staff, in urban locations, and in Canada reported fewer barriers to screening. Long waitlists and limited availability of mental health providers were the most frequent barriers to treatment. Male clinicians and those practicing in the Midwest and Canada reported fewer barriers to treatment. Pediatric rheumatology clinicians perceive a need for improved mental healthcare of adolescents with SLE. Potential strategies to overcome barriers include enhanced mental health training for pediatric rheumatologists, standardized rheumatology-based mental health practices, and better integration of medical and mental health services.


Phosphorylation of CPE binding factor by Eg2 regulates translation of c-mos mRNA.
Full-grown Xenopus oocytes arrest at the G2/M border of meiosis I. Progesterone breaks this arrest, leading to the resumption of the meiotic cell cycles and maturation of the oocyte into a fertilizable egg. In these oocytes, progesterone interacts with an unidentified surface-associated receptor, which induces a non-transcriptional signalling pathway that stimulates the translation of dormant c-mos messenger RNA. Mos, a mitogen-activated protein (MAP) kinase kinase kinase, indirectly activates MAP kinase, which in turn leads to oocyte maturation. The translational recruitment of c-mos and several other mRNAs is regulated by cytoplasmic polyadenylation, a process that requires two 3' untranslated regions, the cytoplasmic polyadenylation element (CPE) and the polyadenylation hexanucleotide AAUAAA. Although the signalling events that trigger c-mos mRNA polyadenylation and translation are unclear, they probably involve the activation of CPEB, the CPE binding factor. Here we show that an early site-specific phosphorylation of CPEB is essential for the polyadenylation of c-mos mRNA and its subsequent translation, and for oocyte maturation. In addition, we show that this selective, early phosphorylation of CPEB is catalysed by Eg2, a member of the Aurora family of serine/threonine protein kinases.


Incorporation of cytosine arabinoside monophosphate into DNA at internucleotide linkages by human DNA polymerase alpha.
The incorporation of cytosine arabinoside monophosphate (araCMP) into DNA at internucleotide linkages by DNA polymerase alpha (DNA pol alpha) has been investigated by using oligonucleotide primed DNA templates. The products of reactions catalyzed by DNA pol alpha in vitro were analyzed on polyacrylamide gels to measure insertion of araCMP, extension from an araCMP 3' terminus, and binding of the enzyme to an araCMP 3' terminus. The results show that insertion of araCMP opposite dGMP in the DNA template is about 3-fold less efficient than insertion of dCMP. Extension from an araCMP 3' terminus by addition of the next complementary nucleotide is approximately 2000-fold less efficient than extension from a correctly base-paired 3' terminus. In the absence of the second substrate, dNTP, DNA pol alpha binds with approximately equal affinities to DNA templates that contain oligonucleotide primers with araCMP or dCMP positioned at the 3' terminus. In the presence of dNTP, the enzyme extends the araCMP 3' terminus or dissociates, but it is not trapped at the araCMP 3' terminus in a nonproductive ternary complex as is observed at the ddCMP 3' terminus. To determine if slow phosphodiester bond formation contributes to the observed extension rate from the araCMP 3' terminus by DNA pol alpha, oligonucleotide primers with araCMP positioned at the 3' terminus were elongated by addition of the alpha-phosphorothioate analogue of the next complementary nucleotide. The rate of extension from araCMP by addition of 2'-deoxyadenosine 5'-O-phosphorothioate (dAMP alpha S) was 6-fold slower than by addition of dAMP, indicating that bond formation is partially rate limiting in the extension reaction. Thus, inefficient extension from the araCMP 3' terminus is the major determinant contributing to the low incorporation frequency of araCMP into DNA by DNA pol alpha, and this inefficiency can be attributed, in part, to slower phosphodiester bond formation at the araCMP 3' terminus.


Naturally grown rucola, Eruca sativa, contains more α-linolenic acid than conventionally grown rucola.
The ratio of dietary n-6/n-3 polyunsaturated fatty acids is higher in the modern Western meal when compared with that of the Paleolithic era. Evidences have been accumulating that the extremely high ratio of dietary n-6/n-3 polyunsaturated fatty acids increases the risk of disease and the deterioration of physical conditions among humans. In this study, the ratio of linoleic acid (C18:2, n-6) and α-linolenic acid (C18:3, n-3) of rucola, Eruca sativa, was compared between naturally grown samples and conventional farming products (n=3 for each). We found that the naturally grown rucola contained significantly higher amount of α-linolenic acid (p=0.026), resulting in the lower ratio of linoleic acid and α-linolenic acid than the conventional (p=0.016). This finding suggests that vegetables cultured in conventional farming method could decrease the health promotion effects that the vegetables originally possess in natural environment.


X-ray crystallographic structures of D-xylose isomerase-substrate complexes position the substrate and provide evidence for metal movement during catalysis.
The X-ray crystallographic structures of the metal-activated enzyme xylose isomerase from Streptomyces olivochromogenes with the substrates D-glucose, 3-O-methyl-D-glucose and in the absence of substrate were determined to 1.96-, 2.19-, and 1.81-A resolution and refined to R-factors of 16.6%, 15.9%, and 16.1%, respectively. Xylose isomerase catalyzes the interconversion between glucose and fructose (xylose and xylulose under physiological conditions) by utilizing two metal cofactors to promote a hydride shift; the metals are bridged by a glutamate residue. This puts xylose isomerase in the small but rapidly growing family of enzymes with a bridged bimetallic active site, in which both metals are involved in the chemical transformation. The substrate 3-O-methylglucose was chosen in order to position the glucose molecule in the observed electron density unambiguously. Of the two essential magnesium ions per active site, Mg-2 was observed to occupy two alternate positions, separated by 1.8 A, in the substrate-soaked structures. The deduced movement was not observed in the structure without substrate present and is attributed to a step following substrate binding but prior to isomerization. The substrates glucose and 3-O-methylglucose are observed in their linear extended forms and make identical interactions with the enzyme by forming ligands to Mg-1 through O2 and O4 and by forming hydrogen bonds with His53 through O5 and Lys182 through O1. Mg-2 has a water ligand that is interpreted in the crystal structure in the absence of substrate as a hydroxide ion and in the presence of substrate as a water molecule. This hydroxide ion may act as a base to deprotonate the glucose O2 and subsequently protonate the product fructose O1 concomitant with hydride transfer. Calculations of the solvent-accessible surface of possible dimers, with and without the alpha-helical C-terminal domain, suggest that the tetramer is the active form of this xylose isomerase.


Elucidation of the effect of brain cortex tetrapeptide Cortagen on gene expression in mouse heart by microarray.
Aging is associated with significant alterations in gene expression in numerous organs and tissues. Anti-aging therapy with peptide bioregulators holds much promise for the correction of age-associated changes, making a screening for their molecular targets in tissues an important question of modern gerontology. The synthetic tetrapeptide Cortagen (Ala-Glu-Asp-Pro) was obtained by directed synthesis based on amino acid analysis of natural brain cortex peptide preparation Cortexin. In humans, Cortagen demonstrated a pronounced therapeutic effect upon the structural and functional posttraumatic recovery of peripheral nerve tissue. Importantly, other effects were also observed in cardiovascular and cerebrovascular parameters. Based on these latter observations, we hypothesized that acute course of Cortagen treatment, large-scale transcriptome analysis, and identification of transcripts with altered expression in heart would facilitate our understanding of the mechanisms responsible for this peptide biological effects. We therefore analyzed the expression of 15,247 transcripts in the heart of female 6-months CBA mice receiving injections of Cortagen for 5 consecutive days was studied by cDNA microarrays. Comparative analysis of cDNA microarray hybridisation with heart samples from control and experimental group revealed 234 clones (1,53% of the total number of clones) with significant changes of expression that matched 110 known genes belonging to various functional categories. Maximum up- and down-regulation was +5.42 and -2.86, respectively. Intercomparison of changes in cardiac expression profile induced by synthetic peptides (Cortagen, Vilon, Epitalon) and pineal peptide hormone melatonin revealed both common and specific effects of Cortagen upon gene expression in heart.


Fortune teller fermions in two-dimensional materials.
Dirac-like electronic states are the main engines powering tremendous advancements in the research of graphene, topological insulators and other materials with these states. Zero effective mass, high carrier mobility and numerous applications are some consequences of linear dispersion that distinguishes Dirac states. Here we report a new class of linear electronic bands in two-dimensional materials with zero electron effective mass and sharp band edges, and predict stable materials with such electronic structures utilizing symmetry group analysis and an ab initio approach. We make a full classification of completely linear bands in two-dimensional materials and find that only two classes exist: Dirac fermions on the one hand and fortune teller-like states on the other hand. The new class supports zero effective mass similar to that of graphene and anisotropic electronic properties like that of phosphorene.


Validation of the vasoactive-inotropic score in predicting pediatric septic shock mortality: A retrospective cohort study.
Mortality in pediatric septic shock remains very high. Vasoactive-inotropic score (VIS) is widely used to predict prognosis in patients with heart disease. It is a simple method that was initially used as a predictor of morbidity and mortality in postoperative patients with congenital heart diseases. Previous reports showed that high VIS score was associated with high mortality in pediatric sepsis. However, its discriminative value remains unclear. We aim to explore the discriminative value of VIS in predicting mortality in pediatric septic shock patients. We conducted a retrospective cohort study on medical records of septic shock patients who received care in the pediatric intensive care unit (PICU). We screened medical records of pediatric patients which were diagnosed with septic shock and admitted to the PICU and received vasoactive/inotropic score for more than 8 h. Other supporting examination results were recorded, such as organ function evaluation for calculation of Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score. The outcome of patients was recorded. The receiver operating curve was constructed to calculate the area under the curve (AUC), sensitivity, and specificity of each cutoff point. We obtained the optimum cutoff point of VIS > 11 with 78.87% sensitivity and 72.22% specificity. AUC positive was 0.779 (P < 0.001); predictive value and negative predictive value were 91.80% and 46.43%, respectively. VIS > 11 has a good ability to predict mortality in children with septic shock.


Unexpected host dependency of Antarctic Nanohaloarchaeota.
In hypersaline environments, Nanohaloarchaeota (Diapherotrites, Parvarchaeota, Aenigmarchaeota, Nanoarchaeota, Nanohaloarchaeota [DPANN] superphylum) are thought to be free-living microorganisms. We report cultivation of 2 strains of Antarctic Nanohaloarchaeota and show that they require the haloarchaeon Halorubrum lacusprofundi for growth. By performing growth using enrichments and fluorescence-activated cell sorting, we demonstrated successful cultivation of Candidatus Nanohaloarchaeum antarcticus, purification of Ca. Nha. antarcticus away from other species, and growth and verification of Ca. Nha. antarcticus with Hrr. lacusprofundi; these findings are analogous to those required for fulfilling Koch's postulates. We use fluorescent in situ hybridization and transmission electron microscopy to assess cell structures and interactions; metagenomics to characterize enrichment taxa, generate metagenome assembled genomes, and interrogate Antarctic communities; and proteomics to assess metabolic pathways and speculate about the roles of certain proteins. Metagenome analysis indicates the presence of a single species, which is endemic to Antarctic hypersaline systems that support the growth of haloarchaea. The presence of unusually large proteins predicted to function in attachment and invasion of hosts plus the absence of key biosynthetic pathways (e.g., lipids) in metagenome assembled genomes of globally distributed Nanohaloarchaeota indicate that all members of the lineage have evolved as symbionts. Our work expands the range of archaeal symbiotic lifestyles and provides a genetically tractable model system for advancing understanding of the factors controlling microbial symbiotic relationships.


Invasive fungal rhinosinusitis: a 15-year experience with 29 patients.
Document a 15-year experience with 29 cases of acute invasive fungal rhinosinusitis (AIFR) and evaluate factors predictive of disease clearance and overall survival. Case series with chart review. Patients were identified by review of department billing records between 1995 and 2010. Medical records were reviewed for patient demographics, disease characteristics, clinical course including surgical and medical therapy, treatment outcomes, and long-term survival. Twenty-nine patients with AIFR were identified. Causes of immunosuppression included hematologic malignancy (n=16), diabetes (n=12), medication (n=10), and acquired immunodeficiency syndrome (n=1), with 10 patients having multiple causes of immunosuppression. Facial pain, swelling and orbital symptoms were the most common presenting symptoms. Fungal organisms included Mucor (n=18) and Aspergillus (n=10) species, with one patient infected with both. Disease-specific survival (DSS) from AIFR was 57%. Intracranial (P=.01) and ethmoid sinus (P=.05) involvement were significantly linked with short-term disease-related mortality. Overall survival (OS) at 6 months was 18%. For OS, intracranial involvement (hazard ratio [HR], 4.47; 95% confidence interval [CI], 1.51-13.22) and cranial neuropathy at presentation (HR, 3.2; 95% CI, 1.3-8.2) were significantly associated with shortened survival. Of the five patients surviving >6 months, two developed long-term major sinonasal complications. DSS and OS remain low for patients with AIFR. Extensive surgical resection in patients with these poor prognostic signs should be considered carefully in light of their poor survival. Long-term survivors are at significant risk of sinonasal complications and should be followed closely.


The lasting effects of spike insoles on postural control in the elderly.
The purpose of the present study was to explore the lasting effects of a tactile sensitivity enhancement induced by spike insoles on the control of stance in the elderly. Healthy elderly subjects (n = 19, mean age = 68.8) and young adults (n = 17, mean age = 24.3) were instructed to stand or to walk for 5 minutes with sandals equipped with spike insoles. Postural control was evaluated four times during unperturbed stance: (1) before putting on the sandals equipped with spike insoles, (2) 5 minutes after standing or walking with them, (3) immediately after placing thin, smooth, and flexible insoles (no spike insoles) into the sandals to avoid the cutaneous contact with the spikes, and (4) after a sitting rest of 5 minutes with the no spike insoles. Sway parameters such as surface area, mean speed and root mean square were recorded. The present results suggest that (1) whatever the session (i.e. standing or walking) and the population, the artificial sensory message elicited by the spikes improved postural sway and, (2) the elderly were particularly perturbed when the tactile sensitivity enhancement device was removed. Whatever the age, the enriched sensory context provided by this tactile sensitivity enhancement device led to a better postural control; its suppression entailed a reweighting of the plantar cutaneous information. The difficulty that the elderly had to adjust the relative contribution of the different inputs probably reflected their poorer central integrative mechanisms for the reconfiguration of the postural set. A reduced peripheral sensitivity may also explain these postural deficits.


Size dependence of harvested BaTiO3 nanoparticles on the electro-optic and dielectric properties of ferroelectric liquid crystal nanocolloids.
The influence of the size of harvested barium titanate nanoparticles on the properties of ferroelectric liquid crystal (FLC) nanocolloids was investigated by electro-optical and dielectric methods. The spontaneous polarization and the switching time are decreased for the liquid crystalline nanocolloids compared to nondoped FLC mixtures of different dipole strengths; this dependence is stronger for small size particles (9 nm) and weaker for larger size particles (26 nm) by the same concentration in weight. The decrease of the Goldstone mode (GM) relaxation frequency and the decrease of the dielectric GM absorption strength of the nanocomposites compared to the nondoped FLC mixture go stepwise with the increase of the nanoparticles diameter. Results have been interpreted via strong interaction between the FLC dipoles and the dipoles of the highly polar barium titanate nanoparticles.


The role of communities in advancing the goals of the Movement for Global Mental Health.
This special section of Transcultural Psychiatry explores the local-global spaces of engagement being opened up by the Movement for Global Mental Health, with particular emphasis on the need for expanded engagement with local communities. Currently the Movement places its main emphasis on scaling up mental health services and advocating for the rights of the mentally ill, framed within universalised western understandings of health, healing and personhood. The papers in this section emphasise the need for greater attention to the impacts of context, culture and local survival strategies on peoples' responses to adversity and illness, greater acknowledgement of the agency and resilience of vulnerable communities and increased attention to the way in which power inequalities and social injustices frame peoples' opportunities for mental health. In this Introduction, we highlight ways in which greater community involvement opens up possibilities for tackling each of these challenges. Drawing on community health psychology, we outline our conceptualisation of "community mental health competence" defined as the ability of community members to work collectively to facilitate more effective prevention, care, treatment and advocacy. We highlight the roles of multi-level dialogue, critical thinking and partnerships in facilitating both the "voice" of vulnerable communities as well as "receptive social environments" where powerful groups are willing to recognise communities' needs and assist them in working for improved well-being. Respectful local-global alliances have a key role to play in this process. The integration of local community struggles for mental health into an energetic global activist Movement opens up exciting possibilities for translating the Movement's calls for improved global mental health from rhetoric to reality.


Risk factors for the onset of non-specific neck pain: a systematic review.
Neck pain is a common musculoskeletal disorder, but little is known about which individuals develop neck pain. This systematic review investigated factors that constitute a risk for the onset of non-specific neck pain. A range of electronic databases and reference sections of relevant articles were searched to identify appropriate articles. Studies investigating risk factors for the onset of non-specific neck pain in asymptomatic populations were included. All studies were prospective with at least 1 year follow-up. 14 independent cohort studies met the inclusion criteria for the review. Thirteen studies were assessed as high quality. Female gender, older age, high job demands, low social/work support, being an ex-smoker, a history of low back disorders and a history of neck disorders were linked to the development of non-specific neck pain. Various clinical and sociodemographic risk factors were identified that have implications for occupational health and health policy. However, there was a lack of good-quality research investigating the predictive nature of many other variables.


Accumulation of cyclic AMP elicited by vasoactive intestinal peptide is potentiated by noradrenaline, histamine, adenosine, baclofen, phorbol esters, and ouabain in mouse cerebral cortical slices: studies on the role of arachidonic acid metabolites and protein kinase C.
In mouse cerebral cortical slices, noradrenaline (NA) potentiates cyclic AMP (cAMP) accumulation elicited by vasoactive intestinal peptide (VIP) through alpha 1-adrenergic receptors. This synergism is inhibited by indomethacin, and the prostaglandins E2 and F2 alpha mimic the effect of NA. In the present study, we observed that the synergism between VIP and NA is not inhibited by the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) or the diacylglycerol-lipase inhibitor RHC 80267, thus further stressing the role of phospholipase A2 activation. Various neuroactive agents that potentiate the stimulatory effect of VIP on cAMP formation were also examined. As with NA, the potentiation by histamine and adenosine is inhibited by indomethacin. In contrast to NA, histamine, and adenosine, the synergistic interaction between phorbol esters and VIP on cAMP formation is abolished by H-7 but not by indomethacin. The potentiation by baclofen, a gamma-aminobutyric acidB receptor agonist, is partially inhibited by the 5-lipoxygenase inhibitor nafazatrom. The synergism between ouabain and VIP is reduced by H-7 but not by indomethacin and nafazatrom. These data indicate that the stimulation of cAMP formation elicited by VIP is under the modulation of various neuroactive agents that trigger diverse intracellular mechanisms to potentiate the effect of the peptide.


Blood pressure management: individualized treatment based on absolute risk and the potential for benefit.
Clinical practice often conflicts with epidemiologic evidence in the management of blood pressure. Antihypertensive therapy is generally prescribed if blood pressure exceeds some arbitrary level, thus committing many persons with minimal cardiovascular risk to long-term drug therapy. By contrast, below that level, regardless of cardiovascular risk, blood pressure reduction is rarely sought. Epidemiologic data, however, consistently show a continuous, positive, linear relationship of the height of both systolic and diastolic blood pressure with the incidence of stroke and heart attack. No threshold level distinguishes those who will have a cardiovascular event from those who will not. In fact, most heart attacks and many strokes occur among persons with "normal" blood pressures. Observational experience suggests that benefit could be obtained from universal blood pressure reduction of even a few millimeters of mercury. This public health strategy can be augmented by identifying those individuals, at every level of blood pressure, whose risk for cardiovascular disease justifies the cost of pharmacologic intervention. Antihypertensive drug therapy will be most efficient and effective if directed at those who, by virtue of their constellation of risk factors or evidence of preclinical vascular disease, are likely to have a heart attack or stroke. The resulting redirection of clinical resources will spare many hypertensive persons whose absolute risk for a cardiovascular event is small, from life-long treatment. At the same time, other persons, currently classified as normotensive, will become candidates for blood pressure reduction because their cardiovascular risk is high.


The role of culture in the context of school-based BMI screening.
The high prevalence of overweight and obesity is a significant public health concern in the United States. Minority populations are disproportionately affected, and the impact of obesity on minority children is especially alarming. In this article we discuss school-based BMI reporting, which is intended to increase parental awareness of their children's weight status. This information could potentially lead parents of overweight and obese children to carefully examine and possibly change their children's diet and activity patterns. However, any program related to child weight status must consider culturally defined aspects of body size and shape. In other words, the cultural context in which information on child BMI is presented to and received by parents must be considered. In this article we review parental perceptions of child weight. Multiple studies have shown that parents of overweight or obese children often fail to correctly perceive their children as overweight. Possible reasons for, and implications of, this misperception of child weight status among minority parents are then explored within a cultural framework. The PEN-3 model is used to examine influences on health behaviors and could help inform the development of a culturally sensitive BMI-notification program for minority parents. Reporting materials congruent with the social and cultural values and practices of the target audience are likely to maximize program effectiveness. A culturally based BMI-notification program should be conceptualized as a small step in a comprehensive plan to reduce childhood obesity and improve the current and future health of minority children.


Virus versus host cell translation love and hate stories.
Regulation of protein synthesis by viruses occurs at all levels of translation. Even prior to protein synthesis itself, the accessibility of the various open reading frames contained in the viral genome is precisely controlled. Eukaryotic viruses resort to a vast array of strategies to divert the translation machinery in their favor, in particular, at initiation of translation. These strategies are not only designed to circumvent strategies common to cell protein synthesis in eukaryotes, but as revealed more recently, they also aim at modifying or damaging cell factors, the virus having the capacity to multiply in the absence of these factors. In addition to unraveling mechanisms that may constitute new targets in view of controlling virus diseases, viruses constitute incomparably useful tools to gain in-depth knowledge on a multitude of cell pathways.


Assessing the public health importance of Schistosoma mansoni in different endemic areas: attributable fraction estimates as an approach.
Assessment of the public health importance of schistosomiasis mansoni is hampered by the nonspecificity of many of its disease symptoms. Parasitologic, clinical, and anamnestic data from two areas in Burundi were used to obtain estimates of the attributable fractions for different disease symptoms at both the population level and within different age strata. A large proportion of individuals had symptoms commonly associated with Schistosoma mansoni infection that were not attributable to this parasite. The clinical indicator with the best test efficiency was shown to be bloody diarrhea. At the population level, 35% of bloody diarrhea cases were attributable to S. mansoni, compared with only 9% of diarrhea cases without blood. The attributable fractions were age-dependent, and in the case of diarrhea (with and without blood), children had a higher proportion of cases attributable to S. mansoni infection than adults. The association between infection and disease symptoms also increased with the intensity of infection. The prevalence of morbidity attributable to S. mansoni was similar for all symptoms, and higher in children than adults. The estimation of attributable fractions provides a simple approach to quantify S. mansoni-related morbidity, which could also be extended to both S. haematobium and S. japonicum. Attributable fraction estimates for these three schistosome species in different endemic areas would greatly aid in the assessment of the health burden of this parasite and the effectiveness of control programs.


Integrating quality improvement and residency education: insights from the AIAMC National Initiative about the roles of the designated institutional official and program director.
Active engagement of both the designated institutional official (DIO) and the program director (PD) is essential to implement any change in graduate medical education (GME). Strategies that are established by the Accreditation Council for Graduate Medical Education or other entities are, in the end, effective only as implemented at the individual program level. The interpretation of national standards or guidelines, and the specific adaptation to the vagaries of individual institutions and programs, can lead to significant variability in implementation and potentially in outcomes. Variability occurs between programs within the same institution and between some specialty programs at different institutions. The National Initiative, sponsored by the Alliance of Independent Academic Medical Centers, was launched in 2007 to demonstrate the effectiveness of GME as a key driver to improve quality, patient safety, and cost-effectiveness of care. This report addresses (1) the key roles of both the DIO and the PD in achieving the goals of the National Initiative, (2) the challenges these goals presented to each role, and (3) some of the tactics drawn from the experiences of the National Initiative in overcoming those challenges. The experience of the National Initiative underscored the synergies of the DIO and PD roles to improve patient care while simultaneously fulfilling their critical responsibilities as institutional and program leaders in GME with even greater effectiveness.


Generation of optical pulses in VCSELs below the static threshold using asymmetric current modulation.
We present a novel method for the generation of sub-nanosecond optical pulses in directly modulated vertical-cavity surface-emitting lasers (VCSELs) that operate, on average, below the cw threshold. Using the spin-flip model we demonstrate that irregular optical pulses in two orthogonal linear polarizations can be generated via asymmetric triangular modulation of period of a few nanoseconds, with a slow rising ramp followed by a fast decreasing one. For an optimal modulation asymmetry the effective threshold reduction is about 20%, the pulse amplitude is maximum and the dispersion of the pulse amplitude is minimum.


Vaccines for measles, mumps, rubella, and varicella in children.
Measles, mumps, rubella, and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness. This is an update of a review published in 2005 and updated in 2012. To assess the effectiveness, safety, and long- and short-term adverse effects associated with the trivalent vaccine, containing measles, rubella, mumps strains (MMR), or concurrent administration of MMR vaccine and varicella vaccine (MMR+V), or tetravalent vaccine containing measles, rubella, mumps, and varicella strains (MMRV), given to children aged up to 15 years. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2019, Issue 5), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2 May 2019), Embase (1974 to 2 May 2019), the WHO International Clinical Trials Registry Platform (2 May 2019), and ClinicalTrials.gov (2 May 2019). We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective cohort studies (PCS/RCS), case-control studies (CCS), interrupted time-series (ITS) studies, case cross-over (CCO) studies, case-only ecological method (COEM) studies, self-controlled case series (SCCS) studies, person-time cohort (PTC) studies, and case-coverage design/screening methods (CCD/SM) studies, assessing any combined MMR or MMRV / MMR+V vaccine given in any dose, preparation or time schedule compared with no intervention or placebo, on healthy children up to 15 years of age. Two review authors independently extracted data and assessed the methodological quality of the included studies. We grouped studies for quantitative analysis according to study design, vaccine type (MMR, MMRV, MMR+V), virus strain, and study settings. Outcomes of interest were cases of measles, mumps, rubella, and varicella, and harms. Certainty of evidence of was rated using GRADE. We included 138 studies (23,480,668 participants). Fifty-one studies (10,248,159 children) assessed vaccine effectiveness and 87 studies (13,232,509 children) assessed the association between vaccines and a variety of harms. We included 74 new studies to this 2019 version of the review. Effectiveness Vaccine effectiveness in preventing measles was 95% after one dose (relative risk (RR) 0.05, 95% CI 0.02 to 0.13; 7 cohort studies; 12,039 children; moderate certainty evidence) and 96% after two doses (RR 0.04, 95% CI 0.01 to 0.28; 5 cohort studies; 21,604 children; moderate certainty evidence). The effectiveness in preventing cases among household contacts or preventing transmission to others the children were in contact with after one dose was 81% (RR 0.19, 95% CI 0.04 to 0.89; 3 cohort studies; 151 children; low certainty evidence), after two doses 85% (RR 0.15, 95% CI 0.03 to 0.75; 3 cohort studies; 378 children; low certainty evidence), and after three doses was 96% (RR 0.04, 95% CI 0.01 to 0.23; 2 cohort studies; 151 children; low certainty evidence). The effectiveness (at least one dose) in preventing measles after exposure (post-exposure prophylaxis) was 74% (RR 0.26, 95% CI 0.14 to 0.50; 2 cohort studies; 283 children; low certainty evidence). The effectiveness of Jeryl Lynn containing MMR vaccine in preventing mumps was 72% after one dose (RR 0.24, 95% CI 0.08 to 0.76; 6 cohort studies; 9915 children; moderate certainty evidence), 86% after two doses (RR 0.12, 95% CI 0.04 to 0.35; 5 cohort studies; 7792 children; moderate certainty evidence). Effectiveness in preventing cases among household contacts was 74% (RR 0.26, 95% CI 0.13 to 0.49; 3 cohort studies; 1036 children; moderate certainty evidence). Vaccine effectiveness against rubella, using a vaccine with the BRD2 strain which is only used in China, is 89% (RR 0.11, 95% CI 0.03 to 0.42; 1 cohort study; 1621 children; moderate certainty evidence). Vaccine effectiveness against varicella (any severity) after two doses in children aged 11 to 22 months is 95% in a 10 years follow-up (rate ratio (rr) 0.05, 95% CI 0.03 to 0.08; 1 RCT; 2279 children; high certainty evidence). Safety There is evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains, but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (rr 1.30, 95% CI 0.66 to 2.56; low certainty evidence). The analyses provide evidence supporting an association between MMR/MMR+V/MMRV vaccines (Jeryl Lynn strain) and febrile seizures. Febrile seizures normally occur in 2% to 4% of healthy children at least once before the age of 5. The attributable risk febrile seizures vaccine-induced is estimated to be from 1 per 1700 to 1 per 1150 administered doses. The analyses provide evidence supporting an association between MMR vaccination and idiopathic thrombocytopaenic purpura (ITP). However, the risk of ITP after vaccination is smaller than after natural infection with these viruses. Natural infection of ITP occur in 5 cases per 100,000 (1 case per 20,000) per year. The attributable risk is estimated about 1 case of ITP per 40,000 administered MMR doses. There is no evidence of an association between MMR immunisation and encephalitis or encephalopathy (rate ratio 0.90, 95% CI 0.50 to 1.61; 2 observational studies; 1,071,088 children; low certainty evidence), and autistic spectrum disorders (rate ratio 0.93, 95% CI 0.85 to 1.01; 2 observational studies; 1,194,764 children; moderate certainty). There is insufficient evidence to determine the association between MMR immunisation and inflammatory bowel disease (odds ratio 1.42, 95% CI 0.93 to 2.16; 3 observational studies; 409 cases and 1416 controls; moderate certainty evidence). Additionally, there is no evidence supporting an association between MMR immunisation and cognitive delay, type 1 diabetes, asthma, dermatitis/eczema, hay fever, leukaemia, multiple sclerosis, gait disturbance, and bacterial or viral infections. AUTHORS' CONCLUSIONS: Existing evidence on the safety and effectiveness of MMR/MMRV vaccines support their use for mass immunisation. Campaigns aimed at global eradication should assess epidemiological and socioeconomic situations of the countries as well as the capacity to achieve high vaccination coverage. More evidence is needed to assess whether the protective effect of MMR/MMRV could wane with time since immunisation.


Prophylactic effects of 1,24,25-trihydroxyvitamin D3 on ovariectomy-induced cancellous bone loss in the rat.
Vitamin D metabolites can prevent estrogen depletion-induced bone loss in ovariectomized (OVX) rats. In this study, we investigated the bone-sparing effects of oral 1alpha,24R,25-trihydroxyvitamin D3 (1,24,25(OH)3D3) in a wide dose range in aged OVX rats. Fifty-three female Fischer-344 rats (6 months old, 170 g BW) were either ovariectomized or sham-operated (SHAM). Eight rats served as baseline controls. Groups of OVX rats (n = 7-8 each) received vehicle alone or graded oral doses of 1,24,25(OH)3D3 (0.05, 0.1, 0.2, and 0.3 microg/kg BW/day), starting five days after surgery. Urine and blood samples were collected one, two, three, and four months after surgery. Serum samples were analyzed for total calcium and alkaline phosphatase. Calcium, hydroxyproline, and collagen crosslinks (HPLC) were determined in urine. After fluorochrome double labeling, the rats were sacrificed four months postsurgery and the first lumbar vertebrae and the proximal tibiae were processed undecalcified for bone histomorphometry. Ovariectomy induced a 28% and a 69% reduction in vertebral and tibial cancellous bone area, respectively. Osteopenia in OVX rats was associated with increased histomorphometric and biochemical indices of bone turnover. The administration of 1,24,25(OH)3D3 to OVX rats dose-dependently increased vertebral and tibial cancellous bone mass, serum calcium, and urinary calcium excretion, and reduced histomorphometric and biochemical indices of bone resorption. 1,24,25(OH)3D3 at doses of 0. 2 and 0.3 microg/kg/day produced strong anabolic effects, especially on vertebral cancellous bone in OVX rats, and increased mineral apposition rate and wall width of completed remodeling units relative to vehicle-treated OVX rats. Even at high doses, 1,24, 25(OH)3D3 did not impair bone mineralization. We conclude that oral administration of 1,24,25(OH)3D3 can effectively prevent estrogen depletion-induced cancellous bone osteopenia in the aged OVX rat model. The therapeutic window for 1,24,25(OH)3D3 in OVX rats, however, is also narrow, comparable to that for calcitriol.


Gonadotropin-releasing hormone antagonists.
Hypothalamic gonadotropin-releasing hormone (GnRH) is a decapeptide that stimulates pituitary synthesis and secretion of gonadotropins and, therefore, gonadal hormones. GnRH antagonists, of which thousands have been formulated, inhibit the hormone from binding to its receptor, inducing a pharmacological hypophysectomy. Peptide derivations of GnRH and non-peptide compounds are both in clinical trials or approved for assisted reproduction. As these compounds reach the market, the use of antagonists might expand to treatment of other hormonally dependent diseases, hormonal male contraception and growth inhibition of extra-pituitary cancer cells expressing GnRH receptors.


Enrichment, detection and clinical significance of circulating tumor cells.
Circulating Tumor Cells (CTCs) are shed from primary or secondary tumors into blood circulation. Accessing and analyzing these cells provides a non-invasive alternative to tissue biopsy. CTCs are estimated to be as few as 1 cell among a few million WBCs and few billion RBCs in 1 ml of patient blood and are rarely found in healthy individuals. CTCs are FDA approved for prognosis of the major cancers, namely, Breast, Colon and Prostate. Currently, more than 400 clinical trials are ongoing to establish their clinical significance beyond prognosis, such as, therapy selection and companion diagnostics. Understanding the clinical relevance of CTCs typically involves isolation, detection and molecular characterization of cells, ideally at single cell level. The need for highly reliable, standardized and robust methodologies for isolating and analyzing CTCs has been widely expressed by clinical thought leaders. In the last decade, numerous academic and commercial technology platforms for isolation and analysis of CTCs have been reported. A recent market report highlighted the presence of more than 100 companies offering products and services related to CTCs. This review aims to capture the state of the art and examines the technical merits and limitations of contemporary technologies for clinical use.


Radiological features in Brachmann-de Lange syndrome.
Brachmann-de Lange syndrome (BDLS) is a well-delineated disorder consisting variably of pre- and postnatal growth deficiency, microbrachycephaly, characteristic face, hypertrichosis, visceral anomalies, and limb defects consisting primarily of variable limb reduction defects, micromelia, and elbow abnormalities. The course is usually marked by initial hypertonicity, low-pitched weak cry, feeding problems, and behavioral problems with marked mental deficiency. In classical cases there is rarely any difficulty in making the diagnosis, but for mildly affected cases, it may be difficult to feel secure about the diagnosis. In an effort to increase the precision of diagnosis for mildly affected cases, we reviewed roentgenograms in 21 cases of Brachmann-de Lange syndrome, as well as previously published descriptions of the radiological manifestations. Unusual radiologic manifestations were related primarily to the limb anomalies, and these were often asymmetric. These manifestations included digital abnormalities, which ranged from acheiria to oligodactyly, hypoplasia of the thumb and first metacarpal, clinodactyly of the fifth finger, or ectrodactyly. Long bone abnormalities included ulnar a/hypoplasia, dysplasia of the radial head, or fusion of the elbow. When there was a single forearm bone, there was often fusion at the elbow and oligodactyly, which made it difficult to determine whether the radius or ulna was absent. Other radiologic manifestations included 13 ribs with precocious sternal fusion, and micrognathia. We suggest that these radiologic manifestations could increase diagnostic precision in mildly affected cases.


Prevalence and Genotype Allocation of Pathogenic Leptospira Species in Small Mammals from Various Habitat Types in Germany.
Small mammals serve as most important reservoirs for Leptospira spp., the causative agents of Leptospirosis, which is one of the most neglected and widespread zoonotic diseases worldwide. The knowledge about Leptospira spp. occurring in small mammals from Germany is scarce. Thus, this study's objectives were to investigate the occurrence of Leptospira spp. and the inherent sequence types in small mammals from three different study sites: a forest in southern Germany (site B1); a National Park in south-eastern Germany (site B2) and a renaturalised area, in eastern Germany (site S) where small mammals were captured. DNA was extracted from kidneys of small mammals and tested for Leptospira spp. by real-time PCR. Positive samples were further analysed by duplex and conventional PCRs. For 14 positive samples, multi locus sequence typing (MLST) was performed. Altogether, 1213 small mammals were captured: 216 at site B1, 456 at site B2 and 541 at site S belonging to following species: Sorex (S.) araneus, S. coronatus, Apodemus (A.) flavicollis, Myodes glareolus, Microtus (Mi.) arvalis, Crocidura russula, Arvicola terrestris, A. agrarius, Mustela nivalis, Talpa europaea, and Mi. agrestis. DNA of Leptospira spp. was detected in 6% of all small mammals. At site B1, 25 small mammals (11.6%), at site B2, 15 small mammals (3.3%) and at site S, 33 small mammals (6.1%) were positive for Leptospira spp. Overall, 54 of the positive samples were further determined as L. kirschneri, nine as L. interrogans and four as L. borgpetersenii while five real-time PCR-positive samples could not be further determined by conventional PCR. MLST results revealed focal occurrence of L. interrogans and L. kirschneri sequence type (ST) 117 while L. kirschneri ST 110 was present in small mammals at all three sites. Further, this study provides evidence for a particular host association of L. borgpetersenii to mice of the genus Apodemus.


Precipitation-based colorimetric multiplex immunoassay in hydrogel particles.
Despite a growing demand for more accessible diagnostic technologies, current methods struggle to simultaneously detect multiple analytes with acceptable sensitivity and portability. Colorimetric assays have been widely used due to their simplicity of signal readout, but the lack of multiplexibility has been a perpetual constraint. Meanwhile, particle-based assays offer multiplex detection by assigning an identity code to each analyte, but they often require lab-based equipment unsuitable for portable diagnostics. Here, by merging the two approaches, this paper reports a colorimetric multiplex immunoassay based on hydrogel microparticles that achieves the best of both worlds. The low-cost portable multiplex assay demonstrates sensitivities as high as and dynamic ranges greater than the lab-based enzyme-linked immunosorbent assay (ELISA). These critical advances are made possible by local precipitation and amplification of insoluble colour dyes inside the hydrogel networks. For the first time, enzymatic accumulation of colour dyes in hydrogel particles is reported and the kinetics of colour development is characterized in this work. By taking advantage of the colour signals in the visible spectrum, the hydrogel microparticles were imaged and analysed using low-cost portable devices. The colorimetric multiplex immunoassay was used to successfully detect three target biomarkers of preeclampsia and validated clinically using healthy and patient-derived plasma samples.


Cancer of the oesophagus in Zimbabwe.
Data for oesophageal cancers were requested from the Cancer Registry of Zimbabwe for the three years 1986-1988. There were 437 cases notified compared with 783 cases recorded in the Government's Statistical returns. There was a ratio of 6.9 males to one female accounting for 13.2 pc of all reported cancers in males and 1.7 pc of cancers in females. Prevalence increased with age to a rate of around 83 per hundred thousand in men aged 55 and older and 19 per hundred thousand in women over 65 years old. Notifications are only received from the Central Hospitals in Harare and Bulawayo. Addresses were not available for 31 pc of patients so that geographical variations could not be determined accurately. However, higher rates occurred in Harare and in the Mashonaland Provinces. It is recommended that cancer notifications should be obtained from all Government, Mission and Private hospitals in Zimbabwe.


Controlling large malpractice claims: the unexpected impact of damage caps.
Indiana's comprehensive malpractice reforms, inaugurated in 1975, include a cap on damages, a mandated medical review before trial, and a state insurance fund to pay claims equal to or greater than $100,000. We have found that the amount of compensation going to claimants with such large malpractice claims in Indiana is, on average, substantially higher than in Michigan and Ohio. Indiana's mean claim severity between 1977 and 1988 was $404,832, while the means for Michigan and Ohio were $290,022 and $303,220, respectively, with the difference between these three means being highly significant. Although data on claim and claimant characteristics reveal considerable interstate variation, the results of regression analyses show that Indiana claim payment amounts are higher than Michigan or Ohio payments, independent of the effect of factors such as sex, age, severity of injury, allegations of negligence, and year of settlement.


Interfacial structure of wild-type and mutant forms of puroindoline-b bound to DPPG monolayers.
The interaction of wild-type puroindoline-b (Pin-b+) and two mutant forms having single residue substitutions (G46S or W44R) with L-alpha-dipalmitoylphosphatidyl-dl-glycerol (DPPG) as a Langmuir monolayer at the air/water interface was investigated by neutron reflectivity (NR) and Brewster angle microscopy (BAM). NR profiles were fitted using a three-layer model to enable differences in penetration of protein between the lipid headgroup and acyl regions to be determined. The data showed similar surface excesses for each of the three proteins at the interface; however, it was revealed that the depth of penetration of protein into the lipid region differed for each protein with Pin-b+ penetrating further into the acyl region of the lipid compared to the mutant forms of the protein that interacted with the headgroup region only. BAM images revealed that the domain structure of the DPPG monolayers was disrupted when Pin-b+ adsorption had reached equilibrium, suggesting protein penetration had led to compression of the lipid region. In contrast, the domain structure was unaffected by the W44R mutant, suggesting no change in compression of the lipid region and hence little or no penetration of protein into the lipid layer.


Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds.
Outgrowth and patterning of the vertebrate limb are controlled by reciprocal interactions between the posterior mesenchyme (polarizing region) and a specialized ectodermal structure, the apical ectodermal ridge (AER). Sonic hedgehog (SHH) signalling by the polarizing region modulates fibroblast growth factor (FGF)4 signalling by the posterior AER, which in turn maintains the polarizing region (SHH/FGF4 feedback loop). Here we report that the secreted bone-morphogenetic-protein (BMP) antagonist Gremlin relays the SHH signal from the polarizing region to the AER. Mesenchymal Gremlin expression is lost in limb buds of mouse embryos homozygous for the limb deformity (Id) mutation, which disrupts establishment of the SHH/FGF4 feedback loop. Grafting Gremlin-expressing cells into ld mutant limb buds rescues Fgf4 expression and restores the SHH/FGF4 feedback loop. Analysis of Shh-null mutant embryos reveals that SHH signalling is required for maintenance of Gremlin and Formin (the gene disrupted by the ld mutations). In contrast, Formin, Gremlin and Fgf4 activation are independent of SHH signalling. This study uncovers the cascade by which the SHH signal is relayed from the posterior mesenchyme to the AER and establishes that Formin-dependent activation of the BMP antagonist Gremlin is sufficient to induce Fgf4 and establish the SHH/FGF4 feedback loop.


Regional infant brain development: an MRI-based morphometric analysis in 3 to 13 month olds.
Elucidation of infant brain development is a critically important goal given the enduring impact of these early processes on various domains including later cognition and language. Although infants' whole-brain growth rates have long been available, regional growth rates have not been reported systematically. Accordingly, relatively less is known about the dynamics and organization of typically developing infant brains. Here we report global and regional volumetric growth of cerebrum, cerebellum, and brainstem with gender dimorphism, in 33 cross-sectional scans, over 3 to 13 months, using T1-weighted 3-dimensional spoiled gradient echo images and detailed semi-automated brain segmentation. Except for the midbrain and lateral ventricles, all absolute volumes of brain regions showed significant growth, with 6 different patterns of volumetric change. When normalized to the whole brain, the regional increase was characterized by 5 differential patterns. The putamen, cerebellar hemispheres, and total cerebellum were the only regions that showed positive growth in the normalized brain. Our results show region-specific patterns of volumetric change and contribute to the systematic understanding of infant brain development. This study greatly expands our knowledge of normal development and in future may provide a basis for identifying early deviation above and beyond normative variation that might signal higher risk for neurological disorders.


Why do surgeons miss malignancies in patients with acute abdominal pain?
The aim of this study was to characterize patients seeking medical advice for acute abdominal pain who were later diagnosed with an intra-abdominal malignancy. Patients with acute abdominal pain were registered between 1997 and 2000, employing a detailed schedule comprising 111 parameters. The diagnoses (n=2395 patients) were re-evaluated one year later. A total of 66 patients (2.8%) were found to have an intra-abdominal malignancy at follow-up, of whom 37 cases had been undetected at discharge. Malignancy of the liver, biliary tract and pancreas constituted 30% and colorectal cancer 32% of the tumours undetected at discharge. Constipation, intestinal obstruction and non-specific abdominal pain (NSAP) were the most common preliminary diagnoses in patients among whom abdominal malignancy was later detected. Except for age and pain duration, the history and clinical investigation provide few clues to suggest an abdominal malignancy in patients with acute abdominal pain. NSAP, of unknown or known etiology, including constipation, should be suspected as a possible sign of abdominal malignancy in all patients over 50 years of age.


SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation.
Amyotrophic Lateral Sclerosis is characterized by a focal onset of symptoms followed by a progressive spread of pathology that has been likened to transmission of infectious prions. Cell-to-cell transmission of SOD1 protein aggregates is dependent on fluid-phase endocytosis pathways, although the precise molecular mechanisms remain to be elucidated. We demonstrate in this paper that SOD1 aggregates interact with the cell surface triggering activation of Rac1 and subsequent membrane ruffling permitting aggregate uptake via stimulated macropinocytosis. In addition, other protein aggregates, including those associated with neurodegenerative diseases (TDP-43, Httex146Q, α-synuclein) also trigger membrane ruffling to gain entry into the cell. Aggregates are able to rupture unstructured macropinosomes to enter the cytosol allowing propagation of aggregation to proceed. Thus, we conclude that in addition to basic proteostasis mechanisms, pathways involved in the activation of macropinocytosis are key determinants in the spread of pathology in these misfolding diseases.


Bartonella alsatica sp. nov., a new Bartonella species isolated from the blood of wild rabbits.
Bartonella species are considered as emerging human pathogens, with at least six different species pathogenic or possibly pathogenic for humans. However, little is known about Bartonella distribution, species polymorphism and pathogenicity in mammalian species. The objective of this work was to determine the presence, the frequency and the distribution of Bartonella species in wild rabbits (Oryctolagus cuniculus) caught in warrens in Alsace, France. Humans may come into contact with wild rabbits when hunting, especially when they are picked up with bare hands and at time of evisceration. Of 30 blood samples collected and cultured from wild rabbits, nine (30%) were positive for organisms morphologically similar to Bartonella spp. The bacteria appeared as small, fastidious, aerobic, oxidase-negative, Gram-negative rods which could be localized within erythrocytes. Their biochemical properties were similar to those of the genus Bartonella. The sequence of the 16S rRNA gene obtained from the rabbit isolates was highly related to the sequences of the different Bartonella species (97.8-99.3% similarity). The high DNA hybridization rate (81-90% similarity) between the three strains isolated from rabbit blood confirmed that they belong to the same bacterial species. Hybridization values, obtained with the nuclease-TCA method, when testing type strains of recognized Bartonella species (9-14% similarity), support the creation of a new species for the rabbit isolates. The name Bartonella alsatica is proposed for these strains isolated from the blood of wild rabbits. The type strain is IBS 382T (= CIP 105477T).


Robust observer-based tracking control of hodgkin-huxley neuron systems under environmental disturbances.
A nervous system consists of a large number of highly interconnected nerve cells. Nerve cells communicate by generation and transmission of short electrical pulses (action potential). In addition, membrane voltage is the only measurable state in nervous systems. A robust observer-based model reference tracking control is proposed for Hodgkin-Huxley (HH) neuron systems to generate a desired reference response in spite of environmental noises, uncertain initial values, and diffusion currents from other interconnected nerve cells. In order to simplify the robust tracking control design of nonlinear stochastic HH neuron systems, a fuzzy interpolation method is employed to interpolate several linear stochastic systems to approximate a nonlinear stochastic HH neuron system so that the nonlinear robust tracking control problem can be solved by the linear matrix inequality (LMI) technique with the help of Robust Control Toolbox in Matlab. The proposed robust observer-based tracking control scheme can provide new methods for desired action potential generation, suppression of oscillations, and blockage of action potential transmission under environmental noise and diffusion currents. These new methods are useful for patients with different neuron system dysfunctions. Finally, three simulation examples of tracking control of nervous systems are given to illustrate the design procedure and confirm the tracking performance of the proposed method.