Aerobactin biosynthesis and transport genes of plasmid ColV-K30 in Escherichia coli K-12.
The iron-regulated aerobactin operon, about 8 kilobase pairs in size, of the Escherichia coli plasmid ColV-K30 was shown by deletion and subcloning analyses to consist of at least five genes for synthesis (iuc, iron uptake chelate) and transport (iut, iron uptake transport) of the siderophore. The gene order iucABCD iutA was established. The genes were mapped within restriction nuclease fragments of a cloned 16.3-kilobase-pair HindIII fragment. Stepwise deletion and subsequent minicell analysis of the resulting plasmids allowed assignment of four of the five genes to polypeptides of molecular masses 63,000, 33,000 53,000, and 74,000 daltons, respectively. The 74-kilodalton protein, the product of gene iutA, is the outer membrane receptor for ferric aerobactin, whereas the remaining three proteins are involved in biosynthesis of aerobactin. The 33-kilodalton protein, the product of gene iucB, was identified as N epsilon-hydroxylysine:acetyl coenzyme A N epsilon-transacetylase (acetylase) by comparison of enzyme activity in extracts from various deletion mutants. The 53-kilodalton protein, the product of gene iucD, is required for oxygenation of lysine. The 63-kilodalton protein, the product of gene iucA, is assigned to the first step of the aerobactin synthetase reaction. The product of gene iucC, so far unidentified, performs the second and final step in this reaction. This is based on the chemical characterization of two precursor hydroxamic acids (N epsilon-acetyl-N epsilon-hydroxylysine and N alpha-citryl-N epsilon-acetyl-N epsilon-hydroxylysine) isolated from a strain carrying a 0.3-kilobase-pair deletion in the iucC gene. The results support the existence of a biosynthetic pathway in which aerobactin arises by oxygenation of lysine, acetylation of the N epsilon-hydroxy function, and condensation of 2 mol of the resulting aminohydroxamic acid with citric acid.


P11 promoter methylation predicts the antidepressant effect of electroconvulsive therapy.
Although electroconvulsive therapy (ECT) is among the most effective treatment options for pharmacoresistant major depressive disorder (MDD), some patients still remain refractory to standard ECT practise. Thus, there is a need for markers reliably predicting ECT non/response. In our study, we have taken a novel translational approach for discovering potential biomarkers for the prediction of ECT response. Our hypothesis was that the promoter methylation of p11, a multifunctional protein involved in both depressive-like states and antidepressant treatment responses, is differently regulated in ECT responders vs. nonresponders and thus be a putative biomarker of ECT response. The chronic mild stress model of MDD was adapted with the aim to obtain rats that are resistant to conventional antidepressant drugs (citalopram). Subsequently, electroconvulsive stimulation (ECS) was used to select responders and nonresponders, and compare p11 expression and promoter methylation. In the rat experiments we found that the gene promoter methylation and expression of p11 significantly correlate with the antidepressant effect of ECS. Next, we investigated the predictive properties of p11 promoter methylation in two clinical cohorts of patients with pharmacoresistant MDD. In a proof-of-concept clinical trial in 11 patients with refractory MDD, higher p11 promoter methylation was found in responders to ECT. This finding was replicated in an independent sample of 65 patients with pharmacoresistant MDD. This translational study successfully validated the first biomarker reliably predicting the responsiveness to ECT. Prescreening of this biomarker could help to identify patients eligible for first-line ECT treatment and also help to develop novel antidepressant treatment procedures for depressed patients resistant to all currently approved antidepressant treatments.


The sugar tax - An opportunity to advance oral health.
The new sugar tax was recently announced by Government, aiming to combat obesity through investment in school sports. Dental professionals should seize this rare opportunity to raise awareness of the other adverse effects of sugar; young children continue to suffer alarmingly high rates of dental cavities in the UK. A significant amount of money raised through the levy must be reinvested into ensuring fluoride toothpaste is more affordable. Since daily use of fluoride toothpaste is the most effective evidence-based oral health preventative measure that is widely used, this should receive tax exemption status from the government as a means of universal oral health prevention. There must also be a re-investment in innovative oral health education so that the next generation of children will alter their mind set about sugar. Oral health prevention advice must be tightly integrated into general health messages.


BATS RECOVERING FROM WHITE-NOSE SYNDROME ELEVATE METABOLIC RATE DURING WING HEALING IN SPRING.
Host responses to infection with novel pathogens are costly and require trade-offs among physiologic systems. One such pathogen is the fungus Pseudogymnoascus destructans (Pd) that causes white-nose syndrome (WNS) and has led to mass mortality of hibernating bats in eastern North America. Although infection with Pd does not always result in death, we hypothesized that bats that survive infection suffer significant consequences that negatively impact the ability of females to reproduce. To understand the physiologic consequences of surviving infection with Pd, we assessed differences in wing damage, mass-specific resting metabolic rate, and reproductive rate between little brown myotis ( Myotis lucifugus) that survived a winter in captivity after inoculation with Pd (WNS survivors) and comparable, uninfected bats. Survivors of WNS had significantly more damaged wing tissue and displayed elevated mass-specific metabolic rates compared with Pd-uninfected bats after emergence from hibernation. The WNS survivors and Pd-uninfected bats did not significantly differ in their reproductive capacity, at least in captivity. However, our metabolic data demonstrated greater energetic costs during spring in WNS survivors compared with uninfected bats, which may have led to other consequences for postpartum fitness. We suggest that, after surviving the energetic constraints of winter, temperate hibernating bats infected with Pd faced a second energetic bottleneck after emerging from hibernation.


Effect of FGF-2 on collagen tissue regeneration by human vertebral bone marrow stem cells.
The effects of fibroblast growth factor-2 (FGF-2) on collagen tissue regeneration by human bone marrow stem cells (hBMSCs) were investigated. hBMSCs were isolated from human vertebral body bone marrow during vertebral surgery and a population of hBMSCs with the characteristics of mesenchymal stem cells was observed. The FGF-2 treatment (5 ng/mL) affected on the colony-forming efficiency, proliferation, and in vitro differentiation of hBMSCs. Insoluble/soluble collagen and hydroxyproline synthesis was significantly enhanced in hBMSCs expanded with FGF-2 and the treatment of FGF-2 caused a reduction in the mRNA expression of collagen type I, but an increase of collagen types II and III along with lysyl oxidase family genes. Collagen formation was also examined using an in vivo assay model by transplanting hBMSCs into immunocompromised mice (n=4) and the histologic and immunohistochemical results revealed that significantly more collagen with a well-organized structure was formed by FGF-2-treated hBMSCs at 8 weeks posttransplantation (P<0.05). The DNA microarray assay demonstrated that genes related to extracellular matrix formation were significantly upregulated. To elucidate the underlying mechanism, chemical inhibitors against extracellular-signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) were treated and following downstream expression was observed. Collectively, FGF-2 facilitated the collagen-producing potency of hBMSCs both in vitro and in vivo, rendering them more suitable for use in collagen regeneration in the clinical field.


High-frequency motility of outer hair cells and the cochlear amplifier.
Outer hair cells undergo somatic elongation-contraction cycles in vitro when electrically stimulated. This "electromotile" response is assumed to underlie the high sensitivity and frequency selectivity of amplification in the mammalian cochlea. This process, presumably operating on a cycle-by-cycle basis at the frequency of the stimulus, is believed to provide mechanical feedback in vivo. However, if driven by the receptor potential of the cell, the mechanical feedback is expected to be severely attenuated at high frequencies because of electrical low-pass filtering by the outer hair cell basolateral membrane. It is proposed that electromotility at high frequencies is driven instead by extracellular potential gradients across the hair cell, and it is shown that this driving voltage is not subject to low-pass filtering and is sufficiently large. It is further shown that if the filtering properties of the cell membrane are canceled, taking advantage of the electrical characteristics of isolated outer hair cells in a partitioning glass microchamber, then the lower bound of the motor's bandwidth is approximately 22 kilohertz, a number determined only by the limitations of our instrumentation.


People living with HIV travel farther to access healthcare: a population-based geographic analysis from rural Uganda.
The availability of specialized HIV services is limited in rural areas of sub-Saharan Africa where the need is the greatest. Where HIV services are available, people living with HIV (PLHIV) must overcome large geographic, economic and social barriers to access healthcare. The objective of this study was to understand the unique barriers PLHIV face when accessing healthcare compared with those not living with HIV in a rural area of sub-Saharan Africa with limited availability of healthcare infrastructure. We conducted a population-based cross-sectional study of 447 heads of household on Bugala Island, Uganda. Multiple linear regression models were used to compare travel time, cost and distance to access healthcare, and log binomial models were used to test for associations between HIV status and access to nearby health services. PLHIV travelled an additional 1.9 km (95% CI (0.6, 3.2 km), p=0.004) to access healthcare compared with those not living with HIV, and they were 56% less likely to access healthcare at the nearest health facility to their residence, so long as that facility lacked antiretroviral therapy (ART) services (aRR=0.44, 95% CI (0.24 to 0.83), p=0.011). We found no evidence that PLHIV travelled further for care if the nearest facility supplies ART services (aRR=0.95, 95% CI (0.86 to 1.05), p=0.328). Among those who reported uptake of care at one of two facilities on the island that provides ART (81% of PLHIV and 68% of HIV-negative individuals), PLHIV tended to seek care at a higher tiered facility that provides ART, even when this facility was not their closest facility (30% of PLHIV travelled further than the closest ART facility compared with 16% of HIV-negative individuals), and travelled an additional 2.2 km (p=0.001) to access that facility, relative to HIV-negative individuals (aRR=1.91, 95% CI (1.00 to 3.65), p=0.05). Among PLHIV, residential distance was associated with access to facilities providing ART (RR=0.78, 95% CI (0.61 to 0.99), p=0.044, comparing residential distances of 3-5 km to 0-2 km; RR=0.71, 95% CI (0.58 to 0.87), p=0.001, comparing residential distances of 6-10 km to 0-2 km). PLHIV travel longer distances for care, a phenomenon that may be driven by both the limited availability of specialized HIV services and preference for higher tiered facilities.


Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.
To compare the capacity of the 2004 diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH-2004) with the capacity of the preliminary diagnostic guidelines for systemic juvenile idiopathic arthritis (JIA)-associated macrophage activation syndrome (MAS) to discriminate MAS complicating systemic JIA from 2 potentially confusable conditions, represented by active systemic JIA without MAS and systemic infection. International pediatric rheumatologists and hemato-oncologists were asked to retrospectively collect clinical information from patients with systemic JIA-associated MAS and confusable conditions. The ability of the guidelines to differentiate MAS from the control diseases was evaluated by calculating the sensitivity and specificity of each set of guidelines and the kappa statistics for concordance with the physician's diagnosis. Owing to the fact that not all patients were assessed for hemophagocytosis on bone marrow aspirates and given the lack of data on natural killer cell activity and soluble CD25 levels, the HLH-2004 guidelines were adapted to enable the diagnosis of MAS when 3 of 5 of the remaining items (3/5-adapted) or 4 of 5 of the remaining items (4/5-adapted) were present. The study sample included 362 patients with systemic JIA and MAS, 404 patients with active systemic JIA without MAS, and 345 patients with systemic infection. The best capacity to differentiate MAS from systemic JIA without MAS was found when the preliminary MAS guidelines were applied. The 3/5-adapted HLH-2004 guidelines performed better than the 4/5-adapted guidelines in distinguishing MAS from active systemic JIA without MAS. The 3/5-adapted HLH-2004 guidelines and the preliminary MAS guidelines with the addition of ferritin levels ≥500 ng/ml discriminated best between MAS and systemic infections. The preliminary MAS guidelines showed the strongest ability to identify MAS in systemic JIA. The addition of hyperferritinemia enhanced their capacity to differentiate MAS from systemic infections. The HLH-2004 guidelines are likely not appropriate for identification of MAS in children with systemic JIA.


Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites.
The parasitic protists of the Trypanosoma genus infect humans and domestic mammals, causing severe mortality and huge economic losses. The most threatening trypanosomiasis is Chagas disease, affecting up to 12 million people in the Americas. We report a way to selectively kill Trypanosoma by blocking glycosomal/peroxisomal import that depends on the PEX14-PEX5 protein-protein interaction. We developed small molecules that efficiently disrupt the PEX14-PEX5 interaction. This results in mislocalization of glycosomal enzymes, causing metabolic catastrophe, and it kills the parasite. High-resolution x-ray structures and nuclear magnetic resonance data enabled the efficient design of inhibitors with trypanocidal activities comparable to approved medications. These results identify PEX14 as an "Achilles' heel" of the Trypanosoma suitable for the development of new therapies against trypanosomiases and provide the structural basis for their development.


Snapping scapula syndrome: diagnosis and management.
Scapulothoracic bursitis and snapping scapula syndrome are rare diagnoses that contribute to considerable morbidity in some patients. These conditions represent a spectrum of disorders characterized by pain with or without mechanical crepitus. They are commonly identified in young, active patients who perform repetitive overhead activities. Causes include anatomic scapular or thoracic variations, muscle abnormalities, and bony or soft-tissue masses. Three-dimensional CT and MRI aid in detecting these abnormalities. Nonsurgical therapy is the initial treatment of choice but is less successful than surgical management in patients with anatomic abnormalities. In many cases, scapular stabilization, postural exercises, or injections eliminate symptoms. When nonsurgical treatment fails, open and endoscopic techniques have been used with satisfactory results. Familiarity with the neuroanatomic structures surrounding the scapula is critical to avoid iatrogenic complications. Although reported outcomes of both open and endoscopic scapulothoracic decompression are encouraging, satisfactory outcomes have not been universally achieved.


Neuron-like differentiation of bone marrow-derived mesenchymal stem cells.
Mesenchymal stem cells (MSCs) are multipotent and give rise to distinctly differentiated cells from all three germ layers. Neuronal differentiation of MSC has great potential for cellular therapy. We examined whether the cluster of mechanically made, not neurosphere, could be differentiated into neuron-like cells by growth factors, such as epidermal growth factor (EGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF). BMSCs grown confluent were mechanically separated with cell scrapers and masses of separated cells were cultured to form cluster BMSCs. As described here cluster of BMSCs were differentiated into neuron-like cells by EGF, HGF, and VEGF. Differentiated cells were analyzed by means of phase-contrast inverted microscopy, reverse transcriptase-polymerase chain reaction (RT-PCR), immunofluorescence, and immunocytochemistry to identify the expression of neural specific markers. For the group with growth factors, the shapes of neuron-like cells was observable a week later, and two weeks later, most cells were similar in shape to neuron-like cells. Particularly, in the group with chemical addition, various shapes of filament structures were seen among the cells. These culture conditions induced MSCs to exhibit a neural cell phenotype, expressing several neuro-glial specific markers. bone marrow-derived mesenchymal stem cells (BMSCs) could be easily induced to form clusters using mechanical scraping, not neurospheres, which in turn could differentiate further into neuron-like cells and might open an attractive possibility for clinical cell therapy for neurodegenerative diseases. In the future, we consider that neuron-like cells differentiated from clusters of BMSCs are needed to be compared and analyzed on a physiological and molecular biological level with preexisting neuronal cells, and studies on the possibility of their transplantation and differentiation capability in animal models are further required.


Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice.
This study addressed the contribution of acidic sphingomyelinase (ASMase) in TNF-alpha-mediated hepatocellular apoptosis. Cultured hepatocytes depleted of mitochondrial glutathione (mGSH) became sensitive to TNF-alpha, undergoing a time-dependent apoptotic cell death preceded by mitochondrial membrane depolarization, cytochrome c release, and caspase activation. Cyclosporin A treatment rescued mGSH-depleted hepatocytes from TNF-alpha-induced cell death. In contrast, mGSH-depleted hepatocytes deficient in ASMase were resistant to TNF-alpha-mediated cell death but sensitive to exogenous ASMase. Furthermore, although in vivo administration of TNF-alpha or LPS to galactosamine-pretreated ASMase(+/+) mice caused liver damage, ASMase(-/-) mice exhibited minimal hepatocellular injury. To analyze the requirement of ASMase, we assessed the effect of glucosylceramide synthetase inhibition on TNF-alpha-mediated apoptosis. This approach, which blunted glycosphingolipid generation by TNF-alpha, protected mGSH-depleted ASMase(+/+) hepatocytes from TNF-alpha despite enhancement of TNF-alpha-stimulated ceramide formation. To further test the involvement of glycosphingolipids, we focused on ganglioside GD3 (GD3) because of its emerging role in apoptosis through interaction with mitochondria. Analysis of the cellular redistribution of GD3 by laser scanning confocal microscopy revealed the targeting of GD3 to mitochondria in ASMase(+/+) but not in ASMase(-/-) hepatocytes. However, treatment of ASMase(-/-) hepatocytes with exogenous ASMase induced the colocalization of GD3 and mitochondria. Thus, ASMase contributes to TNF-alpha-induced hepatocellular apoptosis by promoting the mitochondrial targeting of glycosphingolipids.


Effects of homeopathic medicines on polysomnographic sleep of young adults with histories of coffee-related insomnia.
Homeopathy, a common form of alternative medicine worldwide, relies on subjective patient reports for diagnosis and treatment. Polysomnography offers a modern methodology for evaluating the objective effects of taking homeopathic remedies that clinicians claim exert effects on sleep quality in susceptible individuals. Animal studies have previously shown changes in non rapid eye movement sleep with certain homeopathic remedies. Young adults of both sexes (ages 18-31) with above-average scores on standardized personality scales for either cynical hostility or anxiety sensitivity (but not both) and a history of coffee-induced insomnia participated in the month-long study. At-home polysomnographic recordings were obtained on successive pairs of nights once per week for a total of eight recordings (nights 1, 2, 8, 9, 15, 16, 22, 23). Subjects (N=54) received placebo pellets on night 8 (single-blind) and verum pellets on night 22 (double-blind) in 30c doses of one of two homeopathic remedies, Nux Vomica or Coffea Cruda. Subjects completed daily morning sleep diaries and weekly Pittsburgh sleep quality index scales, as well as profile of mood states scales at bedtime on polysomnography nights. Verum remedies significantly increased PSG total sleep time and NREM, as well as awakenings and stage changes. Changes in actigraphic and self-rated scale effects were not significant. The study demonstrated the feasibility of using in-home, all-night sleep recordings to study homeopathic remedy effects. Findings are similar though not identical to those reported in animals with the same remedies. Possible mechanisms include initial disruption of the nonlinear dynamics of sleep patterns by the verum remedies.


Carvedilol, a new vasodilating beta-adrenoceptor blocker, inhibits oxidation of low-density lipoproteins by vascular smooth muscle cells and prevents leukocyte adhesion to smooth muscle cells.
The present study was undertaken to assess the effect of carvedilol, a new vasodilating beta-adrenoceptor blocker with antioxidant activity, on the oxidation of low-density lipoproteins (LDL) by rat aortic smooth muscle cells (RASMC). LDL oxidation was assessed as thiobarbituric acid reactive substances (TBARS) formation and increase in electrophoretic mobility. Oxidized (ox) LDL-induced cytotoxicity was assessed as lactate dehydrogenase release (LDH) from cells and ox-LDL-enhanced adhesiveness of the RASMC for leukocytes was also determined. Carvedilol inhibited TBARS formation and LDH release from RASMC with IC50 values of 1.74 and 1.62 microM, respectively. Under the same conditions, the IC50 values of probucol and nicardipine were 2.33 and 5.60 microM, respectively, for inhibition of TBARS and 5.16 and 12.10 microM, respectively, for inhibition of LDH release; propranolol, atenolol, pindolol and labetalol, at concentrations up to 100 microM, had virtually no effect on either variable. RASMC-dependent ox-LDL stimulated the adhesive properties of RASMC for both monocytes and neutrophils in a concentration- and time-dependent manner, which were prevented when the RASMC were treated with carvedilol (IC50 2.07 microM for monocytes and 1.12 microM for neutrophils), whereas other beta blockers, at concentrations up to 30 microM, had only mild effects. The monoclonal antirat intercellular adhesion molecule-1 antibody partially inhibited ox-LDL-induced adhesion of RASMC for monocytes and neutrophils. Northern analysis demonstrated that ox-LDL induced intracellular adhesion molecule-1 messenger RNA expression on RASMC, which was inhibited by carvedilol and probucol via inhibition of LDL oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)


Paper supported long-term 3D liver co-culture model for the assessment of hepatotoxic drugs.
Preservation of hepatic phenotype and functions in vitro has always been a great challenge for the reconstruction of liver tissue engineering and in pharmaceutical research studies. Human induced hepatocytes (hiHeps) generated from fibroblasts can be reproducible with almost normal levels of liver specific functions, which are considered as a new source of hepatocytes for biomedical applications. Moreover, paper has served as an attractive biocompatible material for cell-based applications. In this study, we established a simple paper-based scaffold array for creating a 3D liver co-culture model that enabled the assessment of drug induced hepatotoxicity. The hiHeps co-cultured with HUVECs exhibited a 3D like morphology and maintained the liver specific functions of producing albumin and urea for up to 2 months. In addition, the hiHeps in this co-cultured model maintained a higher expression of cytochrome P450 genes as compared with a monolayer culture on a plate and a single culture on paper of hiHeps, revealing a marked enhancement of hepatic functions in the 3D liver co-culture model. Moreover, the 3D liver co-culture model was exposed to acetaminophen (APAP) and pioglitazone, exhibiting near physiological hepatotoxic responses compared to those of the monolayer cultures. Taken together, the low-cost and bioactive paper scaffold could offer great opportunities as 3D in vitro platforms for tissue engineering applications and high-throughput drug testing.


Premature Labor and Neonatal Septicemia Caused by Capnocytophaga Ochracea.
BACKGROUND Capnocytophaga ochracea is a gram-negative anaerobic organism commonly found in human oral flora. It is characteristically sensitive to beta-lactams and resistant to aminoglycosides. CASE REPORT A 23-year-old woman presented with lower abdominal pain and was admitted for premature labor at 24-weeks of gestation. At presentation, the cervix was closed and the membrane was intact; however, contractions continued, the membrane subsequently ruptured before receiving any steroids or magnesium, and the mother gave birth to a 540-gram female baby. At birth, Apgar scores were 1 at 5 minutes, 1 at 10 minutes, and 2 at 15 minutes. On the fifth day of life, the blood culture grew Capnocytophaga species. Consequently, Cefotaxime was started and ampicillin continued for a total of 14 days; however, on the 6th day, the head ultrasound showed grade 4 intraventricular hemorrhage and a Do Not Resuscitate (DNR) order was placed in the chart. The patient's health continued to deteriorate, having multiple episodes of bradycardia and desaturation until cardiac arrest on the 17th day. CONCLUSIONS Capnocytophaga ochracea was isolated from the blood culture of a preterm neonate. It was thought to be the cause of the premature labor and subsequent neonatal septicemia. This case report suggests that the prevalence of Capnocytophaga infections is most likely underestimated and that additional premature labors and abortions could have been caused by Capnocytophaga infections that were never detected. Hence, more studies are needed to investigate the route of transmission.


Prophylaxis against chemotherapy-induced reactivation of hepatitis B virus infection with Lamivudine.
The results of lamivudine therapy in 4 patients with chemotherapy-induced hepatitis B virus (HBV) reactivation are reported. Cancer chemotherapy-induced reactivation is a known complication in patients with chronic HBV infection or history of HBV infection with recovery. Reactivation of HBV infection has a broad spectrum of manifestations ranging from mild elevation of aminotransferase levels to fatal fulminant hepatitis. Lamivudine is a nucleoside analogue and a potent inhibitor of HBV reverse transcription. The 4 patients treated with lamivudine included 1 woman with breast cancer and 3 men with non-Hodgkin lymphoma, ranging from 41 to 63 years of age. All 4 patients were undergoing standard, multi-agent chemotherapy when they presented with HBV reactivation manifested by sudden onset of fatigue, jaundice, and HBV serology consistent with active HBV infection (detectable serum HBV DNA) in the absence of other known causes of acute hepatitis. Lamivudine therapy (100 mg/d in 3 patients and 150 mg/d in 1 patient) was initiated from 1 to 18 days following the diagnosis of HBV reactivation. All 4 patients showed rapid decrease in aminotransferase levels within 2 weeks after initiating lamivudine therapy. Unfortunately, hepatic synthetic function failed to improve in 2 patients, who both died. The remaining 2 patients had suppression of HBV DNA to undetectable levels after 1 and 4 months of treatment and had biochemical and clinical improvement. The 2 patients who died received lamivudine therapy for 8 days and for 3 weeks. There have been no randomized clinical trials to study the role of lamivudine for prophylaxis or treatment of HBV reactivation associated with chemotherapy. However, based on our limited experience, lamivudine may be efficacious in suppressing potentially fatal HBV reactivation secondary to chemotherapy in patients with chronic HBV infection or prior infection with recovery. Patients who undergo chemotherapy should be screened for the presence of markers of chronic hepatitis B infection or previous HBV infection. We recommend that patients with chronic HBV infection (positive HBV DNA and/or positive HBsAg) or history of HBV infection with recovery (positive hepatitis B core antibody with or without HBsAb) be considered for prophylactic lamivudine use to prevent chemotherapy-induced HBV reactivation.


Hemorrhagic Shock and the Microvasculature.
The microvasculature plays a central role in the pathophysiology of hemorrhagic shock and is also involved in arguably all therapeutic attempts to reverse or minimize the adverse consequences of shock. Microvascular studies specific to hemorrhagic shock were reviewed and broadly grouped depending on whether data were obtained on animal or human subjects. Dedicated sections were assigned to microcirculatory changes in specific organs, and major categories of pathophysiological alterations and mechanisms such as oxygen distribution, ischemia, inflammation, glycocalyx changes, vasomotion, endothelial dysfunction, and coagulopathy as well as biomarkers and some therapeutic strategies. Innovative experimental methods were also reviewed for quantitative microcirculatory assessment as it pertains to changes during hemorrhagic shock. The text and figures include representative quantitative microvascular data obtained in various organs and tissues such as skin, muscle, lung, liver, brain, heart, kidney, pancreas, intestines, and mesentery from various species including mice, rats, hamsters, sheep, swine, bats, and humans. Based on reviewed findings, a new integrative conceptual model is presented that includes about 100 systemic and local factors linked to microvessels in hemorrhagic shock. The combination of systemic measures with the understanding of these processes at the microvascular level is fundamental to further develop targeted and personalized interventions that will reduce tissue injury, organ dysfunction, and ultimately mortality due to hemorrhagic shock. Published 2018. Compr Physiol 8:61-101, 2018.


The gender wealth gap:structural and material constraints and implications for later life.
Wealth is an important measure of economic well-being, because while income captures the current state of inequality, wealth has the potential for examining accumulated and historically structured inequality. This presentation documents the extent of gender inequality in wealth for Canadian women and men aged 45 and older. The analysis uses data from the 1999 Canadian Survey of Financial Security, a large nationally representative survey of household wealth in Canada. Wealth is measured by total net worth as measured by total assets minus debt. We test two general hypotheses to account for gender differences in wealth. The differential exposure hypothesis suggests that women report less wealth accumulation because of their reduced access to the material and social conditions of life that foster economic security. The differential vulnerability hypothesis suggests that women report lower levels of wealth because they receive differential returns to material and social conditions of their lives. Support is found for both hypotheses. Much of the gender differences in wealth can be explained by the gendering of work and family roles that restricts women's ability to build up assets over the life course. But beyond this, there are significant gender interaction effects that indicate that women are further penalized by their returns to participation in family life, their health and where they live. When women do work, net of other factors, they are better able to accumulate wealth than their male counterparts.


Musculoskeletal symptoms and computer use among Finnish adolescents--pain intensity and inconvenience to everyday life: a cross-sectional study.
Musculoskeletal symptoms among adolescents are related to the time spent using a computer, but little is known about the seriousness of the symptoms or how much they affect everyday life. The purpose of the present study was to examine the intensity of musculoskeletal pain and level of inconvenience to everyday life, in relation to time spent using a computer. In a survey, 436 school children (12 to 13 and 15 to 16 years of age), answered a questionnaire on musculoskeletal and computer-associated musculoskeletal symptoms in neck-shoulder, low back, head, eyes, hands, and fingers or wrists. Pain intensity (computer-associated symptoms) and inconvenience to everyday life (musculoskeletal symptoms) were measured using a visual analogue scale. Based on the frequency and intensity, three categories were formed to classify pain at each anatomic site: none, mild, and moderate/severe. The association with time spent using the computer was analyzed by multinomial logistic regression. Moderate/severe pain intensity was most often reported in the neck-shoulders (21%); head (20%); and eyes (14%); and moderate/severe inconvenience to everyday life was most often reported due to head (29%), neck-shoulders (21%), and low back (16%) pain. Compared with those using the computer less than 3.6 hours/week, computer use of ≥ 14 hours/week, was associated with moderate/severe increase in computer-associated musculoskeletal pain at all anatomic sites (odds ratio [OR] = 2.9-4.4), and moderate/severe inconvenience to everyday life due to low back (OR = 2.5) and head (OR = 2.0) pain. Musculoskeletal symptoms causing moderate/severe pain and inconvenience to everyday life are common among adolescent computer users. Daily computer use of 2 hours or more increases the risk for pain at most anatomic sites.


A biomechanical study regarding the effect of tissue harvesting from the thorax on its movement during inspiration.
In the practice of plastic surgery, ribs and cartilage are often harvested for use in auto-grafts. This study aimed to elucidate the effect of such harvesting on the inspiration movement of the thorax. Sixteen three-dimensional computer simulation models were produced by reference to the CT data of 16 patients. To simulate the harvesting of ribs and costal cartilages, parts were removed from these thorax models, thereby producing models with different types of defect. By performing finite element calculation after applying contracture forces on the external intercostal muscles and diaphragm, the movement patterns exhibited by the thoraces during inspiration were analyzed. The relationships between the defect types and the movement patterns were evaluated with reference to the dynamic behavior of the sternum and the increase in thoracic volume. Although the removal of costal cartilage can cause asymmetric movement of the thorax, it did not affect the inspiration movement of the thorax. However, removal of two or more ribs not only caused asymmetric movement of the thorax, but also negatively affected that movement. Removal of two or three ribs impaired the expansion of the hemi-thorax on inspiration by 10% and 40%, respectively. The present study is the first to clarify the quantitative effect of tissue harvesting from the thorax on inspiration. The findings will be useful for surgeons when planning operations requiring harvesting of tissue from the thorax.


Kinetic properties of hexokinase under near-physiological conditions. Relation to metabolic arrest in Artemia embryos during anoxia.
Previous analyses of glycolytic metabolites in Artemia embryos indicate that an acute inhibition of glucose phosphorylation occurs during pHi-mediated metabolic arrest under anoxia. We describe here kinetic features of hexokinase purified from brine shrimp embryos in an attempt to explain the molecular basis for this inhibition. At saturating concentrations of cosubstrate, ADP is an uncompetitive inhibitor toward glucose and a partial noncompetitive inhibitor toward ATP (Kis = 0.86 mM, Kii = 1.0 mM, Kid = 1.9 mM). With cosubstrates at subsaturating concentrations, the uncompetitive inhibition versus glucose becomes noncompetitive, while inhibition versus ATP remains partial noncompetitive. The partial noncompetitive inhibition of ADP versus ATP is characterized by a hyperbolic intercept replot. These product inhibition patterns are consistent with a random mechanism of enzyme action that follows the preferred order of glucose binding first and glucose-6-P dissociating last. We propose that inhibition by glucose-6-P (Kis = 65 microM) occurs primarily by competing with ATP at the active site, resulting in the formation of the dead-end complex, enzyme-glucose-glucose-6-P. Versus glucose, inhibition by glucose-6-P is uncompetitive at pH 8.0 and noncompetitive at pH 6.8. Over a physiologically relevant pH range of 8.0 to 6.8 alterations in Km and Ki values do not account for the reduction in glucose phosphorylation, and no evidence suggests that Artemia hexokinase activity is modulated by reversible binding to intracellular structures. Total aluminum in the embryos is 4.01 +/- 0.36 micrograms/g dry weight, or, based upon tissue hydration, 72 microM. This concentration of aluminum dramatically reduces enzyme activity at pH values less than 7.2, even in the presence of physiological metal ion chelators (citrate, phosphate). When pH, aluminum, citrate, phosphate, substrates, and products were maintained at cellular levels measured under anoxia, we can account for a 90% inhibition of hexokinase relative to activity under control (aerobic) conditions.


Plasma concentrations of ascorbic acid and C-reactive protein, and risk of future coronary artery disease, in apparently healthy men and women: the EPIC-Norfolk prospective population study.
High plasma concentrations of ascorbic acid, a marker of fruit and vegetable intake, are associated with low risk of coronary artery disease. Whether this relationship is explained by a reduction in systemic inflammation is unclear. We investigated the relationship between ascorbic acid plasma concentration and coronary artery disease risk, and in addition whether this relationship depended on classical risk factors and C-reactive protein (CRP) concentration. We used a prospective nested case-control design. The study consisted of 979 cases and 1794 controls (1767 men and 1006 women). Increasing ascorbic acid quartiles were associated with lower age, BMI, systolic and diastolic blood pressure, and CRP concentration, but with higher HDL-cholesterol concentration. No associations existed between ascorbic acid concentration and total cholesterol concentration or LDL-cholesterol concentration. When data from men and women were pooled, the risk estimates decreased with increasing ascorbic acid quartiles such that people in the highest ascorbic acid quartile had an odds ratio for future coronary artery disease of 0.67 (95 % CI 0.52, 0.87) compared with those in the lowest quartile (P for linearity=0.001). This relationship was independent of sex, age, diabetes, smoking, BMI, LDL-cholesterol, HDL-cholesterol, systolic blood pressure and CRP level. These data suggest that the risk reduction associated with higher ascorbic acid plasma concentrations, a marker of fruit and vegetable intake, is independent of classical risk factors and also independent of CRP concentration.


Shp1 and Ubx2 are adaptors of Cdc48 involved in ubiquitin-dependent protein degradation.
Known activities of the ubiquitin-selective AAA ATPase Cdc48 (p97) require one of the mutually exclusive cofactors Ufd1/Npl4 and Shp1 (p47). Whereas Ufd1/Npl4 recruits Cdc48 to ubiquitylated proteins destined for degradation by the 26S proteasome, the UBX domain protein p47 has so far been linked exclusively to nondegradative Cdc48 functions in membrane fusion processes. Here, we show that all seven UBX domain proteins of Saccharomyces cerevisiae bind to Cdc48, thus constituting an entire new family of Cdc48 cofactors. The two major yeast UBX domain proteins, Shp1 and Ubx2, possess a ubiquitin-binding UBA domain and interact with ubiquitylated proteins in vivo. Deltashp1 and Deltaubx2 strains display defects in the degradation of a ubiquitylated model substrate, are sensitive to various stress conditions and are genetically linked to the 26S proteasome. Our data suggest that Shp1 and Ubx2 are adaptors for Cdc48-dependent protein degradation through the ubiquitin/proteasome pathway.


Activity-dependent augmentation of spontaneous neurotransmission during endoplasmic reticulum stress.
The endoplasmic reticulum (ER) is an essential cellular compartment responsible for Ca(2+) sequestration, signaling, protein translation, folding as well as transport. Several acute and chronic disease conditions impair ER function leading to ER stress. To study the impact of ER stress on synaptic transmission we applied tunicamycin (TM) or thapsigargin (TG) to hippocampal neurons, which triggered sustained elevation of key ER stress markers. We monitored evoked and spontaneous neurotransmission during 4 d of TM or TG treatment and detected only a 20% increase in paired pulse depression suggesting an increase in neurotransmitter release probability. However, the treatments did not significantly affect the number of active synapses or the size of the total recycling vesicle pool as measured by uptake and release of styryl dye FM1-43. In contrast, under the same conditions, we observed a dramatic fourfold increase in spontaneous excitatory transmission, which could be reversed by chronic treatment with the NMDA receptor blocker AP-5 or by treatment with salubrinal, a selective inhibitor of eukaryotic translation initiation factor 2 (eIF2alpha) dephosphorylation. Furthermore, ER stress caused NMDA receptor-dependent suppression of eukaryotic elongation factor-2 (eEF2) phosphorylation thus reversing downstream signaling mediated by spontaneous release. Together, these findings suggest that chronic ER stress augments spontaneous excitatory neurotransmission and reverses its downstream signaling in a NMDA receptor-dependent manner, which may contribute to neuronal circuitry abnormalities that precede synapse degeneration in several neurological disorders.


Identifying a Relationship Between Physical Frailty and Heart Failure Symptoms.
Heart failure (HF) is a complex clinical syndrome associated with significant symptom burden; however, our understanding of the relationship between symptoms and physical frailty in HF is limited. The aim of this study was to quantify associations between symptoms and physical frailty in adults with HF. A sample of adults with symptomatic HF were enrolled in a cross-sectional study. Physical symptoms were measured with the HF Somatic Perception Scale-Dyspnea subscale, the Epworth Sleepiness Scale, and the Brief Pain Inventory short form. Affective symptoms were measured with the Patient Health Questionnaire-9 and the Brief Symptom Inventory-Anxiety scale. Physical frailty was assessed according to the Frailty Phenotype Criteria: shrinking, weakness, slowness, physical exhaustion, and low physical activity. Comparative statistics and generalized linear modeling were used to quantify associations between symptoms and physical frailty, controlling for Seattle HF Model projected 1-year survival. The mean age of the sample (n = 49) was 57.4 ± 9.7 years, 67% were male, 92% had New York Heart Association class III/IV HF, and 67% had nonischemic HF. Physically frail participants had more than twice the level of dyspnea (P < .001), 75% worse wake disturbances (P < .001), and 76% worse depressive symptoms (P = .003) compared with those who were not physically frail. There were no differences in pain or anxiety. Physically frail adults with HF have considerably worse dyspnea, wake disturbances, and depression. Targeting physical frailty may help identify and improve physical and affective symptoms in HF.


Outcomes of patients with severe tricuspid regurgitation and congestive heart failure.
A substantial number of patients with severe tricuspid regurgitation (TR) and congestive heart failure (CHF) are medically managed without undergoing corrective surgery. We sought to assess the characteristics and outcomes of CHF patients who underwent tricuspid valve surgery (TVS), compared with those who did not. Retrospective observational study involving 2556 consecutive patients with severe TR from the Cleveland Clinic Echocardiographic Database. Cardiac transplant patients or those without CHF were excluded. Survival difference between patients who were medically managed versus those who underwent TVS was compared using Kaplan-Meier survival curves. Multivariate analysis was performed to identify variables associated with poor outcomes. Among a total of 534 patients with severe TR and CHF, only 55 (10.3%) patients underwent TVS. Among the non-surgical patients (n=479), 30% (n=143) had an identifiable indication for TVS. At 38 months, patients who underwent TVS had better survival than those who were medically managed (62% vs 35%; p<0.001). On multivariate analysis, advancing age (HR: 1.23; 95% CI 1.12 to 1.35 per 10-year increase in age), moderate (HR: 1.39; 95% CI 1.01 to 1.90) and severe (HR: 2; 95% CI 1.40 to 2.80) right ventricular dysfunction were associated with higher mortality. TVS was associated with lower mortality (HR: 0.44; 95% CI 0.27 to 0.71). Although corrective TVS is associated with better outcomes in patients with severe TR and CHF, a substantial number of them continue to be medically managed. However, since the reasons for patients not being referred to surgery could not be ascertained, further randomised studies are needed to validate our findings before clinicians can consider surgical referral for these patients.


Ageing Throughout History: The Evolution of Human Lifespan.
It is not surprising that one of the most complex phenomena in nature is that of ageing. It does not only bear biological interest, but it is also associated with cultural, psychological, social and even philosophical issues. It is therefore to be expected that a great deal of research is being performed in order to study the evolution of ageing and, more specifically, the evolution of human ageing. Historical aspects of this evolution will be discussed. Evidence from a variety of sources shows that the human lifespan is increasing, and may well continue to increase to levels that are difficult to predict. In addition, the most important theories about ageing based on evolutionary principles will be examined. Examples are mutation accumulation, antagonistic pleiotropy and the disposable soma theory. Finally, a section about future evolution of human ageing, based upon newly emerging research, will shed some light and provide speculative-provocative ideas about the future of ageing in humans.


Expression analysis of the human testis-specific serine/threonine kinase (TSSK) homologues. A TSSK member is present in the equatorial segment of human sperm.
Two members of the human testis-specific serine/threonine (Ser/Thr) kinase family, TSSK 1 and TSSK 2, were cloned and sequenced from a human testis adaptor-ligated cDNA library using a PCR strategy. Within the cDNA, open reading frames (ORF) were defined encoding proteins of 367 and 358 amino acids respectively, as well as conserved kinase domains typical of the superfamily of Ser/Thr kinases. Both genes were intronless and mapped to chromosomes 5 and 22 respectively. The human and mouse homologues of TSSK 1 and TSSK 2, together with TSSK 3 and SSTK/FKSG82, constitute a kinase subfamily closely related to the calmodulin kinases and SNF/nim 1 kinase subfamilies. Similar to the mouse, tissue expression by northern and dot blot analysis revealed that human TSSK 1 and 2 messages are expressed exclusively in the testis. However, mRNA for these kinases can be detected in other tissues using real-time PCR. In addition, TSKS, the human homologue of a putative substrate of TSSK 1 and 2, was cloned. TSKS had an ORF of 592 amino acids and was also expressed exclusively in the testis as demonstrated by northern and dot blot analyses; however, lower levels of expression in other tissues were detected using real-time PCR. Human TSSK 2 and TSKS interacted in a yeast two-hybrid system and also co-immunoprecipitated after in vitro translation. TSSK 2 expressed in yeast and bacteria was able to autophosphorylate and also phosphorylated recombinant TSKS in vitro. Antibodies against recombinant TSSK 2 demonstrated that a member of the TSSK family was present in human testis and localized to the equatorial segment of ejaculated human sperm. In contrast, TSKS was only found in the testis. The finding of a TSSK family member in mature sperm suggests that this family of kinases might play a role in sperm function.


ECA3, a Golgi-localized P2A-type ATPase, plays a crucial role in manganese nutrition in Arabidopsis.
Calcium (Ca) and manganese (Mn) are essential nutrients required for normal plant growth and development, and transport processes play a key role in regulating their cellular levels. Arabidopsis (Arabidopsis thaliana) contains four P(2A)-type ATPase genes, AtECA1 to AtECA4, which are expressed in all major organs of Arabidopsis. To elucidate the physiological role of AtECA2 and AtECA3 in Arabidopsis, several independent T-DNA insertion mutant alleles were isolated. When grown on medium lacking Mn, eca3 mutants, but not eca2 mutants, displayed a striking difference from wild-type plants. After approximately 8 to 9 d on this medium, eca3 mutants became chlorotic, and root and shoot growth were strongly inhibited compared to wild-type plants. These severe deficiency symptoms were suppressed by low levels of Mn, indicating a crucial role for ECA3 in Mn nutrition in Arabidopsis. eca3 mutants were also more sensitive than wild-type plants and eca2 mutants on medium lacking Ca; however, the differences were not so striking because in this case all plants were severely affected. ECA3 partially restored the growth defect on high Mn of the yeast (Saccharomyces cerevisiae) pmr1 mutant, which is defective in a Golgi Ca/Mn pump (PMR1), and the yeast K616 mutant (Deltapmc1 Deltapmr1 Deltacnb1), defective in Golgi and vacuolar Ca/Mn pumps. ECA3 also rescued the growth defect of K616 on low Ca. Promoter:beta-glucuronidase studies show that ECA3 is expressed in a range of tissues and cells, including primary root tips, root vascular tissue, hydathodes, and guard cells. When transiently expressed in Nicotiana tabacum, an ECA3-yellow fluorescent protein fusion protein showed overlapping expression with the Golgi protein GONST1. We propose that ECA3 is important for Mn and Ca homeostasis, possibly functioning in the transport of these ions into the Golgi. ECA3 is the first P-type ATPase to be identified in plants that is required under Mn-deficient conditions.


Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study.
Recombinant human (h) 5-HT1A receptor-mediated G-protein activation was characterised in membranes of transfected Chinese hamster ovary (CHO) cells by use of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS binding). The potency and efficacy of 21 5-HT receptor agonists and antagonists was determined. The agonists, 5-CT (carboxamidotryptamine) and flesinoxan displayed high affinity (subnanomolar Ki values) and high efficacy (Emax > 90%, relative to 5-HT = 100%). In contrast, ipsapirone, zalospirone and buspirone displayed partial agonist activity. EC50s for agonist stimulation of [35S]GTPgammaS binding correlated well with Ki values from competition binding (r = +0.99). Among the compounds tested for antagonist activity, methiothepin and (+)butaclamol exhibited 'inverse agonist' behaviour, inhibiting basal [35S]GTPgammaS binding. The actions of 17 antipsychotic agents were investigated. Clozapine and several putatively 'atypical' antipsychotic agents, including ziprasidone, quetiapine and tiospirone, exhibited partial agonist activity and marked affinity at h5-HT1A receptors, similar to their affinity at hD2 dopamine receptors. In contrast, risperidone and sertindole displayed low affinity at h5-HT1A receptors and behaved as 'neutral' antagonists, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Likewise the 'typical' neuroleptics, haloperidol, pimozide, raclopride and chlorpromazine exhibited relatively low affinity and 'neutral' antagonist activity at h5-HT1A receptors with Ki values which correlated with their respective Kb values. The present data show that (i) [35S]GTPgammaS binding is an effective method to evaluate the efficacy and potency of agonists and antagonists at recombinant human 5-HT1A receptors. (ii) Like clozapine, several putatively 'atypical' antipsychotic drugs display balanced serotonin h5-HT1A/dopamine hD2 receptor affinity and partial agonist activity at h5-HT1A receptors. (iii) Several 'typical' and some putatively 'atypical' antipsychotic agents displayed antagonist properties at h5-HT1A sites with generally much lower affinity than at hD2 dopamine receptors. It is suggested that agonist activity at 5-HT1A receptors may be of utility for certain antipsychotic agents.


Care Continuum and Postdischarge Outcomes Among HIV-Infected Adults Admitted to the Hospital in Zambia.
We characterized the extent of antiretroviral therapy (ART) experience and postdischarge mortality among hospitalized HIV-infected adults in Zambia. At a central hospital with an opt-out HIV testing program, we enrolled HIV-infected adults (18+ years) admitted to internal medicine using a population-based sampling frame. Critically ill patients were excluded. Participants underwent a questionnaire regarding their HIV care history and CD4 count and viral load (VL) testing. We followed participants to 3 months after discharge. We analyzed prior awareness of HIV-positive status, antiretroviral therapy (ART) use, and VL suppression (VS; <1000 copies/mL). Using Cox proportional hazards regression, we assessed risk factors for mortality. Among 1283 adults, HIV status was available for 1132 (88.2%), and 762 (67.3%) were HIV-positive. In the 239 who enrolled, the median age was 36 years, 59.7% were women, and the median CD4 count was 183 cells/mm3. Active tuberculosis or Cryptococcus coinfection was diagnosed in 82 (34.3%); 93.3% reported prior awareness of HIV status, and 86.2% had ever started ART. In the 64.0% with >6 months on ART, 74.4% had VS. The majority (92.5%) were discharged, and by 3 months, 48 (21.7%) had died. Risk of postdischarge mortality increased with decreasing CD4, and there was a trend toward reduced risk in those treated for active tuberculosis. Most HIV-related hospitalizations and deaths may now occur among ART-experienced vs -naïve individuals in Zambia. Development and evaluation of inpatient interventions are needed to mitigate the high risk of death in the postdischarge period.


Use of Flowchart for Automation of Clinical Protocols in mHealth.
For healthcare professionals to use mobile applications we need someone who knows software development, provide them. In healthcare institutions, health professionals use clinical protocols to govern care, and sometimes these documents are computerized through mobile applications to assist them. This work aims to present a proposal of an application of flow as a way of describing clinical protocols for automatic generation of mobile applications to assist health professionals. The purpose of this research is to enable health professionals to develop applications from the description of their own clinical protocols. As a result, we developed a web system that automates clinical protocols for an Android platform, and we validated with two clinical protocols used in a Brazilian hospital. Preliminary results of the developed architecture demonstrate the feasibility of this study.


Propose of Standards Based IT Architecture to Enrich the Value of Allergy Data by Telemonitoring Data.
Interoperability is a key requirement for any IT-System to be future proof and cost efficient, due to the increasing interaction of IT-Systems in Healthcare. This feasibility study is part of a larger project focusing on the conceptualization and evaluation of interoperable and modular IT-Framework components for exchanging big data information sets. Hence, this project investigates the applicability of a standard based IT-Architecture for the integration of Personal Health Devices data and open data sources. As a proof of concept use case, pollen forecast data from the Medical University of Vienna were combined with Personal Health Device data and a data correlation was investigated. The standards were identified as well as selected in expert's reviewed and the Architecture was designed based on a literature research. Subsequently the prototype was implemented and successfully tested in interoperability tests. The study shows that the architecture meets the requirements. It can be flexibly extended according to further requirements due to its generic setup. However, further extensions of the Interoperability-Connector and a full test setup needs to be realized in future.


Effects of mycotoxins on cytokine production and proliferation in EL-4 thymoma cells.
The thymoma cell line EL4.IL-2 (EL-4) was used as a T-cell model to assess the immunotoxic effects of several mycotoxins produced by the Aspergillus-Penicillium and the Fusarium groups. EL-4 cells were stimulated with phorbol 12-myristate 12-acetate (PMA) in the presence of mycotoxins at various concentrations for 5 d and culture supernatants were analyzed for interleukins (IL) IL-2 and IL-5 by enzyme-linked immunosorbent assay (ELISA). The cytokine effects were further related to proliferation and cell viability using the MTT [3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide] assay with absorbance at 570 nm (A570) as the endpoint indicator. IL-2 and IL-5 levels were dramatically increased by cyclopiazonic acid at 50-1000 ng/ml, whereas IL-2 was significantly decreased at 10 microgram/ml. Proliferation was slightly increased at 100-1000 ng/ml cyclopiazonic acid but markedly depressed at 5 and 10 microgram/ml. When EL-4 cells were exposed to 5 and 10 microgram/ml of ochratoxin A, IL-2 production was markedly increased while IL-5 production was significantly decreased. The A570 was significantly decreased by ochratoxin A at 10 microgram/ml. IL-2 and Il-5 production was almost totally suppressed by patulin at concentrations > or = 500 ng/ml and by T-2 toxin at > or = 5 ng/ml. These effects occurred concurrently with marked depression of A570 in the MTT assay. Although A570 was unaffected by either zearalenone or alpha-zearalenol exposure, both IL-2 and IL-5 levels were significantly elevated by these toxins at 5 or 10 microgram/ml. IL-2 and IL-5 production were not affected in EL-4 cells cultured with either the Aspergillus-Penicillium toxins aflatoxin B1 and secalonic acid or the Fusarium toxins wortmannin, fumonisin B1, or fusaric acid at concentrations up to 10 microgram/ml. In total, the EL-4 culture studies indicated that cyclopiazonic acid, ochratoxin A, zearalenone, and alpha-zearalenol could stimulate cytokine production whereas patulin and T-2 toxin were inhibitory. Cytokine dysregulation was not always related directly to perturbations in proliferation. The results suggest that the EL-4 thymoma cell line could be a simple and effective in vitro model for evaluating immunotoxicity of various classes of environmental chemicals.


Peripheral-type benzodiazepine receptors in the central nervous system: localization to olfactory nerves.
Binding levels of [3H]Ro5-4864, a ligand selective for peripheral-type benzodiazepine receptors, are substantially higher in homogenates of the olfactory bulb than in the rest of the brain. Among peripheral tissues evaluated, high levels of [3H]Ro5-4864 binding are found in the nasal epithelium. Drug displacement studies show that these binding sites are pharmacologically of the peripheral type. Their presence in the nasal epithelium and in the olfactory bulb can be demonstrated in several different mammalian species. Autoradiographic studies of murine nose reveal a bipolar staining pattern around the cell bodies of the olfactory receptor cells, suggesting the presence of peripheral-type benzodiazepine receptors on both processes of these bipolar neurons. In the brain a high density of [3H]Ro5-4864 binding sites occurs in the nerve fiber and glomerular layers of the olfactory bulb. Throughout the rest of the brain [3H]Ro5-4864-associated silver grains are diffusely distributed with intense staining over the choroid plexus and along the ependymal linings of the ventricles. Both the distribution and the ontogenic development of the peripheral-type benzodiazepine receptors differ from the central-type receptors. Intranasal irrigation with 5% ZnSO4 results in a 50% reduction of peripheral-type benzodiazepine receptors in the olfactory bulb without affecting the density of central-type benzodiazepine receptors. Thus, [3H]Ro5-4864 binding sites in the olfactory bulb appear in large part to be localized to olfactory nerves which originate in the nasal epithelium.


PKC delta and NADPH oxidase in retinoic acid-induced neuroblastoma cell differentiation.
The role of reactive oxygen species (ROS) in the regulation of signal transduction processes has been well established in many cell types and recently the fine tuning of redox signalling in neurons received increasing attention. With regard to this, the involvement of NADPH oxidase (NOX) in neuronal pathophysiology has been proposed but deserves more investigation. In the present study, we used SH-SY5Y neuroblastoma cells to analyse the role of NADPH oxidase in retinoic acid (RA)-induced differentiation, pointing out the involvement of protein kinase C (PKC) delta in the activation of NOX. Retinoic acid induces neuronal differentiation as revealed by the increased expression of MAP2, the decreased cell doubling rate, and the gain in neuronal morphological features and these events are accompanied by the increased expression level of PKC delta and p67(phox), one of the components of NADPH oxidase. Using DPI to inhibit NOX activity we show that retinoic acid acts through this enzyme to induce morphological changes linked to the differentiation. Moreover, using rottlerin to inhibit PKC delta or transfection experiments to overexpress it, we show that retinoic acid acts through this enzyme to induce MAP2 expression and to increase p67(phox) membrane translocation leading to NADPH oxidase activation. These findings identify the activation of PKC delta and NADPH oxidase as crucial steps in RA-induced neuroblastoma cell differentiation.


The use of rocks to improve family agriculture in Brazil.
During the second half of the 20th century, the introduction of new chemical agriculture technologies brought about a revolution in food production, but this has also cause deep deterioration in our relationships with the natural environment. In developing tropical countries, record yields were accompanied by rural exodus, widespread deforestation and loss of topsoil. The stonemeal research described herein is an alternative to such practices as it is an environmental friendly and socially responsible technology based on soil rejuvenation and conservation by means of the addition of natural rock powders that are rich in phosphorous, calcium, magnesium, potassium and micronutrients. The research adopted an inter-disciplinary approach and was conducted among small farmers of a rural community located in the state of Minas Gerais, Brazil. The major goal was to demonstrate that there is a harmless cheap and simple alternative to fertilizing degraded or impoverished soils, which allow farmers to sustain high productivity and to remain on their plots of land. Results have confirmed the economic, environmental and productive feasibility and advantage of the stonemeal technique for corn, rise, manioc, sugar cane and horticultural species, when compared to the use of chemical fertilizers. The fertilization of the soil with rocks, allows the understanding of the natural processes, which maintain production levels while building a sustainable fertile soil.


Increased expression of multidrug resistance-associated proteins in bladder cancer during clinical course and drug resistance to doxorubicin.
Overexpression of the P-glycoprotein/multidrug resistance 1 (MDR1) and multidrug resistance protein 1 (MRP1) gene is closely associated with the clinical outcome of various malignancies, and it is involved in responses to some anticancer chemotherapeutic agents including doxorubicin. Six human MRP subfamily members (MRP2-7) with structural similarities to MRP1 have been identified. Recently, the relationships between MRP2 and MRP3 expression levels of some cancer cells and drug sensitivity to doxorubicin have been reported, but the relationship between the clinical samples and drug sensitivity remains unclear. We determined the expressions of the MDR1, MRP1, MRP2 and MRP3 gene in bladder cancer during the clinical course and sought to learn whether the expression was correlated with drug responses to doxorubicin. Doxorubicin, used in chemotherapeutic treatment including intravesical and systemic chemotherapy, is an important anticancer agent for the treatment of bladder cancer. We used quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis for our study, and the sensitivity to doxorubicin in bladder cancer was determined using the in vitro succinate dehydrogenase inhibition test. Using 47 clinical samples of bladder cancer, we confirmed the significant correlation of MDR1, MRP1 and MRP3 mRNA levels with resistance to doxorubicin. We showed that the expression of MDR1, MRP1, MRP2 and MRP3 in recurrent tumors and residual tumors after chemotherapeutic treatment was higher than that in untreated primary tumors. In particular, the MDR1 expression in residual tumors was 5.7-fold higher than that in untreated primary tumors.


Nuclear distribution of transcription factors in relation to sites of transcription and RNA polymerase II.
We have investigated the spatial relationship between sites containing newly synthesized RNA and domains containing proteins involved in transcription, such as RNA polymerase II and the transcription factors TFIIH, Oct1, BRG1, E2F-1 and glucocorticoid receptors, using dual immunofluorescence labelling followed by confocal microscopy on cultured cells. As expected, a high degree of colocalisation between the RNA polymerase II and sites containing newly synthesised RNA was observed. Like the newly synthesised RNA and the RNA polymerase II, we found that all the transcription factors that we studied are distributed more or less homogeneously throughout the nucleoplasm, occupying numerous small domains. In addition to these small domains, TFIIH was found concentrated in coiled bodies and Oct1 in a single large domain of about 1.5 microm in 30% of the cells in an asynchronous HeLa cell culture. Remarkably, we found little or no relationship between the spatial distribution of the glucocorticoid receptor, Oct1 and E2F-1 on the one hand and RNA polymerase II and transcription sites on the other hand. In contrast, a significant but incomplete overlap was observed between the spatial distributions of transcription sites and BRG1 and TFIIH. These results indicate that many of the transcription factor-rich nuclear domains are not actively involved in transcription. They may represent incomplete transcription initiation complexes, inhibitory complexes, or storage sites.


Reversal of Immunoglobulin A Deficiency in Children.
Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in the general population. It is defined as a serum IgA level below or equal to 0.07 g/l with normal IgM and IgG levels in children over the age of 4. However, a few cases of reversal of IgAD at later ages have been observed previously, especially in pediatric patients. This study aimed at investigating the frequency of reversal in a large cohort of children and young adults in order to evaluate the present definition of IgAD. Clinical laboratory records from 654 pediatric IgA deficient patients, 4-13 years of age, were retrieved from five university hospitals in Sweden. Follow up in the children where IgA serum levels had been routinely measured was subsequently performed. In addition, follow up of the IgA-levels was also performed at 4, 8 and 16 years of age in children who were IgA deficient at the age of 4 years in a Swedish population-based birth cohort study in Stockholm (BAMSE). Nine out of 39 (23.1%) children who were identified as IgAD at 4 years of age subsequently increased their serum IgA level above 0.07 g/L. The average age of reversal was 9.53 ± 2.91 years. In addition, 30 out of the 131 (22.9%) children with serum IgAD when sampled between 5 and 9.99 years of age reversed their serum IgA level with time. The BAMSE follow up study showed a reversal of IgAD noted at 4 years of age in 8 out of 14 IgAD children at 16 years of age (5 at 8 years of age) where 4 were normalized their serum IgA levels while 4 still showed low serum levels of IgA, yet above the level defining IgAD. The results indicate that using 4 years of age, as a cut off for a diagnosis of IgAD may not be appropriate. Our findings suggest that a diagnosis of IgAD should not be made before the early teens using 0.07 g/L of IgA in serum as a cut off.


When experiments go wrong: the U.S. perspective.
The view that once prevailed in the U.S.--that research is no more dangerous than the activities of daily life--no longer holds in light of recent experience. Within the past few years, a number of subjects (including normal volunteers) have been seriously injured or killed in research conducted at prestigious institutions. Plainly, when we are talking about research going wrong, we're talking about something very important. We have seen that experiments can go wrong in several ways. Subjects can be injured--physically, mentally, or by having other interests violated. Investigators can commit fraud in data collection or can abuse subjects. And review mechanisms--such as IRBs--don't always work. The two major issues when research goes wrong in any of these ways are, first: What will be done for subjects who have suffered an injury or other wrong? and second: How will future problems be prevented? The present system in the U.S. is better at the second task than the first one. Part of the difficulty in addressing the first lies in knowing what "caused" an apparent injury. Moreover, since until recently the problem of research-related injuries was thought to be a small one, there was considerable resistance to setting up a non-fault compensation system, for fear that it would lead to payment in many cases where such compensation was not deserved. Now, with a further nudge from the NBAC there is renewed interest in developing a formal system to compensate for research injuries. Finally, I have tried to show that our system of local oversight is only partially effective in improving the design of experiments and the consent process in light of "unexpected (adverse) results." As many observers, including the federal General Accounting Office (GAO), have reported, the requirement for "continuing review" of approved research projects is the weak point in the IRB system. The probable solution would be to more strictly apply the requirement that investigators report back any adverse results, de-emphasizing the "screen" introduced by the present language about "unexpected" findings. Yet, despite its weaknesses, there are good aspects to the local basis of our oversight system, and when problems become severe enough, OHRP is likely to evaluate a system and insist on local improvements. Thus, while the U.S. system is far from perfect in responding when research goes wrong, our experience may be useful to others in crafting a system appropriate to their own circumstances. One of the major tasks will be to adequately define what triggers oversight--that is, who reports what to whom and when? The setting of this trigger needs to balance appropriate incentives and penalties. Any system, including our own, will, in my opinion, work much better once an accreditation process is in place, which will offer much more current and detailed information on how each IRB is functioning and what steps are needed to help avoid "experiments going wrong."


Effect of endemic fluorosis on hematological parameters.
Although so many studies exist on effect of fluoride on hematological parameters in experimental animals, a few studies have been conducted to investigate the effects of chronic fluorosis on hematological parameters in humans' subjects with endemic fluorosis. So we aimed to determine the hematological parameters in patients with endemic fluorosis. The study group consisted of 60 patients with endemic fluorosis (27 females, 33 males, and mean age 33.4 ± 9.6 years). An age-, gender-, and body mass index-matched control group was composed of 34 healthy volunteers (11 females, 23 males with a mean age 32.6 ± 5.6 years). Urine fluoride levels of fluorosis patients were significantly higher than control subjects as expected (0.42 ± 0.09 vs 1.92 ± 0.14 mg/l, respectively; P < 0.001). There were no statistically significant differences between the fluorosis group and control group with respect to hematological parameters (complete blood count and ferritin). We concluded that chronic fluorosis has no effect on hematological parameters in patients with endemic fluorosis.


Statistical modelling of network panel data: goodness of fit.
Networks of relationships between individuals influence individual and collective outcomes and are therefore of interest in social psychology, sociology, the health sciences, and other fields. We consider network panel data, a common form of longitudinal network data. In the framework of estimating functions, which includes the method of moments as well as the method of maximum likelihood, we propose score-type tests. The score-type tests share with other score-type tests, including the classic goodness-of-fit test of Pearson, the property that the score-type tests are based on comparing the observed value of a function of the data to values predicted by a model. The score-type tests are most useful in forward model selection and as tests of homogeneity assumptions, and possess substantial computational advantages. We derive one-step estimators which are useful as starting values of parameters in forward model selection and therefore complement the usefulness of the score-type tests. The finite-sample behaviour of the score-type tests is studied by Monte Carlo simulation and compared to t-type tests.


Characteristics and Evolution of sill-driven off-axis hydrothermalism in Guaymas Basin - the Ringvent site.
The Guaymas Basin spreading center, at 2000 m depth in the Gulf of California, is overlain by a thick sedimentary cover. Across the basin, localized temperature anomalies, with active methane venting and seep fauna exist in response to magma emplacement into sediments. These sites evolve over thousands of years as magma freezes into doleritic sills and the system cools. Although several cool sites resembling cold seeps have been characterized, the hydrothermally active stage of an off-axis site was lacking good examples. Here, we present a multidisciplinary characterization of Ringvent, an ~1 km wide circular mound where hydrothermal activity persists ~28 km northwest of the spreading center. Ringvent provides a new type of intermediate-stage hydrothermal system where off-axis hydrothermal activity has attenuated since its formation, but remains evident in thermal anomalies, hydrothermal biota coexisting with seep fauna, and porewater biogeochemical signatures indicative of hydrothermal circulation. Due to their broad potential distribution, small size and limited life span, such sites are hard to find and characterize, but they provide critical missing links to understand the complex evolution of hydrothermal systems.


A cross-sectional matched sample study of nonsuicidal self-injury among young adults: support for interpersonal and intrapersonal factors, with implications for coping strategies.
Young adults are a high-risk group for nonsuicidal self-injury (NSSI). It is important to have a better understanding of these behaviors in order to facilitate effective research, intervention, and treatment. Models have been presented to explain these behaviors where emotion regulation, coping, and support play a role. Yet conflicting results have occurred based on demographic factors such as race and sex. While controlling for the observable demographic factors, this study sought to examine differences between individuals who currently engage in NSSI, engaged in NSSI in the past, and never engaged in NSSI related to emotions, coping strategies, interpersonal support, and ethnic identity and belonging. Participants were selected from freshman students at two universities, in geographically different locations in the United States (N = 282). Participants in this study were matched on demographic factors: race, sex, and university. This led to demographically matched groups (current, past, never engagement in NSSI; n = 94 per group). Groups were compared on intrapersonal factors (i.e., emotions: depression and anxiety; coping strategies: adaptive and maladaptive; interpersonal support: family, friend, and significant other; and ethnic identity and belonging). Descriptive statistics and ANOVA with post hoc Scheffe were utilized to explicate differences between groups. Individuals who never engaged in NSSI reported significantly higher levels of ethnic belonging and interpersonal support and lower levels of depression and anxiety than both groups who engaged in NSSI. Individuals who never self-injured used less adaptive and maladaptive coping strategies than participants who self-injured. Young adults who currently engaged in NSSI reported higher levels of depression and anxiety, higher levels of both types of coping, and perceived less support. It is important to understand the differences between individuals who self-injure in comparison to those who do not so that mental health clinicians can provide more effective services and preventative efforts.


Brief Report: Diabetic Keto-Acidosis (DKA) Induced Hypothermia may be Neuroprotective in Cardiac Arrest.
Despite the decreased survival associated with diabetes with out-of-hospital cardiac arrest and the overall low survival to hospital discharge, we would like to present two cases of OHCA in diabetics who despite prolonged resuscitation efforts had complete neurological recovery likely due to concomitant hypothermia. There is a steady decreasing rate of ROSC with longer durations of CPR so that outcomes are best when <20 minutes compared to prolonged resuscitation efforts (>30-40 minutes). It has been previously recognized that hypothermia prior to cardiac arrest can be neurologically protective even with up to 9 hours of cardiopulmonary resuscitation. Hypothermia has been associated with DKA and although often indicates sepsis with mortality rates of 30-60%, it may indeed be protective if occurring prior to cardiac arrest. The critical factor for neuroprotection may be a slow drop to a temperature <250C prior to OHCA as is achieved in deep hypothermic circulatory arrest for operative procedures of the aortic arch and great vessels. It may be worthwhile continuing aggressive resuscitation efforts even for prolonged periods before attaining ROSC for OHCA in patients found hypothermic from metabolic illnesses as compared to only from environmental exposures (avalanche victims, cold water submersions, etc.) as has been traditionally reported in the medical literature.


Experimental study of progressive tibial lengthening in dogs using the Ilizarov technique. Comparison with and without associated intramedullary K-wires.
A delay in the union of bone regenerate in surgical lengthening procedures and the healing index (HI) are major factors in the quality of the results in progressive bone lengthening. Early removal of the external fixator (EF) is associated with a low rate of postoperative complications, including pin track infection, and with better muscle and joint function recovery. Addition of intramedullary wires (IMWs) to the EF led to a 9-49% decrease in the HI depending on the clinical series. We hypothesized that IMWs may accelerate the ossification process of bone regenerate and tested it in this experimental study. Progressive tibial lengthening of 28 mm was obtained in 12 dogs operated with the classical Ilizarov technique (group I) and in 12 dogs operated with the same technique and addition of two IMWs 1.5 mm in diameter (group II). The following criteria were assessed: HI, X-ray measurements, and histological aspect of the bone regenerate and postoperative complications. The mean HI was 32.3% lower in group II than in group I. The radiological bone union criteria were observed on day 15 of the fixation period in group II versus day 30 in group I. Histology showed that maturation occurred earlier and bone cortices were thicker in group II than group I. Intramedullary ossification was present along the IMW in group II, whereas it was absent in group I. No clinical complications were observed in either group. The presence of the IMWs clearly contributes to stimulation of the ossification processes of the bone regenerate and to acceleration of bone union. IMWs allowed an earlier removal of the external fixator for a 32% time reduction compared to cases without IMWs. In addition, new intramedullary bone formation and presence of IMWs are expected to increase the mechanical resistance of the bone regenerate. Improvement of quantitative and qualitative criteria of bone regenerate in progressive bone lengthening with an EF combined with IMWs was demonstrated in this experimental study. Favorable results encourage the authors to continue using IMWs in addition to the EF in patients treated with long-bone progressive lengthening. II.


The future of anti-EGFR therapy.
We report here on the state of our knowledge of the target--namely, the epidermal growth factor (EGF) and its receptor--and the challenges related to the methods of determination of the epidermal growth factor receptor (EGFR) and associated molecular pathways. A critical review of the anti-EGFR therapeutic strategies is also outlined. The chimeric anti- EGFR monoclonal antibody cetuximab has been approved for EGFR-expressing colorectal tumors in patients who progress after irinotecan-based chemotherapy in combination with irinotecan and in squamous cell head and neck carcinomas for patients with locally advanced disease in combination with radiation therapy or after failure of platinum-based chemotherapy in recurrent or metastatic disease (FDA). Cetuximab has the potential to provide an improvement of clinical outcome also in other indications and tumor types, particularly when used as first-line therapy combined with standard chemotherapy for metastatic disease or in the adjuvant setting. Possible strategies to improve the effectiveness of anti-EGFR agents are suggested and include (i) the use of predictive tools capable of making a more rational selection of patients; (ii) the development of standardized predictive biomarkers as surrogates for early monitoring of drug efficacy; and (iii) adequate study design, statistical analysis and proper end points of efficacy to be applied in future prospective trials.


Prevention of travelers' diarrhea by the tablet formulation of bismuth subsalicylate.
Within 48 hours of arrival in Mexico, 182 US students participated in a study to compare the efficacy of two dosages of bismuth subsalicylate (262 mg per tablet) as a prophylactic agent against diarrhea. The students were randomly assigned to receive two tablets (high dose) or one tablet (low dose) of bismuth subsalicylate four times daily or a placebo four times daily during a three-week period. Among these completing the trial, diarrhea (four or more unformed stools in 24 hours or three in eight hours, plus one other symptom) occurred in seven (14%) of 51 receiving the high-dose regimen compared with 15 (24%) of 63 receiving the low-dose regimen and 23 (40%) of 58 in the placebo group. Protection rates were 65% for high-dose and 40% for low-dose bismuth subsalicylate. Diarrhea caused by enterotoxigenic Escherichia coli was found in one student receiving the high-dose regimen, in no students receiving the low-dose regimen, and in seven placebo-treated subjects. Bismuth subsalicylate was well tolerated; the most common side effects were blackening of tongues and stools. Bismuth subsalicylate use in both dosages was associated with tinnitus at a low, clinically insignificant frequency of 1.2 days per 100 days of treatment. The dosage of two tablets of bismuth subsalicylate four times daily (2.1 g/d) appears to be a safe and effective means of reducing the occurrence of travelers' diarrhea among persons at risk for periods up to three weeks.


Toward the authentication of wines of Nemea denomination of origin through cleaved amplified polymorphic sequence (CAPS)-based assay.
In the present study, we developed a cleaved amplified polymorphic sequence (CAPS)-based assay as a first attempt to detect fraud in grapevine musts with a long-term objective to establish an analytical methodology to authenticate wines of Nemea denomination of origin (Agiorgitiko). The analytical assay makes use of a single nucleotide polymorphism that discriminates Agiorgitiko and Cabernet Sauvignon varieties. The latter grape variety is one of the major adulterants for Nemea wines. Agiorgitiko grapevine must was spiked with Cabernet Sauvignon in several ratios (v/v) from 50 down to 10%, and the subsequent mixes were subjected to alcoholic microfermentation. DNA was extracted from all mixture samples up to the end of the fermentation process and was subjected to the CAPS assay. Both standard agarose gel and lab-on-a-chip capillary electrophoresis illustrated the ability of the method to detect the presence of Cabernet Sauvignon down to 10% throughout the whole fermentation process.


Probable prostate cancer in a pre-Incaic individual from Pukara de la Cueva, northwestern Argentina.
Prostate carcinoma is a common malignant neoplasia that mostly metastasizes to bone in males. Nonetheless, the number of paleopathological cases reported is very small. Most of them were identified in Europe, and only two came from South American individuals. The purpose of this paper is to document the lesions identified in a pre-Columbian (around 1400 AD) individual that corresponds to a middle adult male from Pukara de la Cueva, Jujuy province, in the Northwest region of Argentina. The skeleton was found disarticulated but it is nearly complete and well preserved. The general character of the lesions observed is predominantly proliferative in nature, but osteolytic and mixed patterns were also detected in both axial and appendicular skeleton. Macroscopically, this overall pattern and the distribution of the lesions are compatible with a secondary cancer. Radiological examination showed multiple dense and irregular areas in several bones. The lesions visible by external inspection and by radiographs are in concordance with changes which are documented to occur in the course of prostatic carcinoma. The exuberance and dissemination of the lesions all over the skeleton led infer individual cachexy implying that he would have been assisted by his family and/or social group during the chronic process. Different carcinogenic risk factors associated to this kind of disease are discussed. This analysis adds new evidence of pre-Columbian carcinoma in South American native populations, as knowledge from clinical cases is considered to delineate a differential diagnosis.


Efficacy of silver-bearing external ventricular drainage catheters: a retrospective analysis.
Catheter-related infection of CSF is a potentially life-threatening complication of external ventricular drainage (EVD). When using EVD catheters, contact between the ventricular system and skin surface occurs and CSF infection is possible. The aim of this analysis was to compare the efficacy of silver-bearing EVD catheters for reducing the incidence of infection with standard nonimpregnated EVD catheters in neurosurgical patients with acute hydrocephalus. Two hundred thirty-one consecutive patients were retrospectively reviewed. Of these, 164 were enrolled in the final analysis. Six patient charts were incomplete or missing, 15 patients were excluded because of catheter insertion within the previous 30 days, 6 because of a suspected CSF infection before ventriculostomy, 7 because the catheter was removed < 24 hours after insertion, and 33 patients because of the requirement of bilateral ventriculostomy. The control group with standard nonimpregnated EVD catheters consisted of 90 patients. The study group with silver-bearing EVDs consisted of 74 patients. For assessing the primary outcome, the authors recorded all CSF samples and liquor cell counts routinely obtained in sterile fashion. After removal of the catheters, they also reviewed microbiology reports of the removed catheters to assess colonization of the catheter tips. The occurrence of a positive CSF culture, colonization of the catheter tip, or liquor pleocytosis (white blood cell count > 4/microl) was approximately 2 times less in the study group with silver-bearing EVD catheters than that in the control group (18.9% compared with 33.7%, p = 0.04). Positive CSF cultures alone occurred 2 times less frequently for microorganisms in the study group (2.7% compared with 4.7%, p = 0.55). Silver-bearing catheters were 4 times less likely to become colonized as nonimpregnated EVDs (1.4% compared with 5.8%, p = 0.14). Liquor pleocytosis was half as likely in the study group (17.6% compared with 30.2%, p = 0.06). Although of limited sample size and thus underpowered for subgroup analysis, this analysis indicates that EVD catheters impregnated with silver nanoparticles and an insoluble silver salt may reduce the risk of catheter-related infections in neurosurgical patients.


Effect of hyperglycemia-hyperinsulinemia on whole body and regional fatty acid metabolism.
The effects of combined hyperglycemia-hyperinsulinemia on whole body, splanchnic, and leg fatty acid metabolism were determined in five volunteers. Catheters were placed in a femoral artery and vein and a hepatic vein. U-13C-labeled fatty acids were infused, once in the basal state and, on a different occasion, during infusion of dextrose (clamp; arterial glucose 8.8 +/- 0.5 mmol/l). Lipids and heparin were infused together with the dextrose to maintain plasma fatty acid concentrations at basal levels. Fatty acid availability in plasma and fatty acid uptake across the splanchnic region and the leg were similar during the basal and clamp experiments. Dextrose infusion decreased fatty acid oxidation by 51.8% (whole body), 47.4% (splanchnic), and 64.3% (leg). Similarly, the percent fatty acid uptake oxidized decreased at the whole body level (53 to 29%), across the splanchnic region (30 to 13%), and in the leg (48 to 22%) during the clamp. We conclude that, in healthy men, combined hyperglycemia-hyperinsulinemia inhibits fatty acid oxidation to a similar extent at the whole body level, across the leg, and across the splanchnic region, even when fatty acid availability is constant.


Peierls potential for crowdions in the bcc transition metals.
We present the first derivation of the analytic expression for the Peierls-Nabarro potential for crowdion migration using the double sine-Gordon model. The analysis is guided by the group-specific trend in the shapes of the periodic lattice potentials calculated for the body-centered-cubic transition metals in groups 5B and 6B of the periodic table. We combine density-functional calculations of the crowdion's profile and environment with an extended version of the analytical Frenkel-Kontorova model, and determine the effective potential experienced by the defect's center of mass. This reveals important underlying differences between the metals in these groups, which are inaccessible to either the numerical or analytical approaches alone, and accounts for the previously unexplained significantly higher crowdion migration temperatures observed in the metals of group 6B relative to those of group 5B.


Artisanal shark fishing in Milne Bay Province, Papua New Guinea: biomass estimation from genetically identified shark and ray fins.
Our study is the first detailed examination of species composition using DNA COI barcoding of elasmobranchs from an artisanal fishery of Papua New Guinea. The study is the first in the region to provide biomass estimates based on species confirmation following examination of dried fins. Over 20 species of elasmobranchs were identified from 623 fins from the artisanal fishery in Milne Bay Province of PNG, with Carcharhinus amblyrhynchos and Carcharhinus melanopterus the most abundant species in the catches. Of concern, 21% of fins examined were from IUCN listed threatened species (Vulnerable or Endangered) with 8% of fins from the Endangered scalloped hammerhead (Sphyrna lewini). Following species identifications and use of species-specific length and weight extrapolations, we estimated over 9 t of elasmobranchs contributed to the fin batch. Importantly, the vast majority of the elasmobranchs in this batch were from immature animals. Genetic identification has an important role to play in the ongoing sustainable management of elasmobranchs in artisanal fisheries in PNG and more widely. However in the absence of ongoing genetic testing, recording the species (if known) at the time of catch is more achievable and would provide more robust data for fisheries managers in PNG over the longer term.


Prevalence of hypertension, awareness, treatment, and control in the Hispanic Community Health Study/Study of Latinos.
The prevention and control of hypertension is an essential component for reducing the burden of cardiovascular diseases. Here we describe the prevalence of hypertension in diverse Hispanic/Latino background groups and describe the proportion who are aware of their diagnosis, receiving treatment, and having their hypertension under control. The Hispanic Community Health Study/Study of Latinos is a longitudinal cohort study of 16,415 Hispanics/Latinos, aged 18-74 years from 4 US communities (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA). At baseline (2008-2011) the study collected extensive measurements and completed questionnaires related to research on cardiovascular diseases. Hypertension was defined as measured blood pressure ≥140/90mm Hg or use of antihypertensive medication. The total age-adjusted prevalence of hypertension in this study was 25.5% as compared with 27.4% in non-Hispanic whites in the National Health and Nutrition Examination Survey. Prevalence of hypertension increased with increasing age groups and was highest in Cuban, Puerto Rican, and Dominican background groups. The percent with hypertension who were aware, being treated with medication, or had their hypertension controlled was lower compared with US non-Hispanic whites with hypertension and it was lowest in those without health insurance. These findings indicate a significant deficit in treatment and control of hypertension among Hispanics/Latinos residing in the United States, particularly those without health insurance. Given the relative ease of identification of hypertension and the availability of low-cost medications, enabling better access to diagnostic and treatment services should reduce the burden of hypertension in Hispanic populations.


Parallel adaptive evolution of geographically distant herring populations on both sides of the North Atlantic Ocean.
Atlantic herring is an excellent species for studying the genetic basis of adaptation in geographically distant populations because of its characteristically large population sizes and low genetic drift. In this study we compared whole-genome resequencing data of Atlantic herring populations from both sides of the Atlantic Ocean. An important finding was the very low degree of genetic differentiation among geographically distant populations (fixation index = 0.026), suggesting lack of reproductive isolation across the ocean. This feature of the Atlantic herring facilitates the detection of genetic factors affecting adaptation because of the sharp contrast between loci showing genetic differentiation resulting from natural selection and the low background noise resulting from genetic drift. We show that genetic factors associated with timing of reproduction are shared between genetically distinct and geographically distant populations. The genes for thyroid-stimulating hormone receptor (TSHR), the SOX11 transcription factor (SOX11), calmodulin (CALM), and estrogen receptor 2 (ESR2A), all with a significant role in reproductive biology, were among the loci that showed the most consistent association with spawning time throughout the species range. In fact, the same two SNPs located at the 5' end of TSHR showed the most significant association with spawning time in both the east and west Atlantic. We also identified unexpected haplotype sharing between spring-spawning oceanic herring and autumn-spawning populations across the Atlantic Ocean and the Baltic Sea. The genomic regions showing this pattern are unlikely to control spawning time but may be involved in adaptation to ecological factor(s) shared among these populations.