The mosaic of surface charge in contact electrification.
When dielectric materials are brought into contact and then separated, they develop static electricity. For centuries, it has been assumed that such contact charging derives from the spatially homogeneous material properties (along the material's surface) and that within a given pair of materials, one charges uniformly positively and the other negatively. We demonstrate that this picture of contact charging is incorrect. Whereas each contact-electrified piece develops a net charge of either positive or negative polarity, each surface supports a random "mosaic" of oppositely charged regions of nanoscopic dimensions. These mosaics of surface charge have the same topological characteristics for different types of electrified dielectrics and accommodate significantly more charge per unit area than previously thought.


Development and Psychometric Evaluation of the Vocational Fit Assessment (VFA).
The objective of this study was to determine the psychometric properties of the Vocational Fit Assessment (VFA) by examining its factor structure and subscale reliability. This prospective cross-sectional study used two surveys (one for worker abilities and one for job demands) to collect the data needed for the psychometric evaluation of the VFA. Latent parallel analysis and ordinal exploratory factor analysis were used to iteratively refine VFA subscales. Ten unidimensional subscales emerged from factor analysis of VFA items: (1) Cognitive Abilities, (2) Communication Skills, (3) Computer Skills, (4) Higher Task-Related Abilities, (5) Interpersonal Skills, (6) Lower Task-Related Abilities, (7) Physical Abilities, (8) Safety, (9) Self-Determination, and (10) Work Structure. Subscale internal consistency (ordinal α) was ≥.86 for VFA for worker abilities and ≥.77 for VFA for job demands. The unidimensional structure of VFA subscales and estimates of internal consistency lend initial evidence in support of their reliability and validity.


Assessment of 3-nitropropionic acid-evoked peripheral neuropathy in rats: neuroprotective effects of acetyl-l-carnitine and resveratrol.
Oxidative stress and secondary excitotoxicity, due to cellular energy deficit, are major factors playing roles in 3-nitropropionic acid (3-NPA) induced mitochondrial dysfunction. Acute or chronic exposure to 3-NPA also leads to neuronal degeneration in different brain regions. The present study quantitatively assessed peripheral neuropathy induced by chronic exposure to 3-NPA in rats. The neuroprotective abilities of two antioxidants, acetyl-l-carnitine and resveratrol, were investigated as well. Rats were exposed for up to four weeks to 3-NPA alone or 3-NPA combined with acetyl-l-carnitine or resveratrol, administered peripherally. The experimental outcome was evaluated by neurophysiological, histological, and morphometric analyses. Rats exposed to 3-NPA developed hind limb paresis. Furthermore, a significant decrease in motor nerve conduction velocity (MCV) was detected in tail nerves and axonal degeneration in sciatic nerves (p<0.05). Treatment with resveratrol prevented the functional effects of 3-NPA exposure, whereas treatment with acetyl-l-carnitine, preventing paresis, was not effective to MCV and morphological changes. These data suggest that resveratrol is a good candidate for treatment of metabolic neuropathy. The experimental outcome of this study shows that chronic treatment with 3-NPA in rats is relevant in development of an experimental model of toxic neuropathy.


The effects of bag style on muscle activity of the trapezius, erector spinae and latissimus dorsi during walking in female university students.
Back pain is common in adolescents which has been associated with carrying a bag. However, there is little research examining the effects of bag style in female adolescents. The aim of the study was to investigate the effects of different bag conditions on muscle activity of the trapezius, erector spinae and latissimus dorsi muscles in female university students during walking. Twelve female university students walked on a treadmill for 5 minutes at 1.1 m/s during five conditions; control, 1 strapped rucksack, 2 strapped rucksack, ipsilateral shoulder strap and contralateral shoulder strap, each containing 10% bodyweight. Electromyography for the trapezius, erector spinae and latissimus dorsi was recorded for the last 30 s of each condition. Two-way ANOVA and paired t-tests were used to identify differences between right and left muscles and between bag conditions. Results showed that muscle activity of the left trapezius was significantly higher than the right trapezius during the 1 strap rucksack condition. For the left trapezius, the 2 strapped rucksack and the control condition had significantly lower muscle activity compared to the 1 strapped rucksack and the ipsilateral shoulder strap. For the left erector spinae muscle, there was significantly greater muscle activity when wearing the contralateral shoulder strap compared to the control. For the right erector spinae, significantly lower muscle activity was observed when wearing the 2 strapped rucksack compared to the ipsilateral shoulder strap and contralateral shoulder strap. There were no significant differences in muscle activity of the latissimus dorsi muscles between any of the bag conditions. These findings suggest that a two strapped rucksack should be used when carrying loads to reduce spinal muscle activity which may, in turn, reduce reports of back pain in female adolescents.


Parsimonious Models for Predicting Mortality from Choroidal Melanoma.
To develop parsimonious models for estimating metastasis mortality in patients with choroidal melanoma for situations where use of the Liverpool Uveal Melanoma Prognosticator Online (LUMPO) or Tumor, Node, Metastasis (TNM) staging system is not possible. A backward-selection algorithm identified largest basal tumor diameter (LBTD) and chromosome 3 status (C3S) as the most informative predictors of metastatic death. We defined two prognostic models, based on LBTD with or without known C3S, that took into account competing risks of death from other causes by using the Aalen estimator. The bootstrap procedure was used to estimate discrimination accuracy, expressed by the C-index. The cohort was comprised of 8348 patients with choroidal melanoma, 4174 of whom had known chromosome 3 status; of the 1553 deaths that occurred among these patients, 956 were attributed to metastasis. For LBTD with or without known C3S, the metastatic-death-specific C-indices at 2, 5, and 10 years were 0.85, 0.85, and 0.84 and 0.79, 0.77, and 0.74, respectively, as compared with 0.81, 0.79, and 0.76 for Kaplan-Meier prognostication using the 8th edition of the TNM staging system. We have developed parsimonious models for predicting the absolute risks of metastatic death from choroidal melanoma that take into account competing causes of death and which compare favorably with the current version of the TNM staging system. There is a need for further studies to validate the use of these models in situations where use of the TNM or LUMPO is not possible.


Pharmacokinetics of moxidectin in the southern hairy-nosed wombat (Lasiorhinus latifrons).
Sarcoptic mange, caused by Sarcoptes scabiei var. wombati, could be a significant threat to populations of southern hairy-nosed wombats (Lasiorhinus latifrons; SHNW) in Australia. Treatment is currently based on the off-label use of various parasiticidal drugs, with limited clinical efficacy trials. Our primary aim was to determine the pharmacokinetic parameters of a macrocyclic lactone, moxidectin, to assist in the development of effective treatment protocols. Pharmacokinetic parameters were determined in four female SHNW following a single subcutaneous injection of 0.2 mg/kg moxidectin. Blood samples were collected for 38 days following injection (August-September 2008), for analysis using liquid chromatography and tandem mass spectrometry. The mean peak plasma concentration occurred at 13.6 hr, with a mean peak plasma level of 98.6 ng/ml. The mean elimination half-life was 5.03 days, resulting in a mean area under the curve of 377 ng.day/ml. The peak plasma moxidectin concentration was higher than that seen in livestock species but the plasma elimination half-life was shorter. This study suggests that a single injection of 0.2 mg/kg moxidectin may not be sufficient to clear a mange infection in this species.


Unexpected versatility in bacterial riboswitches.
Bacterial riboswitches are elements present in the 5'-untranslated regions (UTRs) of mRNA molecules that bind to ligands and regulate the expression of downstream genes. Riboswitches typically regulate the expression of protein-coding genes. However, mechanisms of riboswitch-mediated regulation have recently been shown to be more diverse than originally thought, with reports showing that riboswitches can regulate the expression of noncoding RNAs and control the access of proteins, such as transcription termination factor Rho and RNase E, to a nascent RNA. Riboswitches are also increasingly used in biotechnology, with advances in the engineering of synthetic riboswitches and the development of riboswitch-based sensors. In this review we address the emerging roles and mechanisms of riboswitch-mediated regulation in natura and recent progress in the development of riboswitch-based technology.


On the need for an international effort to capture, share and use crystallization screening data.
When crystallization screening is conducted many outcomes are observed but typically the only trial recorded in the literature is the condition that yielded the crystal(s) used for subsequent diffraction studies. The initial hit that was optimized and the results of all the other trials are lost. These missing results contain information that would be useful for an improved general understanding of crystallization. This paper provides a report of a crystallization data exchange (XDX) workshop organized by several international large-scale crystallization screening laboratories to discuss how this information may be captured and utilized. A group that administers a significant fraction of the world's crystallization screening results was convened, together with chemical and structural data informaticians and computational scientists who specialize in creating and analysing large disparate data sets. The development of a crystallization ontology for the crystallization community was proposed. This paper (by the attendees of the workshop) provides the thoughts and rationale leading to this conclusion. This is brought to the attention of the wider audience of crystallographers so that they are aware of these early efforts and can contribute to the process going forward.


MYH biallelic mutation can inactivate the two genetic pathways of colorectal cancer by APC or MLH1 transversions.
MYH associated polyposis is a hereditary syndrome responsible for early colorectal cancer with a distinct genetic pathway from the Familial Adenomatous Polyposis or the Hereditary Non Polyposis Colorectal Cancer syndrome. We have studied a family with three members bearing a biallelic mutation in MYH at c.1185_1186dup. One patient who developed colon cancer had loss of expression of MLH1 on tumoral tissue and microsatellite instability (MSI) phenotype. Analysis of MLH1 based on his blood sample revealed no germline mutation or large genomic deletion. No methylation of the promoter was identified in tumoral DNA. No transversion mutations were identified in APC or KRAS in tumor DNA of this patient. Loss of expression of MLH1 was due to a transversion in intron 7 at position +5 (c.588 + 5G > T) leading to a complete deletion of exon 7 at the RNA level. This observation demonstrates that MLH1 can be a target of MYH transversions leading to MSI phenotype.


Mediterranean diet impact on cardiovascular diseases: a narrative review.
: Cardiovascular disease (CVD) accounts for more than 17 million deaths per year worldwide. It has been estimated that the influence of lifestyle on CVD mortality amounts to 13.7% for smoking, 13.2% for poor diet, and 12% for inactive lifestyle. These results deeply impact both the healthy status of individuals and their skills in working. The impact of CVD on productivity loss accounts for the 24% in total costs for CVD management.Mediterranean diet (MedD) can positively impact on natural history of CVD. It is characterized by a relatively high consumption of inexpensive and genuine food such as cereals, vegetables, legumes, nuts, fish, fresh fruits, and olive oil as the principal source of fat, low meat consumption and low-to-moderate consumption of milk, dairy products, and wine.Its effects on cardiovascular health are related to the significant improvements in arterial stiffness. Peripheral artery disease, coronary artery disease, and chronic heart failure are all positively influenced by the MedD. Furthermore, MedD lowers the risk of sudden cardiac death due to arrhythmias.The present narrative review aims to analyze the effects of MedD on CVD.


Monitoring health systems readiness and inpatient malaria case-management at Kenyan county hospitals.
Change of severe malaria treatment policy from quinine to artesunate, a major malaria control advance in Africa, is compromised by scarce data to monitor policy translation into practice. In Kenya, hospital surveys were implemented to monitor health systems readiness and inpatient malaria case-management. All 47 county referral hospitals were surveyed in February and October 2016. Data collection included hospital assessments, interviews with inpatient health workers and retrospective review of patients' admission files. Analysis included 185 and 182 health workers, and 1162 and 1224 patients admitted with suspected malaria, respectively, in all 47 hospitals. Cluster-adjusted comparisons of the performance indicators with exploratory stratifications were performed. Malaria microscopy was universal during both surveys. Artesunate availability increased (63.8-85.1%), while retrospective stock-outs declined (46.8-19.2%). No significant changes were observed in the coverage of artesunate trained (42.2% vs 40.7%) and supervised health workers (8.7% vs 12.8%). The knowledge about treatment policy improved (73.5-85.7%; p = 0.002) while correct artesunate dosing knowledge increased for patients < 20 kg (42.7-64.6%; p < 0.001) and > 20 kg (70.3-80.8%; p = 0.052). Most patients were tested on admission (88.6% vs 92.1%; p = 0.080) while repeated malaria testing was low (5.2% vs 8.1%; p = 0.034). Artesunate treatment for confirmed severe malaria patients significantly increased (69.9-78.7%; p = 0.030). No changes were observed in artemether-lumefantrine treatment for non-severe test positive patients (8.0% vs 8.8%; p = 0.796). Among test negative patients, increased adherence to test results was observed for non-severe (68.6-78.0%; p = 0.063) but not for severe patients (59.1-62.1%; p = 0.673). Overall quality of malaria case-management improved (48.6-56.3%; p = 0.004), both for children (54.1-61.5%; p = 0.019) and adults (43.0-51.0%; p = 0.041), and in both high (51.1-58.1%; p = 0.024) and low malaria risk areas (47.5-56.0%; p = 0.029). Most health systems and malaria case-management indicators improved during 2016. Gaps, often specific to different inpatient populations and risk areas, however remain and further programmatic interventions including close monitoring is needed to optimize policy translation.


Role of membrane potential in the response of human T lymphocytes to phytohemagglutinin.
We have analyzed the role of membrane potential on T cell activation and cell proliferation. Depolarization of T lymphocytes, by increasing the extracellular concentration of K+ during a 1-hr exposure to PHA, results in a marked inhibition of cell proliferation. In parallel, depolarization of T cells prevented the normal increase in [Ca2+]i seen after PHA binding. In depolarized cells, PHA failed to induce IL 2 secretion, but, in contrast, IL 2 receptor expression was triggered normally and the cells were subsequently responsive to exogenous IL 2. Increasing [Ca2+]i in depolarized cells with the ionophore ionomycin, or bypassing the requirement for an increase in [Ca2+]i with TPA, restored the PHA-induced proliferative response in depolarized cells. These data confirm that a membrane potential-sensitive step, namely, Ca2+ influx and the resulting change in [Ca2+]i, is triggered by PHA. The inhibitory effects of depolarization are mediated through the impairment of IL 2 secretion, but not IL 2 receptor expression. T cell proliferation can therefore be regulated by altering membrane potential, which in turn modulates the extent of the change in [Ca2+]i. This study suggests a role for transmembrane potential in the regulation of the T cell proliferative response.


Cytotoxicity of activated natural killer cells and expression of adhesion molecules in small-cell lung cancer.
Although small-cell lung cancer (SCLC) is sensitive to anticancer agents, most patients with SCLC experience relapse and die within two years. Here, we examined the relationship between natural killer (NK) cells and adhesion molecules on SCLC cell lines. The expression levels of HLA class I, β2-microglobulin, Fas/Apo-1 receptor (FAS) and adhesion molecules on SCLC cell lines were examined by flow cytometry. The cytotoxicity of activated NK cells from SCLC patients was examined using (51)Cr-release assay. HLA class I antigen and β2-microglobulin expression levels in SCLC cell lines were lower than those in healthy volunteers. SCLC cell lines were susceptible to lysis by activated NK cells but this showed no correlation with expression levels of adhesion molecules. Target cell susceptibility to activated NK cells from five SCLC patients correlated with survival benefit; target cell susceptibility to activated NK cells may be a surrogate marker of outcome for patients with SCLC.


Mass transit infrastructure and urban health.
Mass transit is a critical infrastructure of urban environments worldwide. The public uses it extensively, with roughly 9 billion mass transit trips occurring annually in the United States alone according to the U.S. Department of Transportation data. Its benefits per traveler include lower emissions of air pollutants and energy usage and high speeds and safety records relative to many other common modes of transportation that contribute to human health and safety. However, mass transit is vulnerable to intrusions that compromise its use and the realization of the important benefits it brings. These intrusions pertain to physical conditions, security, external environmental conditions, and equity. The state of the physical condition of transit facilities overall has been summarized in the low ratings the American Society of Civil Engineers gives to mass transit, and the large dollar estimates to maintain existing conditions as well as to bring on new improvements, which are, however, many times lower than investments estimated for roadways. Security has become a growing issue, and numerous incidents point to the potential for threats to security in the US. External environmental conditions, such as unexpected inundations of water and electric power outages also make transit vulnerable. Equity issues pose constraints on the use of transit by those who cannot access it. Transit has shown a remarkable ability to rebound after crises, most notably after the September 11, 2001 attacks on the World Trade Center, due to a combination of design and operational features of the system. These experiences provide important lessons that must be captured to provide proactive approaches to managing and reducing the consequences of external factors that impinge negatively on transit.


What Is the Impact of a Previous Femoral Osteotomy on THA? A Systematic Review.
Femoral osteotomies have been widely used to treat a wide range of developmental and degenerative hip diseases. For this purpose, different types of proximal femur osteotomies were developed: at the neck as well as at the trochanteric, intertrochanteric, or subtrochanteric levels. Few studies have evaluated the impact of a previous femoral osteotomy on a THA; thus, whether and how a previous femoral osteotomy affects the outcome of THA remains controversial. In this systematic review, we asked: (1) What are the most common complications after THA in patients who have undergone femoral osteotomy, and how frequently do those complications occur? (2) What is the survival of THA after previous femoral osteotomy? (3) Is the timing of hardware removal associated with THA complications and survivorship? A systematic review was carried out on PubMed, the Cochrane Systematic Reviews Database, Scopus, and Embase databases with the following keywords: "THA", "total hip arthroplasty", and "total hip replacement" combined with at least one of "femoral osteotomy" or "intertrochanteric osteotomy" to achieve the maximum sensitivity of the search strategy. Identified studies were included if they met the following criteria: (1) reported data on THAs performed after femoral osteotomy; (2) recorded THA followup; (3) patients who underwent THA after femoral osteotomy constituted either the experimental group or a control group; (4) described the surgical and clinical complications and survivorship of the THA. The database search retrieved 383 studies, on which we performed a primary evaluation. After removing duplicates and completing a full-text evaluation for the inclusion criteria, 15 studies (seven historically controlled, eight case series) were included in the final review. Specific information was retrieved from each study included in the final analysis. The quality of each study was evaluated with the Methodological Index for Non-randomized Studies (MINORS) questionnaire. The mean MINORS score for the historically controlled studies was 14 of 24 (range, 10-17), whereas for the case series, it was 8.1 of 16 (range, 5-10). The proportion of patients who experienced intraoperative complications during THA ranged from 0% to 17%. The most common intraoperative complication was femoral fracture; other intraoperative complications were difficulties in hardware removal and nerve palsy; 15 studies reported on complications. The survivorship of THA after femoral osteotomy in the 13 studies that answered this question ranged from 43.7% to 100% in studies that had a range of followup from 2 to 20 years. The timing of hardware removal was described in five studies, three of which detailed more complications with hardware removal at the time of THA. This systematic review demonstrated that THA after femoral osteotomy is technically more demanding and may carry a higher risk of complications than one might expect after straightforward THA. Staged hardware removal may reduce the higher risk of intraoperative fracture and infection, but there is no clear evidence in support of this contention. Although survivorship of THA after femoral osteotomy was generally high, the studies that evaluated it were generally retrospective case series, with substantial biases, including selection bias and transfer bias (loss to followup), and so it is possible that survivorship of THA in the setting of prior femoral osteotomy may be lower than reported. Level III, therapeutic study.


Review article: current and emerging therapies for functional dyspepsia.
Functional dyspepsia represents a heterogeneous group of gastrointestinal disorders marked by the presence of upper abdominal pain or discomfort. Although its precise definition has evolved over the last several decades, this disorder remains shrouded in controversy. The symptoms of functional dyspepsia may overlap with those of other functional bowel disorders including irritable bowel syndrome and non-erosive reflux disease. There may be coexistent psychological distress or disease complicating its presentation and response to therapy. Given the prevalence and chronicity of functional dyspepsia, it remains a great burden to society. Suspected physiological mechanisms underlying functional dyspepsia include altered motility, altered visceral sensation, inflammation, nervous system dysregulation and psychological distress. Yet the exact pathophysiological mechanisms that cause symptoms in an individual patient remain difficult to delineate. Numerous treatment modalities have been employed including dietary modifications, pharmacological agents directed at various targets within the gastrointestinal tract and central nervous system, psychological therapies and more recently, complementary and alternative treatments. Unfortunately, to date, all of these therapies have yielded only marginal results. A variety of emerging therapies are being developed for functional dyspepsia. Most of these therapies are intended to normalize pain perception and gastrointestinal motor and reflex function in this group of patients.


Use of Topical Rapamycin as Maintenance Treatment after a Single Session of Fractionated CO2 Laser Ablation: A Method to Enhance Percutaneous Drug Delivery.
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder with an incidence of approximately 1 in 5,000 to 10,000 live births. TSC has various clinical manifestations such as multiple hamartomas in systemic organs, including the skin. Angiofibromas are the most common skin lesions in patients with TSC. Although benign, angiofibromas develop in childhood and puberty, and can be psychosocially disfiguring for patients. Skin lesions in TSC, specifically angiofibromas, have no significant risk of malignant transformation after puberty; thus, they require no treatment if not prominent. However, the presentation of TSC is important owing to its impact on patient cosmesis. Surgical treatment and laser therapy are the mainstream treatments for angiofibromas. Although the evidence is limited, topical mammalian target of rapamycin inhibitors such as sirolimus (rapamycin) are effective in facial angiofibroma treatment. We describe an adult patient with an angiofibroma who had an excellent response to treatment with topical rapamycin after a single session of carbon dioxide (CO2) laser ablation. The patient showed no sign of relapse or recurring lesions for a year. CO2 laser ablation may serve as a new paradigm of treatment for angiofibromas in TSC. Since the selection of laser devices can be limited for some institutions, we suggest a rather basic but highly effective approach for angiofibroma treatment that can be generally applied with the classic CO2 device.


Management of uncommon chemotherapy-induced emergencies.
Chemotherapy can induce various clinical emergencies. Prompt recognition and management of these adverse events are important for avoiding further morbidity and mortality. Some events such as hypersensitivity and extravasation are quite common, whereas emergencies such as neutropenic typhlitis, pancreatitis, and acute haemolysis are very rare. Little information exists on the management of rare chemotherapy-induced emergencies that affect fewer than 1% of patients. We review these uncommon chemotherapy-induced life-threatening emergencies, their pathogenesis and management, and recommendations for rechallenge with the offending chemotherapy.


Effect of calcium supplementation on bone resorption in pregnancy and the early postpartum: a randomized controlled trial in Mexican women.
Calcium needs are physiologically upregulated during pregnancy and lactation to meet demands of the developing fetus and breastfeeding infant. Maternal calcium homeostasis is maintained by hormonal adaptive mechanisms, thus, the role of dietary calcium supplementation in altering maternal responses to fetal-infant demand for calcium is thought to be limited. However, increased calcium absorption is directly related to maternal calcium intake and dietary supplementation has been suggested to prevent transient bone loss associated with childbearing. In a double-blind, randomized placebo-controlled trial, we randomly assigned 670 women in their first trimester of pregnancy to 1,200 mg/day calcium (N = 334) or placebo (N = 336). Subjects were followed through 1-month postpartum and the effect on urinary cross-linked N-telopeptides (NTx) of type I collagen, a specific marker of bone resorption, was evaluated using an intent-to-treat analysis. Women with a baseline and at least one follow-up measurement (N = 563; 84%) were included. Subsequent analyses were conducted stratifying subjects by compliance assessed using pill counts. In random subsets of participants, bone-specific alkaline phosphatase (BAP) (N = 100) and quantitative ultrasound (QUS) (N = 290) were also measured. Calcium was associated with an overall reduction of 15.8% in urinary NTx relative to placebo (p < 0.001). Among those who consumed ≥50%, ≥67%, and ≥75% of pills, respectively, the effect was associated with 17.3%, 21.3%, and 22.1% reductions in bone resorption (all p < 0.001). There was no significant effect of calcium on bone formation measured by BAP. However, by 1-month postpartum, those in the calcium group had significantly lower NTx/BAP ratios than those in the placebo group (p = 0.04) indicating a net reduction in bone loss in the supplement group by the end of follow-up. Among subjects who consumed ≥50% and ≥75% of pills, respectively, calcium was also associated with an increase of 26.3 m/s (p = 0.03) and 59.0 m/s (p = 0.009) in radial SOS relative to placebo by 1-month postpartum. Calcium administered during pregnancy and the early postpartum period, to women with intakes around adequacy, was associated with reduced bone resorption and, thus, may constitute a practical intervention to prevent transient skeletal loss associated with childbearing. ClinicalTrials.gov Identifier NCT00558623.


Distinguishing effects on tumor multiplicity and growth rate in chemoprevention experiments.
In some types of cancer chemoprevention experiments and short-term carcinogenicity bioassays, the data consist of the number of observed tumors per animal and the times at which these tumors were first detected. In such studies, there is interest in distinguishing between treatment effects on the number of tumors induced by a known carcinogen and treatment effects on the tumor growth rate. Since animals may die before all induced tumors reach a detectable size, separation of these effects can be difficult. This paper describes a flexible parametric model for data of this type. Under our model, the tumor detection times are realizations of a delayed Poisson process that is characterized by the age-specific tumor induction rate and a random latency interval between tumor induction and detection. The model accommodates distinct treatment and animal-specific effects on the number of induced tumors (multiplicity) and the time to tumor detection (growth rate). A Gibbs sampler is developed for estimation of the posterior distributions of the parameters. The methods are illustrated through application to data from a breast cancer chemoprevention experiment.


Legal issues in governing genetic biobanks: the Italian framework as a case study for the implications for citizen's health through public-private initiatives.
This paper outlines some of the challenges faced by regulation of genetic biobanking, using case studies coming from the Italian legal system. The governance of genetic resources in the context of genetic biobanks in Italy is discussed, as an example of the stratification of different inputs and rules: EU law, national law, orders made by authorities and soft law, which need to be integrated with ethical principles, technological strategies and solutions. After providing an overview of the Italian legal regulation of genetic data processing, it considers the fate of genetic material and IP rights in the event of a biobank's insolvency. To this end, it analyses two case studies: a controversial bankruptcy case which occurred in Sardinia, one of the first examples of private and public partnership biobanks. Another case study considered is the Chris project: an example of partnership between a research institute in Bolzano and the South Tyrolean Health System. Both cases seem to point in the same direction, suggesting expediency of promoting and improving public-private partnerships to manage biological tissues and biotrust to conciliate patent law and public interest.


Independent losses of a xenobiotic receptor across teleost evolution.
Sensitivity to environmental stressors largely depend on the genetic complement of the organism. Recent sequencing and assembly of teleost fish genomes enable us to trace the evolution of defense genes in the largest and most diverse group of vertebrates. Through genomic searches and in-depth analysis of gene loci in 76 teleost genomes, we show here that the xenosensor pregnane X receptor (Pxr, Nr1i2) is absent in more than half of these species. Notably, out of the 27 genome assemblies that belong to the Gadiformes order, the pxr gene was only retained in the Merluccidae family (hakes) and Pelagic cod (Melanonus zugmayeri). As an important receptor for a wide range of drugs and environmental pollutants, vertebrate PXR regulate the transcription of a number of genes involved in the biotransformation of xenobiotics, including cytochrome P450 enzymes (CYP). In the absence of Pxr, we suggest that the aryl hydrocarbon receptor (Ahr) have evolved an extended regulatory role by governing the expression of certain Pxr target genes, such as cyp3a, in Atlantic cod (Gadus morhua). However, as several independent losses of pxr have occurred during teleost evolution, other lineages and species may have adapted alternative compensating mechanisms for controlling crucial cellular defense mechanisms.


Nutritional effects of the serial transverse enteroplasty procedure in experimental short bowel syndrome.
The serial transverse enteroplasty (STEP) procedure appears beneficial clinically, but the mechanism(s) underlying these effects remains unclear. The present study evaluated the nutritional, hormonal, and morphologic effects of the STEP procedure in a rodent model of short bowel syndrome. With institutional animal care ethics approval, Sprague-Dawley rats underwent an 80% distal bowel resection, anastomosing the 30 cm remnant of jejunum to the ascending colon; at day 14, animals were randomly assigned to control or a STEP procedure (n = 8/group). Animals were pair-fed with normal chow; after a further 3 weeks, intestinal transit, hormonal and metabolic balance studies were done, and intestinal tissues were taken for analysis. The STEP group had increased weight gain (resected: -0.34% +/- 2.9% vs STEP: 2.5% +/- 1.5%), increased bowel length (34.1 +/- 1.5 vs 36.9 +/- 2.2 cm), increased jejunal villus height (555 +/- 59 vs 635 +/- 65 microm), decreased rates of crypt cell apoptosis, increased expression of mRNA for the GLP-2 receptor, and increased postprandial production of glucagon-like peptide 2 (45 +/- 14 vs 65 +/- 12 pmol/L) (P < .05 by Student t test). There were no differences in intestinal transit; absorption of total calories, protein, fat, or carbohydrate; crypt cell proliferation rates; or the expression of intestinal transporter proteins (SGLT-1, GLUT-2, and GLUT-5). The STEP procedure improves weight gain and augments gross and microscopic intestinal morphology in severe experimental short bowel syndrome. Postprandial GLP-2 levels are increased, as is the expression of the GLP-2 receptor; these mechanisms may contribute to these metabolic effects and may be useful in guiding the use of the STEP procedure clinically.


Effects of mechanical tension on protrusive activity and microfilament and intermediate filament organization in an epidermal epithelium moving in culture.
Mechanical tension influences tissue morphogenesis and the synthetic, mitotic, and motile behavior of cells. To determine the effects of tension on epithelial motility and cytoskeletal organization, small, motile clusters of epidermal cells were artificially extended with a micromanipulated needle. Protrusive activity perpendicular to the axis of tension was dramatically suppressed. To determine the ultrastructural basis for this phenomenon, cells whose exact locomotive behavior was recorded cinemicrographically were examined by transmission electron microscopy. In untensed, forward-moving lamellar protrusions, microfilaments appear disorganized and anisotropically oriented. But in cytoplasm held under tension by micromanipulation or by the locomotive activity of other cells within the epithelium, microfilaments are aligned parallel to the tension. In non-spreading regions of the epithelial margin, microfilaments lie in tight bundles parallel to apparent lines of tension. Thus, it appears that tension causes alignment of microfilaments. In contrast, intermediate filaments are excluded from motile protrusions, being confined to the thicker, more central part of the cell. They roughly follow the contours of the cell, but are not aligned relative to tension even when microfilaments in the same cell are. This suggests that the organization of intermediate filaments is relatively resistant to physical distortion and the intermediate filaments may act as passive structural support within the cell. The alignment of microfilaments under tension suggests a mechanism by which tension suppresses protrusive activity: microfilaments aligned by forces exerted through filament-surface or filament-filament interconnections cannot reorient against such force and so cannot easily extend protrusions in directions not parallel to tension.


Antibody of the IgG2 Subclass, Actinobacillus actinomycetemcomitans, and Early-Onset Periodontitis.
Susceptibility to early-onset periodontitis (EOP) appears to be attributable to a gene inherited in an autosomal dominant pattern. This explains why EOP clusters in families and why about half of the family members develop periodontal disease early in life. Manifestation of EOP is variable, with some patients having a localized form restricted to first molars and incisors (LJP) and others with a severe generalized form of periodontitis (SP). The extent and severity of disease is less in patients who are seropositive for Actinobacillus actinomycetemcomitans than in seronegative patients, and this relationship prompted the hypothesis that anti-A. actinomycetemcomitans helps limit disease. The dominant antibody is an IgG2 reactive with the serotypespecific carbohydrate. The incidence of the LJP form of EOP is about 10 times higher in blacks than in whites. Interestingly, blacks have higher levels of serum IgG2, a higher frequency of anti-A. actinomycetemcomitans antibody, and higher serum titers of IgG2 anti-A. actinomycetemcomitans which may help explain why the disease is localized. Studies in progress suggest that smoking reduces serum IgG2 levels in SP patients and is associated with more severe periodontal destruction. In marked contrast, IgG2 does not appear to be reduced in LJP patients who smoke, and smoking does not appear to increase periodontal destruction. We think that IgG2 anti-A. actinomycetemcomitans is playing a role in limiting the extent and severity of disease in patients genetically susceptible to EOP. J Periodontol 1996;67:317-322.


Co-enrollment in multiple HIV prevention trials - experiences from the CAPRISA 004 Tenofovir gel trial.
In settings where multiple HIV prevention trials are conducted in close proximity, trial participants may attempt to enroll in more than one trial simultaneously. Co-enrollment impacts on participant's safety and validity of trial results. We describe our experience, remedial action taken, inter-organizational collaboration and lessons learnt following the identification of co-enrolled participants. Between February and April 2008, we identified 185 of the 398 enrolled participants as ineligible. In violation of the study protocol exclusion criteria, there was simultaneous enrollment in another HIV prevention trial (ineligible co-enrolled, n=135), and enrollment of women who had participated in a microbicide trial within the past 12 months (ineligible not co-enrolled, n=50). Following a complete audit of all enrolled participants, ineligible participants were discontinued via study exit visits from trial follow-up. Custom-designed education program on co-enrollment impacting on participants' safety and validity of the trial results was implemented. Shared electronic database between research units was established to enable verification of each volunteer's trial participation and to prevent future co-enrollments. Interviews with ineligible enrolled women revealed that high-quality care, financial incentives, altruistic motives, preference for sex with gel, wanting to increase their likelihood of receiving active gel, perceived low risk of discovery and peer pressure are the reasons for their enrollment in the CAPRISA 004 trial. Instituting education programs based on the reasons reported by women for seeking enrollment in more than one trial and using a shared central database system to identify co-enrollments have effectively prevented further co-enrollments.


EXPERIMENTAL STUDIES OF THE NASOPHARYNGEAL SECRETIONS FROM INFLUENZA PATIENTS : V. BACTERIUM PNEUMOSINTES AND CONCURRENT INFECTIONS.
During the course of animal experiments with the anaerobic filter-passing organisms cultivated from epidemic influenzal sources, certain pulmonary infections with ordinary bacteria have been observed. The experiments also have shown that the lungs of animals infected with Bacterium pneumosintes are less resistant than normal lungs to infection with ordinary bacteria. The demonstration of this fact invites a comparison of the course of these experimental bacterial infections with the sequence of postinfluenzal pneumonias attributable to similar organisms in man. These observations furnish additional proof of the identity of Bacterium pneumosintes and the active agent derived from the nasopharyngeal secretions of patients in the early hours of epidemic influenza.


Novel properties of the wheat aluminum tolerance organic acid transporter (TaALMT1) revealed by electrophysiological characterization in Xenopus Oocytes: functional and structural implications.
Many plant species avoid the phytotoxic effects of aluminum (Al) by exuding dicarboxylic and tricarboxylic acids that chelate and immobilize Al(3+) at the root surface, thus preventing it from entering root cells. Several novel genes that encode membrane transporters from the ALMT and MATE families recently were cloned and implicated in mediating the organic acid transport underlying this Al tolerance response. Given our limited understanding of the functional properties of ALMTs, in this study a detailed characterization of the transport properties of TaALMT1 (formerly named ALMT1) from wheat (Triticum aestivum) expressed in Xenopus laevis oocytes was conducted. The electrophysiological findings are as follows. Although the activity of TaALMT1 is highly dependent on the presence of extracellular Al(3+) (K(m1/2) of approximately 5 microm Al(3+) activity), TaALMT1 is functionally active and can mediate ion transport in the absence of extracellular Al(3+). The lack of change in the reversal potential (E(rev)) upon exposure to Al(3+) suggests that the "enhancement" of TaALMT1 malate transport by Al is not due to alteration in the transporter's selectivity properties but is solely due to increases in its anion permeability. The consistent shift in the direction of the E(rev) as the intracellular malate activity increases indicates that TaALMT1 is selective for the transport of malate over other anions. The estimated permeability ratio between malate and chloride varied between 1 and 30. However, the complex behavior of the E(rev) as the extracellular Cl(-) activity was varied indicates that this estimate can only be used as a general guide to understanding the relative affinity of TaALMT1 for malate, representing only an approximation of those expected under physiologically relevant ionic conditions. TaALMT1 can also mediate a large anion influx (i.e. outward currents). TaALMT1 is permeable not only to malate but also to other physiologically relevant anions such as Cl(-), NO(3)(-), and SO(4)(2-) (to a lesser degree).


Multi-modal, ultrasensitive, wide-range humidity sensing with Ti3C2 film.
Gravimetric, direct-current electrical, and electrical impedance sensing modes were used to measure response of high surface area 2D Ti3C2 MXene film to water vapor pressures spanning 3 orders of magnitude (20 mTorr-20 Torr). The Ti3C2 film exhibited reproducible reversible response in 0.1%-95% relative humidity (RH) range with a detection limit of <20 mTorr H2O partial pressure (<0.1% RH). DC electrical current-based sensing with 3 mV operating voltage and 0.8 pW power consumption was demonstrated. The highest normalized sensitivity was shown for gravimetric sensing modalities which scale with the overtone number, reaching highest sensitivity of about 12 Hz/% RH at the 9th crystal overtone (45 MHz oscillation).


Cutaneous manifestations of serum sickness in patients receiving antithymocyte globulin.
We have prospectively evaluated the cutaneous manifestations of serum sickness in thirty-five patients treated with horse antithymocyte globulin for bone marrow failure. Twenty-one patients (21/35) were treated with antithymocyte globulin (15 mg/kg/day) for 10 days, and fourteen of thirty-five patients were treated with antithymocyte globulin (15 mg/kg/day) for 14 days and then every other day for an additional 14 days. Clinical evidence of serum sickness developed in thirty patients and included fever and malaise (100%), cutaneous eruptions (93%), arthralgias and myalgias (67%), gastrointestinal complaints (67%), and lymphadenopathy (13%). Cutaneous findings consisted of morbilliform eruptions (n = 19), urticaria (n = 1), or a combination of these two reaction patterns (n = 8). Cutaneous manifestations of serum sickness began on day 7 +/- 1 and lasted for 12 +/- 2 days for the group as a whole. Biopsies of lesional skin revealed mild perivascular lymphohistiocytic infiltrates by light microscopy in these leukopenic patients. Direct immunofluorescence microscopy of lesional skin from patients with serum sickness demonstrated immunoreactants in seven of nine subjects (78%). Immunoreactants were confined to the walls of dermal blood vessels and consisted of IgM (7/9), C3 (6/9), IgE (5/9), and IgA (4/9). IgG (horse or human) was not identified in any of these specimens. Twenty-one patients (21/28) also developed an erythematous eruption on the sides of the fingers, toes, palms, and soles 12 to 48 hours prior to their morbilliform eruption. This study describes the cutaneous manifestations of human serum sickness occurring during therapy with horse antithymocyte globulin, documents a cutaneous sign of serum sickness, and suggests that the cutaneous eruptions associated with human serum sickness are immunologically mediated.


QTL linkage mapping of wing length in zebra finch using genome-wide single nucleotide polymorphisms markers.
Avian wing length is an important trait that covaries with the ecology and migratory behaviour of a species and tends to change rapidly when the conditions are altered. Long-distance migrants typically have longer wings than short-distance migrants and sedentary species, and long-winged species also tend to be more dispersive. Although the substantial heritability of avian wing length is well established, the identification of causal genes has remained elusive. Based on large-scale genotyping of 1404 informative single nucleotide polymorphisms (SNP) in a captive population of 1067 zebra finches, we here show that the within-population variation of relative wing length (h(2) = 0.74 ± 0.05) is associated with standing genetic variation in at least six genomic regions (one genome-wide significant and five suggestive). The variance explained by these six quantitative trait loci (QTL) sums to 36.8% of the phenotypic variance (half of the additive genetic variance), although this likely is an overestimate attributable to the Beavis effect. As avian wing length is primarily determined by the length of the primary feathers, we then searched for candidate genes that are related to feather growth. Interestingly, all of the QTL signals co-locate with Wnt growth factors and closely interacting genes (Wnt3a, Wnt5a, Wnt6, Wnt7a, Wnt9a, RhoU and RhoV). Our findings therefore suggest that standing genetic variation in the Wnt genes might be linked to avian wing morphology, although there are many other genes that also fall within the confidence regions.


Describing objectively measured physical activity levels, patterns, and correlates in a cross sectional sample of infants and toddlers from South Africa.
Physical activity is considered to have health benefits across the lifespan but levels, patterns, and correlates have not been well described in infants and toddlers under the age of two years. This study aimed to describe objectively and subjectively measured physical activity in a group of South African infants aged 3- to 24-months (n = 140), and to investigate individual and maternal correlates of physical activity in this sample. Infants' physical activity was measured using an Axivity AX3 wrist-worn accelerometer for one week and the mean vector magnitude was calculated. In addition, mothers reported the average amount of time their infant spent in various types of activities (including in front of the TV), their beliefs about infants' physical activity, access to equipment in the home environment, and ages of motor development milestone attainment. Analysis of variance (ANOVA) and pair-wise correlations were used to test age and sex differences and associations with potential correlates. There were significant age and sex effects on the distribution of time spent at different physical activity intensities (Wilks' lambda = 0.06, p < 0.01). In all cases, the trend was for boys to spend more time in higher intensity physical activity and less time in lower intensity activity than girls; and for time spent in higher intensity activities to be higher in older children. Time spent outside was higher in boys, and this reached significance at 18-months (F = 3.84, p = 0.02). Less concern around floor play was associated with higher physical activity at 12-months in females only (p = 0.03, r = 0.54), and no other maternal beliefs were correlated with physical activity. The majority (94%) of children were exceeding TV time recommendations. When controlling for age and sex, overall TV time was positively associated with BMI z-score (β=0.01, p = 0.05). This study is the first to show sex and age differences in the patterns of physical activity, and to report on objectively measured and maternal reported physical activity and sedentary behaviour in the first two years of life in South Africa infants. Infants and toddlers should be provided with as many opportunities to be active through play as possible, and TV time should be limited.


The protective role of endogenous melatonin in carrageenan-induced pleurisy in the rat.
Peroxynitrite, a potent cytotoxic oxidant formed by the reaction of nitric oxide (NO) with the superoxide anion, was recently proposed to play a major pathogenic role in the inflammatory process. Here we have investigated the effects of endogenous melatonin, a known scavenger of peroxynitrite, in rats subjected to carrageenan-induced pleurisy. Endogenous melatonin was depleted in rats maintained on 24 h light cycle for 1 wk. In vivo depletion of endogenous melatonin enhanced the carrageenan-induced degree of pleural exudation and polymorphonuclear leukocyte migration in rats subjected to carrageenan-induced pleurisy. Lung myeloperoxidase activity and lipid peroxidation were significantly increased in melatonin-deprived rats. However, the inducible NO synthase in lung samples was unaffected by melatonin depletion. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in lungs from carrageenan-treated rats that was markedly enhanced in melatonin-deprived rats. Furthermore, melatonin depletion significantly increased peroxynitrite formation as measured by the oxidation of the fluorescent dye dihydrorhodamine 123, enhanced DNA damage and the decrease in mitochondrial respiration and reduced the cellular levels of NAD+ in macrophages harvested from the pleural cavity of rats subjected to carrageenan-induced pleurisy. In vivo treatment with exogenous melatonin (15 mg/kg intraperitoneal) significantly reversed the effects of melatonin depletion. Thus, endogenous melatonin plays an important protective role against carrageenan-induced local inflammation.


Streptococcus pneumoniae-induced pulmonary hypertension and systemic hypotension in anesthetized sheep.
Because some patients with Streptococcus pneumoniae bacteremia may present with shock, we reasoned that this organism may produce substances that cause shock. To test this hypothesis, type III pneumococcus supernatant, suspended in 10 ml of sterile water, was infused over 1 min in 8 adult anesthetized sheep. Normal saline was used as a control and had no effect on any of the hemodynamic parameters. Infusion of supernatant resulted in a precipitous fall in cardiac output from a control value of 4.25 +/- 0.54 to 2.80 +/- 0.43 (SE) l/min, a fall in mean systemic arterial pressure from 70 +/- 4 to 49 +/- 8 mmHg, and an increase in the mean pulmonary arterial pressure from 13 +/- 2 to 23 +/- 4 mmHg within 1 min after the infusion was completed. The peak hemodynamic effects were observed at approximately 3 min and returned to normal within 10 min after the infusion was completed. The thromboxane B2 level increased from a control value of 10 +/- 5 to 156 +/- 43 pg/ml at 3 min after the infusion was completed and decreased to 63 +/- 34 pg/ml at 20 min. A second identical dose of pneumococcal supernatant, repeated within 2 h of the first dose, had no effect on hemodynamic variables. Pretreatment with indomethacin, 5 mg/kg body wt, completely blocked the hemodynamic effects of pneumococcal supernatant (n = 3 sheep). Thus, we conclude that S. pneumoniae supernatant contains substances that cause septic shock syndrome through the synthesis of arachidonic acid metabolites and that a sublethal dose of the supernatant causes rapid tachyphylaxis.


Comparative studies of Al-doped ZnO and Ga-doped ZnO transparent conducting oxide thin films.
We have investigated the influences of aluminum and gallium dopants (0 to 2.0 mol%) on zinc oxide (ZnO) thin films regarding crystallization and electrical and optical properties for application in transparent conducting oxide devices. Al- and Ga-doped ZnO thin films were deposited on glass substrates (corning 1737) by sol-gel spin-coating process. As a starting material, AlCl3⋅6H2O, Ga(NO3)2, and Zn(CH3COO)2⋅2H2O were used. A lowest sheet resistance of 3.3 × 103 Ω/□ was obtained for the GZO thin film doped with 1.5 mol% of Ga after post-annealing at 650°C for 60 min in air. All the films showed more than 85% transparency in the visible region. We have studied the structural and microstructural properties as a function of Al and Ga concentrations through X-ray diffraction and scanning electron microscopy analysis. In addition, the optical bandgap and photoluminescence were estimated.


Progressive Aortic Stenosis in Homozygous Familial Hypercholesterolemia After Liver Transplant.
Early onset coronary artery disease and aortic calcifications are characteristic features of patients with homozygous familial hypercholesterolemia. Standard medical therapy includes dietary modification, pharmacotherapy, and lipoprotein apheresis to lower serum low-density lipoprotein cholesterol (LDL-C). Liver transplant is a surgical option for the treatment of homozygous familial hypercholesterolemia and can lead to normal cholesterol levels. Vascular calcifications are known to progress despite standard medical therapy and have been reported after liver transplant in the setting of rejection. We present the first report of progressive severe aortic valve stenosis in a patient despite liver transplant with normalization of lipid levels and no history of graft rejection.


The involvement of intracellular Ca(2+) in 5-HT(1B/1D) receptor-mediated contraction of the rabbit isolated renal artery.
5-Hydroxytryptamine(1B/1D) (5-HT(1B/1D)) receptor coupling to contraction was investigated in endothelium-denuded rabbit isolated renal arteries, by simultaneously measuring tension and intracellular [Ca(2+)], and tension in permeabilized smooth muscle cells. In intact arterial segments, 1 nM - 10 microM 5-HT failed to induce contraction or increase the fura-2 fluorescence ratio (in the presence of 1 microM ketanserin and prazosin to block 5-HT(2) and alpha(1)-adrenergic receptors, respectively). However, in vessels pre-exposed to either 20 mM K(+) or 30 nM U46619, 5-HT stimulated concentration-dependent increases in both tension and intracellular [Ca(2+)]. 1 nM - 10 microM U46619 induced concentration-dependent contractions. In the presence of nifedipine (0.3 and 1 microM) the maximal contraction to U46619 (10 microM) was reduced by around 70%. The residual contraction was abolished by the putative receptor operated channel inhibitor, SKF 96365 (2 microM). With 0.3 microM nifedipine present, 100 nM U46619 evoked similar contraction to 30 nM U46619 in the absence of nifedipine, but contraction to 5-HT (1 nM - 10 microM) was abolished. In permeabilized arterial segments, 10 mM caffeine, 1 microM IP(3) or 100 microM phenylephrine, each evoked transient contractions by releasing Ca(2+) from intracellular stores, whereas 5-HT had no effect. In intact arterial segments pre-stimulated with 20 mM K(+), 5-HT-evoked contractions were unaffected by 1 microM thapsigargin, which inhibits sarco- and endoplasmic reticulum calcium-ATPases. In vessels permeabilized with alpha-toxin and then pre-contracted with Ca(2+) and GTP, 5-HT evoked further contraction, reflecting increased myofilament Ca(2+)-sensitivity. Contraction linked to 5-HT(1B/1D) receptor stimulation in the rabbit renal artery can be explained by an influx of external Ca(2+) through voltage-dependent Ca(2+) channels and sensitization of the contractile myofilaments to existing levels of Ca(2+), with no release of Ca(2+) from intracellular stores.


Developmental changes in spiral artery blood flow in the human placenta observed with colour Doppler ultrasonography.
Our current knowledge of the physiological dilatation of spiral arteries in pregnancy, is based on histology. Real-time ultrasound visualisation of these changes may aid understanding of abnormal placentation. This study aimed to investigate if changes in the spiral artery blood flow can be followed 'in vivo' and explore the novel phenomenon of the larger 'mega-jets'. Colour Doppler ultrasonography was used to identify the most prominent jets at blood from the spiral artery into the intervillous space. Their velocity, width and length were recorded seven set time points during pregnancy. Fifty two uncomplicated, term normotensive pregnancies were studied. Width and length of the jets' Doppler signals increased with gestation, the velocity decreased. The length of the jets shows a bi-modal frequency distribution. The width of the signals of longer ('mega') jets was significantly greater (p = 0.001) than that of the jets (mean 4.3 mm (3.1-5.9) versus 3.8 mm (1.8-5.8) respectively) at 34 weeks. However, there was no significant difference in the peak systolic velocity (p = 0.2). This study confirms that ultrasound can be used to study the gestation dependent changes in the haemodynamics of the placental basal plate predicted, but not proven, by histologic data. The bi-modal distribution of jet lengths suggests that mega-jets are a separate entity to 'normal' jets. That they are significantly wider than 'normal' jets and yet maintain the same velocity of blood flow suggests that they have a greater volume of blood flow. The mechanism for this is hypothesised and their apparent relationship with simple placental lakes discussed.


Oxidative stress in adult dengue patients.
An association between viral diseases and increased oxidative stress has been suggested. The time course of serum levels of total antioxidant status (TAS), peroxidation potential (PP), glutathione (GSH), lipid peroxidation measured as hydroperoxides, and malondyaldehyde and 4-hydroxyalkenals (MDA + 4-HDA), as well as antioxidant enzymatic activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx), were measured in 22 serologically confirmed dengue patients. Most of the patients had dengue fever and three of them had dengue hemorrhagic fever. The redox parameters were compared with those of age- and sex- matched controls. No significant difference was observed for levels of GSH and TAS between patients and controls. Levels of PP, MDA + 4-HDA, and SOD were significantly higher. Levels of GPx and total hydroperoxides were significantly lower in patients in comparison with controls. These findings suggest that the alteration in redox status could result of increased oxidative stress and it may play a role in the pathogenesis of the disease.


Assessing impacts of human-elephant conflict on human wellbeing: An empirical analysis of communities living with elephants around Maasai Mara National Reserve in Kenya.
Human-elephant conflict is an often intractable problem that threatens the contribution of conservation interventions to human wellbeing and securing livelihoods in Africa and Asia. Local human populations living in key elephant ranges are among the world's most poor and vulnerable people. In efforts to address this problem, previous studies have mainly focused on the direct impacts of conflict and applied standard regression models based on the assumption of individual-level homogeneity. More recently, human-elephant conflict has been seen to extend well beyond the physical, to the psychological and social sides of wellbeing. However, the impacts on human wellbeing have not been robustly explored, especially for local communities co-existing with elephants. We evaluated the impacts of conflicts on the wellbeing of local communities around the world-famous Masai Mara National Reserve in Kenya. We conducted 18 focus group discussions with 120 community members in different locations and administered a questionnaire survey to 367 sampled households from 26 sub-locations in Trans Mara. We used descriptive statistics with appropriate statistical tests, including propensity score matching, to evaluate the impacts of conflict on human wellbeing. Before matching, the results of the descriptive statistics showed differences between households experiencing conflicts and those without in terms of gender, age, education level, household size, benefiting from elephant conservation, main occupation and number of income sources. Our matching results indicate the existence of a significant negative and positive impacts on four and one of our eight wellbeing indicators for households that experienced conflicts, respectively. Better conflict mitigation approaches and conservation policies need to be adopted to realize the harmonious and concurrent development of ecological and wellbeing objectives.


Use of PCR coupled with electrospray ionization mass spectrometry for rapid identification of bacterial and yeast bloodstream pathogens from blood culture bottles.
Sepsis is among the top 10 causes of mortality in the United States. Rapid administration of antibiotics is one of the most important contributors to patient survival, yet only a limited number of methods exist for rapid identification of microbes cultivated from bloodstream infections, which can lead to sepsis. While traditional single-target molecular methods have been shown to greatly improve survival for septic patients by enabling rapid deescalation of broad-spectrum antibiotics, multiplex methods offer even greater possibilities. A novel multiplex method, PCR coupled to electrospray ionization mass spectrometry (PCR/ESI-MS), was used to identify the genus and species of microorganisms found to cause human bloodstream infections. DNA was directly extracted from 234 BacT-Alert blood culture bottles, and results were compared to those obtained by clinical reference standard methods. The study results demonstrated 98.7% and 96.6% concordance at the genus and species levels, respectively. Mixtures of microbes were identified in 29 blood culture bottles, including mixed species of the same genus, as well as mixtures containing Gram-positive and Gram-negative organisms, exemplifying the PCR/ESI-MS capability to identify multiple organisms simultaneously without the need for cultivation. This study demonstrates high analytical accuracy in comparison to routine subculture of blood culture bottles and phenotypic identification of microbes. Without foreknowledge of the microorganisms potentially present, the PCR/ESI-MS methods can deliver accurate results in as little as 5 to 6 h after a positive alarm from the automated blood culture system; however, current batch mode testing limits the method's clinical utility at this time.


Characterization of an F-actin-binding domain in the cytoskeletal protein vinculin.
Vinculin, a major structural component of vertebrate cell-cell and cell-matrix adherens junctions, has been found to interact with several other junctional components. In this report, we have identified and characterized a binding site for filamentous actin. These results included studies with gizzard vinculin, its proteolytic head and tail fragments, and recombinant proteins containing various gizzard vinculin sequences fused to the maltose binding protein (MBP) of Escherichia coli. In cosedimentation assays, only the vinculin tail sequence mediated a direct interaction with actin filaments. The binding was saturable, with a dissociation constant value in the micromolar range. Experiments with deletion clones localized the actin-binding domain to a region confined by residues 893-1016 in the 170-residue-long carboxyterminal segment, while the proline-rich hinge connecting the globular head to the rodlike tail was not required for this interaction. In fixed and permeabilized cells (cell models), as well as after microinjection, proteins containing the actin-binding domain specifically decorated stress fibers and the cortical network of fibroblasts and epithelial cells, as well as of brush border type microvilli. These results corroborated the sedimentation experiments. Our data support and extend previous work showing that vinculin binds directly to actin filaments. They are consistent with a model suggesting that in adhesive cells, the NH2-terminal head piece of vinculin directs this molecule to the focal contact sites, while its tail segment causes bundling of the actin filament ends into the characteristic spear tip-shaped structures.


Lipoprotein glomerulopathy treated with LDL-apheresis (Heparin-induced Extracorporeal Lipoprotein Precipitation system): a case report.
Lipoprotein glomerulopathy is a glomerulonephritis which was described for the first time by Saito in 1989 and is currently acknowledged as a separate nosological entity. It is histologically characterized by a marked dilatation of the glomerular capillaries and the presence of lipoprotein thrombi in the glomerular lumens. The dyslipidemic profile is similar to that of type III dyslipoproteinemia with Apolipoprotein E values that are often high; proteinuria and renal dysfunction are present. Proteinuria often does not respond to steroid and cytostatic treatments. The phenotypic expression of lipoprotein glomerulopathy is most probably correlated to a genetic alteration of the lipoprotein metabolism (mutation of the Apolipoprotein E coding gene). In literature, lipoprotein glomerulopathies have mainly been reported in Japanese and Chinese subjects, except for three cases in the Caucasian race, reported in France and the USA. We describe the case of a 60-year-old female, Caucasian patient suffering from lipoprotein glomerulopathy, carrier of a new mutation on the Apolipoprotein E gene (Apolipoprotein E(MODENA)), and treated successfully with low density lipoprotein-apheresis with the Heparin induced extracorporeal lipoprotein precipitation system. After a first phase of therapeutic protocol with statins, the patient was admitted for nephrotic syndrome, renal failure and hypertension. Since conventional treatment alone was not able to control dyslipidemia, aphaeretic treatment with heparin-induced Extracorporeal Lipoprotein Precipitation - apheresis (HELP-apheresis) was started to maintain angiotensin converting enzyme inhibitor therapy for the treatment of hypertension. Treatment with HELP-apheresis led to a complete remission of the proteinuria in a very short time (four months), as well as control of hypercholesterolemia and renal function recovery. According to this case of lipoprotein glomerulopathy, we believe that renal damage expressed by proteinuria correlates to the levels of lipids and, furthermore, the treatment with HELP-apheresis, by lowering low-density lipoprotein cholesterol and triglycerides, may be considered as a therapeutic option in synergy with pharmacological treatment in the treatment of lipoprotein glomerulopathy.


Rapid diagnosis of rabies and post-vaccinal encephalitides.
In an attempt to establish the diagnoses of rabies post-vaccinal encephalitis (PVE) and early rabies encephalitis, paired serum and CSF levels of rabies neutralizing antibody (Rab) and rabies specific-IgM (RIgM) were compared in 12 PVE, 10 rabies and five control patients with similar presenting clinical features. Rapid methods of rabies antigen detection were evaluated in 17 patients. All 12 PVE patients had Rab in their serum and in eight it was also present in the CSF. These same eight had RIgM in the serum, and in seven also in the CSF. The CSF antibodies may have originated in the plasma since six patients had a high albumin quotient indicating leakage across the blood-brain barrier. Among the rabies patients, only the two vaccinated ones had serum Rab; this was also detected in the CSF of one and RIgM was in the CSF of the other. A raised IgG Index, indicating intrathecal synthesis of IgG was seen in five of 12 PVE patients. This did not correlate with the presence of CSF rabies antibody, suggesting production of antibody to other vaccine antigens of neural origin. The diagnosis of rabies encephalitis in life was made by antigen detection in a skin biopsy. No false positive results occurred and the method was as efficient as immunofluorescence of a post-mortem brain biopsy.


Role of electrostatic interactions in binding of thrombin to the fibrinogen γ' chain.
Thrombin binds to the highly anionic fibrinogen γ' chain through anion-binding exosite II. This binding profoundly alters thrombin's ability to cleave substrates, including fibrinogen, factor VIII, and PAR1. However, it is unknown whether this interaction is due mainly to general electrostatic complementarity between the γ' chain and exosite II or if there are critical charged γ' chain residues involved. We therefore systematically determined the contribution of negatively charged amino acids in the γ' chain, both individually and collectively, to thrombin binding affinity. Surface plasmon resonance binding experiments were performed using immobilized γ' chain peptides with charged-to-uncharged amino acid substitutions, i.e., Asp to Asn, Glu to Gln, and pTyr to Tyr. Individually, the substitution of uncharged for charged amino acids resulted in only minor changes in binding affinity, with a maximal change in K(d) from 0.440 to 0.705 μM for the Asp419Asn substitution. However, substitution of all three charged amino acids in a conserved β-turn that is predicted to contact thrombin, pTyr418Tyr, Asp419Asn, and pTyr422Tyr, resulted in the loss of measurable binding, as did substitution of all the flanking charged amino acids. In addition, the binding of the γ' chain to thrombin was weakened in a dose-dependent manner with increasing NaCl concentration, resulting in a net loss of three or four ion pairs between thrombin and the γ' chain. Therefore, although each of the individual charges in the γ' chain contributes only incrementally to the overall binding affinity, the ensemble of the combined charges plays a profound role in the thrombin-γ' chain interactions.


Participation of bone marrow derived cells in cutaneous wound healing.
Bone marrow has long been known to be a source of stem cells capable of regeneration of the hematopoeitic system. Recent reports, however, have indicated that bone marrow might also contain early stem cells that can differentiate into other organ tissues such as skin. While these studies have illustrated that bone marrow stem cells could find their way to the skin, they have not addressed the dynamics of how bone marrow stem cells might participate in the homeostatis and regeneration of skin. In this report we followed green fluorescent protein (GFP) labeled bone marrow transplanted into non-GFP mice in order to determine the participation of bone marrow stem cells in cutaneous wounds. Our results indicate that there are a significant number of bone marrow cells that traffic through both wounded and non-wounded skin. Wounding stimulated the engraftment of bone marrow cells to the skin and induced bone marrow derived cells to incorporate into and differentiate into non-hematopoietic skin structures. This report thus illustrates that bone marrow might be a valuable source of stem cells for the skin and possibly other organs. Wounding could be a stimulus for bone marrow derived stem cells to travel to organs and aid in the regeneration of damaged tissue.


Ultrashort TE chemical shift imaging (UTE-CSI).
A fundamental modification to the conventional chemical shift imaging (CSI) method is described that improves the imaging of species with short T2's (i.e., less than approximately 2 ms). This approach minimizes the delay before each k-space point is collected. This results in different time delays, T(d), for different free induction decay (FID) acquisitions in k-space. On a clinical 1.5 T system this yields an effective delay due to transmit/receive switching of 70 micros and an echo time (TE) from the center of the excitation pulse to the center of k-space of 170 micros, as compared with 1-2 ms for conventional CSI techniques. Using this method, the signal decay before acquisition is greatly reduced, thus enabling imaging of species with very short T2)(e.g., 200 micros) and increasing the signal-to-noise ratio (SNR) of species with intermediate T2. Increases in the SNR of the short T2 components of 23Na in the heart, and 31P acquisitions of bone are about 27% and 400%, respectively, compared to an optimized conventional CSI approach. The imperfections of this approach are also described, and the magnitude of the resultant image artifacts is quantified for different practical imaging situations. These artifacts were not found to be significant in the described applications. This new method allows us to obtain information on short T2 components without degrading the image quality from long T2 components.


Zero-Flow Pressure Measured Immediately After Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Provides the Best Invasive Index for Predicting the Extent of Myocardial Infarction at 6 Months: An OxAMI Study (Oxford Acute Myocardial Infarction).
The aim of this study was to define which measure of microvascular best predicts the extent of left ventricular (LV) infarction. Microvascular injury after ST-segment elevation myocardial infarction (STEMI) is an important determinant of outcome. Several invasive measures of the microcirculation at primary percutaneous coronary intervention (PPCI) have been described. One such measure is zero-flow pressure (Pzf), the calculated pressure at which coronary flow would cease. In 34 STEMI patients, Pzf, hyperemic microvascular resistance (hMR), and index of microcirculatory resistance (IMR) were derived using thermodilution flow/pressure and Doppler flow/pressure wire assessment of the infarct-related artery following PPCI. The extent of infarction was determined by blinded late gadolinium enhancement on cardiac magnetic resonance at 6 months post-PPCI. Infarction of ≥24% total LV mass was used as a categorical cutoff in receiver-operating characteristic curve analysis. Pzf was superior to both hMR and IMR for predicting ≥24% infarction area under the curve: 0.94 for Pzf versus 0.74 for hMR (p = 0.04) and 0.54 for IMR (p = 0.003). Pzf ≥42 mm Hg was the optimal cutoff value, offering 100% sensitivity and 73% specificity. Patients with Pzf ≥42 mm Hg also had a lower salvage index (61.3 ± 8.1 vs. 44.4 ± 16.8, p = 0.006) and 6-month ejection fraction (62.4 ± 3.6 vs. 49.9 ± 9.6, p = 0.002). In addition, there were significant direct relationships between Pzf and troponin area under the curve (rho = 0.55, p = 0.002), final infarct mass (rho = 0.75, p < 0.0001), percentage of LV infarction and percent transmurality of infarction (rho = 0.77 and 0.74, respectively, p < 0.0001), and inverse relationships with myocardial salvage index (rho = -0.53, p = 0.01) and 6-month ejection fraction (rho = -0.73, p = 0.0001). Pzf measured at the time of PPCI is a better predictor of the extent of myocardial infarction than hMR or IMR. Pzf may provide important prognostic information at the time of PPCI and merits further investigation in clinical studies with relevant outcome measures.


Vaccination strategies for epidemic cholera in Haiti with implications for the developing world.
In October 2010, a virulent South Asian strain of El Tor cholera began to spread in Haiti. Interventions have included treatment of cases and improved sanitation. Use of cholera vaccines would likely have further reduced morbidity and mortality, but such vaccines are in short supply and little is known about effective vaccination strategies for epidemic cholera. We use a mathematical cholera transmission model to assess different vaccination strategies. With limited vaccine quantities, concentrating vaccine in high-risk areas is always most efficient. We show that targeting one million doses of vaccine to areas with high exposure to Vibrio cholerae, enough for two doses for 5% of the population, would reduce the number of cases by 11%. The same strategy with enough vaccine for 30% of the population with modest hygienic improvement could reduce cases by 55% and save 3,320 lives. For epidemic cholera, we recommend a large mobile stockpile of enough vaccine to cover 30% of a country's population to be reactively targeted to populations at high risk of exposure.


Immuno-viral therapy as a new approach for the treatment of brain tumors.
The central nervous system (CNS) has been considered an immunologically privileged site; however, recent evidence suggests that activated T cells cross the intact blood-brain barrier and that a series of immunological events is initiated when T cells recognize CNS antigens. Therefore, brain tumors might be selectively eliminated by T cells activated with antigens specific for the tumors. Using a conditionally replicating herpes simplex virus-1 (HSV-1) mutant, G207, we developed a novel therapeutic approach for metastatic brain tumors that combines viral therapy with immunotherapy. G207 replicates selectively within tumor cells and causes tumor cell destruction without local or systemic toxicity, because its replication in normal cells is highly attenuated. Furthermore, the inoculation of tumors outside the CNS with G207 induces systemic immune responses not only to HSV but also to tumor antigens. In our strategy, in which both the metastatic brain tumor and the primary tumor outside the CNS are inoculated with G207, the HSV-infected brain tumor can be eliminated by the combined effects of the direct oncolysis and the induced anti-HSV and antitumor T cells. Recently, the safety of directly inoculating the human brain with G207 has been shown. These results indicate that our therapeutic approach using G207 may hold promise for the treatment of metastatic brain tumors.


Encapsulated human mesenchymal stem cells (eMSCs) as a novel anti-cancer agent targeting breast cancer stem cells: Development of 3D primed therapeutic MSCs.
Breast cancer is a leading cause of mortality in women across the globe. The major reason for its recurrence and high mortality is due to the presence of a drug refractory and self-renewing population of cells, the cancer stem cells (CSCs). Mesenchymal stem cells (MSCs) have recently emerged as a promising cell-based therapeutic agent for the treatment of different cancer types. However, the anti-tumor effect of MSCs has been indicated to be substantially reduced by their in vivo tumor-trophic migration property and direct cell-to-cell integration with tumor stromal elements. To address this drawback, the present study uses a biomaterial, sodium alginate, for the encapsulation of MSCs from the perinatal tissue, Wharton's jelly (WJMSCs) into microbeads, to study the effect of WJMSCs beads on breast CSCs derived from two breast cancer cell lines, MDA-MB-231 and MCF7. Encapsulation with sodium alginate facilitated the prevention of direct cell-to-cell interaction and these microbeads provided a three-dimensional (3D) microenvironment for the encapsulated WJMSCs (eWJMSCs). Compared to two dimensional (2D) culture, eWJMSC increased proliferation of WJMSCs with an increase in pluripotency genes, epithelial to mesenchymal transition (EMT), immune-modulation, and angiogenesis. Interestingly, the tumor invasion suppressor protein E-cadherin was highly expressed in eWJMSCs as shown by Western blot analysis. In addition, eWJMSCs had an increased secretion of anti-inflammatory cytokines VEGF, TGF-β, TNF-α, IFN-γ, IL-10 and -6, and IL-3β when compared to 2D culture. Treatment of CSCs with eWJMSCs reduced cell viability, inhibited migration, and exerted an anti-angiogenic effect. eWJMSCs treatment of CSCs increased caspase 3/7 activity, nitric oxide production, and reactive oxygen species production, suggesting its anti-tumorigenic activity. Gene expression analysis revealed that CSCs treated with eWJMSCs had a downregulation of pro-proliferation markers, drug transporters, epithelial-mesenchymal transition-associated markers, and angiogenesis related genes. The mode of anti-proliferative action of WJMSCs beads was possibly through inhibition of the Wnt/β-catenin signaling pathway as indicated by the upregulation of the Wnt antagonists sFRP4 and DKK1. These data suggest that alginate-encapsulated WJMSCs could be an efficient cell contact-free system for developing stem cell-based therapies for CSCs.


MicroRNAs in Cancer Biology and Therapy: Current Status and Perspectives.
The study of a class of small non-coding RNA molecules, named microRNAs (miRNAs), has advanced our understanding of many of the fundamental processes of cancer biology and the molecular mechanisms underlying tumor initiation and progression. MiRNA research has become more and more attractive as evidence is emerging that miRNAs likely play important regulatory roles virtually in all essential bioprocesses. Looking at this field over the past decade it becomes evident that our understanding of miRNAs remains rather incomplete. As research continues to reveal the mechanisms underlying cancer therapy efficacy, it is clear that miRNAs contribute to responses to drug therapy and are themselves modified by drug therapy. One important area for miRNA research is to understand the functions of miRNAs and the relevant signaling pathways in the initiation, progression and drug-resistance of tumors to be able to design novel, effective targeted therapeutics that directly target pathologically essential miRNAs and/or their target genes. Another area of increasing importance is the use of miRNA signatures in the diagnosis and prognosis of various types of cancers. As the study of non-coding RNAs is increasingly more popular and important, it is without doubt that the next several years of miRNA research will provide more fascinating results.


Statin use and risk of delirium in the critically ill.
Delirium is common in intensive care unit (ICU) patients and is a predictor of worse outcomes and neuroinflammation is a possible mechanism. The antiinflammatory actions of statins may reduce delirium. To determine whether critically ill patients receiving statin therapy had a reduced risk of delirium than those not on statins. A prospective cohort analysis of data from consecutive ICU patients admitted to a UK mixed medical and surgical critical care unit between August 2011 and February 2012; the Confusion Assessment Method for ICU was used to determine the days each patient was assessed as being free of delirium during ICU admission. Delirium-free days, daily administration of statins, and serum C-reactive protein (CRP) were recorded. Four hundred and seventy consecutive critical care patients were followed, of whom 151 patients received statins. Using random-effects multivariable logistic regression, statin administration the previous evening was associated with the patient being assessed as free of delirium (odds ratio, 2.28; confidence interval, 1.01-5.13; P < 0.05) and with lower CRP (β = -0.52; P < 0.01) the following day. When the association between statin and being assessed as free of delirium was controlled for CRP, the effect size became nonsignificant (odds ratio, 1.56; confidence interval, 0.64-3.79; P = 0.32). Ongoing statin therapy is associated with a lower daily risk of delirium in critically ill patients. An ongoing clinical trial, informed by this study, is investigating if statins are a potential therapy for delirium in the critically ill.


[Pericardial effusion due to metastatic prostate cancer: a case report].
We describe a patient whose complaints were related to pericardial effusion due to prostatic carcinoma. An 80-year-old man was admitted to our hospital because of chest discomfort and dyspnea. The chest radiograph revealed cardiomegaly and computed tomographic scan showed a large pericardial effusion. Pericardiocentesis revealed sanguinous exudates. Cytologic study suggested metastatic adenocarcinoma or malignant mesothelioma. He died suddenly because of ventricular tachycardia. At autopsy, the major finding was poorly differentiated adenocarcinoma of the prostate with metastases to the mediastinum.


What Is Gender Dysphoria? A Critical Systematic Narrative Review.
In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, the American Psychiatric Association has changed the diagnosis of gender identity disorder to gender dysphoria (GD). In this critical narrative review we ask: What is gender dysphoria? We report on some of the inconsistencies in the articles that foreground distress while obfuscating the fact that not all trans and intersex people suffer stress or impaired functioning, and the inappropriate referencing to intersex people in the diagnostic criterion, claims about the GD diagnosis contributing to the depathologization of and reducing stigma surrounding trans people, the conceptualizations of "gender dysphoric" research subjects, and finally we question the etiological approaches using GD as a conceptual framework. We further suggest that there are a number of methodological issues that need to be resolved to be able to claim that the GD diagnosis can be validated. To shed light on these paradoxes and methodological issues in the DSM-5, we report on the content validity of GD by reviewing research articles postdiagnostic inception. These findings will contribute to the debate about the validity of GD as a diagnosis for the 21st century for those people who need to live a different gender to that assigned at birth.


Mutations in CLCN5 chloride channel in Japanese patients with low molecular weight proteinuria.
Mutations in the CLCN5 gene have been demonstrated in three disorders of hypercalciuric nephrolithiasis, i.e., Dent's disease, X-linked recessive nephrolithiasis, and X-linked recessive hypophosphatemic rickets. Recently, a number of Japanese children with low molecular weight proteinuria (LMWP) showing symptoms similar to those shown by patients with Dent's disease in British families have also been reported to have mutations in the CLCN5 gene. The present study examines five unrelated Japanese families with LMWP, two of which lacked any signs other than LMWP, and three of which had several signs other than LMWP, i.e., hypercalciuria, aminoaciduria, hypophosphatemia, and rickets. One nonsense (E118X) and one missense (W22G) mutation were found in three patients in the two families having only LMWP. One genomic deletion including exons 5 to 8 in the CLCN5 gene was found in a patient with hypophosphatemic rickets, and a nonsense mutation (R347X) was found in one patient with LMWP and slight hypercalciuria. No mutations of the exons and exon-intron boundaries in the CLCN5 gene were found in one patient with LMWP, aminoaciduria, and hypokalemia. In addition to the predicted loss of chloride channel function in these nonsense and deletion mutations, the loss of function in the missense mutation W22G was confirmed in the Xenopus oocyte expression system. These results clarified four novel mutations in the CLCN5 genes, and additionally suggested that the loss-of-function mutation of the CLCN5 does not necessarily lead to hypercalciuria and nephrocalcinosis in the early stage of the disease, and that LMWP is an early and essential manifestation of disorders of the CLC-5 chloride channel.


Negative autoregulation matches production and demand in synthetic transcriptional networks.
We propose a negative feedback architecture that regulates activity of artificial genes, or "genelets", to meet their output downstream demand, achieving robustness with respect to uncertain open-loop output production rates. In particular, we consider the case where the outputs of two genelets interact to form a single assembled product. We show with analysis and experiments that negative autoregulation matches the production and demand of the outputs: the magnitude of the regulatory signal is proportional to the "error" between the circuit output concentration and its actual demand. This two-device system is experimentally implemented using in vitro transcriptional networks, where reactions are systematically designed by optimizing nucleic acid sequences with publicly available software packages. We build a predictive ordinary differential equation (ODE) model that captures the dynamics of the system and can be used to numerically assess the scalability of this architecture to larger sets of interconnected genes. Finally, with numerical simulations we contrast our negative autoregulation scheme with a cross-activation architecture, which is less scalable and results in slower response times.


Health Risks and Potential Sources of Contamination of Groundwater Used by Public Schools in Vhuronga 1, Limpopo Province, South Africa.
Public schools in most rural areas of South Africa depend on untreated groundwater due to unreliable water supply by the municipalities. This has the potential to cause water-related health problems to school children. Temperature, pH, and electrical conductivity (EC) were measured in situ. Chemical (fluoride, chloride, sulphate, phosphate, nitrate, magnesium, calcium, sodium, and potassium) and microbial (Escherichia coliform (E. coli), Salmonella typhimurium, and Shigella flexneri) water quality parameters were analysed in groundwater samples from 10 public schools in Vhuronga 1 to determine suitability for use. Quantitative microbial risk assessment was carried out to determine risks of infection and illness due to consumption of groundwater. Correlation analysis was used to identify potential sources of contamination. All physical and most chemical water quality parameters were within guidelines for domestic water use. A high proportion of schools had high levels of microbial organisms. Risks of infection per day were relatively low for all schools. The annual risks of infection due to E. coli and Shigella flexneri for most schools was high, with maximum values of 89.11 and 83.75%, respectively. Maximum risks of illness per year were 31.19, 30.37, and 29.31% for E. coli, Salmonella typhimurium, and Shigella flexneri, respectively. Correlation analysis indicated potential contamination of groundwater by agricultural activities, domestic waste, and faecal contamination from pit latrines. Preventive and mitigation measures to minimise such risks, including locating boreholes at safe distances from pit latrines, prevention/minimisation of pollution of groundwater from agricultural activities, and point-of-use treatment of groundwater by the schools are therefore essential.


What states are doing to simplify health plan choice in the insurance marketplaces.
The new health insurance marketplaces aim to improve consumers' purchasing experiences by setting uniform coverage levels for health plans and giving them tools to explore their options. Marketplace administrators may choose to limit the number and type of plans offered to further simplify consumer decision-making. This issue brief examines the policies set by some state-based marketplaces to simplify plan choices: adopting a meaningful difference standard, limiting the number of plans or benefit designs insurers may offer, or requiring standardized benefit designs. Eleven states and the District of Columbia took one or more of these actions for 2014, though their policies vary in terms of their prescriptiveness. Tracking the effects of these different approaches will enhance understanding of how best to enable consumers to make optimal health insurance purchasing decisions and set the stage for future refinements.


Sickle cell disease and pulmonary hypertension in Africa: a global perspective and review of epidemiology, pathophysiology, and management.
Secondary pulmonary hypertension (PAH) has been shown to have a prevalence of 30% in patients with sickle cell disease (SCD) with mortality rates of 40% at 40 months after diagnosis in the United States. The burden of SCD is highest in sub-Saharan Africa, especially in Nigeria (West Africa), where approximately 6 million people are afflicted. The true global incidence, prevalence, and burden of SCD and its associated end organ complications however remain unknown. Chronic hemolysis represents a prominent mechanistic pathway in the pathogenesis of SCD-associated pulmonary hypertension via a nitric oxide (NO) scavenging and abrogation of NO salutatory effects on vascular function, including smooth muscle relaxation, downregulation of endothelial adhesion molecules and inhibition of platelet activation. Many known infectious risk factors for PAH are also hyperendemic in Africa, including Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS), chronic hepatitis B and C, and possibly malaria. Interactions between these infectious complications and SCD-related hemolysis could yield an even higher prevalence of pulmonary hypertension and compound the existing global health systems challenges in managing SCD. Indeed, our preliminary analysis of African immigrants currently in the United States suggests that pulmonary hypertension represents a significant complication of SCD in the African subcontinent. There is clearly a need to include Africa and other parts of the world with high SCD prevalence in future comprehensive studies on the epidemiology and treatment of end organ complications of an aging SCD population world-wide.


Pickled food and risk of gastric cancer--a systematic review and meta-analysis of English and Chinese literature.
Ecological and experimental studies have suggested an increased risk of gastric cancer in relation to consumption of pickled vegetables in East Asia. We conducted a meta-analysis of epidemiologic observational studies to evaluate the existing evidence. Searching PubMed, Vip Chinese Periodical, and China National Knowledge Infrastructure databases, we found a total of 60 studies, 50 case-control, and 10 prospective. We compared gastric cancer risk in pickled vegetable/food users versus nonusers (11 studies) or versus those in the lowest reported category of use (49 studies). Pooled results were computed with random-effects models. Among case-control studies, 30 showed significant increased risk and one showed significant decreased risk. Among prospective studies, two showed a significant increased risk but none showed a significant decreased risk. The OR (95% CI) was 1.52 (1.37-1.68) for the overall association, 1.56 (1.39-1.75) for case-control, and 1.32 (1.10-1.59) for cohort studies. The OR (95% CI) was 1.89 (1.29-2.77) in Korean, 1.86 (1.61-2.15) in Chinese, and 1.16 (1.04-1.29) in Japanese studies, and 1.14 (0.96-1.35) in studies from other countries. There was high heterogeneity in overall and subgroup analyses. There was little evidence for publication bias. Our results suggest a potential 50% higher risk of gastric cancer associated with intake of pickled vegetables/foods and perhaps stronger associations in Korea and China. The results of this study may offer ways to reduce the risk of gastric cancer in highly populated areas with high incidence of gastric cancer.