Strengthening health workforce capacity through work-based training.
Although much attention has been given to increasing the number of health workers, less focus has been directed at developing models of training that address real-life workplace needs. Makerere University School of Public Health (MakSPH) with funding support from the Centers for Disease Control and Prevention (CDC) developed an eight-month modular, in-service work-based training program aimed at strengthening the capacity for monitoring and evaluation (M&E) and continuous quality improvement (CQI) in health service delivery. This capacity building program, initiated in 2008, is offered to in-service health professionals working in Uganda. The purpose of the training is to strengthen the capacity to provide quality health services through hands-on training that allows for skills building with minimum work disruptions while encouraging greater involvement of other institutional staff to enhance continuity and sustainability. The hands-on training uses practical gaps and challenges at the workplace through a highly participatory process. Trainees work with other staff to design and implement 'projects' meant to address work-related priority problems, working closely with mentors. Trainees' knowledge and skills are enhanced through short courses offered at specific intervals throughout the course. Overall, 143 trainees were admitted between 2008 and 2011. Of these, 120 (84%) from 66 institutions completed the training successfully. Of the trainees, 37% were Social Scientists, 34% were Medical/Nursing/Clinical Officers, 5.8% were Statisticians, while 23% belonged to other professions. Majority of the trainees (80%) were employed by Non-Government Organizations while 20% worked with the public health sector. Trainees implemented 66 projects which addressed issues such as improving access to health care services; reducing waiting time for patients; strengthening M&E systems; and improving data collection and reporting. The projects implemented aimed to improve trainees' skills and competencies in M&E and CQI and the design of the projects was such that they could share these skills with other staff, with minimal interruptions of their work. The modular, work-based training model strengthens the capacity of the health workforce through hands-on, real-life experiences in the work-setting and improves institutional capacity, thereby providing a practical example of health systems strengthening through health workforce capacity building.


The genome of the truffle-parasite Tolypocladium ophioglossoides and the evolution of antifungal peptaibiotics.
Two major mycoparasitic lineages, the family Hypocreaceae and the genus Tolypocladium, exist within the fungal order, Hypocreales. Peptaibiotics are a group of secondary metabolites almost exclusively described from Trichoderma species of Hypocreaceae. Peptaibiotics are produced by nonribosomal peptide synthetases (NRPSs) and have antibiotic and antifungal activities. Tolypocladium species are mainly truffle parasites, but a few species are insect pathogens. The draft genome sequence of the truffle parasite Tolypocladium ophioglossoides was generated and numerous secondary metabolite clusters were discovered, many of which have no known putative product. However, three large peptaibiotic gene clusters were identified using phylogenetic analyses. Peptaibiotic genes are absent from the predominantly plant and insect pathogenic lineages of Hypocreales, and are therefore exclusive to the largely mycoparasitic lineages. Using NRPS adenylation domain phylogenies and reconciliation of the domain tree with the organismal phylogeny, it is demonstrated that the distribution of these domains is likely not the product of horizontal gene transfer between mycoparasitic lineages, but represents independent losses in insect pathogenic lineages. Peptaibiotic genes are less conserved between species of Tolypocladium and are the product of complex patterns of lineage sorting and module duplication. In contrast, these genes are more conserved within the genus Trichoderma and consistent with diversification through speciation. Peptaibiotic NRPS genes are restricted to mycoparasitic lineages of Hypocreales, based on current sampling. Phylogenomics and comparative genomics can provide insights into the evolution of secondary metabolite genes, their distribution across a broader range of taxa, and their possible function related to host specificity.


Effect of the load size on the efficiency of microwave heating under stop flow and continuous flow conditions.
A novel heating efficiency analysis of the microwave heated stop-flow (i.e. stagnant liquid) and continuous-flow reactors has been presented. The thermal losses to the surrounding air by natural convection have been taken into account for heating efficiency calculation of the microwave heating process. The effect of the load diameter in the range of 4-29 mm on the heating efficiency of ethylene glycol was studied in a single mode microwave cavity under continuous flow and stop-flow conditions. The variation of the microwave absorbing properties of the load with temperature was estimated. Under stop-flow conditions, the heating efficiency depends on the load diameter. The highest heating efficiency has been observed at the load diameter close to the half wavelength of the electromagnetic field in the corresponding medium. Under continuous-flow conditions, the heating efficiency increased linearly. However, microwave leakage above the propagation diameter restricted further experimentation at higher load diameters. Contrary to the stop-flow conditions, the load temperature did not raise monotonously from the inlet to outlet under continuous-flow conditions. This was due to the combined effect of lagging convective heat fluxes in comparison to volumetric heating. This severely disturbs the uniformity of the electromagnetic field in the axial direction and creates areas of high and low field intensity along the load Length decreasing the heating efficiency as compared to stop-flow conditions.


Differential contribution of descending serotonergic and noradrenergic systems to central Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5 (DAMGO) and morphine-induced antinociception in mice.
Differences in antinociceptive (inhibition of tail-flick response) action of morphine and Tyr-D-Ala2-Gly-NMePhe4-ol5 (DAMGO) were demonstrated by intracerebroventricular (i.c.v.) administration of these agonists along with intrathecal (i.t.) administration of a variety of antagonists: yohimbine, methysergide, naloxone and nor-binaltorphimine. Intracerebroventricular morphine analgesia was antagonized by either i.t. yohimbine or methysergide, whereas i.c.v. DAMGO analgesia was only antagonized by i.t. methysergide. Thus, for i.c.v. morphine-induced analgesia, descending spinal noradrenergic and serotonergic systems were involved, whereas for DAMGO analgesia, only the serotonergic system was involved. The dose-response curve for i.c.v. morphine reached a plateau at high doses, whereas i.c.v. DAMGO analgesia peaked at 10 ng and then decreased thereafter, producing a bell-shaped dose-response curve. This decrement in analgesic response could be reversed by low doses of i.t. methysergide and i.t. pindolol. It was concluded that activation of serotonin-1 (5-HT1) receptors plays a role in the decrease in analgesia from high doses of DAMGO. Combinations of i.t. morphine with i.t. 5-HT or i.t. clonidine produced additive or greater analgesic responses. Combinations of i.t. DAMGO with i.t. 5-HT or i.t. clonidine produced less than additive interactions. Part of the latter responses appeared to be due to activation of 5-HT1 receptors; blockade of these receptors by pindolol enhanced i.t. DAMGO-induced analgesia. Morphine and DAMGO differ further because i.c.v. morphine activated a descending antianalgesic pathway mediated by spinal dynorphin A(1-17), whereas i.c.v. DAMGO at a high dose did not. Thus, morphine and DAMGO differ in their modes of antinociceptive action as measured by the tail-flick response.


Effect of baseline micronutrient and inflammation status on CD4 recovery post-cART initiation in the multinational PEARLS trial.
Nutritional deficiency and inflammation may impact CD4+ T cell recovery during combination antiretroviral therapy (cART), particularly in resource-limited settings where malnutrition is prevalent. The aim of this study was to investigate the relationship of micronutrient and inflammation biomarkers to CD4 recovery after cART initiation. We conducted a secondary analysis of a random sub-cohort sample (n = 270) from a multinational randomized trial of cART regimen efficacy among 1571 cART-naïve adults. We measured pre-cART serum levels of micronutrients (Vitamin A, B6, B12, D, total carotenoids, selenium, and iron) and inflammation (C-reactive protein, soluble CD14 (sCD14), IFNγ, TNFα, Interleukin-6, and C-X-C motif chemokine 10 (CXCL10/IP10), EndoCab (IgM)) biomarkers. Biomarker status (i.e. micronutrient deficiency vs. sufficiency and elevated vs. low inflammation) was defined using established cutoffs or quartiles. Mixed-effects linear regression models were used to determine the association of baseline (pre-cART) concentrations of individual biomarkers with CD4 recovery through 96 weeks post-cART initiation. In models adjusting for time-dependent viral load and baseline CD4 count, age, sex, body mass index, country, treatment regimen, anemia and hypoalbuminemia status, pre-cART vitamin D deficiency was associated with lower CD4 recovery (-14.9 cells/mm3, 95% CI: -27.9, -1.8) compared to sufficiency. In contrast, baseline selenium deficiency (20.8 cells/mm3, 95% CI: 3.3, 38.3), vitamin A deficiency (35.9 cells/mm3, 95% CI: 17.6, 54.3) and high sCD14 (23.4 cells/mm3, 95% CI: 8.9, 37.8) were associated with higher CD4 recovery compared to sufficient/low inflammation status. In summary, baseline vitamin D deficiency was associated with diminished CD4 recovery after cART initiation; impaired CD4 recovery may contribute to the poor clinical outcomes recently observed in individuals with vitamin D deficiency. Vitamin A, selenium and sCD14 were associated with CD4 recovery but future studies are needed to further explore these relationships.


Histologically validated scoring system for the assessment of hock burn in broilers.
The assessment of bird-based welfare indicators plays an important role in the evaluation of bird welfare. The aim of the study was to histologically validate a visual scoring system for hock burn in broilers and to detect threshold values of a visual score to define welfare-relevant alterations in terms of mild lesions or ulcers of the hock. We collected 200 hocks of 39- to 42-day-old Ross 308 broilers after the slaughter process. Each hock was scored visually ("macro scores" 0-4) and evaluated histologically ("micro scores" 0-3), with high scores representing more severe lesions. Although we found a tendency for higher micro scores with increasing macro scores, an exact allocation of macro to micro scores was not possible. For example, macro score 1 could represent micro scores 1, 2 and 3, whereas macro scores 3 and 4 always represented micro score 3 (ulcer). The conditional probability of certain micro scores for given macro scores was estimated using a multinomial logistic regression model. Ulcer showed the highest probability at macro score 1, whereas mild lesions were not found to have an estimated highest probability at any macro score. The depth of inflammation of hock burn lesions increased with increasing macro scores up to macro score 3 with an average depth of 1019 µm. Visually more severe and deeper lesions were also histologically rated with higher scores. Thus, considering limitations, the herein validated macroscopic assessment scheme for hock burn allows an estimation of histological alterations in hocks of broilers.RESEARCH HIGHLIGHTS Histological validation of a visual assessment scheme for hock burn in broilers.Tendency for higher micro scores with increasing macro scores.Estimation of histological score via macro score possible with limitations.Histological depth of inflammation increased with an increasing macro score.


Morphology engineering of high performance binary oxide electrodes.
Advances in materials have preceded almost every major technological leap since the beginning of civilization. On the nanoscale and microscale, mastery over the morphology, size, and structure of a material enables control of its properties and enhancement of its usefulness for a given application, such as energy storage. In this review paper, our aim is to present a review of morphology engineering of high performance oxide electrode materials for electrochemical energy storage. We begin with the chemical bonding theory of single crystal growth to direct the growth of morphology-controllable materials. We then focus on the growth of various morphologies of binary oxides and their electrochemical performances for lithium ion batteries and supercapacitors. The morphology-performance relationships are elaborated by selecting examples in which there is already reasonable understanding for this relationship. Based on these comprehensive analyses, we proposed colloidal supercapacitor systems beyond morphology control on the basis of system- and ion-level design. We conclude this article with personal perspectives on the directions toward which future research in this field might take.


Mechanism of action of camptothecin.
Camptothecin (CPT) class of compounds has been demonstrated to be effective against a broad spectrum of tumors. Their molecular target has been firmly established to be human DNA topoisomerase I (topo I). CPT inhibits topo I by blocking the rejoining step of the cleavage/religation reaction of topo-I, resulting in accumulation of a covalent reaction intermediate, the cleavable complex. The primary mechanism of cell killing by CPT is S-phase-specific killing through potentially lethal collisions between advancing replication forks and topo-I cleavable complexes. Collisions with the transcription machinery have also been shown to trigger the formation of long-lived covalent topo-I DNA complexes, which contribute to CPT cytotoxicity. Two novel repair responses to topo-I-mediated DNA damage involving covalent modifications of topo-I have been discovered. The first involves activation of the ubiquitin/26S proteasome pathway, leading to degradation of topo-I (CPT-induced topo-I downregulation). The second involves SUMO conjugation to topo-I. The potentials roles of these new mechanisms for repair of topo-I-mediated DNA damage in determining CPT sensitivity/resistance in tumor cells are discussed.


SIRT3 deacetylates ATP synthase F1 complex proteins in response to nutrient- and exercise-induced stress.
Adenosine triphosphate (ATP) synthase uses chemiosmotic energy across the inner mitochondrial membrane to convert adenosine diphosphate and orthophosphate into ATP, whereas genetic deletion of Sirt3 decreases mitochondrial ATP levels. Here, we investigate the mechanistic connection between SIRT3 and energy homeostasis. By using both in vitro and in vivo experiments, we demonstrate that ATP synthase F1 proteins alpha, beta, gamma, and Oligomycin sensitivity-conferring protein (OSCP) contain SIRT3-specific reversible acetyl-lysines that are evolutionarily conserved and bind to SIRT3. OSCP was further investigated and lysine 139 is a nutrient-sensitive SIRT3-dependent deacetylation target. Site directed mutants demonstrate that OSCP(K139) directs, at least in part, mitochondrial ATP production and mice lacking Sirt3 exhibit decreased ATP muscle levels, increased ATP synthase protein acetylation, and an exercise-induced stress-deficient phenotype. This work connects the aging and nutrient response, via SIRT3 direction of the mitochondrial acetylome, to the regulation of mitochondrial energy homeostasis under nutrient-stress conditions by deacetylating ATP synthase proteins. Our data suggest that acetylome signaling contributes to mitochondrial energy homeostasis by SIRT3-mediated deacetylation of ATP synthase proteins.


Differential utilization of nuclear and extranuclear receptor signaling pathways in the actions of estrogens, SERMs, and a tissue-selective estrogen complex (TSEC).
Estrogens act through nuclear and extranuclear initiated pathways involving estrogen receptors (ERs) to regulate gene expression and activate protein kinases. We investigated the involvement of extracellular signal-regulated kinase2 (ERK2) and ERα in the activities of estradiol (E2), conjugated estrogens (CEs), selective estrogen receptor modulators (SERMs), and a Tissue-Selective Estrogen Complex (TSEC), a combination of a SERM and CE that has a blended activity. We found that CE and individual CE components were generally less effective than E2 in ERK2 recruitment to chromatin binding sites of E2-regulated genes. Likewise, CE was much less agonistic than E2 in stimulation of proliferation of ERα-positive breast cancer cells. The SERM bazedoxifene (BZA) fully suppressed proliferation stimulated by E2 or CE and reversed gene stimulation by CE or E2, as did the antiestrogen Faslodex. Thus, the balance of biological activities mediated through nuclear ERα vs. ERK2-mediated activities is different for CE vs. E2, with CE showing lower stimulation of kinase activity. Furthermore, at the BZA to CE concentrations in TSEC, BZA antagonized CE stimulation of gene expression and proliferation programs in ERα-positive breast cancer cells. The studies provide molecular underpinnings of the different ways in which SERMs and estrogens support or antagonize one another in regulating the chromatin binding of ERα and ERK2, and modulating gene and cell activities. They illuminate how the combined actions of two classes of ER ligands (SERM and CE, present in TSEC) can achieve unique modes of regulation and efficacy.


Association of primary biliary cirrhosis and rheumatoid arthritis.
Primary biliary cirrhosis (PBC) and rheumatoid arthritis (RA) are chronic medical conditions in which, although the etiology is uncertain, autoimmune features predominate. These two conditions are, in fact, multisystemic diseases, with a multitude of manifestations that are not limited to their target end organ. It has been well established that patients with PBC may have musculoskeletal complaints and patients with RA may have evidence of hepatic dysfunction. Both of these conditions are fairly rare, with RA being found in approximately 1% of the population and PBC being found in approximately 20/100,000 women and 2/100,000 men.The likelihood of these uncommon conditions occurring in the same patient is very rare and unusual. We have identified a unique group of 25 patients who have met disease-defining criteria for both RA and PBC. Awareness of this combination should prompt rheumatologists to assess for PBC with antimitochondrial antibody testing in patients with abnormal liver tests and also to raise awareness that abnormal liver tests in RA patients are not always due to drugs.


Homeopathic Arnica montana for post-tonsillectomy analgesia: a randomised placebo control trial.
To evaluate the efficacy of Homeopathic Arnica in reducing the morbidity following tonsillectomy. Randomised double blind, placebo controlled trial at a tertiary referral centre. 190 patients over the age of 18 undergoing tonsillectomy were randomised into intervention and control groups receiving either Arnica 30c or identical placebo, 2 tablets 6 times in the first post-operative day and then 2 tablets twice a day for the next 7 days. The primary outcome measure was the change in pain scores (visual analogue scale) recorded by the patient on a questionnaire over 14 days post-operatively; Secondary outcome measures were: analgesia consumption, visits to the GP or hospital, antibiotic usage, the day on which their swallowing returned to normal and the day on which they returned to work. 111 (58.4%) completed questionnaires were available for analysis. The Arnica group had a significantly larger drop in pain score from day 1 to day 14 (28.3) compared to the placebo group (23.8) with p < 0.05. The two groups did not differ significantly on analgesic consumption or any of the other secondary outcome measures (number of post-operative visits to GP, use of antibiotics and secondary haemorrhage readmissions). The results of this trial suggest that Arnica montana given after tonsillectomy provides a small, but statistically significant, decrease in pain scores compared to placebo.


Phylum level change in the cecal and fecal gut communities of rats fed diets containing different fermentable substrates supports a role for nitrogen as a factor contributing to community structure.
Fermentation differs between the proximal and distal gut but little is known regarding how the bacterial communities differ or how they are influenced by diet. In order to investigate this, we compared community diversity in the cecum and feces of rats by 16S rRNA gene content and DNA shot gun metagenomics after feeding purified diets containing different fermentable substrates. Gut community composition was dependent on the source of fermentable substrate included in the diet. Cecal communities were dominated by Firmicutes, and contained a higher abundance of Lachnospiraceae compared to feces. In feces, community structure was shifted by varying degrees depending on diet towards the Bacteroidetes, although this change was not always evident from 16S rRNA gene data. Multi-dimensional scaling analysis (PCoA) comparing cecal and fecal metagenomes grouped by location within the gut rather than by diet, suggesting that factors in addition to substrate were important for community change in the distal gut. Differentially abundant genes in each environment supported this shift away from the Firmicutes in the cecum (e.g., motility) towards the Bacteroidetes in feces (e.g., Bacteroidales transposons). We suggest that this phylum level change reflects a shift to ammonia as the primary source of nitrogen used to support continued microbial growth in the distal gut.


Intermittent parathyroid hormone treatment can promote linear growth in the ovariectomized growing rat.
To compare the effect of intermittent parathyroid hormone (PTH) treatment with that of estrogen treatment on epiphyseal growth in ovariectomized rats, 46 Sprague-Dawley female rats aged 9-10 weeks (about 200-220 g) were either ovariectomized or sham operated. From 6 weeks after ovariectomy (ovx), rats were daily injected with subcutaneous human recombinant PTH (1-84)-dosed 30 micrograms/kg (the low dose PTH-treated group) or 300 micrograms/kg (the high dose PTH-treated group), 17 beta-estradiol (the 17 beta-estradiol-treated group, 30 micrograms/kg) or vehicle (the ovx-alone group), 5 times a week for 4 weeks. The decalcified sections of the distal femoral epiphyseal plate were analyzed on light microscopy after H&E stain, and the lengths of the zones of proliferation, maturing and hypertrophic chondrocytes were measured. The length of the growth plate, the zone of proliferation and the zone of hypertrophic chondrocyte in the ovx-alone group were significantly shorter than those of the sham-operated group. The treatment of 17 beta-estradiol speeded up the differentiation of cells from proliferating chondrocytes to maturing and hypertrophic chondrocytes even though the length of the growth plate was comparable to that of the sham-operated group. Both low and high dose PTH treatments increased the length of the growth plate, and those lengths were comparable to that of the sham-operated group. The fractions of proliferating, maturing and hypertrophic zone in the low dose PTH-treated group were also comparable to those of the sham-operated group. However, high dose PTH treatment slowed down the differentiation of cells from proliferating chondrocytes to maturing and hypertrophic chondrocytes to a greater extent, and therefore the fraction of proliferating chondrocytes of the high dose PTH-treated group was larger than that of the low dose PTH-treated group (73.8 +/- 1.8 Vs 63.3 +/- 1.3%, p < 0.005). From these results, we showed that intermittent PTH treatment could promote linear growth in the ovariectomized growing rat. We propose that PTH may be an alternative drug candidate for promoting linear growth of long bones without the risk for early closure of the growth plate.


Dissolution kinetic behavior of drug nanoparticles and their conformity to the diffusion model.
Advances in nanomedicine are expected to escalate in the coming years, particularly related to the availability and delivery of optimum dosage. It is crucial that the dissolution behavior of such novel dosage forms be adequately scrutinized to maximize their therapeutic benefits. In this work, the dissolution behavior of irregularly shaped nanoparticles was analyzed using a modified negative-two-thirds-root diffusion model (with shape factor, sigma, incorporated into the equation to describe shape evolution). The model was shown to be effective in describing the transition from peanut-shape nanoparticles (connected by bridges) to discrete spheres during the dissolution process. Due to the eventual aggregation of the discrete spheres in solution, description of the dissolution behavior was limited to the aggregate as a whole. Scanning electron microscopy, diffusion layer thickness calculations, and sonication studies provide information to show that, during dissolution, the bridges dissolve, yielding discrete spheres which then aggregate randomly in solution. Viscosity experiments reveal that the dissolution behavior was predominantly diffusion-controlled. The dissolution behavior of irregularly shaped nanoparticles in solution is described as going from bridged particles to discrete particles, to aggregates, and finally to full dissolution.


Ribavirin resistance in hepatitis C virus replicon-containing cell lines conferred by changes in the cell line or mutations in the replicon RNA.
Ribavirin (RBV), used in combination with alpha interferon to treat hepatitis C virus (HCV) infections, is a guanosine nucleotide analog that can increase the error rate of viral RNA-dependent RNA polymerases, imbalance intracellular nucleotide pools, and cause toxicity in many cell types. To determine potential mechanisms of RBV resistance during HCV RNA replication, we passaged HCV replicon-containing cell lines in the presence of increasing concentrations of RBV. RBV-resistant, HCV replicon-containing cell lines were generated, and the majority of RBV resistance was found to be conferred by changes in the cell lines. The resistant cell lines were defective in RBV import, as measured by [(3)H]RBV uptake experiments. These cell lines displayed reduced RBV toxicity and reduced error accumulation during infection with poliovirus, whose replication is known to be sensitive to RBV-induced error. For one RBV-resistant isolate, two mutations in the replicon RNA contributed to the observed phenotype. Two responsible mutations resided in the C-terminal region of NS5A, G404S, and E442G and were each sufficient for low-level RBV resistance. Therefore, RBV resistance in HCV replicon cell lines can be conferred by changes in the cell line or by mutations in the HCV replicon.


Primary bone carcinosarcoma: chondrosarcoma and squamous cell carcinoma with keratin pearl formation.
Malignant bone tumors with epithelial differentiation are extremely rare. Only one case of primary malignant bone tumor with distinct squamous cell carcinoma and chondrosarcoma has ever been reported. Reported herein is a case of primary malignant bone tumor with distinct squamous cell carcinoma and chondrosarcoma, so-called carcinosarcoma of bone, arising in the femur of a 53-year-old man. The tumor was located within the femur and was diagnosed by curettage as a well-differentiated chondrosarcoma. No primary tumor was detected in any other organ. Within a few months the tumor had rapidly grown toward the soft tissue, and hemipelvectomy was performed. Examination of the surgical specimen revealed that the tumor was mainly composed of undifferentiated spindle sarcoma cells with scattered foci of chondrosarcoma and of squamous cell carcinoma with keratin pearl formation. The patient died approximately 6 months postoperatively. At autopsy multiple metastases were detected in the heart, both lungs, muscles, and lymph nodes. Interestingly, the chondrosarcoma and squamous cell carcinoma components were observed in several metastatic foci. The tumors in both the previously reported case and the present case contained components of chondrosarcoma and squamous cell carcinoma with keratin pearl formation, and this combination of histological features may be a unique characteristic of carcinosarcoma of bone.


The value of pregnancy complication history for 10-year cardiovascular disease risk prediction in middle-aged women.
Women with a history of hypertensive disorders of pregnancy (HDP; preeclampsia and gestational hypertension) or delivering low birth weight offspring (LBW; < 2500 g) have twice the risk of cardiovascular disease (CVD). We aimed to study the extent to which history of these pregnancy complications improves CVD risk prediction above and beyond conventional predictors. Parous women attended standardized clinical visits in Sweden. Data were linked to registries of deliveries and CVD. Participants were followed for a first CVD event within 10 years from age 50 (n = 7552) and/or 60 years (n = 5360) and the predictive value of each pregnancy complication above and beyond conventional predictors was investigated. History of LBW offspring was associated with increased risk of CVD when added to conventional predictors in women 50 years of age [Hazard ratio 1.68, 95% Confidence interval (CI) 1.19, 2.37] but not at age 60 (age interaction p = 0.04). However, at age 50 years CVD prediction was not further improved by information on LBW offspring, except that a greater proportion of the women who developed CVD were assigned to a higher risk category (categorical net reclassification improvement for events 0.038, 95% CI 0.003, 0.074). History of HDP was not associated with CVD when adjusted for reference model predictors. In conclusion, a history of pregnancy complications can identify women with increased risk of CVD midlife. However, considered with conventional risk factors, history of HDP or having delivered LBW offspring did not meaningfully improve 10-year CVD risk prediction in women age 50 years or older.


BAX INHIBITOR-1 is required for full susceptibility of barley to powdery mildew.
BAX INHIBITOR-1 (BI-1) is one of the few proteins known to have cross-kingdom conserved functions in negative control of programmed cell death. Additionally, barley BI-1 (HvBI-1) suppresses defense responses and basal resistance to the powdery mildew fungus Blumeria graminis f. sp. hordei and enhances resistance to cell death-provoking fungi when overexpressed in barley. Downregulation of HvBI-1 by transient-induced gene silencing or virus-induced gene silencing limited susceptibility to B. graminis f. sp. hordei, suggesting that HvBI-1 is a susceptibility factor toward powdery mildew. Transient silencing of BI-1 did not limit supersusceptibility induced by overexpression of MLO. Transgenic barley plants harboring an HvBI-1 RNA interference (RNAi) construct displayed lower levels of HvBI-1 transcripts and were less susceptible to powdery mildew than wild-type plants. At the cellular level, HvBI-1 RNAi plants had enhanced resistance to penetration by B. graminis f. sp. hordei. These data support a function of BI-1 in modulating cell-wall-associated defense and in establishing full compatibility of B. graminis f. sp. hordei with barley.


Hematogenous osteomyelitis in childhood can relapse many years later into adulthood: A retrospective multicentric cohort study in France.
To describe the epidemiological, clinical, laboratory, and radiological features and the management of adult patients who experienced a relapse between 2003 and 2015 of an acute hematogenous osteomyelitis acquired in childhood.A retrospective multicentric cohort study was conducted in 5 centers in France.Thirty-seven patients were included. The median age was 40 years (28-56), and 26 (70%) were male. The first site of infection was the distal femur (n = 23, 62%). The median time between the osteomyelitis in childhood and the relapse in adulthood was 26 years (13-45). Thirty-four (92%) patients reported inflammatory local clinical manifestations, 17 (46%) draining fistula, 10 (27%) fever. Most patients had intramedullary gadolinium deposition (with or without abscess) on magnetic resonance imaging. Most relapses were monomicrobial infections (82%). Staphylococcus aureus was the most commonly found microorganism (82%), expressing a small colony variant phenotype in 3 cases. Most patients (97%) had a surgical treatment, and the median duration of antibiotics for the relapse was 12 weeks. All patients had a favorable outcome, no patient died and no further relapse occurred. We count 2 femoral fractures on osteotomy site.Osteomyelitis in childhood can relapse later in adulthood, especially in patients with lack of care during the initial episode. Osteotomy and prolonged antimicrobial therapy are required for clinical remission.


Postpartum sex taboos and child growth in Tanzania: Implications for child care.
The social context and cultural meaning systems shape caregivers' perceptions about child growth and inform their attention to episodes of poor growth. Thus, understanding community members' beliefs about the aetiology of poor child growth is important for effective responses to child malnutrition. We present an analysis of caregivers' narratives on the risks surrounding child growth during postpartum period and highlight how the meanings attached to these risks shape child care practices. We collected data using 19 focus group discussions, 30 in-depth interviews and five key informant interviews with caregivers of under-five children in south-eastern Tanzania. Parental non-adherence to postpartum sexual abstinence norms was a dominant cultural explanation for poor growth and development in a child, including different forms of malnutrition. In case sexual abstinence is not maintained or when a mother conceives while still lactating, caregivers would wean their infants abruptly and completely to prevent poor growth. Mothers whose babies were growing poorly were often stigmatized for breaking sex taboos by the community and by health care workers. The stigma that mothers face reduced their self-esteem and deterred them from taking their children to the child health clinics. Traditional rather than biomedical care was often sought to remedy growth problems in children, particularly when violation of sexual abstinence was suspected. When designing culturally sensitive interventions aimed at promoting healthy child growth and effective breastfeeding in the community, it is important to recognize and address people's existing misconceptions about early resumption of sexual intercourse and a new pregnancy during lactation period.


Temporal contiguity and ageing: The role of memory organization in cognitive decline.
The temporal contiguity effect is the tendency to form associations between items presented in nearby study positions. In the present study, we explored whether temporal contiguity predicted conversion to cognitively unimpaired-declining (CUD) status from a baseline of unimpaired older adults. Data from 419 participants were drawn from the Wisconsin Registry of Alzheimer's Prevention (WRAP) data set and analysed with binary logistic regressions. Temporal contiguity was calculated using the Rey Auditory Verbal Learning Test. Other predictors included age, years of education, sex, APOE-ε4 status, and other measures of memory recall. Lower temporal contiguity predicted conversion to CUD after accounting for covariates. These findings support the hypothesis that temporal organization in memory is related to cognitive decline and suggest that temporal contiguity may be used for studies of early detection.


Artemisinin: large community studies.
Prospective randomized trials with oral artemisinin derivatives have been conducted in over 1000 patients to determine the optimum treatment of multi-drug resistant falciparum malaria on the Thai-Burmese border. These drugs have proved valuable in 3 settings. (i) Primary treatment of uncomplicated malaria in combination with mefloquine, when they accelerate the rate of recovery, eliminate the risk of dangerous early failures, and if given for 3 d or more improve overall cure rates; (ii) treatment of recrudescent infections, which otherwise have a high failure rate; and (iii) oral treatment of patients with high parasitaemias (> or = 4%) but no clinical evidence of severity (a group who would usually receive parenteral quinine). The parenteral formulation of artemether is absorbed if given rectally, and this may offer a practical alternative method of treating severe malaria in rural areas.


Nanoscale stimulation of osteoblastogenesis from mesenchymal stem cells: nanotopography and nanokicking.
Mesenchymal stem cells (MSCs) have large regenerative potential to replace damaged cells from several tissues along the mesodermal lineage. The potency of these cells promises to change the longer term prognosis for many degenerative conditions currently suffered by our aging population. We have endeavored to demonstrate our ability to induce osteoblatogenesis in MSCs using high-frequency (1000-5000 Hz) piezo-driven nanodisplacements (16-30 nm displacements) in a vertical direction. Osteoblastogenesis has been determined by the upregulation of osteoblasic genes such as osteonectin (ONN), RUNX2 and Osterix, assessed via quantitative real-time PCR; the increase of osteocalcin (OCN) and osteopontin (OPN) at the protein level and the deposition of calcium phosphate determined by histological staining. Intriguingly, we have observed a relationship between nanotopography and piezo-stimulated mechanotransduction and possibly see evidence of two differing osteogenic mechanisms at work. These data provide confidence in nanomechanotransduction for stem cell differentiation without dependence on soluble factors and complex chemistries. In the future it is envisaged that this technology may have beneficial therapeutic applications in the healthcare industry, for conditions whose overall phenotype maybe characterized by weak or damaged bones (e.g., osteoporosis and bone fractures), and which can benefit from having an increased number of osteoblastic cells in vivo.


Systematic assessment of analytical methods for drug sensitivity prediction from cancer cell line data.
Large-scale pharmacogenomic screens of cancer cell lines have emerged as an attractive pre-clinical system for identifying tumor genetic subtypes with selective sensitivity to targeted therapeutic strategies. Application of modern machine learning approaches to pharmacogenomic datasets have demonstrated the ability to infer genomic predictors of compound sensitivity. Such modeling approaches entail many analytical design choices; however, a systematic study evaluating the relative performance attributable to each design choice is not yet available. In this work, we evaluated over 110,000 different models, based on a multifactorial experimental design testing systematic combinations of modeling factors within several categories of modeling choices, including: type of algorithm, type of molecular feature data, compound being predicted, method of summarizing compound sensitivity values, and whether predictions are based on discretized or continuous response values. Our results suggest that model input data (type of molecular features and choice of compound) are the primary factors explaining model performance, followed by choice of algorithm. Our results also provide a statistically principled set of recommended modeling guidelines, including: using elastic net or ridge regression with input features from all genomic profiling platforms, most importantly, gene expression features, to predict continuous-valued sensitivity scores summarized using the area under the dose response curve, with pathway targeted compounds most likely to yield the most accurate predictors. In addition, our study provides a publicly available resource of all modeling results, an open source code base, and experimental design for researchers throughout the community to build on our results and assess novel methodologies or applications in related predictive modeling problems.


MINE: Module Identification in Networks.
Graphical models of network associations are useful for both visualizing and integrating multiple types of association data. Identifying modules, or groups of functionally related gene products, is an important challenge in analyzing biological networks. However, existing tools to identify modules are insufficient when applied to dense networks of experimentally derived interaction data. To address this problem, we have developed an agglomerative clustering method that is able to identify highly modular sets of gene products within highly interconnected molecular interaction networks. MINE outperforms MCODE, CFinder, NEMO, SPICi, and MCL in identifying non-exclusive, high modularity clusters when applied to the C. elegans protein-protein interaction network. The algorithm generally achieves superior geometric accuracy and modularity for annotated functional categories. In comparison with the most closely related algorithm, MCODE, the top clusters identified by MINE are consistently of higher density and MINE is less likely to designate overlapping modules as a single unit. MINE offers a high level of granularity with a small number of adjustable parameters, enabling users to fine-tune cluster results for input networks with differing topological properties. MINE was created in response to the challenge of discovering high quality modules of gene products within highly interconnected biological networks. The algorithm allows a high degree of flexibility and user-customisation of results with few adjustable parameters. MINE outperforms several popular clustering algorithms in identifying modules with high modularity and obtains good overall recall and precision of functional annotations in protein-protein interaction networks from both S. cerevisiae and C. elegans.


Evaluation of Antibacterial Effect of Propolis and its Application in Mouthwash Production.
Our purpose was to determine the antibacterial properties of propolis and to evaluate its use as an antibacterial mouthwash with minimal complications. In this experimental laboratory study, an alcoholic propolis extract was prepared. The minimum inhibitory concentration (MIC) was calculated for four bacterial species including Staphylococcus aureus (S. aureus), Streptococcus mutans (S. mutans), Lactobacillus acidophilus (L. acidophilus), and Enterococcus faecalis (E. faecalis) using agar dilution. According to the MIC, a propolis antibacterial mouthwash was produced and compared to water, chlorhexidine (CHX), and Listerine using laboratory rats for clinical examination. Salivary specimens of rats were collected at 12 hours, 1 week, and 2 weeks after using the mouthwash and examined by real-time polymerase chain reaction (RT-PCR). Data were analyzed using one-way analysis of variance (ANOVA) and repeated measures ANOVA (α=0.05). The results of agar dilution by the number of colony-forming units showed the lowest MIC for S. aureus and the highest for L. acidophilus. Our RT-PCR findings indicated that water alone had no effect on the level of oral bacteria. Propolis mouthwash showed a significant difference with CHX and Listerine (P<0.05) in terms of the number of S. mutans, E. faecalis, and L. acidophilus colonies, while CHX and Listerine were less efficient. There was no significant difference between CHX and propolis (P=0.110) regarding S. aureus colonies, but Listerine had a lower efficacy than either (P<0.05). According to the results, propolis mouthwash was more efficient against the studied oral bacteria compared to CHX and Listerine.


Assessment of decisional capacity: Prevalence of medical illness and psychiatric comorbidities.
Studies on decisional capacity have primarily focused on cognitive disorders, whereas noncognitive disorders remain understudied. The purpose of our study was to assess decisional capacity across a wide spectrum of medical and psychiatric disorders. More than 2,500 consecutive consults were screened for decisional capacity, and 336 consults were reviewed at Bellevue Hospital Center in New York. Sociodemographic and medical variables, medical and psychiatric diagnoses, as well as decisional capacity assessments were recorded and analyzed. Consults for decisional capacity were most commonly called for in male patients with cognitive and substance abuse disorders. Less commonly, consults were called for patients with mood or psychotic disorders. Overall, about two thirds of patients (64.7%) were deemed not to have decisional capacity. Among medical diagnoses, neurological disorders contributed to decisional incapacity, and among the psychiatric diagnoses, cognitive disorders were most frequently documented in cases lacking decisional capacity (54.1%) and interfered more commonly with decisional capacity than substance abuse or psychotic disorders (37.2 and 25%). In contrast, patients with mood disorders usually retained their decisional capacity (32%). Generally, the primary treatment team's assessment was accurate and was confirmed by the psychiatric service. Although decisional capacity assessments were most commonly requested for patients with substance abuse and cognitive disorders, the latter generally affected the ability to make healthcare decisions the most. Further, cognitive disorders were much more likely to impair the ability to make appropriate healthcare decisions than substance abuse or psychotic disorders.


Estrogenic agonism and antagonism of the soy isoflavone genistein in uterus, bone and lymphopoiesis in mice.
The isoflavone genistein (Gen) is a naturally occurring phytoestrogen found in high concentrations in soy. The biological effects of Gen have been extensively studied. The immunomodulating properties of Gen are, however, less well investigated and the results are contradictory. Our aim was to study possible estrogen agonistic and antagonistic properties of Gen in uterus, bone, lymphopoiesis and B-cell function by comparing effects in castrated and intact female mice, respectively. Oophorectomized (OVX) and sham-operated mice were treated with s.c. doses of 17beta-estradiol (E2) (0.16 mg/kg), Gen (50 mg/kg), or vehicle (olive oil) as control. Effects on bone mineral density (BMD) were studied using peripheral quantitative computerized tomography, uterine and thymus weights were examined, lymphopoiesis in thymus and bone marrow was analyzed using flow cytometry, and the frequency of immunoglobulin-producing B cells in bone marrow and spleen was studied using an ELISPOT assay. Gen was clearly antagonizing endogenous estrogen in sham-operated female mice as shown by inhibiting the uterine weight and by increasing the frequency of B lymphopoietic cells in bone marrow. The only agonistic effect of Gen was shown by increased BMD in OVX mice. Our results are discussed in the context of estrogen receptor biology.


The impact of bisphenol A and triclosan on immune parameters in the U.S. population, NHANES 2003-2006.
Exposure to environmental toxicants is associated with numerous disease outcomes, many of which involve underlying immune and inflammatory dysfunction. To address the gap between environmental exposures and immune dysfunction, we investigated the association of two endocrine-disrupting compounds (EDCs) with markers of immune function. Using data from the 2003-2006 National Health and Nutrition Examination Survey, we compared urinary bisphenol A (BPA) and triclosan levels with serum cytomegalovirus (CMV) antibody levels and diagnosis of allergies or hay fever in U.S. adults and children ≥ 6 years of age. We used multivariate ordinary least squares linear regression models to examine the association of BPA and triclosan with CMV antibody titers, and multivariate logistic regression models to investigate the association of these chemicals with allergy or hay fever diagnosis. Statistical models were stratified by age (< 18 years and ≥ 18 years). In analyses adjusted for age, sex, race, body mass index, creatinine levels, family income, and educational attainment, in the ≥ 18-year age group, higher urinary BPA levels were associated with higher CMV antibody titers (p < 0.001). In the < 18-year age group, lower levels of BPA were associated with higher CMV antibody titers (p < 0.05). However, triclosan, but not BPA, showed a positive association with allergy or hay fever diagnosis. In the < 18-year age group, higher levels of triclosan were associated with greater odds of having been diagnosed with allergies or hay fever (p < 0.01). EDCs such as BPA and triclosan may negatively affect human immune function as measured by CMV antibody levels and allergy or hay fever diagnosis, respectively, with differential consequences based on age. Additional studies should be done to investigate these findings.


Short term fluctuations in air pollution and hospital admissions of the elderly for respiratory disease.
Several recent studies have reported associations between short term changes in air pollution and respiratory hospital admissions. This relationship was examined in two cities with substantially different levels of sulphur dioxide (SO2) but similar levels of airborne particles in an attempt to separate the effects of the two pollutants. Significant differences in weather between the two cities allowed the evaluation of that potential confounder also. Daily counts of admissions to all hospitals for respiratory disease (ICD 9 460-519) were constructed for persons aged 65 years and older in two cities - New Haven, Connecticut and Tacoma, Washington. Each city was analysed separately. Average daily concentrations of SO2, inhalable particles (PM10), and ozone were computed from all monitors in each city, and daily average temperature and humidity were obtained from the US weather service. Daily respiratory admission counts were regressed on temperature, humidity, day of the week indicators, and air pollution. A 19 day weighted moving regression filter was used to remove all seasonal and subseasonal patterns from the data. Possible U-shaped dependence of admissions on temperature was dealt with using indicator variables for eight categories each of temperature and humidity. Each pollutant was first examined individually and then multiple pollutant models were fitted. All three pollutants were associated with respiratory hospital admissions of the elderly. The PM10 associations were little changed by control for either ozone or SO2. The ozone association was likewise independent of the other pollutants. The SO2 association was substantially attenuated by control for ozone in both cities, and by control for PM10 in Tacoma. The magnitude of the effect was small (relative risk 1.06 in New Haven and 1.10 in Tacoma for a 50 micrograms/m3 increase in PM10, for example) but, given the ubiquitous exposure, this has some public health significance. Air pollution concentrations within current guidelines were associated with increased respiratory hospital admissions of the elderly. The strongest evidence for an independent association was for PM10, followed by ozone. These results are consistent with other studies and suggest that lowering air pollution concentrations would have some impact on public health.


Primary health care as a philosophical and practical framework for nursing education: rhetoric or reality?
At least three decades after primary health care (PHC) took nursing by storm it is time to re-examine the philosophical shift to a PHC framework in pre-registration nursing curricula and overview factors which may hinder or promote full integration of PHC as a course philosophy and a contemporary approach to professional practice. Whilst nurse education has traditionally focused on preparing graduates for practice in the acute care setting, there is continuing emphasis on preparing nurses for community based primary health roles, with a focus on illness prevention and health promotion. This is driven by growing evidence that health systems are not responding adequately to the needs and challenges of diverse populations, as well as economic imperatives to reduce the burden of disease associated with the growth of chronic and complex diseases and to reduce the costs associated with the provision of health care. Nursing pre-registration programs in Australia and internationally have philosophically adopted PHC as a curriculum model for preparing graduates with the necessary competencies to function effectively across a range of settings. Anecdotal evidence, however, suggests that when adopted as a program philosophy PHC is not always well integrated across the curriculum. In order to develop a strong and resilient contemporary nursing workforce prepared for practice in both acute and community settings, pre-registration nursing programs need to comprehensively consider and address the factors impacting on the curricula integration of PHC philosophy.


The morphometry of consecutive segments in cerebral arteries of normotensive and spontaneously hypertensive rats.
The media cross-sectional area, the media thickness, the internal radius and the ratio between media thickness and internal radius were determined in consecutive sections of extraparenchymal cerebral arteries of 7- and 12-month-old normotensive and spontaneously hypertensive rats. The study included intracranial pial and basal arteries as well as extracranial cervical arteries. In the chronically hypertensive rats the media to radius ratio was consistently higher than in normotensive rats over the entire calibre spectrum investigated (radius 5-400 micron). The increase of the ratio in the extracranial arteries of the hypertensive rats was exclusively due to a thicker media. In the basal intracranial arteries the increase of ratio was due to a thicker media and/or a smaller internal radius in 7- and 12-month-old rats with moderate hypertension (mean arterial pressure, MAP 171 +/- 8 and 177 +/- 7 mm Hg respectively). In 7-month-old rats with severe hypertension (MAP 204 +/- 11 mm Hg) the increase of ratio was mainly due to a smaller internal radius. The observed structural alterations are likely to be of hemodynamic importance.


Very large capacitance enhancement in a two-dimensional electron system.
Increases in the gate capacitance of field-effect transistor structures allow the production of lower-power devices that are compatible with higher clock rates, driving the race for developing high-κ dielectrics. However, many-body effects in an electronic system can also enhance capacitance. Onto the electron system that forms at the LaAlO(3)/SrTiO(3) interface, we fabricated top-gate electrodes that can fully deplete the interface of all mobile electrons. Near depletion, we found a greater than 40% enhancement of the gate capacitance. Using an electric-field penetration measurement method, we show that this capacitance originates from a negative compressibility of the interface electron system. Capacitance enhancement exists at room temperature and arises at low electron densities, in which disorder is strong and the in-plane conductance is much smaller than the quantum conductance.


Contributions of differential p53 expression in the spontaneous immortalization of a chicken embryo fibroblast cell line.
The present study was carried out to determine whether the p53 pathway played a role in the spontaneous immortalization of the SC-2 chicken embryo fibroblast (CEF) cell line that has been in continuous culture for over three years. The SC-2 cell line emerged from an extended crisis period with a considerably slower growth rate than primary CEF cells. The phenotype of the SC-2 cells changed dramatically at about passage 80, appearing smaller than at earlier passages (e.g., passage 43) and possessing a small, compact morphology. This morphological change coincided with an increase in growth rate. Passage 43 SC-2 cells expressed undetectable levels of p53 mRNA, but by passage 95, the levels were elevated compared to primary passage 6 CEF cells and similar to levels in senescent CEF cells. However, the high level of p53 mRNA detected in passage 95 SC-2 cells did not correlate to functional protein activity. The expression levels of the p53-regulated p21WAF1 gene were significantly decreased in all SC-2 passages that were analyzed. Examination of the Rb pathway revealed that E2F-1 and p15INK4b expression fluctuated with increasing passages, with levels higher in passage 95 SC-2 cells compared to primary passage 6 CEF cells. The present study suggests that altered expression of genes involved in the p53 and Rb pathways, specifically, p53 and p21WAF1, may have contributed to the immortalization of the SC-2 CEF cell line.


Effects of supplementation with a calcium-rich marine-derived multi-mineral supplement and short-chain fructo-oligosaccharides on serum lipids in postmenopausal women.
Recent literature suggests that Ca supplements have adverse effects on cardiovascular health. The effects of a Ca-rich supplement administered alone or in combination with short-chain fructo-oligosaccharides (scFOS) on serum lipids in postmenopausal women were examined using secondary data from a 24-month double-blind randomised controlled study. A total of 300 postmenopausal women were randomly assigned to daily supplements of 800 mg of Ca (2·4 g Aquamin) (Ca), 800 mg of Ca with 3 g of scFOS (CaFOS) or control (maltodextrin) (MD). A full lipid profile, body composition, blood pressure and a range of cytokines were measured at baseline and after 24 months. Intention-to-treat ANCOVA assessed treatment effects between the groups. A significant time-by-treatment effect was observed for LDL and total cholesterol for the Ca and CaFOS groups, with both groups having lower LDL and total cholesterol concentrations compared with MD after 24 months. The control group had mean (5·2 mmol/l) total cholesterol concentrations above the normal range (≤ 5 mmol/l) at 24 months, whereas values remained within the normal range in the treatment groups. There was no significant treatment effect on HDL-cholesterol, TAG, body composition, blood pressure or cytokine concentrations at 24 months, with the exception of IL-4, where there was a significant increase in the CaFOS group compared with the placebo. This study demonstrates a lipid-lowering effect of both the Ca-rich supplement alone and the supplement with scFOS. At the 4-year follow-up, there was no significant difference between the groups for reported diagnosed cardiovascular conditions.


The Anti-Inflammatory Effect of Algae-Derived Lipid Extracts on Lipopolysaccharide (LPS)-Stimulated Human THP-1 Macrophages.
Algae contain a number of anti-inflammatory bioactive compounds such as omega-3 polyunsaturated fatty acids (n-3 PUFA) and chlorophyll a, hence as dietary ingredients, their extracts may be effective in chronic inflammation-linked metabolic diseases such as cardiovascular disease. In this study, anti-inflammatory potential of lipid extracts from three red seaweeds (Porphyra dioica, Palmaria palmata and Chondrus crispus) and one microalga (Pavlova lutheri) were assessed in lipopolysaccharide (LPS)-stimulated human THP-1 macrophages. Extracts contained 34%-42% total fatty acids as n-3 PUFA and 5%-7% crude extract as pigments, including chlorophyll a, β-carotene and fucoxanthin. Pretreatment of the THP-1 cells with lipid extract from P. palmata inhibited production of the pro-inflammatory cytokines interleukin (IL)-6 (p < 0.05) and IL-8 (p < 0.05) while that of P. lutheri inhibited IL-6 (p < 0.01) production. Quantitative gene expression analysis of a panel of 92 genes linked to inflammatory signaling pathway revealed down-regulation of the expression of 14 pro-inflammatory genes (TLR1, TLR2, TLR4, TLR8, TRAF5, TRAF6, TNFSF18, IL6R, IL23, CCR1, CCR4, CCL17, STAT3, MAP3K1) by the lipid extracts. The lipid extracts effectively inhibited the LPS-induced pro-inflammatory signaling pathways mediated via toll-like receptors, chemokines and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling molecules. These results suggest that lipid extracts from P. lutheri, P. palmata, P. dioica and C. crispus can inhibit LPS-induced inflammatory pathways in human macrophages. Therefore, algal lipid extracts should be further explored as anti-inflammatory ingredients for chronic inflammation-linked metabolic diseases.


First experience with imaging core wires.
This study is the first assessment of feasibility and clinical usefulness of an imaging wire. The device used is a 0.018" flexible cable mounting a 30 MHz piezoelectric crystal at the end. The only possible application of the wire in its current configuration is the assessment of balloon expansion with over-the-wire balloon catheters. In this study, 17 lesions were examined in 14 patients. Despite careful removal of the air, no image could be obtained with the balloon deflated or through the shaft of conventional balloon catheters. When the balloon was inflated to 1-4 atm the circular echo-free cross-section of the balloon became visible, surrounded by the dense line of the balloon membrane and by the vessel wall. By examining the stent area at different balloon pressures, it was possible to determine the stent recoil between maximal balloon expansion and lowest balloon pressure allowing a readable ultrasound image. These encouraging preliminary observations confirm the feasibility of the use of an ultrasound guidewire for monitoring balloon expansion during stent implantation. After high pressure inflation, a moderate reduction of the stent lumen was observed during deflation, compatible with the small recoil predicted for the stainless-steel mesh stent used.


Model system to define pharmacokinetic requirements for antimalarial drug efficacy.
Malaria presents a tremendous public health burden, and new therapies are needed. Massive compound libraries screened against Plasmodium falciparum have yielded thousands of lead compounds, resulting in an acute need for rational criteria to select the best candidates for development. We reasoned that, akin to antibacterials, antimalarials might have an essential pharmacokinetic requirement for efficacy: action governed either by total exposure or peak concentration (AUC/CMAX), or by duration above a defined minimum concentration [time above minimum inhibitory concentration (TMIC)]. We devised an in vitro system for P. falciparum, capable of mimicking the dynamic fluctuations of a drug in vivo. Using this apparatus, we find that chloroquine is TMIC-dependent, whereas the efficacy of artemisinin is driven by CMAX. The latter was confirmed in a mouse model of malaria. These characteristics can explain the clinical success of two antimalarial drugs with widely different kinetics in humans. Chloroquine, which persists for weeks, is ideally suited for its TMIC mechanism, whereas great efficacy despite short exposure (t1/2 in blood 3 hours or less) is attained by CMAX-driven artemisinins. This validated preclinical model system can be used to select those antimalarial lead compounds whose CMAX or TMIC requirement for efficacy matches pharmacokinetics obtained in vivo. The apparatus can also be used to explore the kinetic dependence of other pharmacodynamic endpoints in parasites.


A collection of intrinsic disorder characterizations from eukaryotic proteomes.
Intrinsically disordered proteins and protein regions lack a stable three-dimensional structure under physiological conditions. Several proteomic investigations of intrinsic disorder have been performed to date and have found disorder to be prevalent in eukaryotic proteomes. Here we present descriptive statistics of intrinsic disorder features for ten model eukaryotic proteomes that have been calculated from computational disorder prediction algorithms. The data descriptor also provides consensus disorder annotations as well as additional physical parameters relevant to protein disorder, and further provides protein existence information for all proteins included in our analysis. The complete datasets can be downloaded freely, and it is envisaged that they will be updated periodically with new proteomes and protein disorder prediction algorithms. These datasets will be especially useful for assessing protein disorder, and conducting novel analyses that advance our understanding of intrinsic disorder and protein structure.


How coffee affects metabolic syndrome and its components.
Metabolic syndrome, with its increasing prevalence, is becoming a major public health problem throughout the world. Many risk factors including nutrition play a role in the emergence of metabolic syndrome. Of the most-consumed beverages in the world, coffee contains more than 1000 components such as caffeine, chlorogenic acid, diterpenes and trigonelline. It has been proven in many studies that coffee consumption has a positive effect on chronic diseases. In this review, starting from the beneficial effects of coffee on health, the relationship between coffee consumption and metabolic syndrome and its components has been investigated. There are few studies investigating the relationship between coffee and metabolic syndrome, and the existing ones put forward different findings. The factors leading to the differences are thought to stem from coffee variety, the physiological effects of coffee elements, and the nutritional ingredients (such as milk and sugar) added to coffee. It is reported that consumption of coffee in adults up to three cups a day reduces the risk of Type-2 diabetes and metabolic syndrome.


Combining meta-epidemiological study datasets on commercial funding of randomised clinical trials: Database, methods, and descriptive results of the COMFIT study.
Randomised trials are often funded by commercial companies and methodological studies support a widely held suspicion that commercial funding may influence trial results and conclusions. However, these studies often have a risk of confounding and reporting bias. The risk of confounding is markedly reduced in meta-epidemiological studies that compare fairly similar trials within meta-analyses, and risk of reporting bias is reduced with access to unpublished data. Therefore, we initiated the COMmercial Funding In Trials (COMFIT) study aimed at investigating the impact of commercial funding on estimated intervention effects in randomised clinical trials based on a consortium of researchers who agreed to share meta-epidemiological study datasets with information on meta-analyses and trials included in meta-epidemiological studies. Here, we describe the COMFIT study, its database, and descriptive results. We included meta-epidemiological studies with published or unpublished data on trial funding source and results or conclusions. We searched five bibliographic databases and other sources. We invited authors of eligible meta-epidemiological studies to join the COMFIT consortium and to share data. The final construction of the COMFIT database involves checking data quality, identifying trial references, harmonising variable categories, and removing non-informative meta-analyses as well as correlated meta-analyses and trial results. We included data from 17 meta-epidemiological studies, covering 728 meta-analyses and 6841 trials. Seven studies (405 meta-analyses, 3272 trials) had not published analyses on the impact of commercial funding, but shared unpublished data on funding source. On this basis, we initiated the construction of a combined database. Once completed, the database will enable comprehensive analyses of the impact of commercial funding on trial results and conclusions with increased statistical power and a markedly reduced risk of confounding and reporting bias.


Hierarchical unilamellar vesicles of controlled compositional heterogeneity.
Eukaryotic life contains hierarchical vesicular architectures (i.e. organelles) that are crucial for material production and trafficking, information storage and access, as well as energy production. In order to perform specific tasks, these compartments differ among each other in their membrane composition and their internal cargo and also differ from the cell membrane and the cytosol. Man-made structures that reproduce this nested architecture not only offer a deeper understanding of the functionalities and evolution of organelle-bearing eukaryotic life but also allow the engineering of novel biomimetic technologies. Here, we show the newly developed vesicle-in-water-in-oil emulsion transfer preparation technique to result in giant unilamellar vesicles internally compartmentalized by unilamellar vesicles of different membrane composition and internal cargo, i.e. hierarchical unilamellar vesicles of controlled compositional heterogeneity. The compartmentalized giant unilamellar vesicles were subsequently isolated by a separation step exploiting the heterogeneity of the membrane composition and the encapsulated cargo. Due to the controlled, efficient, and technically straightforward character of the new preparation technique, this study allows the hierarchical fabrication of compartmentalized giant unilamellar vesicles of controlled compositional heterogeneity and will ease the development of eukaryotic cell mimics that resemble their natural templates as well as the fabrication of novel multi-agent drug delivery systems for combination therapies and complex artificial microreactors.


Mucolipin co-deficiency causes accelerated endolysosomal vacuolation of enterocytes and failure-to-thrive from birth to weaning.
During the suckling period, intestinal enterocytes are richly endowed with endosomes and lysosomes, which they presumably utilize for the uptake and intracellular digestion of milk proteins. By weaning, mature intestinal enterocytes replace those rich in lysosomes. We found that mouse enterocytes before weaning express high levels of two endolysosomal cation channels, mucolipins 3 and 1 -products of Trpml3 and Trpml1 genes; moreover neonatal enterocytes of mice lacking both mucolipins (Trpml3-/-;Trpml1-/-) vacuolated pathologically within hours of birth and remained so until weaning. Ultrastructurally and chemically these fast-forming vacuoles resembled those that systemically appear in epithelial cells of mucolipidosis type IV (MLIV) patients, which bear mutations in Trpml1. Hence, lack of both mucolipins 1 and 3 causes an accelerated MLIV-type of vacuolation in enterocytes. The vacuoles were aberrant hybrid organelles with both endosomal and lysosomal components, and were not generated by alterations in endocytosis or exocytosis, but likely by an imbalance between fusion of lysosomes and endosomes and their subsequent scission. However, upon extensive vacuolation enterocytes displayed reduced endocytosis from the intestinal lumen, a defect expected to compromise nutrient uptake. Mice lacking both mucolipins suffered a growth delay that began after birth and continued through the suckling period but recovered after weaning, coinciding with the developmental period of enterocyte vacuolation. Our results demonstrate genetic redundancy between lysosomal mucolipins 3 and 1 in neonatal enterocytes. Furthermore, our Trpml3-/-;Trpml1-/- mice represent a polygenic animal model of the poorly-understood, and often intractable, neonatal failure-to-thrive with intestinal pathology. Our results implicate lysosomes in neonatal intestinal pathologies, a major cause of infant mortality worldwide, and suggest transient intestinal dysfunction might affect newborns with lysosomal storage disorders. Finally, we conclude that mucolipin-endowed lysosomes in the young play an evolutionarily-conserved role in the intracellular digestion of maternally-provided nutrients, whether milk in mammals or yolk in oviparous species.


Emerging investigator series: mercury mobility and methylmercury formation in a contaminated agricultural flood plain: influence of flooding and manure addition.
The fate and the methylation of mercury (Hg) in the terrestrial environment are still poorly understood and although the main drivers of release and methylation of mercury in soils are known (low redox potential and microbial carbon availability) their interactions are not well understood. This is of concern since many agriculturally used floodplains, where the recurring flooding and agricultural practices (e.g. manure amendments) may have an impact on the fate and the biomethylation of Hg, are at the same time Hg-contaminated. In this study, we modified and validated existing methods to extract and analyze methylmercury (MeHg) by HPLC-ICP-MS in soils and we assessed the Hg and MeHg concentrations in three fields situated in a Hg polluted agricultural floodplain. Further, we incubated the top soil from the three studied fields for 11 days under flooded conditions in presence or absence of 2 mass% of cow manure, a common agricultural amendment in the area. Total Hg and MeHg concentrations ranged from <limit of detection (LOD, 0.012 mg kg-1) to 28.2 mg kg-1 and from 1.2 to 7.8 μg kg-1 respectively. Hg was released to the soil solution after 12 hours with a maximum between day 2 and day 7. MeHg levels in the soil solution were <LOD although it was found in the soil before and after the incubation. The addition of cow manure to saturated soils led to an increase in the MeHg concentrations of the soil solid phase by up to fivefold to a maximum of 26.4 ± 1.1 μg kg-1 (n = 3). Our study demonstrates that the combination of low redox potential because of flooding with common agricultural practices such as the amendment of manures enhances the formation of toxic MeHg.


Accumulation of Amyloid Beta (Aβ) Peptide on Blood Vessel Walls in the Damaged Brain after Transient Middle Cerebral Artery Occlusion.
It is well known that amyloid beta (Aβ) peptides are generated in blood vessels, released into the brain during thrombosis, and temporarily accumulate in this organ after injury. Here we demonstrate that 24 h after transient middle cerebral artery occlusion (tMCAO), one of the standard models of focal ischemic stroke, Aβ peptide accumulates in the brain, concentrating on the blood vessel walls. Because Aβ oligomers are known to induce significant damage to brain cells, they act as an additional damaging factor during ischemic stroke. Considering that they have been shown to form ion channels in cells, affecting osmotic balance, we used an Aβ peptide channel blocker, tromethamine (2-amino-2-(hydroxymethyl) propane-1,3-diol), to prevent this additional injury. Tromethamine injected 0.1 g/100 g body weight intraperitoneally at 5 min before tMCAO decreased water content in the damaged hemisphere, as measured by dry brain weight. Congo red staining, which binds only to Aβ oligomer plaques (amyloid), showed that there was no significant presence of plaques. Therefore, we suggest that Aβ peptide oligomers are responsible for some of the brain damage during stroke and that blockage of the ion channels that they form could be beneficial in treating this complex neurological syndrome.


Endogenous versus exogenous lithium clearance for evaluation of dopamine-induced changes in renal tubular function.
1. The present randomized, double-blind cross-over study compared endogenous and exogenous lithium clearance (CLi) for estimation of the effect of dopamine on tubular sodium reabsorption. Twelve normal, salt-repleted male subjects were investigated on three different occasions with either placebo or 450 mg or 600 mg of lithium given in random order at 22.00 hours. After an overnight fast, renal clearance studies were performed during a 1 h baseline period and subsequently during the second hour of an infusion of 3 micrograms min-1 kg-1 of dopamine. 2. Baseline values of endogenous CLi and fractional excretion of lithium (FELi) [27.0 (23.5-30.5) ml/min and 24.2 (20.3-28.2)% (means with 95% confidence interval)] were lower than exogenous values [lithium, 450 mg: 32.7 (29.9-35.4) ml/min (P < 0.05) and 27.4 (25.2-29.6)% (P < 0.05); lithium, 600 mg: 33.4 (29.2-37.6)ml/min (P < 0.05) and 28.6 (26.3-31.0)% (P < 0.01)]. Both test doses of lithium increased the baseline sodium clearance (CNa), but glomerular filtration rate and urine flow rate remained unchanged. 3. Dopamine increased CNa to similar values on the three study days. CLi increased to 40.9 (35.5-46.5) ml/min (endogenous lithium, P < 0.001), 43.2 (40.8-45.6) ml/min (450 mg of lithium, P < 0.01) and 44.9 (41.3-48.4) ml/min (600 mg of lithium, P < 0.001), respectively. FELi increased to 32.2 (27.5-37.0)% (P < 0.01), 35.4 (33.0-37.7)% (P < 0.01) and 35.9 (32.8-38.9)% (P < 0.01), respectively. Values during dopamine infusion did not differ significantly. 4. The lower baseline values of endogenous CLi and FELi compared with exogenous values suggest that CLi in humans depends on the plasma concentrations of lithium. However, the effect of dopamine on CLi and FELi was expressed to the same extent with endogenous and exogenous lithium, indicating that the two methods are interchangeable for estimation of dopamine-induced changes in tubular function.


Protection and reversal of hepatic fibrosis by red wine polyphenols in hyperhomocysteinemic mice.
Hyperhomocysteinemia leads to several clinical manifestations and, particularly, liver disease. Lowering homocysteine through nutrition or other means might offer preventive or therapeutic benefits. Polyphenols are natural compounds known for their antioxidant and healing properties for vessels. In a previous study we have shown a beneficial effect of a red wine polyphenolic extract (PE) administration on plasma homocysteine level in cystathionine beta synthase deficient mice, a murine model of hyperhomocysteinemia. These mice also develop hepatic fibrosis. As increased matrix metalloproteinase (MMP) 2 has been shown to be involved in the development of hepatic fibrosis, we then focused on the effect of PE administration on expression and activity of MMP-2 in liver of hyperhomocysteinemic mice and its impact on hepatic fibrosis development. PE was added for four weeks to the drinking water of heterozygous cystathionine beta synthase-deficient mice fed a high-methionine diet. Effects of PE administration were examined by histological analysis with Sirius red staining, zymography, immunobloting, real-time quantitative reverse transcriptase polymerase chain reaction, peroxynitrite level, catalase activity and nicotinamide adenine dinucleotide phosphate oxidase activity. We show that administration of PE had a beneficial effect (i) on MMP-2 expression via modulation of nitrotyrosine-modified total protein level and (ii) on MMP-2 activity via modulation of its activator/inhibitor balance. We also demonstrated a reversal effect of PE supplementation on hepatic fibrosis development. Our results demonstrate a preventive action of PE administration on biomarkers of hepatic dysfunction due to hyperhomocysteinemia.


Influence of bone marrow-derived hematopoietic cells on the tumor response to radiotherapy: experimental models and clinical perspectives.
In this review, we highlight some of recent studies underscoring the importance of the tumor microenvironment, especially the role of bone marrow-derived myeloid cells, in restoring tumor growth after irradiation. Myeloid cells are hematopoietic cells that give rise to monocytes and macrophages in the peripheral blood and tissues. These cells have been shown to be proangiogenic in tumors promoting tumor growth. We also discuss our previously unpublished results on the effect of irradiation on the tumor vasculature including pericyte and basement membrane coverage to the endothelium of tumor blood vessels. We summarize the clinical significance of these studies including the use of MMP-9 inhibitors, administering white blood cell boosters, or planning safety margin of tumor volumes, in order to improve overall clinical benefits in cancer patients treated with radiotherapy.


Mycotoxins in pet food: a review on worldwide prevalence and preventative strategies.
Mycotoxins contaminate cereal grains worldwide, and their presence in pet food has been a potential health threat to companion animals. Aflatoxins, ochratoxin A, and Fusarium mycotoxins have been found in both raw ingredients and final products of pet food around the globe. Aflatoxin, a hepatotoxin and carcinogen, has caused several food poisoning outbreaks in dogs, and aflatoxin content is regulated in pet food in many countries. Ochratoxin A and Fusarium mycotoxins including trichothecenes, zearalenone, and fumonisins may have chronic effects on the health of companion animals. Grain processing, sampling error, analytical methods, conjugated mycotoxins, storage conditions, and synergistic interactions are common challenges faced by the pet food industry. Food-processing techniques such as sieving, washing, pearling, ozonation, and acid-based mold inhibition reduce the mycotoxin content of cereal grains. Dietary supplementation with large neutral amino acids, antioxidants, and omega-3 polysaturated fatty acids as well as inclusion of mycotoxin-sequestering agents and detoxifying microbes may ameliorate the harmful effects of mycotoxins in contaminated pet food.


Purification and properties of L-3-glycerophosphate dehydrogenase from pig brain mitochondria.
L-3-Glycerophosphate dehydrogenase (EC 220.127.116.11) was purified from pig brain mitochondria by extraction with deoxycholate, ion-exchange chromatography and (NH4)2SO4 fractionation in cholate, and preparative isoelectric focusing in Triton X-100. Sodium dodecyl sulphate/polyacrylamide gel electrophoresis shows that the purified enzyme consists of a single subunit of mol.wt. 75 000. The enzyme contains non-covalently bound FAD and low concentrations of iron and acid labile sulphide. No substrate reducible e.p.r. signals were detected. The conditions of purification, particularly the isoelectric focusing step, lead to considerable loss of FAD and possibly iron-sulphur centres. It is therefore not possible to decide with certainty whether the enzyme is a flavoprotein or a ferroflavoprotein. The enzyme catalyses the oxidation of L-3-glycerophosphate by a variety of electron acceptors, including ubiquinone analogues. A number if compounds known to inhibit ubiquinone oxidoreduction by other enzymes of the respiratory chain failed to inhibit L-3-glycerophosphate dehydrogenase, except at very high concentrations.


Pharmacological targeting of α3β4 nicotinic receptors improves peripheral insulin sensitivity in mice with diet-induced obesity.
Treatment with the α3β4 nicotinic acetylcholine receptor (nAChR) agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), improves glucose tolerance in diet-induced obese (DIO) mice, but the physiological and molecular mechanisms are unknown. DMPP (10 mg/kg body weight, s.c.) was administered either in a single injection (acute) or daily for up to 14 days (chronic) in DIO wild-type (WT) and Chrnb4 knockout (KO) mice and glucose tolerance, tissue-specific tracer-based glucose metabolism, and insulin signalling were assessed. In WT mice, but not in Chrnb4 KO mice, single acute treatment with DMPP induced transient hyperglycaemia, which was accompanied by high plasma adrenaline (epinephrine) levels, upregulated hepatic gluconeogenic genes, and decreased hepatic glycogen content. In contrast to these acute effects, chronic DMPP treatment in WT mice elicited improvements in glucose tolerance already evident after three consecutive days of DMPP treatment. After seven days of DMPP treatment, glucose tolerance was markedly improved, also in comparison with mice that were pair-fed to DMPP-treated mice. The glycaemic benefit of chronic DMPP was absent in Chrnb4 KO mice. Chronic DMPP increased insulin-stimulated glucose clearance into brown adipose tissue (+69%), heart (+93%), gastrocnemius muscle (+74%) and quadriceps muscle (+59%), with no effect in white adipose tissues. After chronic DMPP treatment, plasma adrenaline levels did not increase following an injection with DMPP. In glucose-stimulated skeletal muscle, we detected a decreased phosphorylation of the inhibitory Ser640 phosphorylation site on glycogen synthase and a congruent increase in glycogen accumulation following chronic DMPP treatment. Our data suggest that DMPP acutely induces adrenaline release and hepatic glycogenolysis, while chronic DMPP-mediated activation of β4-containing nAChRs improves peripheral insulin sensitivity independently of changes in body weight via mechanisms that could involve increased non-oxidative glucose disposal into skeletal muscle.


Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families.
Type 1 diabetes is a common, multifactorial disease with strong familial clustering (genetic risk ratio [lambda(S)] approximately 15). Approximately 40% of the familial aggregation of type 1 diabetes can be attributed to allelic variation of HLA loci in the major histocompatibility complex on chromosome 6p21 (locus-specific lambda(S) approximately 3). Three other disease susceptibility loci have been clearly demonstrated based on their direct effect on risk, INS (chromosome 11p15, allelic odds ratio [OR] approximately 1.9), CTLA4 (chromosome 2q33, allelic OR approximately 1.2), and PTPN22 (chromosome 1p13, allelic OR approximately 1.7). However, a large proportion of type 1 diabetes clustering remains unexplained. We report here on a combined linkage analysis of four datasets, three previously published genome scans, and one new genome scan of 254 families, which were consolidated through an international consortium for type 1 diabetes genetic studies (www.t1dgc.org) and provided a total sample of 1,435 families with 1,636 affected sibpairs. In addition to the HLA region (nominal P = 2.0 x 10(-52)), nine non-HLA-linked regions showed some evidence of linkage to type 1 diabetes (nominal P < 0.01), including three at (or near) genome-wide significance (P < 0.05): 2q31-q33, 10p14-q11, and 16q22-q24. In addition, after taking into account the linkage at the 6p21 (HLA) region, there was evidence supporting linkage for the 6q21 region (empiric P < 10(-4)). More than 80% of the genome could be excluded as harboring type 1 diabetes susceptibility genes of modest effect (lambda(S) > or = 1.3) that could be detected by linkage. This study represents one of the largest linkage studies ever performed for any common disease. The results demonstrate some consistency emerging for the existence of susceptibility loci on chromosomes 2q31-q33, 6q21, 10p14-q11, and 16q22-q24 but diminished support for some previously reported locations.


Extracting 3D Parametric Curves from 2D Images of Helical Objects.
Helical objects occur in medicine, biology, cosmetics, nanotechnology, and engineering. Extracting a 3D parametric curve from a 2D image of a helical object has many practical applications, in particular being able to extract metrics such as tortuosity, frequency, and pitch. We present a method that is able to straighten the image object and derive a robust 3D helical curve from peaks in the object boundary. The algorithm has a small number of stable parameters that require little tuning, and the curve is validated against both synthetic and real-world data. The results show that the extracted 3D curve comes within close Hausdorff distance to the ground truth, and has near identical tortuosity for helical objects with a circular profile. Parameter insensitivity and robustness against high levels of image noise are demonstrated thoroughly and quantitatively.


Utilization of combined remote sensing techniques to detect environmental variables influencing malaria vector densities in rural West Africa.
The use of remote sensing has found its way into the field of epidemiology within the last decades. With the increased sensor resolution of recent and future satellites new possibilities emerge for high resolution risk modeling and risk mapping. A SPOT 5 satellite image, taken during the rainy season 2009 was used for calculating indices by combining the image's spectral bands. Besides the widely used Normalized Difference Vegetation Index (NDVI) other indices were tested for significant correlation against field observations. Multiple steps, including the detection of surface water, its breeding appropriateness for Anopheles and modeling of vector imagines abundance, were performed. Data collection on larvae, adult vectors and geographic parameters in the field, was amended by using remote sensing techniques to gather data on altitude (Digital Elevation Model = DEM), precipitation (Tropical Rainfall Measurement Mission = TRMM), land surface temperatures (LST). The DEM derived altitude as well as indices calculations combining the satellite's spectral bands (NDTI = Normalized Difference Turbidity Index, NDWI Mac Feeters = Normalized Difference Water Index) turned out to be reliable indicators for surface water in the local geographic setting. While Anopheles larvae abundance in habitats is driven by multiple, interconnected factors - amongst which the NDVI - and precipitation events, the presence of vector imagines was found to be correlated negatively to remotely sensed LST and positively to the cumulated amount of rainfall in the preceding 15 days and to the Normalized Difference Pond Index (NDPI) within the 500 m buffer zone around capture points. Remotely sensed geographical and meteorological factors, including precipitations, temperature, as well as vegetation, humidity and land cover indicators could be used as explanatory variables for surface water presence, larval development and imagines densities. This modeling approach based on remotely sensed information is potentially useful for counter measures that are putting on at the environmental side, namely vector larvae control via larviciding and water body reforming.


A strategy for regulatory action when new adverse effects of a licensed product emerge.
Regulatory agencies grant product licences (marketing authorizations) for medicinal products in the light of evidence that the balance between benefit and harm in the population is favourable. Here we consider a framework for allowing regulatory agencies to make rational decisions when reviewing product licences in the light of new information about harms that change that balance. The regulator can revoke the product licence, restrict the product's availability or change the 'label' in different ways. We examine the features of the adverse effect that may be relevant in making the decision: namely, individual differences in susceptibility; the possibility of monitoring; and the availability of protective strategies. The balance of benefit and harm, and the time-course and dose relation of the adverse effect play important roles in the decision-making process. We set out how these factors can help determine the logical response to new information on the balance between benefit and harm, and provide a series of relevant examples. We believe that when regulatory agencies have to decide how to amend the product licence of a drug when new serious adverse effects cause concern, they would find it useful to adopt a framework of this kind, using different strategies for different cases. Our proposed framework could also be useful in risk management planning during drug development.


Wastewater treatment models in teaching and training: the mismatch between education and requirements for jobs.
As mathematical modeling of wastewater treatment plants has become more common in research and consultancy, a mismatch between education and requirements for model-related jobs has developed. There seems to be a shortage of skilled people, both in terms of quantity and in quality. In order to address this problem, this paper provides a framework to outline different types of model-related jobs, assess the required skills for these jobs and characterize different types of education that modelers obtain "in school" as well as "on the job". It is important to consider that education of modelers does not mainly happen in university courses and that the variety of model related jobs goes far beyond use for process design by consulting companies. To resolve the mismatch, the current connection between requirements for different jobs and the various types of education has to be assessed for different geographical regions and professional environments. This allows the evaluation and improvement of important educational paths, considering quality assurance and future developments. Moreover, conclusions from a workshop involving practitioners and academics from North America and Europe are presented. The participants stressed the importance of non-technical skills and recommended strengthening the role of realistic modeling experience in university training. However, this paper suggests that all providers of modeling education and support, not only universities, but also software suppliers, professional associations and companies performing modeling tasks are called to assess and strengthen their role in training and support of professional modelers.


Position of the American Dietetic Association and Dietitians of Canada: Vegetarian diets.
It is the position of the American Dietetic Association and Dietitians of Canada that appropriately planned vegetarian diets are healthful, nutritionally adequate, and provide health benefits in the prevention and treatment of certain diseases. Approximately 2.5% of adults in the United States and 4% of adults in Canada follow vegetarian diets. A vegetarian diet is defined as one that does not include meat, fish, or fowl. Interest in vegetarianism appears to be increasing, with many restaurants and college foodservices offering vegetarian meals routinely. Substantial growth in sales of foods attractive to vegetarians has occurred, and these foods appear in many supermarkets. This position paper reviews the current scientific data related to key nutrients for vegetarians, including protein, iron, zinc, calcium, vitamin D, riboflavin, vitamin B-12, vitamin A, n-3 fatty acids, and iodine. A vegetarian, including vegan, diet can meet current recommendations for all of these nutrients. In some cases, use of fortified foods or supplements can be helpful in meeting recommendations for individual nutrients. Well-planned vegan and other types of vegetarian diets are appropriate for all stages of the life cycle, including during pregnancy, lactation, infancy, childhood, and adolescence. Vegetarian diets offer a number of nutritional benefits, including lower levels of saturated fat, cholesterol, and animal protein as well as higher levels of carbohydrates, fiber, magnesium, potassium, folate, and antioxidants such as vitamins C and E and phytochemicals. Vegetarians have been reported to have lower body mass indices than nonvegetarians, as well as lower rates of death from ischemic heart disease; vegetarians also show lower blood cholesterol levels; lower blood pressure; and lower rates of hypertension, type 2 diabetes, and prostate and colon cancer. Although a number of federally funded and institutional feeding programs can accommodate vegetarians, few have foods suitable for vegans at this time. Because of the variability of dietary practices among vegetarians, individual assessment of dietary intakes of vegetarians is required. Dietetics professionals have a responsibility to support and encourage those who express an interest in consuming a vegetarian diet. They can play key roles in educating vegetarian clients about food sources of specific nutrients, food purchase and preparation, and any dietary modifications that may be necessary to meet individual needs. Menu planning for vegetarians can be simplified by use of a food guide that specifies food groups and serving sizes.


C-reactive protein and neutrophil count laboratory test requests from primary care: what is the demand and would substitution by point-of-care technology be viable?
AIMS : C-reactive protein (CRP) and neutrophil count (NC) are important diagnostic indicators of inflammation. Point-of-care (POC) technologies for these markers are available but rarely used in community settings in the UK. To inform the potential for POC tests, it is necessary to understand the demand for testing. We aimed to describe the frequency of CRP and NC test requests from primary care to central laboratory services, describe variability between practices and assess the relationship between the tests. We described the number of patients with either or both laboratory tests, and the volume of testing per individual and per practice, in a retrospective cohort of all adults in general practices in Oxfordshire, 2014-2016. 372 017 CRP and 776 581 NC tests in 160 883 and 275 093 patients, respectively, were requested from 69 practices. CRP was tested mainly in combination with NC, while the latter was more often tested alone. The median (IQR) of CRP and NC tests/person tested was 1 (1-2) and 2 (1-3), respectively. The median (IQR) tests/practice/week was 36 (22-52) and 72 (50-108), and per 1000 persons registered/practice/week was 4 (3-5) and 8 (7-9), respectively. The median (IQR) CRP and NC concentrations were 2.7 (0.9-7.9) mg/dL and 4.1 (3.1-5.5)×109/L, respectively. The high demand for CRP and NC testing in the community, and the range of results falling within the reportable range for current POC technologies highlight the opportunity for laboratory testing to be supplemented by POC testing in general practice.