The unusually poor physical health status of Cambodian refugees two decades after resettlement.
To better document the health status of Cambodian refugees, the physical health functioning, disability, and general health status of Cambodian refugees was compared to that of non-refugee Asian immigrants with similar demographic characteristics. Data were collected between October 2003 and February 2005, from 490 face-to-face interviews conducted with a stratified probability sample of households from the Cambodian community in Long Beach, California. Data on the health status of the general adult population (n = 56,270) was taken from the California Health Interview Survey, a telephone interview of a representative sample California residents. Cambodian refugees reported exceedingly poor health when compared to both the general population to the Asian participants. This disparity was only slightly reduced when Cambodian refugees were compared to the subsample of Asian immigrants who were matched on gender, age, income, and urbanicity. Although Cambodians refugees are older and poorer than the general population, their poor health cannot be fully attributed to these risk factors. Research is needed to guide health policy and practices aimed at eliminating this health disparity.


The mortality in Gaza in July-September 2014: a retrospective chart-review study.
The majority of Gazans who were killed or injured in the 2014 Israel-Gaza war were civilians, and one-fourth of the population were internally displaced. As the Gaza Strip is a small territory, the whole population was exposed to the war and its effects on the health care system, supplies and infrastructure. Our aim was to assess the overall, sex and age-group mortality in Gaza for the period July-September 2014 that was not caused by war injuries, and the proportion of non-trauma deaths among adults that occurred outside hospital wards. A comparison was made with the mortality for the same period in 2013. Date, sex, age, cause and place of each death that was not attributed to war-related physical trauma were collected from death notification forms or death records in Gaza hospitals for the period 01 July to 30 September 2014. The same information was extracted from the local death register for all deaths in the same period in 2013. The mean age at death was 52.4 years in 2014 and 49.7 in 2013, and about 50 % were older than 60 years in both years. The crude non-trauma death rates among adults were 11.6 per 10,000 population in 2014 and 11.3 in 2013, and the age standardised 13.2 and 12.4, respectively. Higher death rates in 2014 were observed among elderly and women. Cardiovascular disease was the most common cause of death among adults of both sexes, and infectious diseases caused less than 10 % in both periods. Three maternal deaths were observed in 2013 and six in 2014 (p = 0.17). The proportion of deaths that occurred in a hospital ward was 71.5 % in 2013 and 51.2 % in 2014. The mortality from communicable diseases was low in Gaza. We did not detect a higher overall background mortality in the 2014 period compared to 2013, but the observed age and sex distribution differed. The proportion of non-trauma deaths among adults that occurred in a hospital ward was markedly lower during the war. The living conditions and health care situation in Gaza point to the need for close monitoring of mortality.


Savant: genome browser for high-throughput sequencing data.
The advent of high-throughput sequencing (HTS) technologies has made it affordable to sequence many individuals' genomes. Simultaneously the computational analysis of the large volumes of data generated by the new sequencing machines remains a challenge. While a plethora of tools are available to map the resulting reads to a reference genome, and to conduct primary analysis of the mappings, it is often necessary to visually examine the results and underlying data to confirm predictions and understand the functional effects, especially in the context of other datasets. We introduce Savant, the Sequence Annotation, Visualization and ANalysis Tool, a desktop visualization and analysis browser for genomic data. Savant was developed for visualizing and analyzing HTS data, with special care taken to enable dynamic visualization in the presence of gigabases of genomic reads and references the size of the human genome. Savant supports the visualization of genome-based sequence, point, interval and continuous datasets, and multiple visualization modes that enable easy identification of genomic variants (including single nucleotide polymorphisms, structural and copy number variants), and functional genomic information (e.g. peaks in ChIP-seq data) in the context of genomic annotations. Savant is freely available at http://compbio.cs.toronto.edu/savant.


Vitamin E supplementation decreases muscular and oxidative damage but not inflammatory response induced by eccentric contraction.
The purpose of this study was to investigate the effects of vitamin E supplementation on muscular and oxidative damage, as well as the inflammatory response induced by eccentric exercise (EE) in humans. Twenty-one participants with a mean age of 22.5 +/- 4 years, weight of 68.2 +/- 4.9 kg, and height of 173 +/- 4.3 cm were selected and divided randomly into two groups: supplemented (S) (n = 11) and placebo (P) (n = 10). Fourteen days after starting supplementation, subjects performed EE (three sets until exhaustion with elbow flexion and extension on the Scott bench, 80% 1 RM). Blood samples were collected on days 0, 2, 4, and 7 after EE. Muscle soreness (MS), lactate dehydrogenase (LDH) activity, lipid peroxidation, protein carbonylation, tumor necrosis factor-alpha (TNF-alpha), and interleukin 10 (IL-10) levels were determined. We measured a significant increase in MS, LDH, lipid peroxidation, and carbonylation in both groups on days 2, 4, and 7 after eccentric contractions (EC). Values of the supplement group were lower than those of the placebo group at 4 and 7 days after EC in all parameters. Both groups showed significantly increased TNF-alpha on the second day and IL-10 concentration on the fourth and seventh days after EE. The results suggest that vitamin E supplementation represents an important factor in the defense against oxidative stress and muscle damage but not against the inflammatory response in humans.


Presence of eubacteria in biopsies from Crohn's disease inflammatory lesions as determined by 16S rRNA gene-based PCR.
The aim of this study was to search for putative microbial agents in Crohn's disease (CD) tissues by bacterial broad-range 16S rDNA PCR combined with genus- and species-specific DNA hybridisation analysis. Biopsies taken both surgically and endoscopically from the terminal ileum of 11 CD patients and 11 control patients were investigated. Significant amounts of eubacteria were demonstrated in biopsies taken endoscopically from both affected and unaffected individuals; the biopsies taken at surgery from control patients were negative. Three of five biopsies taken surgically from CD patients harboured Helicobacter spp.-, Mycobacterium paratuberculosis-, Listeria monocytogenes- and Escherichia coli-like 16S rDNA sequences. These findings show the importance of the sampling method chosen when combined with molecular typing of eubacteria in intestinal tissues. The mixed bacterial flora found in the surgical biopsies from CD patients supports the idea that the enteric microflora enters primary lesions where secondary bacterial colonisers may elicit a chronic inflammatory syndrome.


The association for surgical education CESERT grant program: the first 15 years.
The Association for Surgical Education established the Center for Excellence in Surgical Education Research and Training (CESERT) program in 1999 to support innovative research and education projects and programs that will advance surgical education. We sought to examine scholarly outcomes of the projects during the first 15 years of the program. E-mail surveys were sent to the 24 researchers who were awarded CESERT grants. Data collection focused on recipient professional experiences, publications, and presentations stemming from CESERT-funded research and impact on career development. For grant recipients who were unable to complete the survey, we obtained publication information on studies authored by the grant recipients that described the same grant-funded topic, described similar methods, and fell within the study timeline. Complete survey data were obtained from 18 of the 24 grant recipients. Grants were most commonly awarded to General Surgeons (40%) and Education and Psychology PhDs (24%). Overall, 23 of the 25 projects had reached completion at the time of contact, and from these, 70 articles were published or in press. Abstract presentations were more common, with respondents documenting 84 projects locally, nationally, and internationally. Grant awards ranged from $8,122 to $97,000, with an average of $39,026. In total, the Association for Surgical Education Foundation distributed $988,000 in grant funding from 1999 to 2013. Respondents reported that CESERT funding was critical to their career as it legitimized their pursuit of educational research, helped them establish multidisciplinary and multi-institutional collaborations, provided greater visibility for their research, and helped them develop an understanding of educational principles and grant writing skills. Overall, the CESERT program has produced remarkable results. The careful review process and monitoring protocol have ensured that high-potential studies are funded and successful. These data support continued efforts to garner resources such that CESERT grants may be awarded to fund high-quality, high-impact projects.


The differentiation code.
In code biology we seek a presumably arbitrary, and thus symbolic relationship between two or more entities, such as the relationship of the DNA triplet code to amino acids. Here we review the differentiation code from the code biology point of view. We observe that lineage trees of mosaic organisms can be subsumed as special cases of differentiation trees of regulating embryos. The latter can be empirically discovered as a bifurcating tree of contraction and expansion differentiation waves that recursively divide the embryo into its cell types. A binary digit, 0 or 1, assigned to each wave results in a binary number corresponding to each cell type, and may be called the differentiation code for that cell type. The differentiation tree has a correspondence in the genome, in terms of the genome's logical structure. For a given cell type, the path to it from the zygote is marked epigenetically on the genome. Thus the differentiation code symbolically maps an epigenetically marked subset of the logical structure of the genome to the phenotype of a particular cell type. The waves involved and signal transduction from the cell state splitter to the genome are intermediaries in this relationship, and may also be arbitrary choices, and thus part of the code. In full, differentiation code ⇔ history along the differentiation tree of the differentiation wave types leading to a given cell type ⇔ contraction or expansion of the cell's cell state splitter ⇔ activation of one of two signal transduction pathways from the cell state splitter to the nucleus ⇔ activation of one of two readied gene cascades (the "nuclear state splitter") ⇔ epigenetic marking of the selected portion of the logical path. Each wave is in effect a cybernetic control system that results in differentiation of a set of cells and initiation of two new waves (cybernetic systems) as its goals. The differentiation code forms a basis for open evolution and its appearance was one of the major evolutionary transitions.


Non-accidental health impacts of wildfire smoke.
Wildfires take a heavy toll on human health worldwide. Climate change may increase the risk of wildfire frequency. Therefore, in view of adapted preventive actions, there is an urgent need to further understand the health effects and public awareness of wildfires. We conducted a systematic review of non-accidental health impacts of wildfire and incorporated lessons learned from recent experiences. Based on the literature, various studies have established the relationship between one of the major components of wildfire, particulate matter (particles with diameter less than 10 µm (PM10) and less than 2.5 µm (PM2.5)) and cardiorespiratory symptoms in terms of Emergency Rooms visits and hospital admissions. Associations between wildfire emissions and various subclinical effects have also been established. However, few relationships between wildfire emissions and mortality have been observed. Certain segments of the population may be particularly vulnerable to smoke-related health risks. Among them, people with pre-existing cardiopulmonary conditions, the elderly, smokers and, for professional reasons, firefighters. Potential action mechanisms have been highlighted. Overall, more research is needed to better understand health impact of wildfire exposure.


Moxifloxacin-Gelrite in situ ophthalmic gelling system against photodynamic therapy for treatment of bacterial corneal inflammation.
In this study, six in situ gelling formulations based on Gelrite were prepared and evaluated for the retained ophthalmic delivery of Moxifloxacin (Mox). The effectiveness of the best developed formula G5 was compared with photodynamic therapy (PDT), the recent expanding approach for the treatment of ophthalmologic disorders after the assessment of optimum photodynamic inactivation parameters that permit efficient pathogens eradication. It was found that, Staphylococcus aureus (S. aureus) (Gram-positive) was more susceptible to effective lethal photosensitization that reaches 93.5% reduction in viable count than Escherichia coli (E. coli) (Gramnegative) of 76.1% using 3 mg/mL Hematoporphyrin (HP), illuminated by 630 nm Light Emitting Diode (LED) at 9 J/cm(2) and incubated for 15 min. Following topical instillation of G5 to rabbits corneas, higher amount of Mox was retained in the aqueous humor up to 24 h with significant 6-fold increase in the C(max) and AUC((0-∞)) compared to vigamox commercial eye drops. After post corneal infection with S. aureus, both approaches were effectively treating the infection without causing ocular irritation or collateral damage to corneal tissue where G5 showed remarkable improvement after four days compared to seven days of PDT treatment.


Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver.
The androgen receptor (AR) is expressed in many cell types and the androgen/AR signaling has been found to have important roles in modulating tumorigenesis and metastasis in several cancers including prostate, bladder, kidney, lung, breast and liver. However, whether AR has differential roles in the individual cells within these tumors that contain a variety of cell types remains unclear. Generation of AR knockout (ARKO) mouse models with deletion of AR in selective cells within tumors indeed have uncovered many unique AR roles in the individual cell types during cancer development and progression. This review will discuss the results obtained from various ARKO mice and different human cell lines with special attention to the cell type- and tissue-specific ARKO models. The understanding of various results showing the AR indeed has distinct and contrasting roles in each cell type within many hormone-related tumors (as stimulator in bladder, kidney and lung metastases vs as suppressor in prostate and liver metastases) may eventually help us to develop better therapeutic approaches by targeting the AR or its downstream signaling in individual cell types to better battle these hormone-related tumors in different stages.


Global Proteome and Phospho-proteome Analysis of Merlin-deficient Meningioma and Schwannoma Identifies PDLIM2 as a Novel Therapeutic Target.
Loss or mutation of the tumour suppressor Merlin predisposes individuals to develop multiple nervous system tumours, including schwannomas and meningiomas, sporadically or as part of the autosomal dominant inherited condition Neurofibromatosis 2 (NF2). These tumours display largely low grade features but their presence can lead to significant morbidity. Surgery and radiotherapy remain the only treatment options despite years of research, therefore an effective therapeutic is required. Unbiased omics studies have become pivotal in the identification of differentially expressed genes and proteins that may act as drug targets or biomarkers. Here we analysed the proteome and phospho-proteome of these genetically defined tumours using primary human tumour cells to identify upregulated/activated proteins and/or pathways. We identified over 2000 proteins in comparative experiments between Merlin-deficient schwannoma and meningioma compared to human Schwann and meningeal cells respectively. Using functional enrichment analysis we highlighted several dysregulated pathways and Gene Ontology terms. We identified several proteins and phospho-proteins that are more highly expressed in tumours compared to controls. Among proteins jointly dysregulated in both tumours we focused in particular on PDZ and LIM domain protein 2 (PDLIM2) and validated its overexpression in several tumour samples, while not detecting it in normal cells. We showed that shRNA mediated knockdown of PDLIM2 in both primary meningioma and schwannoma leads to significant reductions in cellular proliferation. To our knowledge, this is the first comprehensive assessment of the NF2-related meningioma and schwannoma proteome and phospho-proteome. Taken together, our data highlight several commonly deregulated factors, and indicate that PDLIM2 may represent a novel, common target for meningioma and schwannoma.


Evaluation of Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test and PCR for direct detection of Mycobacterium tuberculosis in clinical specimens.
The Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test (AMTD) is a direct specimen assay for the identification of Mycobacterium tuberculosis from respiratory samples. rRNA is amplified, and the product is detected with a specific chemiluminescent probe. We performed a retrospective evaluation of three separate respiratory specimens from each of 250 patients by using the AMTD and compared the results with those of microscopy, culturing, and a patient chart review. From the latter results, 198 patients (594 specimens) were found negative for M. tuberculosis by culturing and clinical criteria. The overall specificity of the AMTD after discrepancy resolution was 98.5% (585 of 594). There were 52 patients with culture-proven and/or clinically diagnosed tuberculosis. Of these 156 specimens, the organism was cultured from 142 (91%), and acid-fast microscopy was positive for 105 (67.3%). The AMTD was positive for 142 (91%) specimens from these patients. Tuberculosis patient samples were tested by a PCR assay which uses primers for amplification of the IS6110 insertion sequence of the M. tuberculosis complex. The PCR assay detected 144 of the 156 (92.3%) specimens. Overall, when three specimens per patient were examined, the AMTD found all 52 patients positive for tuberculosis, while the PCR assay found 51 patients positive by agarose gel analysis and all 52 patients positive by Southern blot hybridization.


Interleukin 1-dependent paracrine granulopoiesis in chronic granulocytic leukemia of the juvenile type.
Marrow and peripheral blood cells from nine children with juvenile chronic granulocytic leukemia (JCGL) demonstrated intense (94 +/- 16% maximum) spontaneous granulocyte/macrophage colony growth but cells from five children with the adult variety of CGL did not. This unusual pattern of colony growth depended upon a stimulatory protein(s) produced by mononuclear phagocytes. No GM-CSA activity was found in any chromatofocused fraction of JCGL monocyte-conditioned media but an activity that induced GM-CSA in umbilical vein endothelial cells was detected at pI 6.9-7.2. Moreover, the CSA-inducing monokine was neutralized by an anti-IL-1 antibody in vitro and, in the one case so tested, the same antibody also inhibited "spontaneous" colony growth. Therefore granulocyte/macrophage colony growth in JCGL is characteristically abnormal and distinguishes JCGL from the adult form of the disease. This abnormality depends upon the production, by mononuclear phagocytes, of IL-1 which, in turn, stimulates the release of high levels of colony stimulating activity by other cells. The high proliferative activity of CFU-GM we found in JCGL patients, and the high levels of GM-CSA found in their serum are compatible with the view that the in vitro abnormality reflects a similar abnormality in vivo.


G protein-coupled receptor 120 signaling regulates ghrelin secretion in vivo and in vitro.
Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is produced predominantly in the stomach. It has been reported that endogenous ghrelin levels are increased by fasting and decreased immediately after feeding and that fasting-induced ghrelin release is controlled by the sympathetic nervous system. However, the mechanisms of plasma ghrelin decrement after feeding are poorly understood. Here, we studied the control of ghrelin secretion using ghrelin-producing cell lines and found that these cells express high levels of mRNA encoding G-protein coupled receptor 120 (GPR120). Addition of GW-9508 (a GPR120 chemical agonist) and α-linolenic acid (a natural ligand for GPR120) inhibited the secretion of ghrelin by ∼50 and 70%, respectively. However, the expression levels of preproghrelin and ghrelin O-acyltransferase (GOAT) mRNAs were not influenced by GW-9508. In contrast, the expression levels of prohormone convertase 1 were decreased significantly by GW-9508 incubation. Moreover, we observed that the inhibitory effect of GW-9508 on ghrelin secretion was blocked by a small interfering RNA (siRNA) targeting the sequence of GPR120. Furthermore, pretreatment with GW-9508 blocked the effect of the norepinephrine (NE)-induced ghrelin elevation in ghrelin cell lines. In addition, we showed that GW-9508 inhibited ghrelin secretion via extracellular signal-regulated kinase activity in ghrelin cell lines. Finally, we found that GW-9508 decreased plasma ghrelin levels in mice. These results suggest that the decrease of ghrelin secretion after feeding is induced partially by long-chain fatty acids that act directly on gastric GPR120-expressing ghrelin cells.


Evaluating the Efficacy of Knowledge-Transfer Interventions on Animal Health Knowledge of Rural Working Equid Owners in Central Ethiopia: A Cluster-Randomized Controlled Trial.
The objectives of this study were to evaluate the efficacy of several knowledge-transfer interventions about donkey health, utilizing a cluster-randomized controlled trial (c-RCT), on the long-term knowledge change (~6 months post intervention) of Ethiopian rural working equid owners. Knowledge transfer interventions included: an audio programme, a village meeting and a diagrammatic hand-out, which were also compared to a control group, which received no intervention. All interventions addressed identical learning objectives. Thirty-two villages were randomly selected and interventions randomly assigned to blocks of eight villages. All participants in a village received the same intervention, and knowledge levels were assessed by questionnaire administration both pre and post intervention. Data analysis included multilevel linear and logistic regression models (allowing for clustering of individuals within villages) to evaluate the change in knowledge between the different knowledge-transfer interventions, and to look at other factors associated with change in knowledge. A total of 516 randomly selected participants completed pre-intervention questionnaires, 476 undertook a post-dissemination questionnaire ~6 months later, a follow-up response rate of 92%. All interventions significantly improved the overall knowledge score on the post intervention questionnaire compared to the control group, with the diagrammatic hand-out [coefficient (coef) 10.0, S.E. = 0.5] and the village meeting (coef 8.5, S.E = 0.5) having a significantly greater impact than the audio programme (coef 4.0, S.E = 0.5). There were differences in learning across interventions, learning objectives, age and education levels of the participants. Participants with higher levels of formal education had greater knowledge change but this varied across interventions. In conclusion, knowledge of donkey health was substantially increased by a diagrammatic hand-out and the impact of this simple, low-cost intervention should be further evaluated in other communities in low-income countries. This study should assist in the design and development of effective knowledge-transfer materials for adult learning for rural villagers in low-income countries.


Analysis of the molecular basis of calmodulin defects that affect ion channel-mediated cellular responses: site-specific mutagenesis and microinjection.
The ability of microinjected calmodulin to temporarily restore an ion channel-mediated behavioral phenotype of a calmodulin mutant in Paramecium tetraurelia (cam1) is dependent on the amino acid side chain that is present at residue 101, even when there is extensive variation in the rest of the amino acid sequence. Analysis of conservation of serine-101 in calmodulin suggests that the ability of calmodulin to regulate this ion channel-associated cell function may be a biological role of calmodulin that is widely distributed phylogenetically. A series of mutant calmodulins that differ only at residue-101 were produced by in vitro site-specific mutagenesis and expression in Escherichia coli, purified to chemical homogeneity, and tested for their ability to temporarily restore a wild-type behavioral phenotype to cam1 (pantophobiacA1) Paramecium. Calmodulins with glycine-101 or tyrosine-101 had minimal activity; calmodulins with phenylalanine-101 or alanine-101 had no detectable activity. However, as a standard of comparison, all of the calmodulins were able to activate a calmodulin-regulated enzyme, myosin light chain kinase, that is sensitive to point mutations elsewhere in the calmodulin molecule. Overall, these results support the hypothesis that the structural features of calmodulin required for the transduction of calcium signals varies with the particular pathway that is being regulated and provide insight into why inherited mutations of calmodulin at residue 101 are nonlethal and selective in their phenotypic effects.


Pancreatic panniculitis as the first manifestation of visceral disease--case report.
Pancreatic panniculitis is a rare pathological condition affecting 2-3% of patients with pancreatic disease. In 40% of cases the condition precedes manifestations of pancreatic disease. We report the case of a 71-year-old female who presented with an erythematous tender node which had appeared one month previously, progressing to ulceration and yellowish exudation. No abdominal symptoms. Biopsy revealed fat necrosis and vacuolated macrophages represented by amorphous amphophilic areas. Laboratory examination and CT scan revealed chronic pancreatitis. It is assumed that release of pancreatic enzymes such as trypsin may enhance the permeability of the microcirculation leading to lipase and amylase causing the subcutaneous fat necrosis observed in the lesions. Histology showed "ghost cells" and, firstly, septal panniculitis, followed later by lobular panniculitis. Treatment focused on resolution of the underlying pancreatic disease.


In ovo time-lapse analysis of chick hindbrain neural crest cell migration shows cell interactions during migration to the branchial arches.
Hindbrain neural crest cells were labeled with DiI and followed in ovo using a new approach for long-term time-lapse confocal microscopy. In ovo imaging allowed us to visualize neural crest cell migration 2-3 times longer than in whole embryo explant cultures, providing a more complete picture of the dynamics of cell migration from emergence at the dorsal midline to entry into the branchial arches. There were aspects of the in ovo neural crest cell migration patterning which were new and different. Surprisingly, there was contact between neural crest cell migration streams bound for different branchial arches. This cell-cell contact occurred in the region lateral to the otic vesicle, where neural crest cells within the distinct streams diverted from their migration pathways into the branchial arches and instead migrated around the otic vesicle to establish a contact between streams. Some individual neural crest cells did appear to cross between the streams, but there was no widespread mixing. Analysis of individual cell trajectories showed that neural crest cells emerge from all rhombomeres (r) and sort into distinct exiting streams adjacent to the even-numbered rhombomeres. Neural crest cell migration behaviors resembled the wide diversity seen in whole embryo chick explants, including chain-like cell arrangements; however, average in ovo cell speeds are as much as 70% faster. To test to what extent neural crest cells from adjoining rhombomeres mix along migration routes and within the branchial arches, separate groups of premigratory neural crest cells were labeled with DiI or DiD. Results showed that r6 and r7 neural crest cells migrated to the same spatial location within the fourth branchial arch. The diversity of migration behaviors suggests that no single mechanism guides in ovo hindbrain neural crest cell migration into the branchial arches. The cell-cell contact between migration streams and the co-localization of neural crest cells from adjoining rhombomeres within a single branchial arch support the notion that the pattern of hindbrain neural crest cell migration emerges dynamically with cell-cell communication playing an important guidance role.


Ultra high-dimensional semiparametric longitudinal data analysis.
As ultra high-dimensional longitudinal data are becoming ever more apparent in fields such as public health and bioinformatics, developing flexible methods with a sparse model is of high interest. In this setting, the dimension of the covariates can potentially grow exponentially as exp(n1/2) with respect to the number of clusters n. We consider a flexible semiparametric approach, namely, partially linear single-index models, for ultra high-dimensional longitudinal data. Most importantly, we allow not only the partially linear covariates but also the single-index covariates within the unknown flexible function estimated nonparametrically to be ultra high dimensional. Using penalized generalized estimating equations, this approach can capture correlation within subjects, can perform simultaneous variable selection and estimation with a smoothly clipped absolute deviation penalty, and can capture nonlinearity and potentially some interactions among predictors. We establish asymptotic theory for the estimators including the oracle property in ultra high dimension for both the partially linear and nonparametric components, and we present an efficient algorithm to handle the computational challenges. We show the effectiveness of our method and algorithm via a simulation study and a yeast cell cycle gene expression data.


DARPin-assisted crystallography of the CC2-LZ domain of NEMO reveals a coupling between dimerization and ubiquitin binding.
NEMO is an integral part of the IkappaB kinase complex and serves as a molecular switch by which the NF-kappaB signaling pathway can be regulated. Oligomerization and polyubiquitin (poly-Ub) binding, mediated through the regulatory CC2-LZ domain, were shown to be key features governing NEMO function, but the relationship between these two activities remains unclear. In this study, we solved the structure of this domain in complex with a designed ankyrin repeat protein, which helps its crystallization. We generated several NEMO mutants in this domain, including those associated with human diseases incontinentia pigmenti and immunodeficiency with or without anhidrotic ectodermal dysplasia. Analytical ultracentrifugation and thermal denaturation experiments were used to evaluate the dimerization properties of these mutants. A fluorescence-based assay was developed, as well, to quantify the interaction to monoubiquitin and poly-Ub chains. Moreover, the effect of these mutations was investigated for the full-length protein. We show that a proper folding of the ubiquitin-binding domain, termed NOA/UBAN/NUB, into a stable coiled-coil dimer is required but not sufficient for efficient interaction with poly-Ub. In addition, we show that binding to poly-Ub and, to a lesser extent, to monoubiquitin increases the stability of the NOA coiled-coil dimer. Collectively, these data provide structural insights into how several pathological mutations within and outside of the CC2-LZ's NOA ubiquitin binding site affect IkappaB kinase activation in the NF-kappaB signaling pathway.


Physical activity in pregnancy: a qualitative study of the beliefs of overweight and obese pregnant women.
Whilst there has been increasing research interest in interventions which promote physical activity during pregnancy few studies have yielded detailed insights into the views and experiences of overweight and obese pregnant women themselves. The qualitative study described in this paper aimed to: (i) explore the views and experiences of overweight and obese pregnant women; and (ii) inform interventions which could promote the adoption of physical activity during pregnancy. The study was framed by a combined Subtle Realism and Theory of Planned Behaviour (TPB) approach. This enabled us to examine the hypothetical pathway between beliefs and physical activity intentions within the context of day to day life. The study sample for the qualitative study was chosen by stratified, purposive sampling from a previous study of physical activity measurements in pregnancy. Research participants for the current study were recruited on the basis of Body Mass Index (BMI) at booking and parity. Semi-structured, in-depth interviews were conducted with 14 overweight and obese pregnant women. Data analysis was undertaken using a Framework Approach and was informed by TPB. Healthy eating was often viewed as being of greater importance for the health of mother and baby than participation in physical activity. A commonly cited motivator for maintaining physical activity during pregnancy is an aid to reducing pregnancy-related weight gain. However, participants often described how they would wait until the postnatal period to try and lose weight. A wide range of barriers to physical activity during pregnancy were highlighted including both internal (physical and psychological) and external (work, family, time and environmental). The study participants also lacked access to consistent information, advice and support on the benefits of physical activity during pregnancy. Interventions to encourage recommended levels of physical activity in pregnancy should be accompanied by accessible and consistent information about the positive effects for mother and baby. More research is required to examine how to overcome barriers to physical activity and to understand which interventions could be most effective for overweight/obese pregnant women. Midwives should be encouraged to do more to promote activity in pregnancy.


Caesarean Birth in Romania: Safe Motherhood Between Ethical, Medical and Statistical Arguments.
The number of caesarean sections increased significantly in Romania. In 2012, caesarean sections accounted for 41.2% of total births, according to a study of the Romanian National School for Public Health. This estimation is in agreement with the statistical data on caesarean sections recorded in one of the most important hospitals in Bucharest, Romania, Filantropia Hospital. Many factors have influenced the large number and sharply increasing trend of caesarean sections, from the historical ones, with roots in the communist regime, when abortions were outlawed, to current day doctors' medical practices and mothers' beliefs and fears related to the process of labor and the newborn's health. This paper aims to examine the pros and cons for caesarean birth. The analysis is presented from three perspectives: expressed by the doctor/medical caregiver, the patient/mother and some of the third parties indirectly involved in the medical decision: the foetus/newborn, the hospital/medical unit and the society as a whole, knowing that ethics is beyond the legal, economic or administrative frames.


Frailty, Quality of Life, and Loneliness of Aging in Native and Diasporic Chinese Adults.
Global migration has increased in the past century, and aging in a foreign country is relevant to the Chinese diaspora. With regard to migration, this study focuses on the places of aging as the context of older Chinese adults. This study aimed to describe the general health and wellbeing of this population with respect to their location. This study has a cross sectional design. Participants were recruited who were "aging in place" from Tianjin, China (199 participants), and "aging out of place" from the Netherlands (134 participants). Data from April to May 2019 in China and November 2018 to March 2019 in the Netherlands were aggregated. frailty, QoL and loneliness were used in both samples. T-tests and regression analyses demonstrated that social domains of frailty and QoL, as well as loneliness and frailty prevalence characterized the major differences between both places of aging. A correlation analysis and visual correlation network revealed that frailty, quality of life (QoL), and loneliness were more closely related in the aging out of place sample. Social domains of frailty and QoL, as well as the prevalence of loneliness and frailty, characterized the major differences between both places of aging. The findings indicate that frailty, QoL, and loneliness have a complex relationship, confirming that loneliness is a major detriment to the general wellbeing of older Chinese adults aging out of place. This study examined the places of aging of the larger Chinese population and allows a comprehensive understanding of health and wellbeing. The social components, especially loneliness, among the aging out of place Chinese community should receive more attention practice and clinical wise. On the other hand, frailty as well as its prevention is of more importance for the Chinese community aging in place.


Artificial Intelligence-Based Screening for Mycobacteria in Whole-Slide Images of Tissue Samples.
This study aimed to develop and validate a deep learning algorithm to screen digitized acid fast-stained (AFS) slides for mycobacteria within tissue sections. A total of 441 whole-slide images (WSIs) of AFS tissue material were used to develop a deep learning algorithm. Regions of interest with possible acid-fast bacilli (AFBs) were displayed in a web-based gallery format alongside corresponding WSIs for pathologist review. Artificial intelligence (AI)-assisted analysis of another 138 AFS slides was compared to manual light microscopy and WSI evaluation without AI support. Algorithm performance showed an area under the curve of 0.960 at the image patch level. More AI-assisted reviews identified AFBs than manual microscopy or WSI examination (P < .001). Sensitivity, negative predictive value, and accuracy were highest for AI-assisted reviews. AI-assisted reviews also had the highest rate of matching the original sign-out diagnosis, were less time-consuming, and were much easier for pathologists to perform (P < .001). This study reports the successful development and clinical validation of an AI-based digital pathology system to screen for AFBs in anatomic pathology material. AI assistance proved to be more sensitive and accurate, took pathologists less time to screen cases, and was easier to use than either manual microscopy or viewing WSIs.


Seed Location Impacts Whole-Brain Structural Network Comparisons between Healthy Elderly and Individuals with Alzheimer's Disease.
Whole-brain networks derived from diffusion tensor imaging (DTI) data require the identification of seed and target regions of interest (ROIs) to assess connectivity patterns. This study investigated how initiating tracts from gray matter (GM) or white matter (WM) seed ROIs impacts (1) structural networks constructed from DTI data from healthy elderly (control) and individuals with Alzheimer's disease (AD) and (2) between-group comparisons using these networks. DTI datasets were obtained from the Alzheimer's disease Neuroimaging Initiative database. Deterministic tractography was used to build two whole-brain networks for each subject; one in which tracts were initiated from WM ROIs and another in which they were initiated from GM ROIs. With respect to the first goal, in both groups, WM-seeded networks had approximately 400 more connections and stronger connections (as measured by number of streamlines per connection) than GM-seeded networks, but shared 94% of the connections found in the GM-seed networks. With respect to the second goal, between-group comparisons revealed a stronger subnetwork (as measured by number of streamlines per connection) in controls compared to AD using both WM-seeded and GM-seeded networks. The comparison using WM-seeded networks produced a larger (i.e., a greater number of connections) and more significant subnetwork in controls versus AD. Global, local, and nodal efficiency were greater in controls compared to AD, and between-group comparisons of these measures using WM-seeded networks had larger effect sizes than those using GM-seeded networks. These findings affirm that seed location significantly affects the ability to detect between-group differences in structural networks.


Chicken soup inhibits neutrophil chemotaxis in vitro.
Chicken soup has long been regarded as a remedy for symptomatic upper respiratory tract infections. As it is likely that the clinical similarity of the diverse infectious processes that can result in "colds" is due to a shared inflammatory response, an effect of chicken soup in mitigating inflammation could account for its attested benefits. To evaluate this, a traditional chicken soup was tested for its ability to inhibit neutrophil migration using the standard Boyden blindwell chemotaxis chamber assay with zymosan-activated serum and fMet-Leu-Phe as chemoattractants. Chicken soup significantly inhibited neutrophil migration and did so in a concentration-dependent manner. The activity was present in a nonparticulate component of the chicken soup. All of the vegetables present in the soup and the chicken individually had inhibitory activity, although only the chicken lacked cytotoxic activity. Interestingly, the complete soup also lacked cytotoxic activity. Commercial soups varied greatly in their inhibitory activity. The present study, therefore, suggests that chicken soup may contain a number of substances with beneficial medicinal activity. A mild anti-inflammatory effect could be one mechanism by which the soup could result in the mitigation of symptomatic upper respiratory tract infections.


Ischaemic Priapism and Glucose-6-Phosphate Dehydrogenase Deficiency: A Mechanism of Increased Oxidative Stress?
Ischaemic priapism is a devastating urological condition that has the potential to cause permanent erectile dysfunction. The disorder has been associated with numerous medical conditions and the use of pharmacotherapeutic agents. The aetiology is idiopathic in a number of cases. There are two prior case reports of the association of ischaemic priapism and glucose-6-phosphate dehydrogenase (G6PD) deficiency. We report on a third case of priapism associated with G6PD deficiency and review recently described molecular mechanisms of increased oxidative stress in the pathophysiology of ischaemic priapism. The case report of a 32-year old Afro-Caribbean male with his first episode of major ischaemic priapism is described. Screening for common causes of ischaemic priapism, including sickle cell disease was negative. Glucose-6-phosphate dehydrogenase deficiency was discovered on evaluation for priapism. Penile aspiration was performed and erectile function was good post treatment.Glucose-6-phosphate dehydrogenase deficiency is a cause for ischaemic priapism and should be a part of the screening process in idiopathic causes of the disorder. Increased oxidative stress occurs in G6PD deficiency and may lead to priapism.


Bimanual coordination: an unbalanced field of research.
Using more than one limb to perform functional, goal-directed actions is arguably one of the most important abilities that human beings possess. In many everyday tasks, the hands, in particular, must be used to accomplish all manner of goals. From buttoning a shirt to opening a jam jar and driving to work, good bimanual coordination is of great utility. In addition to the tasks mentioned above, there are also other tasks involving the functional use of more than one limb, including walking or cycling and typing a report. With a little thought, it becomes apparent that there is at least one important difference between these categories of coordination tasks. On one hand, in some tasks the effectors must perform markedly different motor outputs that are bound together in some functionally defined and usually object-oriented manner (e.g., buttoning a shirt) yet, in others, the effectors produce very similar motor outputs but in a specific temporal order, which may or may not repeat itself periodically (e.g., walking and cycling compared to typing or drumming). In this short article, I will argue that the second category of coordination task and, in particular, cyclical coordination, has been studied extensively and, at least at the level of behavior, is relatively well understood. In contrast the former category of bimanual task is seldom studied and, even at the descriptive level, is rather poorly understood. One of the reasons for this may be the complexity of such tasks and the technical difficulties involved in attempting to study them. By highlighting some key studies, I hope to illustrate that such tasks can be fruitfully studied in the laboratory. Last, since the neural control processes underlying both classes of coordination task are not yet well known, I aim to draw attention to the potential value of the interventional technique of Transcranial Magnetic Stimulation (TMS) as a tool for investigating the functions of brain regions contributing to bimanual coordination.


Putting all the pieces together: exploring workforce issues in mental health nursing.
The problems of establishing sufficient numbers of adequately skilled mental health nurses with the motivation to work in this field over the long term are well known. Recruitment and retention remain problematic particularly in light of the ageing workforce. Nursing workloads, stress and burnout, workplace violence and aggression, for example are frequently identified as major contributors to these problems. While these factors have been identified and articulated, the relationship between them has received significantly less attention. This paper provides an overview of the relationship between these factors and subsequently emphasises the need for them to be considered collectively rather than individually. More effective and sustainable workforce planning will be facilitated through recognition of the complexity of mental health nursing rather than by artificially reducing it to component parts.


Regulation of TATA-binding protein binding by the SAGA complex and the Nhp6 high-mobility group protein.
Transcriptional activation of the yeast HO gene involves the sequential action of DNA-binding and chromatin-modifying factors. Here we examine the role of the SAGA complex and the Nhp6 architectural transcription factor in HO regulation. Our data suggest that these factors regulate binding of the TATA-binding protein (TBP) to the promoter. A gcn5 mutation, eliminating the histone acetyltransferase present in SAGA, reduces the transcription of HO, but expression is restored in a gcn5 spt3 double mutant. We conclude that the major role of Gcn5 in HO activation is to overcome repression by Spt3. Spt3 is also part of SAGA, and thus two proteins in the same regulatory complex can have opposing roles in transcriptional regulation. Chromatin immunoprecipitation experiments show that TBP binding to HO is very weak in wild-type cells but markedly increased in an spt3 mutant, indicating that Spt3 reduces HO expression by inhibiting TBP binding. In contrast, it has been shown previously that Spt3 stimulates TBP binding to the GAL1 promoter as well as GAL1 expression, and thus, Spt3 regulates these promoters differently. We also find genetic interactions between TBP and either Gcn5 or the high-mobility-group protein Nhp6, including multicopy suppression and synthetic lethality. These results suggest that, while Spt3 acts to inhibit TBP interaction with the HO promoter, Gcn5 and Nhp6 act to promote TBP binding. The result of these interactions is to limit TBP binding and HO expression to a short period within the cell cycle. Furthermore, the synthetic lethality resulting from combining a gcn5 mutation with specific TBP point mutations can be suppressed by the overexpression of transcription factor IIA (TFIIA), suggesting that histone acetylation by Gcn5 can stimulate transcription by promoting the formation of a TBP/TFIIA complex.


Potato virus Y; the Andean connection.
Potato virus Y (PVY) causes disease in potatoes and other solanaceous crops. The appearance of its necrogenic strains in the 1980s made it the most economically important virus of potatoes. We report the isolation and genomic sequences of 32 Peruvian isolates of PVY which, together with 428 published PVY genomic sequences, gave an alignment of 460 sequences. Of these 190 (41%) were non-recombinant, and 162 of these provided a dated phylogeny, that corresponds well with the likely history of PVY, and show that PVY originated in South America which is where potatoes were first domesticated. The most basal divergences of the PVY population produced the N and C: O phylogroups; the origin of the N phylogroup is clearly Andean, but that of the O and C phylogroups is unknown, although they may have been first to establish in European crops. The current PVY population originated around 156 CE. PVY was probably first taken from South America to Europe in the 16th century in tubers. Most of the present PVY diversity emerged in the second half of the 19th century, after the Phytophthora infestans epidemics of the mid-19th century destroyed the European crop and stimulated potato breeding. Imported breeding lines were shared, and there was no quarantine. The early O population was joined later by N phylogroup isolates and their recombinants generated the R1 and R2 populations of damaging necrogenic strains. Our dating study has confirmed that human activity has dominated the phylodynamics of PVY for the last two millennia.


Pharmacokinetics of orally administered melatonin in critically ill patients.
Critically ill patients exhibit reduced melatonin secretion, both in nocturnal peaks and basal daytime levels. Oral melatonin supplementation may be useful for known sedative and antioxidant properties. Its early enteral absorption and daily pharmacokinetics were determined in two cohorts of six high-risk patients in this prospective trial. During their third and fourth Intensive Care Unit (ICU) day, they underwent two different sets of repeated blood samples to detect serum melatonin levels through radio-immuno-assay. Cohort 1: samples taken at 20:00, 20:45, 21:30, 24:00, 03:00, 06:00, 14:00, 20:00 to describe the daily pharmacokinetics. Cohort 2: 20:00, 20:05, 20:10, 20:20, 20:30, 20:45 to study the early absorption. On ICU day 3, endogenous levels were measured, while the absorption of exogenous melatonin was determined on ICU day 4 after administration, at 20:00, of 3 mg melatonin. All basal levels were below the expected values. Following enteral administration, pharmacological levels were already reached in 5 min, with a serum peak after 16 min (half-absorption time: 3 min 17 s). The maximum serum level observed was 11040 pg/mL and the disappearance rate indicated a half-elimination time of 1 hr 34 min. Serum melatonin levels decreased significantly after midnight; pharmacological levels were maintained up to 10 hr following administration. No excessive sleepiness was reported in this patient group. Critically ill patients exhibited reduced melatonin secretion, as reported in the literature. Despite the critical illness, the oral bioavailability was satisfactory: serum levels after oral administration showed basically unchanged intestinal absorption, while disappearance rate was slower than reported elsewhere in healthy volunteers.


Isolation of ligand-centered borocations in molybdenum complexes containing a triaminoborane-bridged diphosphorus ligand.
Metal complexes that form isolable, ligand-centered borenium ions (i.e. reactive three-coordinate boron cations) are rare, especially with highly-versatile diphosphorus ligands. Here we report the first structurally-characterized examples of ligand-centered borocations in a class of diphosphorus ligands derived from the bicyclic triaminoborane 1,8,10,9-triazaboradecalin (TBD). Treating (PhTBDPhos)Mo(CO)4 (1) with HOTf or HNTf2 resulted in protonation of the bridgehead α-nitrogen on the TBD backbone and formation of ligand-centered borenium ions (1-HOTf and 1-HNTf2, respectively), whereas reaction of 1 with HBF4·Et2O resulted in protonation of two α-nitrogen atoms and fluoride abstraction from BF4- to form a four-coordinate borocation in [1-H2F][BF4]. Single-crystal XRD data confirmed the formation of the borocations, and multinuclear NMR and IR spectroscopy studies were used to interrogate the electronic environment at molybdenum and boron. The 11B NMR resonances for the borenium ions in 1-HOTf and 1-HNTf2 (δ 29.5 and 29.6 ppm) were more deshielded than the resonance for 1 (δ 25.9 ppm), consistent with the decreased electron density at boron. The 31P NMR data revealed similar trends in response to increasing protonation on the TBD backbone, and aligned well with small, stepwise increases in Mo-CO stretching frequencies that followed the order borane (1) < borenium (1-HOTf and 1-HNTf2) < boronium ([1-H2F][BF4]). Density functional theory calculations conducted on 1, 1-HOTf, and [1-H2F][BF4] revealed subtle changes in boron and nitrogen atomic charges consistent with those calculated for more well-established borenium ions in metal-free systems. Overall, the results confirm previous observations of latent borenium ion reactivity in TBDPhos complexes.


UK DRAFFT: a randomised controlled trial of percutaneous fixation with Kirschner wires versus volar locking-plate fixation in the treatment of adult patients with a dorsally displaced fracture of the distal radius.
In high-income countries, 6% of all women will have sustained a fracture of the wrist (distal radius) by the age of 80 years and 9% by the age of 90 years. Advances in orthopaedic surgery have improved the outcome for patients: many such fractures can be treated in a plaster cast alone, but others require surgical fixation to hold the bone in place while they heal. The existing evidence suggests that modern locking-plate fixation provides improved functional outcomes, but costs more than traditional wire fixation. In this multicentre trial, we randomly assigned 461 adult patients having surgery for an acute dorsally displaced fracture of the distal radius to either percutaneous Kirschner-wire fixation or locking-plate fixation. The primary outcome measure was the Patient-Rated Wrist Evaluation© (PRWE) questionnaire at 12 months after the fracture. In this surgical trial, neither the patients nor the surgeons could be blind to the intervention. We also collected information on complications and combined costs and quality-adjusted life-years (QALYs) to assess cost-effectiveness. The baseline characteristics of the two groups were well balanced and over 90% of patients completed follow-up. Both groups of patients recovered wrist function by 12 months. There was no clinically relevant difference in the PRWE questionnaire score at 3 months, 6 months or 12 months [difference at 12 months: -1.3; 95% confidence interval (CI) -4.5 to 1.8; p=0.398]. There was no difference in the number of complications in each group and small differences in QALY gains (0.008; 95% CI -0.001 to 0.018); Kirschner-wire fixation represents a cost-saving intervention (-£727; 95% CI -£588 to -£865), particularly in younger patients. Contrary to the existing literature, and against the increasing use of locking-plate fixation, this trial shows that there is no difference between Kirschner wires and volar locking plates for patients with dorsally displaced fractures of the distal radius. A Kirschner-wire fixation is less expensive and quicker to perform. Current Controlled Trials ISRCTN31379280. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 17. See the NIHR Journals Library website for further project information.


14 Days of supplementation with blueberry extract shows anti-atherogenic properties and improves oxidative parameters in hypercholesterolemic rats model.
The effects of supplementation with blueberry (BE) extract (Vaccinium ashei Reade) for 14 consecutive days on biochemical, hematological, histopathological and oxidative parameters in hypercholesterolemic rats were investigated. After supplementation with lyophilized extract of BE, the levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides were decreased. Histopathological analysis showed significant decrease (p < 0.05) of aortic lesions in hypercholesterolemic rats. Oxidative parameters showed significant reductions (p < 0.05) in oxidative damage to lipids and proteins and an increase in activities of antioxidant enzymes such as catalase, superoxide dismutase and glutathione peroxidase. The BE extract showed an important cardioprotective effect by the improvements in the serum lipid profile, antioxidant system, particularly in reducing oxidative stress associated with hypercholesterolemia and anti-atherogenic effect in rats.


A Systematic Review of the Soft-Tissue Connections Between Neck Muscles and Dura Mater: The Myodural Bridge.
Systematic review. To elucidate the existence of soft tissue connections between the neck muscles and cervical dura mater. Several studies discuss the existence of a cervical myodural bridge; however, conflicting data have been reported. Searches were conducted in the PubMed, Web of Science, Cochrane Library, and PEDro databases. Studies reporting original data regarding the continuity of non-post-surgical soft tissue between the cervical muscles and dura mater were reviewed. Two reviewers independently selected articles, and a third one resolved disagreements. Another two researchers extracted the methodology of the study, the anatomical findings, and evaluated the quality of the studies using Quality Appraisal for Cadaveric Studies Scale. A different third researcher resolved disagreements. Twenty-six studies were included. A soft tissue connection between the rectus capitis posterior minor, the rectus capitis posterior major, and the obliquus capitis inferior muscles seems to be proved with a strong level of evidence for each one of them. Controversy exists about the possible communication between the dura mater and the upper trapezius, rhomboideus minor, serratus posterior superior, and splenius capitis by means of the ligamentum nuchae. Finally, there is limited evidence about the existence of a soft tissue connection between rectus capitis anterior muscle and the dura mater. There is a continuity of soft tissue between the cervical musculature and the cervical dura mater; this might have physiological, pathophysiological, and therapeutic implications, and going some way to explaining the effect of some therapies in craniocervical disorders. N/A.


Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response.
The p38 mitogen-activated protein kinase pathway regulates innate immune responses in evolutionarily diverse species. We have previously shown that the Caenorhabditis elegans p38 mitogen-activated protein kinase, PMK-1, functions in an innate immune response pathway that mediates resistance to a variety of microbial pathogens. Here, we show that tir-1, a gene encoding a highly conserved Toll/IL-1 resistance (TIR) domain protein, is also required for C. elegans resistance to microbial pathogens. RNA interference inactivation of tir-1 resulted in enhanced susceptibility to killing by pathogens and correspondingly diminished PMK-1 phosphorylation. Unlike all known TIR-domain adapter proteins, overexpression of the human TIR-1 homologue, SARM, in mammalian cells was not sufficient to induce expression of NF-kappaB or IRF3-dependent reporter genes that are activated by Toll-like receptor signaling. These data reveal the involvement of a previously uncharacterized, evolutionarily conserved TIR domain protein in innate immunity that is functionally distinct from other known TIR domain signaling adapters.


Host plants of the non-swarming edible bush cricket Ruspolia differens.
The edible Ruspolia differens (Orthoptera: Tettigoniidae) is a widely-consumed insect in East Africa but surprisingly little is known of its host plant use in the field. We studied host plants used by non-swarming R. differens for 15 months, in central Uganda. In particular, we assessed the use of host plant species with respect to host cover in the field and host parts used by R. differens, also recording their sex, developmental stages, and colour morph. Ruspolia differens were found on 19 grass and two sedge species and they were observed predominantly (99% of 20,915 observations) on seven grasses (namely, Panicum maximum, Brachiaria ruziziensis, Chloris gayana, Hyparrhenia rufa, Cynodon dactylon, Sporobolus pyramidalis, and Pennisetum purpureum). Ruspolia differens was most frequently observed on the most common grass of each study site but P. maximum, and S. pyramidalis were used more frequently than expected from their cover in the field. Furthermore, R. differens were observed predominantly on inflorescences (97% of feeding observations) and much less frequently on the leaves (3.0%), stems (0.1%), and inflorescence stalks (0.1%) of grasses and sedges. Host use was not independent of sex, developmental stage, or colour morph. Panicum maximum was the preferred host of the youngest nymphs of R. differens. Overall, our findings indicate that a continuous supply of diverse grass resources with inflorescences is necessary for the management and conservation of wild populations of R. differens.


Oxidative and nitrosative-based signaling and associated post-translational modifications orchestrate the acclimation of citrus plants to salinity stress.
Reactive oxygen and nitrogen species are involved in a plethora of cellular responses in plants; however, our knowledge on the outcomes of oxidative and nitrosative signaling is still unclear. To better understand how oxidative and nitrosative signals are integrated to regulate cellular adjustments to external conditions, local and systemic responses were investigated in the roots and leaves of sour orange plants (Citrus aurantium L.) after root treatment with hydrogen peroxide (H(2) O(2) ) or sodium nitroprusside (a nitric oxide donor), followed by NaCl stress for 8 days. Phenotypic and physiological data showed that pre-exposure to these treatments induced an acclimation to subsequent salinity stress that was accompanied by both local and systemic H(2) O(2) and nitric oxide (NO) accumulation. Combined histochemical and fluorescent probe approaches showed the existence of a vascular-driven long-distance reactive oxygen species and NO signaling pathway. Transcriptional analysis of genes diagnostic for H(2) O(2) and NO signaling just after treatments or after 8 days of salt stress revealed tissue- and time-specific mechanisms controlling internal H(2) O(2) and NO homeostasis. Furthermore, evidence is presented showing that protein carbonylation, nitration and S-nitrosylation are involved in acclimation to salinity stress. In addition, this work enabled characterization of potential carbonylated, nitrated and nitrosylated proteins with distinct or overlapping signatures. This work provides a framework to better understand the oxidative and nitrosative priming network in citrus plants subjected to salinity conditions.


Late replication in an X-autosome translocation in the mouse: correlation with genetic inactivation and evidence for selective effects during embryogenesis.
A technique involving 5-bromodeoxyuridine, 33258 Hoechst, and fluorescence microscopy has been used to analyze replication kinetics in cells from embryonic and adult mice bearing the Cattanach [T(X;7)ICt] translocation in a balanced or an unbalanced form. In balanced 9- and 13-day female embryos, the translocated X was late replicating in 28 and 22% of the cells, respectively, whereas it was late replicating in only 13% of adult cells. In contrast, in unbalanced females, the translocated X was late replicating in 62 and 70% of 9- and 13-day embryos and in 70% of adult cells. Such divergent late replication frequencies suggest the operation, during development, of selection against cells with extreme genetic imbalance. Within a late-replicating translocated X chromosome, the autosomal segment itself replicated late approximately half of the time, regardless of karyotypic balance. The late replication data are consistent with the measurements of levels of mitochondrial malic enzyme (MOD-2, whose locus is on the autosomal segment) activity in these mice [Eicher E. & Coleman, D. (1977) Genetics 85, 647-658]. The present study also shows a dissociation between the replication timing in X chromatin distal and proximal to the autosomal segment, supporting the hypothesis of at least two inactivation centers in the X chromosome.


Cellular retinol-binding protein type I (CRBP-I) regulates adipogenesis.
Adipogenesis is governed by a well-documented cascade of transcription factors. However, less is known about non-transcription factors that govern early stages of adipogenesis. Here we show that cellular retinol-binding protein type I (CRBP-I), a small cytosolic binding protein for retinol and retinaldehyde, is specifically restricted to preadipocytes in white adipose tissue. The absence of CRBP-I in mice (CRBP-I-KO mice) leads to increased adiposity. Despite increased adiposity, CRBP-I-KO mice remain more glucose tolerant and insulin sensitive during high-fat-diet feeding. 3T3-L1 cells deficient in CRBP-I or mouse embryonic fibroblasts derived from CRBP-I-KO mice had increased adipocyte differentiation and triglyceride (TG) accumulation. This was due to increased expression and activity of PPAR gamma, while other transcription factor pathways in early and late differentiation remained unchanged. Conversely, the overexpression of CRBP-I in 3T3-L1 cells results in decreased TG accumulation. In conclusion, CRBP-I is a cytosolic protein specifically expressed in preadipocytes that regulates adipocyte differentiation in part by affecting PPAR gamma activity.


High-throughput quantitation of inorganic nanoparticle biodistribution at the single-cell level using mass cytometry.
Inorganic nanoparticles (NPs) are studied as drug carriers, radiosensitizers and imaging agents, and characterizing nanoparticle biodistribution is essential for evaluating their efficacy and safety. Tracking NPs at the single-cell level with current technologies is complicated by the lack of reliable methods to stably label particles over extended durations in vivo. Here we demonstrate that mass cytometry by time-of-flight provides a label-free approach for inorganic nanoparticle quantitation in cells. Furthermore, mass cytometry can enumerate AuNPs with a lower detection limit of ∼10 AuNPs (3 nm core size) in a single cell with tandem multiparameter cellular phenotyping. Using the cellular distribution insights, we selected an amphiphilic surface ligand-coated AuNP that targeted myeloid dendritic cells in lymph nodes as a peptide antigen carrier, substantially increasing the efficacy of a model vaccine in a B16-OVA melanoma mouse model. This technology provides a powerful new level of insight into nanoparticle fate in vivo.


Tissue capillary supply--it's quality not quantity that counts!
This article explores how common misunderstandings about the microcirculation - that capillary supply varies directly with O(2) demand, that local capillary supply in muscle is determined by fibre type and that it is appropriate to model capillary distribution as either random or in a fixed geometric pattern - arise from quantifying capillarity by simple measures of quantitative extent, rather than the more functionally relevant qualitative distribution. We show that the latter approach reveals exquisite control of angiogenesis that determines the location of new vessels with astonishing accuracy, motivating a reappraisal of the physiological remodelling process and a new approach to computational investigations into peripheral O(2) transport.


Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.
A recent meta-analysis demonstrated that statin therapy is associated with excess risk of developing diabetes mellitus. To investigate whether intensive-dose statin therapy is associated with increased risk of new-onset diabetes compared with moderate-dose statin therapy. We identified relevant trials in a literature search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (January 1, 1996, through March 31, 2011). Unpublished data were obtained from investigators. We included randomized controlled end-point trials that compared intensive-dose statin therapy with moderate-dose statin therapy and included more than 1000 participants who were followed up for more than 1 year. Tabular data provided for each trial described baseline characteristics and numbers of participants developing diabetes and experiencing major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization). We calculated trial-specific odds ratios (ORs) for new-onset diabetes and major cardiovascular events and combined these using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I(2) statistic. In 5 statin trials with 32,752 participants without diabetes at baseline, 2749 developed diabetes (1449 assigned intensive-dose therapy, 1300 assigned moderate-dose therapy, representing 2.0 additional cases in the intensive-dose group per 1000 patient-years) and 6684 experienced cardiovascular events (3134 and 3550, respectively, representing 6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 (95% confidence interval [CI], 1.04-1.22; I(2) = 0%) for new-onset diabetes and 0.84 (95% CI, 0.75-0.94; I(2) = 74%) for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events. In a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy.


Associations between intimate partner violence, childcare practices and infant health: findings from Demographic and Health Surveys in Bolivia, Colombia and Peru.
Child health is significantly poorer in homes with intimate partner violence (IPV). However, a possible link to parental provision of childcare has been neglected. Utilizing data from Demographic and Health Surveys, this study examined the association between IPV and illness signs in children 0-59 months in Bolivia (n = 3586), Colombia (n = 9955) and Peru (n = 6260), taking into account socio-demographic factors, childcare and severe child physical punishment. Data were collected in the years 2008, 2010 and 2012 for Bolivia, Colombia and Peru respectively. The study found weak but persistent effects of IPV on illness signs in Bolivia (OR 1.37, 95% CI 1.14-1.63) and Peru (OR 1.49, 95% CI 1.26-1.77), after adjusting for the effects of childcare. These effects were not observed in Colombia. The results call for a mix of qualitative and quantitative research that can map direct, mediating and moderating patterns of relationships between IPV, childcare practices and child health. Can good childcare mitigate the negative effects of IPV? Can poor childcare exacerbate the negative effects of IPV? Such interactions were not observed in the present study, but should be the focus of much more intensive investigation, to help inform child health promotion. Answers could lead to better interventions to improve child health, and perhaps to tackle IPV.


Demand and access to mental health services: a qualitative formative study in Nepal.
Nepal is experiencing a significant 'treatment gap' in mental health care. People with mental disorders do not always receive appropriate treatment due to a range of structural and individual issues, including stigma and poverty. The PRIME (Programme for Improving Mental Health Care) programme has developed a mental health care plan to address this issue in Nepal and four other low and middle income countries. This study aims to inform the development of this comprehensive care plan by investigating the perceptions of stakeholders at different levels of the care system in the district of Chitwan in southern Nepal: health professionals, lay workers and community members. It focuses specifically on issues of demand and access to care, and aims to identify barriers and potential solutions for reaching people with priority mental disorders. This qualitative study consisted of key informant interviews (33) and focus group discussions (83 participants in 9 groups) at community and health facility levels. Data were analysed using a framework analysis approach. As well as pragmatic barriers at the health facility level, mental health stigma and certain cultural norms were found to reduce access and demand for services. Respondents perceived the lack of awareness about mental health problems to be a major problem underlying this, even among those with high levels of education or status. They proposed strategies to improve awareness, such as channelling education through trusted and respected community figures, and responding to the need for openness or privacy in educational programmes, depending on the issue at hand. Adapting to local perceptions of stigmatised treatments emerged as another key strategy to improve demand. This study identifies barriers to accessing care in Nepal that reach beyond the health facility and into the social fabric of the community. Stakeholders in PRIME's integrated care plan advocate strategic awareness raising initiatives to improve the reach of integrated services in this low-income setting.


Gold Nanorod Assemblies: The Roles of Hot-Spot Positioning and Anisotropy in Plasmon Coupling and SERS.
Plasmon-coupled colloidal nanoassemblies with carefully sculpted "hot-spots" and intense surface-enhanced Raman scattering (SERS) are in high demand as photostable and sensitive plasmonic nano-, bio-, and chemosensors. When maximizing SERS signals, it is particularly challenging to control the hot-spot density, precisely position the hot-spots to intensify the plasmon coupling, and introduce the SERS molecule in those intense hot-spots. Here, we investigated the importance of these factors in nanoassemblies made of a gold nanorod (AuNR) core and spherical nanoparticle (AuNP) satellites with ssDNA oligomer linkers. Hot-spot positioning at the NR tips was made possible by selectively burying the ssDNA in the lateral facets via controlled Ag overgrowth while retaining their hybridization and assembly potential at the tips. This strategy, with slight alterations, allowed us to form nanoassemblies that only contained satellites at the NR tips, i.e., directional anisotropic nanoassemblies; or satellites randomly positioned around the NR, i.e., nondirectional nanoassemblies. Directional nanoassemblies featured strong plasmon coupling as compared to nondirectional ones, as a result of strategically placing the hot-spots at the most intense electric field position of the AuNR, i.e., retaining the inherent plasmon anisotropy. Furthermore, as the dsDNA was located in these anisotropic hot-spots, this allowed for the tag-free detection down to 10 dsDNA and a dramatic SERS enhancement of 1.6 × 108 for the SERS tag SYBR gold, which specifically intercalates into the dsDNA. This dramatic SERS performance was made possible by manipulating the anisotropy of the nanoassemblies, which allowed us to emphasize the critical role of hot-spot positioning and SERS molecule positioning in nanoassemblies.


Street lighting for preventing road traffic injuries.
Road traffic crashes are a major cause of death and injury, especially in low and middle-income countries. It is estimated that road traffic injuries will have risen from ninth to third in world disease burden rankings by 2020, accounting for 2.3 million deaths globally. Street lighting has been suggested as a relatively low cost intervention with the potential to prevent traffic crashes. To assess the effects of street lighting on injuries caused by road traffic crashes. We searched the Cochrane Injuries Group's Specialised Register, CENTRAL, MEDLINE, EMBASE, TRANSPORT, Australian Transport Index. We also searched the Internet and checked reference lists of relevant papers. The search was not restricted by language or publication status. The searches were conducted to October 2008. Randomised controlled trials, non-randomised controlled trials and controlled before-after studies, comparing new street lighting with unlit roads, or improved street lighting with the pre-existing lighting level. Two authors screened search results, extracted data, assessed risk of bias and analysed the data. We found 16 controlled before-after studies of street lighting, all reporting crash data, of which 14 contributed data to the meta-analysis. Seven trials included a designated control site, the other nine collected data at one site with the daytime data being used as the control. The methodological quality of the trials was generally poor.Three trials compared street lighting with an area control on total crashes; pooled rate ratio (RR) = 0.45 (95% Confidence Interval (CI) 0.29 to 0.69). Two trials compared street lighting with an area control on total injury crashes (all severities); RR = 0.78 (95% CI 0.63 to 0.97). No trials compared the number of fatal crashes with an area control.Ten trials compared street lighting with a day time control on total crashes; pooled RR = 0.68 (95% CI 0.56 to 0.83). Five trials compared street lighting with a day time control on total injury crashes; pooled RR = 0.68 (95% CI 0.59 to 0.79). Three trials compared street lighting with a day time control on fatal crashes; pooled RR = 0.33 (95% CI 0.17 to 0.66). The results from this systematic review suggests that street lighting may prevent road traffic crashes, injuries and fatalities. However, further well designed studies are needed to determine the effectiveness of street lighting in middle and low-income countries.


Drawing a fine line on endogenous retroelement activity.
Endogenous retroelements (EREs) are essential motors of evolution yet require careful control to prevent genomic catastrophes, notably during the vulnerable phases of epigenetic reprogramming that occur immediately after fertilization and in germ cells. Accordingly, a variety of mechanisms restrict these mobile genetic units. Previous studies have revealed the importance of KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor, KAP1, in the early embryonic silencing of endogenous retroviruses and so-called SVAs, but the implication of this transcriptional repression system in the control of LINE-1, the only known active autonomous retrotransposon in the human genome, was thought to be marginal. Two recent studies straighten the record by revealing that the KRAB/KAP system is key to the control of L1 in embryonic stem (ES) cells, and go further in demonstrating that DNA methylation and KRAB/KAP1-induced repression contribute to this process in an evolutionally dynamic fashion. These results shed light on the delicate equilibrium between higher vertebrates and endogenous retroelements, which are not just genetic invaders calling for strict control but rather a constantly renewed and nicely exploitable source of evolutionary potential.


Anisotropic swelling and fracture of silicon nanowires during lithiation.
We report direct observation of an unexpected anisotropic swelling of Si nanowires during lithiation against either a solid electrolyte with a lithium counter-electrode or a liquid electrolyte with a LiCoO(2) counter-electrode. Such anisotropic expansion is attributed to the interfacial processes of accommodating large volumetric strains at the lithiation reaction front that depend sensitively on the crystallographic orientation. This anisotropic swelling results in lithiated Si nanowires with a remarkable dumbbell-shaped cross section, which develops due to plastic flow and an ensuing necking instability that is induced by the tensile hoop stress buildup in the lithiated shell. The plasticity-driven morphological instabilities often lead to fracture in lithiated nanowires, now captured in video. These results provide important insight into the battery degradation mechanisms.


The added value of ultrasound muscle measurements in patients with COPD: An exploratory study.
Malnutrition and sarcopenia are common nutrition (-related) disorders in patients with COPD and are associated with negative health outcomes and mortality. This study aims to correlate ultrasound measured rectus femoris size with fat-free mass and muscle function in patients with COPD. Patients with COPD, at the start of a pulmonary rehabilitation program, were asked to participate in this study. Rectus femoris (RF) size (thickness in cm, cross-sectional area [CSA] in cm2) was determined by ultrasound. Fat-free mass index (FFMI in kg/m2) was estimated with bioelectrical impedance analyses, using a disease-specific equation. Handgrip strength (HGS) was measured in kilograms and the five times sit to stand test (in seconds, higher scores indicating decreased strength) was performed to assess leg muscle power. The Incremental Shuttle Walk Test (ISWT, in m) was used to assess maximal exercise capacity. In total, 44 patients with COPD (mean age 59.8 ± 8.6 years, 43% male, median FEV1%pred 37 [IQR = 23-52]) were included. Greater RF-CSA and thickness were associated with higher FFMI (r = 0.57, p < 0.001; r = 0.53, p = 0.003, respectively) and HGS (CSA r = 0.58, p < 0.001, thickness r = 0.48, p = 0.009). No significant correlations between RF-thickness, CSA, and leg muscle power were found (r = -0.33, p = 0.091; r = -0.35, p = 0.073, respectively). Furthermore, no correlation between RF size and maximal exercise capacity was observed (thickness r = 0.21, p = 0.297, CSA r = 0.22, p = 0.274). This exploratory study shows that in patients with COPD, rectus femoris size is moderately correlated with FFMI and HGS. Future studies should focus on the role of ultrasound in evaluating nutritional status.


Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study.
To follow up a UK national cohort of women admitted to hospital with confirmed 2009/H1N1 influenza in pregnancy in order to obtain a complete picture of pregnancy outcomes and estimate the risks of adverse fetal and infant outcomes. National cohort study. 221 hospitals with obstetrician led maternity units in the UK. 256 women admitted to hospital with confirmed 2009/H1N1 in pregnancy during the second wave of pandemic infection between September 2009 and January 2010; 1220 pregnant women for comparison. Rates of stillbirth, perinatal mortality, and neonatal mortality; odds ratios for infected versus comparison women. Perinatal mortality was higher in infants born to infected women (10 deaths among 256 infants; rate 39 (95% confidence interval 19 to 71) per 1000 total births) than in infants of uninfected women (9 deaths among 1233 infants; rate 7 (3 to 13) per 1000 total births) (P < 0.001). This was principally explained by an increase in the rate of stillbirth (27 per 1000 total births v 6 per 1000 total births; P = 0.001). Infants of infected women were also more likely to be born prematurely than were infants of comparison women (adjusted odds ratio 4.0, 95% confidence interval 2.7 to 5.9). Infected women who delivered preterm were more likely to be infected in their third trimester (P = 0.046), to have been admitted to an intensive care unit (P < 0.001), and to have a secondary pneumonia (P = 0.001) than were those who delivered at term. This study suggests an increase in the risk of poor outcomes of pregnancy in women infected with 2009/H1N1, which reinforces the message from studies of maternal risk alone. The health of pregnant women is an important public health priority in future waves of this and other influenza pandemics.


Cost-Effectiveness Of A Workplace Ban On Sugar-Sweetened Beverage Sales: A Microsimulation Model.
Sugar-sweetened beverages (SSBs) increase chronic disease risk. We estimated the impact on employee health and health care spending of banning SSB sales in California-based health care organizations. We used survey data from a large, multisite health care organization in California, sampling 2,276 employees three months before and twelve months after a workplace SSB sales ban was imposed. We incorporated the survey data into a simulation model to estimate chronic disease incidence and costs. We estimated that an SSB ban as effective as the one observed would save about $300,000 per 10,000 people over ten years among similar employers, as a result of averted health care and productivity spending-after both SSB sales losses and non-SSB beverage sales gains were accounted for. Sales bans would typically need to reduce SSB consumption by 2.2 ounces per person per day for lost revenue to be fully offset if there were no increase in non-SSB beverage sales.


Vesicular stomatitis virus inhibits mitotic progression and triggers cell death.
Vesicular stomatitis virus (VSV) infects and kills a wide range of cell types; however, the mechanisms involved in VSV-mediated cell death are not fully understood. Here we show that VSV infection interferes with mitotic progression, resulting in cell death. This effect requires the interaction of VSV matrix (M) protein with the Rae1-Nup98 complex in mitosis, which is associated with a subset of ribonucleoproteins (RNPs). VSV displaced Rae1 from spindle poles, caused spindle abnormalities and triggered substantial cell death during metaphase. These effects were attenuated in cells infected with VSV expressing a mutant M protein that does not bind efficiently to the Rae1-Nup98-RNP complex. In cells that progressed to late mitosis, M protein prevented proper nuclear formation and chromatin decondensation. VSV is an oncolytic (anti-tumour) agent as it preferentially replicates and kills tumour cells. As tumour cells have a high mitotic index, VSV-mediated mitotic cell death probably contributes to its oncolytic activity.


Exudative v/s transudative ascites: differentiation based on fluid echogenicity on high resolution sonography.
Real time sonography was performed in 52 patients with ascites to evaluate the accuracy of sonography in differentiating an exudative from a transudative collection. The echogenicity of ascites was graded I, II and III using the echogenicity of normal abdominal viscera as comparative standard reference points. Grade I collections (31 patients) were either absolutely anechoic, or showed few internal echoes secondary to particulate matter. Grade II collections (7 patients) were hypoechoic as compared to the liver and spleen. Grade III collections (14 patients) had an echogenicity similar to or greater than that of the liver and spleen. The results of diagnostic aspiration in all patients were then compared to the sonographic grade of the ascitic fluid. All transudates (28 patients) had a Grade I echogenicity. Only 3 patients with an exudative ascites had a Grade I echogenicity. The remaining 21 patients with an exudative collection had an echogenicity equal to or greater than Grade II. Using these results, an ascitic fluid echogenicity of Grade I had a 92.32% sensitivity, 100% specificity, a positive predictive value of 1 and a negative predictive value of 0.875 in diagnosing transudates. An ascitic fluid echogenicity of Grade II or more had a sensitivity of 87.5%, specificity of 100%, a positive predictive value of 1 and a negative predictive value of 0.903 in diagnosing transudates.


Migratory birds reinforce local circulation of avian influenza viruses.
Migratory and resident hosts have been hypothesized to fulfil distinct roles in infectious disease dynamics. However, the contribution of resident and migratory hosts to wildlife infectious disease epidemiology, including that of low pathogenic avian influenza virus (LPAIV) in wild birds, has largely remained unstudied. During an autumn H3 LPAIV epizootic in free-living mallards (Anas platyrhynchos) - a partially migratory species - we identified resident and migratory host populations using stable hydrogen isotope analysis of flight feathers. We investigated the role of migratory and resident hosts separately in the introduction and maintenance of H3 LPAIV during the epizootic. To test this we analysed (i) H3 virus kinship, (ii) temporal patterns in H3 virus prevalence and shedding and (iii) H3-specific antibody prevalence in relation to host migratory strategy. We demonstrate that the H3 LPAIV strain causing the epizootic most likely originated from a single introduction, followed by local clonal expansion. The H3 LPAIV strain was genetically unrelated to H3 LPAIV detected both before and after the epizootic at the study site. During the LPAIV epizootic, migratory mallards were more often infected with H3 LPAIV than residents. Low titres of H3-specific antibodies were detected in only a few residents and migrants. Our results suggest that in this LPAIV epizootic, a single H3 virus was present in resident mallards prior to arrival of migratory mallards followed by a period of virus amplification, importantly associated with the influx of migratory mallards. Thus migrants are suggested to act as local amplifiers rather than the often suggested role as vectors importing novel strains from afar. Our study exemplifies that a multifaceted interdisciplinary approach offers promising opportunities to elucidate the role of migratory and resident hosts in infectious disease dynamics in wildlife.


A transgenic mouse model of the ubiquitin/proteasome system.
Impairment of the ubiquitin/proteasome system has been proposed to play a role in neurodegenerative disorders such as Alzheimer and Parkinson diseases. Although recent studies confirmed that some disease-related proteins block proteasomal degradation, and despite the existence of excellent animal models of both diseases, in vivo data about the system are lacking. We have developed a model for in vivo analysis of the ubiquitin/proteasome system by generating mouse strains transgenic for a green fluorescent protein (GFP) reporter carrying a constitutively active degradation signal. Administration of proteasome inhibitors to the transgenic animals resulted in a substantial accumulation of GFP in multiple tissues, confirming the in vivo functionality of the reporter. Moreover, accumulation of the reporter was induced in primary neurons by UBB+1, an aberrant ubiquitin found in Alzheimer disease. These transgenic animals provide a tool for monitoring the status of the ubiquitin/proteasome system in physiologic or pathologic conditions.


Perspective of the frontolateral craniotomies.
The pterional craniotomy is one of the most frequently surgical approaches used in neurosurgery and currently it has become a mainsteam. It allows excellent microsurgical exposure of anterior and posterior regions of the arterial circle of Willis, supra and paraselar regions, the superior orbital fissure of sphenoid bone, cavernous sinus, orbit, temporal lobe, midbrain and the frontal lobe. Like others techniques, the pterional craniotomy presented disadvantages related to dissection of the temporal muscle. From the first fronto lateral craniotomy described by Dandy to expose the optic chiasm and the pituitary we pass through the Yasargil's classical description of craniotomy centered in fronto-temporal sylvian fissure until reaching the recent"minipterional craniotomy", modifications of the pterional craniotomy were proposed to reduce the extra cranial tissue trauma and reduce the area of craniotomy without affecting the exposure of surgical targets, thus improving their aesthetic and functional results. An historical analysis of the frontolateral approaches has demonstrated that they have evolved from larger craniotomies to smaller ones, however only the minipterional craniotomy is able to offer similar surgical exposure.


Assessing behind armor blunt trauma (BABT) under NIJ standard-0101.04 conditions using human torso models.
Although soft armor vests serve to prevent penetrating wounds and dissipate impact energy, the potential of nonpenetrating injury to the thorax, termed behind armor blunt trauma, does exist. Currently, the ballistic resistance of personal body armor is determined by impacting a soft armor vest over a clay backing and measuring the resulting clay deformation as specified in National Institute of Justice (NIJ) Standard-0101.04. This research effort evaluated the efficacy of a physical Human Surrogate Torso Model (HSTM) as a device for determining thoracic response when exposed to impact conditions specified in the NIJ Standard. The HSTM was subjected to a series of ballistic impacts over the sternum and stomach. The pressure waves propagating through the torso were measured with sensors installed in the organs. A previously developed Human Torso Finite Element Model (HTFEM) was used to analyze the amount of tissue displacement during impact and compared with the amount of clay deformation predicted by a validated finite element model. All experiments and simulations were conducted at NIJ Standard test conditions. When normalized by the response at the lowest threat level (Level I), the clay deformations for the higher levels are relatively constant and range from 2.3 to 2.7 times that of the base threat level. However, the pressures in the HSTM increase with each test level and range from three to seven times greater than Level I depending on the organ. The results demonstrate the abilities of the HSTM to discriminate between threat levels, impact conditions, and impact locations. The HTFEM and HSTM are capable of realizing pressure and displacement differences because of the level of protection, surrounding tissue, and proximity to the impact point. The results of this research provide insight into the transfer of energy and pressure wave propagation during ballistic impacts using a physical surrogate and computational model of the human torso.


Comparison of high fibre diets, basal insulin supplements, and flexible insulin treatment for non-insulin dependent (type II) diabetics poorly controlled with sulphonylureas.
To compare high fibre diet, basal insulin supplements and a regimen of insulin four times daily in non-insulin dependent (type II) diabetic patients who were poorly controlled with sulphonylureas. Run in period lasting 2-3 months during which self monitoring of glucose concentration was taught, followed by six months on a high fibre diet, followed by six months' treatment with insulin in those patients who did not respond to the high fibre diet. Teaching hospital diabetic clinics. 33 patients who had had diabetes for at least two years and had haemoglobin A1 concentrations over 10% despite receiving nearly maximum doses of oral hypoglycaemic agents. No absolute indications for treatment with insulin. During the high fibre diet daily fibre intake was increased by a mean of 16 g (95% confidence interval 12 to 20 g.) Twenty five patients were then started on once daily insulin. After three months 14 patients were started on four injections of insulin daily. Control of diabetes (haemoglobin A1 concentration less than or equal to 10% and fasting plasma glucose concentration less than or equal to 6 mmol/l) or completion of six months on insulin treatment. No change in weight, diet, or concentrations of fasting glucose or haemoglobin A1 occurred during run in period. During high fibre diet there were no changes in haemoglobin A1 concentrations, but mean fasting glucose concentrations rose by 1.7 mmol/l (95% confidence interval 0.9 to 2.5, p less than 0.01). With once daily insulin mean concentrations of fasting plasma glucose fell from 12.6 to 7.6 mmol/l (p less than 0.001) and haemoglobin A1 from 14.6% to 11.2% (p less than 0.001). With insulin four times daily concentrations of haemoglobin A1 fell from 11.5% to 9.6% (p less than 0.02). Lipid concentrations were unchanged by high fibre diet. In patients receiving insulin the mean cholesterol concentrations fell from 7.1 to 6.4 mmol/l (p less than 0.0001), high density lipoprotein concentrations rose from 1.1 to 1.29 mmol/l (p less than 0.01), and triglyceride concentrations fell from 2.67 to 1.86 mmol/l (p less than 0.05). Patients taking insulin gained weight and those taking it four times daily gained an average of 4.2 kg. High fibre diets worsen control of diabetes in patients who are poorly controlled with oral hypoglycaemic agents. Maximum improvements in control of diabetes were achieved by taking insulin four times daily.