Hibernation in an antarctic fish: on ice for winter.
Active metabolic suppression in anticipation of winter conditions has been demonstrated in species of mammals, birds, reptiles and amphibians, but not fish. This is because the reduction in metabolic rate in fish is directly proportional to the decrease in water temperature and they appear to be incapable of further suppressing their metabolic rate independently of temperature. However, the Antarctic fish (Notothenia coriiceps) is unusual because it undergoes winter metabolic suppression irrespective of water temperature. We assessed the seasonal ecological strategy by monitoring swimming activity, growth, feeding and heart rate (f(H)) in N. coriiceps as they free-ranged within sub-zero waters. The metabolic rate of wild fish was extrapolated from f(H )recordings, from oxygen consumption calibrations established in the laboratory prior to fish release. Throughout the summer months N. coriiceps spent a considerable proportion of its time foraging, resulting in a growth rate (G(w)) of 0.18 +/- 0.2% day(-1). In contrast, during winter much of the time was spent sedentary within a refuge and fish showed a net loss in G(w) (-0.05 +/- 0.05% day(-1)). Whilst inactive during winter, N. coriiceps displayed a very low f(H), reduced sensory and motor capabilities, and standard metabolic rate was one third lower than in summer. In a similar manner to other hibernating species, dormancy was interrupted with periodic arousals. These arousals, which lasted a few hours, occurred every 4-12 days. During arousal activity, f(H) and metabolism increased to summer levels. This endogenous suppression and activation of metabolic processes, independent of body temperature, demonstrates that N. coriiceps were effectively 'putting themselves on ice' during winter months until food resources improved. This study demonstrates that at least some fish species can enter a dormant state similar to hibernation that is not temperature driven and presumably provides seasonal energetic benefits.


Biotechnology and food systems in developing countries.
Even in a world with adequate food supplies in global markets, which is the situation today, biotechnology offers important opportunities to developing countries in four domains. First, many agronomically hostile or degraded environments require major scientific breakthroughs to become productive agricultural systems. Few of these breakthroughs are likely to be achieved through traditional breeding approaches. Second, biofortification offers the promise of greater quantities and human availabilities of micronutrients from traditional staple foods, with obvious nutritional gains for poor consumers, especially their children. Third, many high yielding agricultural systems are approaching their agronomic potential. Radically new technologies will be required to sustain productivity growth in these systems, and only modern genetic technology offers this hope. Finally, many cropping systems use large quantities of chemical inputs, such as herbicides, pesticides and fertilizers that can be unhealthy for people and soils alike. Biotechnology offers the potential to reduce the need for these inputs in economically and environmentally sustainable ways. Applying these new technologies to society's basic foods raises obvious concerns for both human and ecological health. For some, these concerns have become outright fear, and this has mobilized a backlash against genetically modified foods in any form. These concerns (and fears) must be addressed carefully and rationally so that the public understands the risks (which are not zero) and benefits (which might be enormous). Only the scientific community has the expertise and credibility to build this public understanding.


Pulmonary and blood stream infections in adult living donor and cadaveric liver transplant patients.
Infectious complications occur in approximately 50% of cadaveric liver transplant (CDLT) recipients. Living-donor liver transplantation (LDLT) is an established alternative to shorten the waiting time. Currently, the incidence of pulmonary infections after LDLT and the microbiologic causes are unknown. In the present cohort study, we compared the incidence and profiles of pulmonary and blood stream infections (BSI) between LDLT and CDLT recipients. We hypothesized a lower incidence in LDLT recipients. The clinical course of 55 LDLT recipients consecutively transplanted between January 2003 and December 2006 was analyzed. The 173 CDLT recipients who were transplanted in the same period served as a control group. Patients were treated in a single Intensive Care Unit, applying standardized postoperative care. Mean model for end-stage liver disease score did not differ between LDLT and CDLT recipients (14.2 vs. 13.3). The overall incidence of pulmonary and BSI for both groups was 8% and 24%, respectively. Pulmonary infections were experienced by 18% of LDLT versus 5% of CDLT recipients (P=0.005) and BSI occurred in 33% of LDLT versus 21% of CDLT recipients (P=0.1). In contrast to our hypothesis, LDLT recipients experienced significantly more pulmonary infections and a trend toward increased higher incidence of BSI. These findings emphasize the need for future research on the causative agents and prevention of infection in LDLT recipients. The observation that patients with pulmonary infection had a significantly reduced 1-year survival rate underscores the importance of our observations.


Unraveling a mechanism of honey antibacterial action: polyphenol/H₂O₂-induced oxidative effect on bacterial cell growth and on DNA degradation.
Several compounds with antibacterial activities were identified in honey however, a mechanism by which they lead to bacterial growth inhibition and bacterial death remains still unknown. We recently found that honeys possess DNA degrading activity mediated by honey hydrogen peroxide and an unknown honey component(s). Here we provide evidence that active honeys (MIC90 of 6.25-12.5% v/v) possessed significantly higher levels of phenolics (p<0.02) of higher radical scavenging activities (p<0.005) than honeys of average activity. Removal of H2O2 by catalase eliminated bacteriostatic activities caused by both phenolics and H2O2 suggesting that the growth inhibition resulted from the coupling chemistry between these compounds. Both phenolics and H2O2 were involved in DNA degradation by honeys. Treatment of plasmid DNA with H2O2 alone did not affect the DNA integrity but H2O2 removal from honey by catalase prevented DNA degradation. Polyphenols extracted from honeys degraded plasmid DNA in the presence of H2O2 and Cu(II) in the Fenton-type reaction. The extent of DNA degradation was inversely related to the polyphenol concentration in this system as well as in honeys. At low content, honey polyphenols exerted pro-oxidant activity damaging to DNA. In conclusion, honey phenolics with pro-oxidant activities were necessary intermediates that conferred oxidative action of H2O2. Phenolic/H2O2-induced oxidative stress constituted the mechanism of honey bacteriostatic and DNA damaging activities.


Ferromagnetic Heating for Vessel Sealing and Division: Utility and Comparative Study to Ultrasonic and Bipolar Technologies.
Vessel sealing technologies have improved surgical efficiency and outcomes. Ferromagnetic technology has potential utility in this area. The aim of this study was to evaluate ferromagnetic heating in sealing and dividing vessels. A novel ferromagnetic (FM) sealer, FMsealer, was developed for sealing and dividing vessels. Using a swine in vivo model, the following endpoints were evaluated: (1) proof of concept, (2) 21-day survival surgery, and (3) comparison with ultrasonic (US) and/or bipolar (BP) devices for subjective outcomes. Seal burst strengths were measured in vitro. Mann-Whitney and Student's t test were used. After showing proof of concept, 5 swine underwent survival splenectomy, nephrectomy, hysterectomy, and mesenteric vessel division (arteries ranging from 1 to 7 mm in diameter) with necropsy after day 21 showing no evidence of surgical site bleeding. FM was equivalent to BP in tissue retention and superior to BP in spread/tissue desiccation, sticking, and charring (P ≤ .01). The FM was superior to US and BP in speed of 10 cm mesentery division (mean ± SD seconds): FM (12.9 ± 1.0 seconds), US (23.3 ± 4.4 seconds), BP (46.1 ± 5.2 seconds) (P ≤ .01 FM vs US or BP). Seal burst strength and success of sealing a 5-mm carotid artery were as follows (mean ± SD mmHg, % success burst strength >240 mm Hg): FM (710 ± 206 mm Hg, 94% success), US (848 ± 565 mm Hg, 79%), and BP (619 ± 373 mm Hg, 83%). Ferromagnetic heating is an effective and efficient technology for sealing and dividing of vessels. An initial prototype of the FMsealer compared favorably with commercially available products based on ultrasonic and bipolar technologies.


Cellular expression, trafficking, and function of two isoforms of human ULBP5/RAET1G.
The activating immunoreceptor NKG2D is expressed on Natural Killer (NK) cells and subsets of T cells. NKG2D contributes to anti-tumour and anti-viral immune responses in vitro and in vivo. The ligands for NKG2D in humans are diverse proteins of the MIC and ULBP/RAET families that are upregulated on the surface of virally infected cells and tumours. Two splicing variants of ULBP5/RAET1G have been cloned previously, but not extensively characterised. We pursue a number of approaches to characterise the expression, trafficking, and function of the two isoforms of ULBP5/RAET1G. We show that both transcripts are frequently expressed in cell lines derived from epithelial cancers, and in primary breast cancers. The full-length transcript, RAET1G1, is predicted to encode a molecule with transmembrane and cytoplasmic domains that are unique amongst NKG2D ligands. Using specific anti-RAET1G1 antiserum to stain tissue microarrays we show that RAET1G1 expression is highly restricted in normal tissues. RAET1G1 was expressed at a low level in normal gastrointestinal epithelial cells in a similar pattern to MICA. Both RAET1G1 and MICA showed increased expression in the gut of patients with celiac disease. In contrast to healthy tissues the RAET1G1 antiserum stained a wide variety or different primary tumour sections. Both endogenously expressed and transfected RAET1G1 was mainly found inside the cell, with a minority of the protein reaching the cell surface. Conversely the truncated splicing variant of RAET1G2 was shown to encode a soluble molecule that could be secreted from cells. Secreted RAET1G2 was shown to downregulate NKG2D receptor expression on NK cells and hence may represent a novel tumour immune evasion strategy. We demonstrate that the expression patterns of ULBP5RAET1G are very similar to the well-characterised NKG2D ligand, MICA. However the two isoforms of ULBP5/RAET1G have very different cellular localisations that are likely to reflect unique functionality.


[Is there really something wrong with the formalization processes of the anticipated will? Insist on DATs or (finally) promote advance care planning (ACP)?]
The author analyzes the possible paths for the formalization of the anticipated will regarding the care provided for by law no. 219/2017, identifying them in the advance treatment provisions (DAT) and in the shared care planning (advance care planning) of which he examines the merits and related defects. He proposes to invest better and more in shared care planning, indicating the advantages and opportunities that derive from its gradual formation within the care relationship, while signaling the need to proceed promptly with the appointment of the trustee, provided in an optional form by the law. He then addresses the role exercised by this representative figure which is to assist the care team throughout the disease trajectory and not only when it is necessary to honor the wishes and preferences expressed by the person when he was in a position to do so, and he does it criticizing the choice made by the legislator who indicated it in full possession of the ability to understand and want.


Utilisation of hydrogen peroxide in the treatment of recurrent bacterial vaginosis.
The authors have evaluated the real efficacy of using hydrogen peroxide for previously treated recurrent bacterial vaginosis that is resistant to other forms of treatment. The study included 58 women aged between 18 and 42 years old. Vaginal irrigations with 30 ml of hydrogen peroxide (3%) were prescribed in the evening for a week. The follow-up was carried out 3 months after the end of treatment. The results clearly show that the use of hydrogen peroxide in vagina can eliminate the main symptoms of bacterial vaginosis, and in particular the malodorous leucoxanthorrhea in 89% of cases at 3 months after the end of treatment, a result that is comparable to that obtained using metronidazole or clindamycin as a vaginal cream. Moreover, hydrogen peroxide facilitates the restoration of normal vaginal bacterial flora (represented by H202-producing lactobacillus) in 100% of cases and normal acid pH (pH<4.5) in 98% of cases; it also fosters the disappearance of clue cells from vaginal smears and anaerobic pathogenic flora from vaginal secretions in 100% of cases. The amine test became negative in 97.8% of cases. All results underwent statistical analysis and were found to be statistically significant. Hydrogen peroxide represents a valid alternative to conventional treatments for recurrent bacterial vaginosis, and associates the absence of collateral effects with low costs, excellent tolerability and real therapeutic efficacy.


Molecules, wing pattern and distribution: an approach to species delimitation in the "loxurina group" (Lepidoptera: Lycaenidae: Penaincisalia).
The wide range of morphological variations in the "loxurina group" makes taxa identification difficult, and despite several reviews, serious taxonomical confusion remains. We make use of DNA data in conjunction with morphological appearance and available information on species distribution to delimit the boundaries of the "loxurina" group species previously established based on morphology. A fragment of 635 base pairs within the mtDNA gene cytochrome oxidase I (COI) was analysed for seven species of the "loxurina group". Phylogenetic relationships among the included taxa were inferred using maximum parsimony and maximum likelihood methods. Penaincisalia sigsiga (Bálint et al), P. cillutincarae (Draudt), P. atymna (Hewitson) and P. loxurina (C. Felder & R. Felder) were easily delimited as the morphological, geographic and molecular data were congruent. Penaincisalia ludovica (Bálint & Wojtusiak) and P. loxurina astillero (Johnson) represent the same entity and constitute a sub-species of P. loxurina. However, incongruence among morphological, genetic, and geographic data is shown in P. chachapoya (Bálint & Wojtusiak) and P. tegulina (Bálint et al). Our results highlight that an integrative approach is needed to clarify the taxonomy of these neotropical taxa, but more genetic and geographical studies are still required.


Altered plasma adipokine levels and in vitro adipocyte differentiation in pediatric type 1 diabetes.
Type 1 diabetes (T1D) is considered a proinflammatory condition. Adipose tissue involvement seems evident because adiponectin levels correlate with disease remission and administration of leptin suppresses the low-grade systemic inflammation in mice with T1D. Whether adipose tissue involvement in T1D already occurs at a young age is yet unknown. The aim was to explore the extent of adipokine alterations in pediatric T1D and gain more insight into the mechanisms underlying the involvement of adipose tissue. First, plasma adipokine profiling (24 adipokines) of 20 children with onset T1D, 20 children with long-standing T1D, and 17 healthy controls was performed using a recently developed and validated multiplex immunoassay. Second, the effects of diabetic plasma factors on preadipocyte proliferation and differentiation were studied in vitro. In children with onset and long-standing T1D, plasma adipokine profiling showed increased levels of various adipokines acting at the crossroads of adipose tissue function and inflammation, including CCL2/monocyte chemoattractant protein-1 and the novel adipokines cathepsin S, chemerin, and tissue inhibitor of metalloproteinase-1 (P < 0.05). Furthermore, onset and long-standing diabetic plasma significantly induced preadipocyte proliferation and adipocyte differentiation in vitro (P < 0.05). Two candidate plasma factors, glucose and the saturated fatty acid palmitic acid, did not affect proliferation or adipocyte differentiation in vitro but were found to increase CCL2 (monocyte chemoattractant protein-1) secretion by adipocytes. The adipogenic effects of diabetic plasma in vitro and the altered adipokine levels in vivo suggest adipose tissue involvement in the low-grade inflammation associated with T1D, already in pediatric patients.


Vitamin D and Omega 3 Field Study on Progression of Type 1 Diabetes.
Chronic inflammation has been linked to the progression of type 1 diabetes (T1D). Supplementation with vitamin D and omega-3 fatty acids, which have anti-inflammatory properties, may slow or stop the progression of T1D. A field study is underway to assess the relationship between these nutrients and T1D progression among auto-antibody positive individuals who have not been diagnosed with T1D. The T1D Prevention Field Study is currently recruiting participants to complete online health surveys and home blood-spot tests for 25-hydroxyvitamin D [25(OH)D], Omega-3 Index, AA:EPA Ratio, high-sensitivity C-reactive protein, and HbA1c every three to four months for 5 years. Participants (or their parents/guardians) are given information about the importance of achieving a 25(OH)D level between 40-60 ng/ml and an AA:EPA Ratio between 1.5-3.0 to reduce inflammation. However, participants are free to choose their own supplement or dietary regimens. Data analysis will focus on associations between vitamin D and omega-3 status and progression of T1D. Initial enrollment in the T1D Prevention Field Study includes 103 participants from fifteen countries; total enrollment is expected to reach at least 400 participants by the end of 2022. The field study approach allows for cost-effective research that capitalizes on new technologies for recruitment, data collection, and blood level testing from home. However, some challenges have arisen. Many individuals are reading the open source protocols and some choose to supplement and test on their own so incentives may be needed to increase enrollment. Additionally, some participants do not have access to auto-antibody testing or are unable to get access to their test results; therefore, there is a need to provide blood spot auto-antibody testing through the field study.


The mutagenicity of sodium fluoride to L5178Y [wild-type and TK+/- (3.7.2c)] mouse lymphoma cells.
L5178Y wild-type and TK+/- (3.7.2c) cells were treated with sodium fluoride over a range of concentrations (10-500 micrograms ml-1) and treatment times (4, 16 and 48 h) covering less than 10-100% survival. The mutant frequency at five genetic loci (resistance to ouabain, 6-thioguanine, excess thymidine, methotrexate and 1-beta-D-arabinofuranosyl cytosine) was assayed in wild-type cells and trifluorothymidine in TK+/- cells. No significant induced mutation at any locus was observed after 4 h of treatment. Sixteen hours of treatment with high concentrations of sodium fluoride did not induce resistance to ouabain, but resulted in some significant induction of 6-thioguanine, 1-beta-D-arabinofuranosyl cytosine and methotrexate resistance, although the results were variable between experiments and no dose-response was observed. At the thymidine kinase locus, a dose-related increase in mutant frequency to excess thymidine and trifluorothymidine resistance was observed. The maximum induction was approximately eight times the control frequency after TK+/- cells were treated with the highly toxic concentration of 500 micrograms ml-1 of sodium fluoride for 16 h. These observations, and an analysis of the colony size of trifluorothymidine-resistant mutants in TK+/- cells, suggest that sodium fluoride is clastogenic to dividing cultured mammalian cells at high, toxic concentrations. Further work is desirable to investigate the mechanism by which chromosomes are damaged at high concentrations of fluoride, since without such a mechanistic understanding, extrapolation of our data to the human situation must be insecure. Nevertheless, the knowledge available at present gives no reason to expect any genotoxic effects in human tissues at levels of fluoride ions to which they are currently exposed in the general population.


Differential TIMP3 expression affects tumor progression and angiogenesis in melanomas through regulation of directionally persistent endothelial cell migration.
The angiogenic potential of solid tumors, or the ability to initiate neovasculature development from pre-existing host vessels, is facilitated by soluble factors secreted by tumor cells and involves breaching of extracellular matrix barriers, endothelial cell (EC) proliferation, migration and reassembly. We evaluated the angiogenic potential of human melanoma cell lines differing in their degree of aggressiveness, based on their ability to regulate directionally persistent EC migration. We observed that conditioned-medium (CM) of the aggressive melanoma cell line BLM induced a high effective migratory response in ECs, while CMs of Mel57 and 1F6 had an inhibitory effect. Further, the melanoma cell lines exhibited a varied expression profile of tissue inhibitor of metalloproteinase-3 (TIMP3), detectable in the CM. TIMP3 expression inversely correlated with aggressiveness of the melanoma cell line, and ability of the respective CMs to induce directed EC migration. Interestingly, TIMP3 expression was found to be silenced in the BLM cell line, concurrent with its role as a tumor suppressor. Treatment with recombinant human TIMP3 and CM of modified, TIMP3 expressing, BLM cells mitigated directional EC migration, while CM of TIMP3 silenced 1F6 cells induced directed EC migration. The functional implication of TIMP3 expression on tumor growth and angiogenic potential in melanoma was evaluated in vivo. We observed that TIMP3 expression reduced tumor growth, angiogenesis and macrophage infiltration of BLM tumors while silencing TIMP3 increased tumor growth and angiogenesis of 1F6 tumors. Taken together, our results demonstrate that TIMP3 expression correlates with inhibition of directionally persistent EC migration and adversely affects the angiogenic potential and growth of melanomas.


In vitro effects of long-chain acylcarnitines on the permeability, transepithelial electrical resistance and morphology of rat colonic mucosa.
Absorption-enhancing properties of the long-chain acylcarnitines (C12-C18) were examined in vitro utilizing a modified Sweetana-Grass diffusion cell system. Transepithelial electrical resistance (TEER) and drug permeability (P) of rat colonic mucosa were used as parameters to determine the potency, selectivity and reversibility of acylcarnitine-enhancing effects. All long-chain acylcarnitines induced a rapid, concentration-dependent decrease in mucosal TEER. The minimum or threshold concentration (Ct) which produced a rapid decrease in mucosal TEER was determined for each acylcarnitine. Tissues treated with either palmitoyl or lauroyl carnitine at their Ct showed significantly better recovery of TEER after removal of the enhancers from the diffusion cells as compared to the other long-chain acylcarnitines. In addition, palmitoyl and lauroyl carnitine treatment significantly enhanced the mucosal permeability to small, hydrophilic markers without adversely altering tissue morphology. Following enhancer replacement with buffer alone and the subsequent recovery of TEER, mucosal permeability was observed to return to near control levels. At higher concentrations of palmitoyl and lauroyl (5 x Ct), P increased nearly 2-fold over that observed at the Ct; however, epithelial barrier morphology was compromised. This study shows that colonic mucosal tissue mounted in modified Sweetana-Grass diffusion cells may be a useful model for examining the mechanism(s) of absorption enhancer activity. Moreover, the results present evidence that the long-chain acylcarnitines may enhance drug absorption via two different concentration-dependent pathways.


The ventral hippocampus is involved in multi-goal obstacle-rich spatial navigation.
A large body of evidence shows that the hippocampus is necessary for successful spatial navigation. Various studies have shown anatomical and functional differences between the dorsal (DHC) and ventral (VHC) portions of this structure. The DHC is primarily involved in spatial navigation and contains cells with small place fields. The VHC is primarily involved in context and emotional encoding contains cells with large place fields and receives major projections from the medial prefrontal cortex. In the past, spatial navigation experiments have used relatively simple tasks that may not have required a strong coordination along the dorsoventral hippocampal axis. In this study, we tested the hypothesis that the DHC and VHC may be critical for goal-directed navigation in obstacle-rich environments. We used a learning task in which animals memorize the location of a set of rewarded feeders, and recall these locations in the presence of small or large obstacles. We report that bilateral DHC or VHC inactivation impaired spatial navigation in both large and small obstacle conditions. Importantly, this impairment did not result from a deficit in the spatial memory for the set of feeders (i.e., recognition of the goal locations) because DHC or VHC inactivation did not affect recall performance when there was no obstacle on the maze. We also show that the behavioral performance of the animals was correlated with several measures of maze complexity and that these correlations were significantly affected by inactivation only in the large object condition. These results suggest that as the complexity of the environment increases, both DHC and VHC are required for spatial navigation.


Post-transcriptional regulation in the nucleus and cytoplasm: study of mean time to threshold (MTT) and narrow escape problem.
Messenger RNAs (mRNAs) can be repressed and degraded by small non-coding RNA molecules. In this paper, we formulate a coarsegrained Markov-chain description of the post-transcriptional regulation of mRNAs by either small interfering RNAs (siRNAs) or microRNAs (miRNAs). We calculate the probability of an mRNA escaping from its domain before it is repressed by siRNAs/miRNAs via calculation of the mean time to threshold: when the number of bound siRNAs/miRNAs exceeds a certain threshold value, the mRNA is irreversibly repressed. In some cases, the analysis can be reduced to counting certain paths in a reduced Markov model. We obtain explicit expressions when the small RNA bind irreversibly to the mRNA and we also discuss the reversible binding case. We apply our models to the study of RNA interference in the nucleus, examining the probability of mRNAs escaping via small nuclear pores before being degraded by siRNAs. Using the same modelling framework, we further investigate the effect of small, decoy RNAs (decoys) on the process of post-transcriptional regulation, by studying regulation of the tumor suppressor gene, PTEN: decoys are able to block binding sites on PTEN mRNAs, thereby reducing the number of sites available to siRNAs/miRNAs and helping to protect it from repression. We calculate the probability of a cytoplasmic PTEN mRNA translocating to the endoplasmic reticulum before being repressed by miRNAs. We support our results with stochastic simulations.


3D structure determination of amyloid fibrils using solid-state NMR spectroscopy.
The amyloid fold is structurally characterized by a typical cross-β architecture, which is under debate to represent an energy-favourable folding state that many globular or natively unfolded proteins can adopt. Being initially solely associated with amyloid fibrils observed in the propagation of several neurodegenerative disorders, the discovery of non-pathological (or "functional") amyloids in many native biological processes has recently further intensified the general interest invested in those cross-β supramolecular assemblies. The insoluble and non-crystalline nature of amyloid fibrils and their usually inhomogeneous appearance on the mesoscopic level pose a challenge to biophysical techniques aiming at an atomic-level structural characterization. Solid-state NMR spectroscopy (SSNMR) has granted breakthroughs in structural investigations on amyloid fibrils ranging from the assessment of the impact of polymorphism in disease development to the 3D atomic structure determination of amyloid fibrils. First landmark studies towards the characterization of atomic structures and interactions involving functional amyloids have provided new impulses in the understanding of the role of the amyloid fold in native biological functions. Over the last decade many strategies have been developed in protein isotope labelling, NMR resonance assignment, distance restraint determination and 3D structure calculation of amyloid fibrils based on SSNMR approaches. We will here discuss the emerging concepts and state-of-the-art methods related to the assessment of amyloid structures and interactions involving amyloid entities by SSNMR.


Exposure to Family and Friend Homicide in a Nationally Representative Sample of Youth.
This study examines the lifetime prevalence and distribution of family/friend homicide exposure among children and adolescents age 2 to 17 in the United States, and assesses the impact of family/friend homicide on emotional and behavioral outcomes, while controlling for potential co-occurring factors. Data were collected by telephone about the experiences of youth in 2008, 2011, or 2014, as part of the National Surveys of Children's Exposure to Violence (NatSCEV). Analyses are based on a pooled sample (n =11,771) from these three surveys. Approximately 8% of all children and youth ages 2 to 17 were exposed to a family/friend homicide. Older adolescents, Black youth, those living in single parent and nonparent family households, those from lower socioeconomic status households, and youth living in large cities were overrepresented among youth experiencing family or friend homicide. Exposed youth were also substantially more likely to be poly-victims, experience other major adversities, and live in neighborhoods with more community disorder. Exposure to family/friend homicide was significantly related to trauma symptoms. However, when other co-occurring factors were taken into account, only family/friend homicide that occurred within the last 2 years remained significant. With respect to delinquency, only nonfamily homicide exposure remained significant with these other factors controlled. Findings suggest that family/friend homicide represents a powerful marker for a broad level of victimization risk and adversity, demonstrating that family/friend murder is often just one relatively small part of a more complicated life of adversity. Although recent exposure is certainly distressing to youth, it is the wider, co-occurring context of poly-victimization and other types of adversity that appears most impactful in the longer term.


From damage to discovery via virtual unwrapping: Reading the scroll from En-Gedi.
Computer imaging techniques are commonly used to preserve and share readable manuscripts, but capturing writing locked away in ancient, deteriorated documents poses an entirely different challenge. This software pipeline-referred to as "virtual unwrapping"-allows textual artifacts to be read completely and noninvasively. The systematic digital analysis of the extremely fragile En-Gedi scroll (the oldest Pentateuchal scroll in Hebrew outside of the Dead Sea Scrolls) reveals the writing hidden on its untouchable, disintegrating sheets. Our approach for recovering substantial ink-based text from a damaged object results in readable columns at such high quality that serious critical textual analysis can occur. Hence, this work creates a new pathway for subsequent textual discoveries buried within the confines of damaged materials.


Understanding marital conflict 7 years later from prenatal representations of marriage.
We examine how representations of marriage, assessed prenatally, predict different types of marital conflict (cooperation, avoidance/capitulation, stonewalling, and child involvement in parental conflict) at 7 years postpartum (N=132 individuals). We assessed representations of marriage prenatally by interviewing spouses about their own parents' marriage, and then rated the content and insightfulness of their memories. Results show that marital representations characterized by higher insight predict higher cooperation and lower child involvement in parental conflict, whereas content of marital representations was not a significant predictor of marital conflict. Further, individuals who remember negative memories from their parents' marriage with high insight were lowest on child involvement in parental conflict, whereas those who remember negative memories with low insight were highest on child involvement in parental conflict. Finally, women who remember negative content with high insight report the highest cooperation, whereas women who remember negative content with low insight report the lowest cooperation. For men, however, marital representations were less effective in predicting later cooperation. We conclude that marital representations, even when assessed prenatally, influence certain types of marital conflict 7 years later. Using such findings, therapists could help spouses gain insight into how the memories of their parents' marriage relate to the use of specific conflict strategies in their marriage.


Quinine blocks specific gap junction channel subtypes.
We demonstrate that the antimalarial drug quinine specifically reduces currents through gap junctions formed by some connexins (Cx) in transfected mammalian cells, but does not affect other gap junction types. Quinine blocked Cx36 and Cx50 junctional currents in a reversible and concentration-dependent manner with half maximal blocking concentrations of 32 and 73 microM, respectively; Hill coefficients for block by quinine were about 2 for both connexins. In contrast, quinine did not substantially block gap junction channels formed by Cx26, Cx32, Cx40, and Cx43, and only moderately affected Cx45 junctions. To determine the location of the binding site of quinine (pKa = 8.7), we investigated the effect of quinine at various external and internal pH values and the effect of a permanently charged quaternary derivative of quinine. Our results indicate that the binding site for quinine is intracellular, possibly within the pore. Single-channel studies indicated that exposure to quinine induced slow transitions between open and fully closed states that decreased open probability of the channel. Quinine thus offers a potentially useful method to block certain types of gap junction channels, including those between neurons that are formed by Cx36. Moreover, quinine derivatives that are excluded from other types of membrane channels may provide molecules with connexin-specific as well as connexin-selective blocking activity.


Residues and metabolites of selected persistent halogenated hydrocarbons in blood specimens from a general population survey.
The National Center for Health Statistics collaborated with the National Human Monitoring Program of the U.S. Environmental Protection Agency (EPA) in a four-year study to assess the exposure of the general population to selected pesticides through analysis of blood serum and urine specimens. Specimens were collected on a national probability half-sample of persons 12-74 years of age from 64 locations across the United States comprising the sample areas in the Second National Health and Examination Survey (NHANES II) and analyzed for selected organochlorine, carbamate, chlorophenoxy and organophosphorus pesticides. Medical, nutritional and pesticide usage data are also available for each sample person. Results of the blood serum analyses indicate that the general population is being exposed to some of these types of pesticides. For selected pesticide residues, the percent quantifiable positives and median serum levels by age group are presented for three regions of the United States. Since 1970, EPA has conducted a national probability sampling of human adipose tissue. Specimens obtained on a survey design representative of the general population were analyzed for selected organochlorine pesticides and toxic chemicals. Findings from the 1979 survey also indicate exposure of the general population to some of these chemicals.


Revealing the Origins of Mechanically Induced Fluorescence Changes in Organic Molecular Crystals.
Mechanofluorochromic molecular materials display a change in fluorescence color through mechanical stress. Complex structure-property relationships in both the crystalline and amorphous phases of these materials govern both the presence and strength of this behavior, which is usually deemed the result of a mechanically induced phase transition. However, the precise nature of the emitting species in each phase is often a matter of speculation, resulting from experimental data that are difficult to interpret, and a lack of an acceptable theoretical model capable of capturing complex environmental effects. With a combined strategy using sophisticated experimental techniques and a new theoretical approach, here the varied mechanofluorochromic behavior of a series of difluoroboron diketonates is shown to be driven by the formation of low-energy exciton traps in the amorphous phase, with a limited number of traps giving rise to the full change in fluorescence color. The results highlight intrinsic structural links between crystalline and amorphous phases, and how these may be exploited for further development of powerful mechanofluorochromic assemblies, in line with modern crystal engineering approaches.


The role of mainstreamness and interdisciplinarity for the relevance of scientific papers.
Is it possible to tell how interdisciplinary and out-of-the-box scientific papers are, or which papers are mainstream? Here we use the bibliographic coupling network, derived from all physics papers that were published in the Physical Review journals in the past century, to try to identify them as mainstream, out-of-the-box, or interdisciplinary. We show that the network clusters into scientific fields. The position of individual papers with respect to these clusters allows us to estimate their degree of mainstreamness or interdisciplinarity. We show that over the past decades the fraction of mainstream papers increases, the fraction of out-of-the-box decreases, and the fraction of interdisciplinary papers remains constant. Studying the rewards of papers, we find that in terms of absolute citations, both, mainstream and interdisciplinary papers are rewarded. In the long run, mainstream papers perform less than interdisciplinary ones in terms of citation rates. We conclude that to avoid a unilateral trend towards mainstreamness a new incentive scheme is necessary.


Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes.
The seemingly inexorable decline in insulin independence after islet transplant alone (ITA) has raised concern about its clinical utility. We hypothesized that induction immunosuppression therapy determines durability of insulin independence. We analyzed the proportion of insulin-independent patients following final islet infusion in four groups of ITA recipients according to induction immunotherapy: University of Minnesota recipients given FcR nonbinding anti-CD3 antibody alone or T cell depleting antibodies (TCDAb) and TNF-α inhibition (TNF-α-i) (group 1; n = 29); recipients reported to the Collaborative Islet Transplant Registry (CITR) given TCDAb+TNF-α-i (group 2; n = 20); CITR recipients given TCDAb without TNF-α-i (group 3; n = 43); and CITR recipients given IL-2 receptor antibodies (IL-2RAb) alone (group 4; n = 177). Results were compared with outcomes in pancreas transplant alone (PTA) recipients reported to the Scientific Registry of Transplant Recipients (group 5; n = 677). The 5-year insulin independence rates in group 1 (50%) and group 2 (50%) were comparable to outcomes in PTA (group 5: 52%; p>>0.05) but significantly higher than in group 3 (0%; p = 0.001) and group 4 (20%; p = 0.02). Induction immunosuppression was significantly associated with 5-year insulin independence (p = 0.03), regardless of maintenance immunosuppression or other factors. These findings support potential for long-term insulin independence after ITA using potent induction therapy, with anti-CD3 Ab or TCDAb+TNF-α-i.


Community control of helminth infections of man by mass and selective chemotherapy.
The design of mass and targetted community-based chemotherapy programmes for the control of the major helminth infections of man is discussed in relation to the population and transmission dynamics of the parasites. Rapid reinfection following a single mass or targetted anthelmintic application is shown to be a universal feature of helminth transmission, as a consequence of the regulatory or feed-back mechanisms controlling population abundance within both individuals and the community as a whole. Control of reinfection requires repeated community treatment where the intensity of application and the interval between treatments are dependent on the reproductive life-expectancy of the adult worm, the net force of transmission prior to control (the basic reproductive rate) and the factors which create aggregation in the distribution of parasite loads within the population. Selective or targetted treatment is shown to be most effective for the control of morbidity as opposed to the control of transmission. The impact of targetted treatment depends critically on the factors that generate heterogeneity in parasite burdens and on whether or not selectivity is based on a single or repeated identification of the 'wormy' fraction of the community. Monte Carlo simulation studies are employed to assess the likely impacts of different control strategies on average parasite abundance/person and the distributions of parasite loads within populations. Future epidemiological research needs are discussed in relation to theoretical work and recent field studies of predisposition to heavy infection.


Association of Evidence-Based Care Processes With Mortality in Staphylococcus aureus Bacteremia at Veterans Health Administration Hospitals, 2003-2014.
Staphylococcus aureus bacteremia is common and frequently associated with poor outcomes. Evidence indicates that specific care processes are associated with improved outcomes for patients with S aureus bacteremia, including appropriate antibiotic prescribing, use of echocardiography to identify endocarditis, and consultation with infectious diseases (ID) specialists. Whether use of these care processes has increased in routine care for S aureus bacteremia or whether use of these processes has led to large-scale improvements in survival is unknown. To examine the association of evidence-based care processes in routine care for S aureus bacteremia with mortality. This retrospective observational cohort study examined all patients admitted to Veterans Health Administration (VHA) acute care hospitals who had a first episode of S aureus bacteremia from January 1, 2003, through December 31, 2014. Use of appropriate antibiotic therapy, echocardiography, and ID consultation. Thirty-day all-cause mortality. Analyses included 36 868 patients in 124 hospitals (mean [SD] age, 66.4 [12.5] years; 36 036 [97.7%] male), including 19 325 (52.4%) with infection due to methicillin-resistant S aureus and 17 543 (47.6%) with infection due to methicillin-susceptible S aureus. Risk-adjusted mortality decreased from 23.5% (95% CI, 23.3%-23.8%) in 2003 to 18.2% (95% CI, 17.9%-18.5%) in 2014. Rates of appropriate antibiotic prescribing increased from 2467 (66.4%) to 1991 (78.9%), echocardiography from 1256 (33.8%) to 1837 (72.8%), and ID consultation from 1390 (37.4%) to 1717 (68.0%). After adjustment for patient characteristics, cohort year, and other care processes, receipt of care processes was associated with lower mortality, with adjusted odds ratios of 0.74 (95% CI, 0.68-0.79) for appropriate antibiotics, 0.73 (95% CI, 0.68-0.78) for echocardiography, and 0.61 (95% CI, 0.56-0.65) for ID consultation. Mortality decreased progressively as the number of care processes that a patient received increased (adjusted odds ratio for all 3 processes compared with none, 0.33; 95% CI, 0.30-0.36). An estimated 57.3% (95% CI, 48.4%-69.9%) of the decrease in mortality between 2003 and 2014 could be attributed to increased use of these evidence-based care processes. Mortality associated with S aureus bacteremia decreased significantly in VHA hospitals, and a substantial portion of the decreasing mortality may have been attributable to increased use of evidence-based care processes. The experience in VHA hospitals demonstrates that increasing application of these care processes may improve survival among patients with S aureus bacteremia in routine health care settings.


NADH binding properties of rabbit lens lambda-crystallin.
The present investigation aims to evaluate the NADH binding ability of lambda-crystallin, a taxon-specific enzyme-crystallin, in the rabbit lens. A lambda/betaL1-crystallin fraction was separated from the rabbit lens soluble fraction by gel filtration and the enzyme-crystallin was partially purified by subsequent affinity column chromatography. Analysis of NADH bound to the lambda-crystallin preparation was performed using spectrophotometric and enzymological methods. Binding of added NADH to the enzyme-crystallin preparation was also analyzed using a simple ultrafiltration method, which was theoretically equivalent to equilibrium dialysis, to study additional NADH binding to the protein. The prepared lambda-crystallin samples clearly exhibited an absorption maximum at 340 nm, even though they were thoroughly dialyzed. This was due to the presence of nondialyzable NADH bound tightly to the protein. The bound NADH was removed by charcoal treatment, and extracted by 0.1% SDS or 70 degrees C heat treatment. A dissociation constant (Kd) of less than 5 nM indicated tight binding of NADH. The quantity of bound NADH in the 88% purified 33 kDa enzyme-crystallin was estimated to be 20.5 nmol/mg protein, suggesting a stoichiometry of 0.7 mol of the nucleotide/mol of the 33 kDa protein. Additional looser binding of added NADH to lambda-crystallin was observed in both the lambda/betaL1-crystallin fraction (including the full-length 33 kDa protein: 34%; 25-30 kDa proteins, most of which might be generated by cleavage of the 33 kDa protein: 64%) and the partially purified enzyme-crystallin. It was assumed from the analysis of binding titration that some (about 30%) of the 33 kDa protein and most of the lower molecular weight proteins still possessed the ability to loosely bind NADH. Kd values of their lower affinity binding were determined to be 2 or 6 microM. From the present study, we conclude that lambda-crystallin plays a sufficiently important role as a NADH binding protein to maintain high levels of this nucleotide in the rabbit lens.


Continuous-wave laser operation of a dipole antenna terahertz microresonator.
Resonators and the way they couple to external radiation rely on very different concepts if one considers devices belonging to the photonic and electronic worlds. The terahertz frequency range, however, provides intriguing possibilities for the development of hybrid technologies that merge ideas from both fields in novel functional designs. In this paper, we show that high-quality, subwavelength, whispering-gallery lasers can be combined to form a linear dipole antenna, which creates a very efficient, low-threshold laser emission in a collimated beam pattern. For this purpose, we employ a terahertz quantum-cascade active region patterned into two 19-μm-radius microdisks coupled by a suspended metallic bridge, which simultaneously acts as an inductive antenna and produces the dipole symmetry of the lasing mode. Continuous-wave vertical emission is demonstrated at approximately 3.5 THz in a very regular, low-divergence (±10°) beam, with a high slope efficiency of at least 160 mW A-1 and a mere 6 mA of threshold current, which is ensured by the ultra-small resonator size (VRES/λ3≈10-2). The extremely low power consumption and the superior beam brightness make this concept very promising for the development of miniaturized and portable THz sources to be used in the field for imaging and sensing applications as well as for exploring novel optomechanical intracavity effects.


Essential role for proteinase-activated receptor-2 in arthritis.
Using physiological, pharmacological, and gene disruption approaches, we demonstrate that proteinase-activated receptor-2 (PAR-2) plays a pivotal role in mediating chronic inflammation. Using an adjuvant monoarthritis model of chronic inflammation, joint swelling was substantially inhibited in PAR-2-deficient mice, being reduced by more than fourfold compared with wild-type mice, with virtually no histological evidence of joint damage. Mice heterozygous for PAR-2 gene disruption showed an intermediate phenotype. PAR-2 expression, normally limited to endothelial cells in small arterioles, was substantially upregulated 2 weeks after induction of inflammation, both in synovium and in other periarticular tissues. PAR-2 agonists showed potent proinflammatory effects as intra-articular injection of ASKH95, a novel synthetic PAR-2 agonist, induced prolonged joint swelling and synovial hyperemia. Given the absence of the chronic inflammatory response in the PAR-2-deficient mice, our findings demonstrate a key role for PAR-2 in mediating chronic inflammation, thereby identifying a novel and important therapeutic target for the management of chronic inflammatory diseases such as rheumatoid arthritis.


Cryptic impacts of temperature variability on amphibian immune function.
Ectothermic species living in temperate regions can experience rapid and potentially stressful changes in body temperature driven by abrupt weather changes. Yet, among amphibians, the physiological impacts of short-term temperature variation are largely unknown. Using an ex situ population of Cryptobranchus alleganiensis, an aquatic North American salamander, we tested the hypothesis that naturally occurring periods of temperature variation negatively impact amphibian health, either through direct effects on immune function or by increasing physiological stress. We exposed captive salamanders to repeated cycles of temperature fluctuations recorded in the population's natal stream and evaluated behavioral and physiological responses, including plasma complement activity (i.e. bacteria killing) against Pseudomonas aeruginosa, Escherichia coli and Aeromonas hydrophila. The best-fit model (ΔAICc=0, wi=0.9992) revealed 70% greater P. aeruginosa killing after exposure to variable temperatures and no evidence of thermal acclimation. The same model predicted 50% increased E. coli killing, but had weaker support (ΔAICc=1.8, wi=0.2882). In contrast, plasma defenses were ineffective against A. hydrophila, and other health indicators (leukocyte ratios, growth rates and behavioral patterns) were maintained at baseline values. Our data suggest that amphibians can tolerate, and even benefit from, natural patterns of rapid warming/cooling. Specifically, temperature variation can elicit increased activity of the innate immune system. This immune response may be adaptive in an unpredictable environment, and is undetectable by conventional health indicators (and hence considered cryptic). Our findings highlight the need to consider naturalistic patterns of temperature variation when predicting species' susceptibility to climate change.


Brachyspira hyodysenteriae and other strongly beta-haemolytic and indole-positive spirochaetes isolated from mallards (Anas platyrhynchos).
The aims of the current study were to collect intestinal spirochaetes (genus Brachyspira) from farmed and wild mallards (Anas platyrhynchos) and to identify and classify those isolates that phenotypically resembled Brachyspira hyodysenteriae, an enteric pathogen of pigs. The isolation rate of Brachyspira spp. was high from both farmed (93 %) and wild mallards (78 %). In wild mallards, it appeared that Brachyspira spp. were more likely to be found in migratory birds (multivariate analysis: RR = 1.8, 95 % CI 1.1-3.1) than in mallards sampled in a public park. Pure cultures of putative B. hyodysenteriae were obtained from 22 birds. All five isolates from farmed mallards and ten randomly selected isolates with this phenotype were used for further studies. All isolates from farmed mallards and two of the isolates from wild mallards were PCR-positive for the tlyA gene of B. hyodysenteriae. Two isolates from farmed mallards were selected for pulsed field gel electrophoresis (PFGE) and randomly amplified polymorphic DNA (RAPD) analysis. These isolates clustered with the type and reference strains of B. hyodysenteriae. 16S rDNA sequence analysis performed on 11 of the strains showed that they were all closely related to each other and to the B. hyodysenteriae-Brachyspira intermedia cluster. Three of the mallard isolates had 16S rDNA sequences that were identical to those of B. hyodysenteriae strains R1 and NIV-1 previously isolated from common rheas (Rhea americana). To conclude, the isolates from farmed mallards and two isolates from wild mallards were classified as B. hyodysenteriae based on the fact that they could not be differentiated by any of the applied methods from type, reference and field strains of B. hyodysenteriae. The remaining isolates could not be assigned irrefutably to any of the presently recognized Brachyspira species. These results point to a broader host spectrum of B. hyodysenteriae than is generally recognized, and to the presence in mallards of strongly beta-haemolytic and indole-producing spirochaetes that possess many, but not all, of the currently recognized characteristics of B. hyodysenteriae.


Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers.
The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.


Oxidized proteins in astrocytes generated in a hyperbaric atmosphere induce neuronal apoptosis.
In the present study, we investigated the influence of the oxidative damage to astrocytes on neuronal cell survival using cultures of rat cerebral astrocytes and neurons. The exposure of astrocytes to hyperbaric oxygen induced a time-dependent apoptotic cell death, as observed by DNA ladder assessment. When astrocytes damaged by oxidative stress were cocultured with normal neurons from the cerebrum of a newborn rat, neuronal cell death was markedly induced, although normal astrocytes not subjected to hyperoxia cocultured with normal neurons showed no neuronal cell apoptosis. It was found that either the supernatant from the homogenate of astrocytes cultured in hyperbaric oxygen atmosphere or a protein mixture extracted from the supernatant induced neuronal cell death. The level of protein carbonyls, an index of protein oxidation analysis, in cultured astrocytes increased significantly with oxidative stress, and vitamin E inhibited the increase in the level of such oxidized proteins in astrocytes. Furthermore, a two-dimensional (2D) electrophoresis of a protein mixture extracted from the supernatant showed several changes in proteins. These results imply that reactive oxygen species (ROS) induced by oxidative stress attack astrocytes to induce oxidatively denatured proteins in the cells that act as a neurotoxic factor, and that vitamin E protects neurons by inhibiting astrocyte apoptosis caused by oxidative stress.


Glycosaminoglycan accumulation in primary culture of rabbit intervertebral disc cells.
With the heterogeneity of the intervertebral disc as the focus, intervertebral discs from normal young rabbits were separated into nucleus pulposus (NP), inner anulus fibrosus (IAF), and outer anulus fibrosus (OAF) zones. Disc cells from each zone were isolated and propagated under monolayer and within agarose gel culture. The metabolism of these cultured disc cells was examined in terms of glycosaminoglycan (GAG) accumulation. The object was to study the metabolism of disc cells derived from each zone and characterize them on the basis of GAG accumulation and composition. It has been shown that three-dimensional culture systems, such as within-agarose gels or in alginate beads, permit long-term maintenance of the articular chondrocyte phenotype in vitro. However, little has been reported on how the metabolism of intervertebral disc cells, especially GAG accumulation, is affected by different culture conditions. Cells from each zone were subjected to monolayer or three-dimensional culture for up to 12 days. GAG accumulation in the different culture systems was analyzed using chemical, histologic, and immunohistologic methods. Differences of GAG and DNA content among NP, IAF, and OAF cells were statistically evaluated by analysis of variance. The data of keratin sulfate content in three-dimensional culture were compared with that in monolayer culture using nonparametric Mann-Whitney U test. Monolayer culture revealed that increases in GAG content were significantly higher in IAF cells than in OAF cells. However, in three-dimensional culture GAG content was similar in the two groups. AF cells in three-dimensional cultures showed immunohistochemical localization of chondroitin sulfate and keratan sulfate, suggesting the existence of pericellular matrix. High performance liquid chromatography confirmed the expression of keratan sulfate in cultured cells. GAG accumulation in cultures of cells from different zones of the intervertebral disc varied according to the culture conditions used. The importance of choosing the appropriate culture systems to meet the objectives of a study should be emphasized.


Optimizing Clinical Trial Design to Maximize Evidence Generation in Pediatric HIV.
For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to-child HIV transmission. Innovative randomized controlled trial (RCT) designs enable several questions relevant to children's treatment and care to be answered within the same study. We reflect on key considerations, and, with examples, discuss the relative merits of different RCT designs for addressing multiple scientific questions including parallel multi-arm RCTs, factorial RCTs, and cross-over RCTs. We discuss inclusion of several populations (eg, untreated and pretreated children; children and adults) in "basket" trials; incorporation of secondary randomizations after enrollment and use of nested substudies (particularly PK and formulation acceptability) within large RCTs. We review the literature on trial designs across other disease areas in pediatrics and rare diseases and discuss their relevance for addressing questions relevant to HIV-infected children; we provide an example of a Bayesian trial design in prevention of mother-to-child HIV transmission and consider this approach for future pediatric trials. Finally, we discuss the relevance of these approaches to other areas, in particular, childhood tuberculosis and hepatitis.


Slowed recovery of rod photoresponse in mice lacking the GTPase accelerating protein RGS9-1.
Timely deactivation of the alpha-subunit of the rod G-protein transducin (Galphat) is essential for the temporal resolution of rod vision. Regulators of G-protein signalling (RGS) proteins accelerate hydrolysis of GTP by the alpha-subunits of heterotrimeric G proteins in vitro. Several retinal RGS proteins can act in vitro as GTPase accelerating proteins (GAP) for Galphat. Recent reconstitution experiments indicate that one of these, RGS9-1, may account for much of the Galphat GAP activity in rod outer segments (ROS). Here we report that ROS membranes from mice lacking RGS9-1 hydrolyse GTP more slowly than ROS membranes from control mice. The Gbeta5-L protein that forms a complex with RGS9-1 was absent from RGS9-/- retinas, although Gbeta5-L messenger RNA was still present. The flash responses of RGS9-/- rods rose normally, but recovered much more slowly than normal. We conclude that RGS9-1, probably in a complex with Gbeta5-L, is essential for acceleration of hydrolysis of GTP by Galphat and for normal recovery of the photoresponse.


Underweight and mortality.
According to most prospective studies, being underweight (BMI<18·5 kg/m2) is associated with significantly higher mortality than being of normal weight, especially among smokers. We aimed to explore in a generally lean population whether being underweight is significantly associated with increased all-cause mortality. Prospective cohort study. Korea Medical Insurance Corporation study with 14 years of follow-up. After excluding deaths within the first 5 years of follow-up (1993-1997) to minimize reverse causation and excluding participants without information about smoking and health status, 94 133 men and 48 496 women aged 35-59 years in 1990 were included. We documented 5411 (5·7 %) deaths in men and 762 (1·6 %) in women. Among never smokers, hazard ratios (HR) for underweight individuals were not significantly higher than those for normal-weight individuals (BMI=18·5-22·9 kg/m2): HR=0·87 (95 % CI 0·41, 1·84, P=0·72) for underweight men and HR=1·12 (95 % CI 0·76, 1·65, P=0·58) for underweight women. Among ex-smokers, HR=0·86 (95 % CI 0·38, 1·93, P=0·72) for underweight men and HR=3·77 (95 % CI 0·42, 32·29, P=0·24) for underweight women. Among current smokers, HR=1·60 (95 % CI 1·28, 2·01, P<0·001) for underweight men and HR=2·07 (95 % CI 0·43, 9·94, P=0·36) for underweight women. The present study does not support that being underweight per se is associated with increased all-cause mortality in Korean men and women.


Study on risk factors in adolescents admitted with deliberate self-harm in Tata main hospital, Jamshedpur.
Suicide ranks as the second cause of death worldwide among 15-19 years olds, with at least one lakh adolescents dying by suicide every year. Therefore, research on understanding the dynamics of suicide attempts in adolescents can be used as a means of suicide prevention. The objective of this study is to understand the psychological, social, and personality factors contributing to deliberate self-harm/suicide attempt in patients of adolescent age group admitted to Tata Main Hospital, Jamshedpur. This study was carried out at Tata Main Hospital Jamshedpur. Consecutive suicide attempters up to the age of 19 years referred from medical or surgical wards over a period of 1 year are taken up for study. Data were collected on socio-demographic sheet and specific pro forma to collect various risk factors contributing to this behavior specifically designed for this study. Data were analyzed using descriptive statistics and Chi-square test. Majority of the suicide attempters were females of younger age, lower-middle income status, urban background, and students. Two-third (68%) of the attempter had at least one psychiatric diagnosis. Nearly 75% of the suicide attempts were committed after a precipitating factor. The risk factors associated with suicide attempts in included increased family conflicts, peer-interpersonal problems, perceived humiliations and personality traits. The early identification and treatment of vulnerable populations with risk factors for suicide across the lifespan will help in planning and implementing strategies for prevention.


Factors associated with mortality in febrile patients in a government referral hospital in the Kenema district of Sierra Leone.
There is a paucity of data on the etiologies and outcomes of febrile illness in rural Sierra Leone, especially in the Lassa-endemic district of Kenema. We conducted a retrospective study of patients with subjective or documented fever (T ≥ 38.0°C) who were admitted to a rural tertiary care hospital in Kenema between November 1, 2011 and October 31, 2012. Of 854 patients admitted during the study period, 429 (50.2%) patients had fever on admission. The most common diagnoses were malaria (27.3%), pneumonia (5.1%), and Lassa fever (4.9%). However, 53.4% of febrile patients had no diagnosis at discharge. The in-hospital mortality rate was 18.9% and associated with documented temperature ≥ 38.0°C (adjusted odds ratio [AOR] = 2.89, P = 0.001) and lack of diagnosis at discharge (AOR = 2.04, P = 0.03). Failure to diagnose the majority of febrile adults and its association with increased mortality highlight the need for improved diagnostic capacity to improve patient outcomes.


[Nursing diagnosis of the patient in the immediate postoperative period].
The aim of this study was to identify the nursing diagnoses that are more frequent in patients in immediate post-operative period. Data were collected and recorded on specially cards, through evaluation of 28 patients in the first two hours after the admission of the patient. The nursing diagnoses were set by one of the authors, based on Taxonomy I, proposed by North American Nursing Diagnosis Association--NANDA. The diagnoses that occurred mostly were: Risk for injury (100.0%), Risk for infection (92.8%), Sensory perceptual alterations (89.2%), Risk for aspiration (82.1%), Impaired physical mobility (71.4%), Impaired tissue integrity (82.1%) and Hypothermia (67.8%).


Precise calibration of a GNSS antenna array for adaptive beamforming applications.
The use of global navigation satellite system (GNSS) antenna arrays for applications such as interference counter-measure, attitude determination and signal-to-noise ratio (SNR) enhancement is attracting significant attention. However, precise antenna array calibration remains a major challenge. This paper proposes a new method for calibrating a GNSS antenna array using live signals and an inertial measurement unit (IMU). Moreover, a second method that employs the calibration results for the estimation of steering vectors is also proposed. These two methods are applied to the receiver in two modes, namely calibration and operation. In the calibration mode, a two-stage optimization for precise calibration is used; in the first stage, constant uncertainties are estimated while in the second stage, the dependency of each antenna element gain and phase patterns to the received signal direction of arrival (DOA) is considered for refined calibration. In the operation mode, a low-complexity iterative and fast-converging method is applied to estimate the satellite signal steering vectors using the calibration results. This makes the technique suitable for real-time applications employing a precisely calibrated antenna array. The proposed calibration method is applied to GPS signals to verify its applicability and assess its performance. Furthermore, the data set is used to evaluate the proposed iterative method in the receiver operation mode for two different applications, namely attitude determination and SNR enhancement.


Signal transduction by the Wnt family of ligands.
The Wnt genes encode a large family of secreted polypeptides that mediate cell-cell communication in diverse developmental processes. The loss or inappropriate activation of Wnt expression has been shown to alter cell fate, morphogenesis and mitogenesis. Recent progress has identified Wnt receptors and components of an intracellular signalling pathway that mediate Wnt-dependent transcription. This review will highlight this 'core' Wnt signal-transduction pathway, but also aims to reveal the potential diversity of Wnt signalling targets. Particular attention will be paid to the overlap between developmental biology and oncogenesis, since recent progress shows Wnt signalling forms a paradigm for an interdisciplinary approach.


Regional cerebral blood flow estimated by 133-xenon inhalation.
A method is described for estimating the clearance rate and fractional blood flow of the fast (gray matter) compartment of the brain from the first ten minutes of 122 XE clearance curves, following a one-minute inhalation. Computer-simulated data were used to test the adequacy of the two-compartmental model employed, and to evaluate the stability of the parameters in the presence of random noise. A comparison was made between this approach and the previously reported three-compartmental analysis. Regional cerbral blood flow data were obtained on 48 young control subjects and 20 elderly demented patients. Hemispheral, regional, and test-retest variations were determined, as well as differences between the groups.


Efficient molecular subtype classification of high-grade serous ovarian cancer.
High-grade serous carcinomas (HGSCs) account for approximately 70% of all epithelial ovarian cancers diagnosed. Using microarray gene expression profiling, we previously identified four molecular subtypes of HGSC: C1 (mesenchymal), C2 (immunoreactive), C4 (differentiated), and C5 (proliferative), which correlate with patient survival and have distinct biological features. Here, we describe molecular classification of HGSC based on a limited number of genes to allow cost-effective and high-throughput subtype analysis. We determined a minimal signature for accurate classification, including 39 differentially expressed and nine control genes from microarray experiments. Taqman-based (low-density arrays and Fluidigm), fluorescent oligonucleotides (Nanostring), and targeted RNA sequencing (Illumina) assays were then compared for their ability to correctly classify fresh and formalin-fixed, paraffin-embedded samples. All platforms achieved > 90% classification accuracy with RNA from fresh frozen samples. The Illumina and Nanostring assays were superior with fixed material. We found that the C1, C2, and C4 molecular subtypes were largely consistent across multiple surgical deposits from individual chemo-naive patients. In contrast, we observed substantial subtype heterogeneity in patients whose primary ovarian sample was classified as C5. The development of an efficient molecular classifier of HGSC should enable further biological characterization of molecular subtypes and the development of targeted clinical trials.


Overestimating fish counts by non-instantaneous visual censuses: consequences for population and community descriptions.
Increasingly, underwater visual censuses (UVC) are used to assess fish populations. Several studies have demonstrated the effectiveness of protected areas for increasing fish abundance or provided insight into the natural abundance and structure of reef fish communities in remote areas. Recently, high apex predator densities (>100,000 individuals x km(-2)) and biomasses (>4 tonnes x ha(-1)) have been reported for some remote islands suggesting the occurrence of inverted trophic biomass pyramids. However, few studies have critically evaluated the methods used for sampling conspicuous and highly mobile fish such as sharks. Ideally, UVC are done instantaneously, however, researchers often count animals that enter the survey area after the survey has started, thus performing non-instantaneous UVC. We developed a simulation model to evaluate counts obtained by divers deploying non-instantaneous belt-transect and stationary-point-count techniques. We assessed how fish speed and survey procedure (visibility, diver speed, survey time and dimensions) affect observed fish counts. Results indicate that the bias caused by fish speed alone is huge, while survey procedures had varying effects. Because the fastest fishes tend to be the largest, the bias would have significant implications on their biomass contribution. Therefore, caution is needed when describing abundance, biomass, and community structure based on non-instantaneous UVC, especially for highly mobile species such as sharks. Based on our results, we urge that published literature state explicitly whether instantaneous counts were made and that survey procedures be accounted for when non-instantaneous counts are used. Using published density and biomass values of communities that include sharks we explore the effect of this bias and suggest that further investigation may be needed to determine pristine shark abundances and the existence of inverted biomass pyramids. Because such studies are used to make important management and conservation decisions, incorrect estimates of animal abundance and biomass have serious and significant implications.


Cyclic changes in glycemia assessed by continuous glucose monitoring system during multiple complete menstrual cycles in women with type 1 diabetes.
Many women with diabetes notice changes in glucose control perimenstrually. To describe the pattern of changes in glucose control throughout the complete menstrual cycle, and the reproducibility of these changes, we performed a pilot study evaluating glycemic profiles continuously for three cycles in four women with type 1 diabetes. All participants had hemoglobin A1c <7.5% and regular menstrual periods off oral contraceptives. They used Medtronic MiniMed (Northridge, CA) Continuous Glucose Monitoring System (CGMS) devices continuously for three complete menstrual cycles, checked capillary glucose measurements six times daily, changed their own sensors every 3 days, and were seen seven times per menstrual cycle to download data and draw blood. Prolonged monitoring was safely carried out over three consecutive menstrual cycles. We observed two different patterns of glycemic control in relation to the menstrual cycle in these women. The first pattern, seen in two women, was characterized by increased frequency of hyperglycemia in the luteal phase. One of these women also had a hyperglycemic peak in the follicular phase. In the other two women, no characteristic cycle-related pattern was noted. The glucose profiles appeared reproducible between cycles in all women, but varied between women. Thus the menstrual cycle has a reproducible effect on glucose control in a subset of women with type 1 diabetes. Prolonged use of continuous glucose monitoring was safe in the subjects studied, and is the first method clinically available to monitor glucose control over prolonged periods in individuals with diabetes.


[Retrospective review and analysis of the results of taiwan nurses association nursing projects from 2004 to 2005].
Although a nursing project is one of the important N4 professional competence training courses in the clinical ladder system, little research on its effectiveness can be found. This study therefore aimed to analyze the demographics, hospital characteristics, scores, and pass rates for the Taiwan Nurses Association's 2004 to 2005 nursing projects and to compare the differences between them. The design was retrospective content analysis and the data sources were nursing project reviewer sheets from the years 2004 and 2005. Data were analyzed using descriptive statistics, such as number, percentage, mean, standard deviation, and Chi-square test, or Fisher exact test. We analyzed 1,062 nursing projects. Of these, 423 projects had third reviewers. After that, 2,547 reviewer sheets were used as final samples. The average project score was 59.7 points (SD = 9.3 points) and the majority of the projects were categorized as administrative and from medical centers, or private hospitals in northern areas of Taiwan. The pass rate was found to be higher in public hospitals, however, than in private hospitals. Almost all the projects (n = 2,515; 98.7%) included reviewers'comments. There was no significant difference between project pass rate and clinical specialty, scope, hospital location, and level of hospital accreditation (p > .05). A significant difference was found, however, between project scores and hospital characteristics (p = .01). These findings may serve as references in the development of future requirements for nursing projects in the clinical ladder system, to improve the quality and quantity of such projects.


Induction of metamorphosis decreases nitric oxide synthase gene expression in larvae of the marine mollusc Ilyanassa obsoleta (say).
Many marine organisms spend the early part of their lives as larvae suspended in the water column before metamorphosing into benthic reproductive adults. Metamorphosis does not occur until a larva has become competent to respond to appropriate stimuli and after a suitable habitat for the young juvenile has been encountered. The gaseous neurotransmitter nitric oxide is thought to be important in the regulation of metamorphosis by holding the organism in the larval state. We have investigated expression of the neuronal nitric oxide synthase (nNOS) gene in larval and metamorphosing individuals of the marine mud snail Ilyanassa obsoleta. Our results indicate that nNOS is expressed at constant levels throughout larval development. In contrast, expression of nNOS decreases markedly during the first 24 h of metamorphosis. Our observations support previous findings that demonstrate that nitric oxide is present in larvae though competence. The decrease in nNOS gene expression that occurs during metamorphosis corresponds with a previously described reduction in nNOS activity.


Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation.
Hhex encodes a homeodomain transcription factor that is widely expressed in hematopoietic stem and progenitor cell populations. Its enforced expression induces T-cell leukemia and we have implicated it as an important oncogene in early T-cell precursor leukemias where it is immediately downstream of an LMO2-associated protein complex. Conventional Hhex knockouts cause embryonic lethality precluding analysis of adult hematopoiesis. Thus, we induced highly efficient conditional knockout (cKO) using vav-Cre transgenic mice. Hhex cKO mice were viable and born at normal litter sizes. At steady state, we observed a defect in B-cell development that we localized to the earliest B-cell precursor, the pro-B-cell stage. Most remarkably, bone marrow transplantation using Hhex cKO donor cells revealed a more profound defect in all hematopoietic lineages. In contrast, sublethal irradiation resulted in normal myeloid cell repopulation of the bone marrow but markedly impaired repopulation of T- and B-cell compartments. We noted that Hhex cKO stem and progenitor cell populations were skewed in their distribution and showed enhanced proliferation compared to WT cells. Our results implicate Hhex in the maintenance of LT-HSCs and in lineage allocation from multipotent progenitors especially in stress hematopoiesis.


The patient perspective in research on major depression.
Although thousands of studies have examined the genetics, epidemiology, etiology, biology, treatment and prevention of major depressive disorder, we still lack very basic knowledge about what patients with depressive disorders need. Despite the thousands of studies that have been conducted on major depression and the hundreds of randomized trials that have examined the effects of treatments, many patients still do not know how to cope with the daily problems caused by depressive disorders. In this Commentary the need for more research on the perspectives of patients is described. This research should guide treatment studies as well as basic research much more than it currently does. This perpective is especially important to understand and solve the undertreatment of depression, one of the major problems in this area. Up to 50% of depressed patients do not seek treatment, resulting in huge avoidable disease burden and economic costs. In order to solve this problem we need a better understanding of the problems patients encounter in daily life, and what factors contribute to the reasons for seeking treatment or not. Research from the patients' perspective is also necessary to meet the currently unmet information needs of patients, including information about the nature and causes of depression, stigma, medication, treatment and coping with the daily problems of having depression.


The effect of withdrawal of dopaminergic medication on simple and choice reaction time and the use of advance information in Parkinson's disease.
Eight patients with Parkinson's disease performed simple reaction time (SRT), uncued, partially and fully cued four choice (CRT) tasks. They were tested on two occasions; on their normal dose of dopaminergic medication and following withdrawal of such medication for an average of 14.4 hours. Disability as rated on the Webster scale was greater in the drug reduced state. Although RTs were generally slower when tested in the drug reduced state than when on medication, few differences emerged. Withdrawal of dopaminergic medication had no effect on unwarned SRT and unwarned and uncued CRT performance. Both on and off medication, the patients benefited from a warning signal presented before the imperative stimulus. In both medication states, the speeding up of RT was greatest with a warning signal presented 200 ms before S2. When the imperative stimulus was unwarned, the temporal predictability of its occurrence speeded RT more when on medication than when off. Advance movement parameter information was used by patients to pre-programme responses both on and off medication. In both medication states, the fully cued CRT was the same as SRT only with the 3200 ms S1-S2 interval. Medication state had no effect on movement time or the number of errors. It is suggested that slowness in motor readiness and motor programming may not be specific to striatal dopamine deficiency but rather a nonspecific concomitant of brain damage.


Extragenic suppressors of the Arabidopsis det1 mutant identify elements of flowering-time and light-response regulatory pathways.
Light regulation of seeding morphogenesis is mediated by photoreceptors that perceive red, far-red, blue and UV light. Photomorphogenetic mutants of Arabidopsis have identified several of the primary photoreceptors, as well as a set of negative regulators of seedling photomorphogenesis, including DET1, that appear to act downstream of the photoreceptors. To study the regulatory context in which DET1 acts to repress photomorphogenesis, we used a simple morphological screen to isolate extragenic mutations in six loci, designated ted (for reversal of the det phenotype), that partially or fully suppress the seeding morphological phenotype of det1-1. Genetic analyses indicate that mutations in the ted4 and ted5 loci identify new alleles of the previously described photomorphogenetic loci hy1 and hy5, respectively. Molecular analyses indicate that the ted mutations partially suppress the dark-grown gene expression phenotype of det1-1, and that the mechanism of suppression does not involve direct remediation of the splicing defect caused by the det1-1 mutation. The ted mutations also partially suppress the light-grown morphological phenotype of mature det1-1 plants, and ted1 and ted2 suppress a daylength insensitivity phenotype of det1. TED1, TED2 and TED3 are newly described genes, whose function appears closely associated with that of DET1. In addition, alleles of ted1 are associated with a moderate late-flowering phenotype, suggesting that TED1 plays a role in the pathways that regulate both seedling morphogenesis and the initiation of flowering.


Thermal and pressure pain sensitivity in patients with unilateral shoulder pain: comparison of involved and uninvolved sides.
Cross-sectional. In the examination of patients with unilateral shoulder pain, pain provocation testing to compare the involved and uninvolved sides has been considered useful. However, side-to-side comparisons of experimental pain sensitivity in patients with unilateral shoulder pain are not widely reported in the literature. To compare experimental pain sensitivity between the involved and uninvolved sides in patients with unilateral shoulder pain. In consecutive patients seeking operative treatment for shoulder pain, sensitivity measures of bilateral pressure pain threshold at the shoulder and forearm, and thermal pain threshold, tolerance, and temporal summation at the forearm, were examined. Pressure sensitivity was tested with a Fischer pressure algometer, and thermal sensitivity with a computer-controlled Medoc neurosensory analyzer. The involved and uninvolved sides were compared with an analysis of variance. Influence of sex and location of testing were considered as covariates in the analysis. Fifty-nine consecutively recruited participants completed experimental pain sensitivity testing. Participants reported significantly lower pressure pain thresholds in the involved side compared to the uninvolved side (F1,56 = 4.96, P = .030). In addition, female compared to male participants demonstrated lower pressure pain thresholds in the bilateral shoulder regions (F1,56 = 10.84, P = .002). There was no difference in thermal pain sensitivity between sides. Average clinical pain intensity was negatively correlated with pressure pain threshold at the involved local site (r = -0.284, P = .029), indicating an influence of clinical pain intensity on local pressure pain. The results of this study provide evidence for higher experimental pressure pain sensitivity in the involved side of patients with unilateral shoulder pain and no difference between sides for thermal pain sensitivity. Females demonstrated higher pain sensitivity than males to pressure stimuli at the local shoulder region but not at the distal regions. Future studies should incorporate multiple stimuli when describing the pain profile of clinical populations.


Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation.
Prenatal exposure to infection is a recognized environmental risk factor for neuropsychiatric disorders of developmental origins such as autism or schizophrenia. Experimental work in animals indicates that this link is mediated by maternal immune activation (MIA) involving interactions between cytokine-associated inflammatory events, oxidative stress, and other pathophysiological processes such as hypoferremia and zinc deficiency. Maternal administration of the viral mimic polyriboinosinic-polyribocytidylic acid (poly(I:C)) in mice produces several behavioral phenotypes in adult offspring of relevance to autism spectrum disorder (ASD) and other neurodevelopmental disorders. Here, we investigated whether some of these phenotypes might also present in juveniles. In addition, given the known immunomodulatory and neuroprotective effects of vitamin D, we also investigated whether the co-administration of vitamin D could block MIA-induced ASD-related behaviors. We co-administered the hormonally active form of vitamin D, 1α,25 dihydroxy vitamin D3 (1,25OHD), simultaneously with poly(I:C) and examined (i) social interaction, stereotyped behavior, emotional learning and memory, and innate anxiety-like behavior in juveniles and (ii) the levels of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α in maternal plasma and fetal brains. We show that like adult offspring that were exposed to MIA, juveniles display similar deficits in social approach behavior. Juvenile MIA offspring also show abnormal stereotyped digging and impaired acquisition and expression of tone-cued fear conditioning. Importantly, our study reveals that prenatal administration of 1,25OHD abolishes all these behavioral deficits in poly(I:C)-treated juveniles. However, prenatal administration of vitamin D had no effect on pro-inflammatory cytokine levels in dams or in fetal brains suggesting the anti-inflammatory actions of vitamin D are not the critical mechanism for its preventive actions in this ASD animal model. This work raises the possibility that early dietary supplementation with vitamin D may open new avenues for a successful attenuation or even prevention of neurodevelopmental disorders following maternal inflammation during pregnancy.


Antibiotic Overconsumption in Pregnant Women With Urinary Tract Symptoms in Uganda.
Urinary tract infections (UTIs) are one of the most common bacterial infections in women. During pregnancy physiological changes, like frequency, mimic UTI symptoms, and therefore bacteriological cultures are needed to confirm the diagnosis. However, in developing countries antibiotic therapy is commonly initiated without culture confirmation. We investigated the prevalence of bacteriuria among pregnant women with and without UTI symptoms in Uganda. In total 2 562 urine samples were evaluated with nitrite and leukocyte esterase tests, using urine culture and/or dipslide with species identification as reference. The prevalence of culture-proven UTI among pregnant women with UTI symptoms was 4%. Since treatment is initiated based only on the presence of symptoms, 96% were erroneously given antibiotics. Further, there is a high prevalence of resistance to commonly used antibiotics, with 18 % ESBL and 36 % multidrug resistant Escherichia coli strains. Nitrite, leukocyte esterase tests, and urine microscopy alone were of poor diagnostic value. Using dipslide, gynecologists and nurses, not trained in microbiology, were mostly able to identify E. coli and negative cultures. Mixed Gram-negative flora, suggesting fecal contamination was, however, in the majority of cases interpreted as a single pathogenic bacterium and would have resulted in antibiotic treatment. To prevent excessive use of antibiotics, dipslide possibly supported by a combination of nitrite and leukocyte esterase tests can be used. Trained frontline health care professionals correctly diagnosed E. coli UTI and negative urine cultures, which would help preventing antibiotic misuse. In addition, regular screening for antibiotic resistance would improve correct treatment.


Obesity and diabetes in blacks.
Diabetes mellitus is more prevalent in the American Black population than in the White population. The prevalence is increasing in Blacks, and there is evidence that it is accompanied by a greater severity of diabetic complications. In addition, mortality figures are higher in Blacks, and Black women are more seriously affected than Black men. Although the reasons for this are unclear, some factors stand out as important. These include obesity, socioeconomic status, and genetics. Obesity is a severe problem in Blacks, particularly in women. Both the degree and the distribution of fat may contribute greatly to the prevalence of diabetes in Blacks. Although the prevalence of obesity is higher in the poor economic groups, multivariate analysis suggests that poverty cannot explain all of the excess obesity that occurs in the Black population. More research is needed into a possible genetic predisposition of Blacks to obesity and diabetes and into the interrelationship between the two conditions in this racial group.


New Route for "Cold-Passivation" of Defects in Tin-Based Oxides.
Transparent conductive oxides (TCOs) are essential in technologies coupling light and electricity. For Sn-based TCOs, oxygen deficiencies and undercoordinated Sn atoms result in an extended density of states below the conduction band edge. Although shallow states provide free carriers necessary for electrical conductivity, deeper states inside the band gap are detrimental to transparency. In zinc tin oxide (ZTO), the overall optoelectronic properties can be improved by defect passivation via annealing at high temperatures. Yet, the high thermal budget associated with such treatment is incompatible with many applications. Here, we demonstrate an alternative, low-temperature passivation method, which relies on cosputtering Sn-based TCOs with silicon dioxide (SiO2). Using amorphous ZTO and amorphous/polycrystalline tin dioxide (SnO2) as representative cases, we demonstrate through optoelectronic characterization and density functional theory simulations that the SiO2 contribution is twofold. First, oxygen from SiO2 passivates the oxygen deficiencies that form deep defects in SnO2 and ZTO. Second, the ionization energy of the remaining deep defect centers is lowered by the presence of silicon atoms. Remarkably, we find that these ionized states do not contribute to sub-gap absorptance. This simple passivation scheme significantly improves the optical properties without affecting the electrical conductivity, hence overcoming the known transparency-conductivity trade-off in Sn-based TCOs.


Effects of subchronic exposure to glyphosate in juvenile oysters (Crassostrea gigas): From molecular to individual levels.
Glyphosate-based herbicides are extensively used and can be measured in aquatic ecosystems, including coastal waters. The effect of glyphosate on non-target organisms is an issue of worldwide concern. The aim of this study was to investigate the effects of subchronic exposure to glyphosate in juvenile oysters, Crassostrea gigas. Yearling oysters were exposed to three concentrations of glyphosate (0.1, 1 and 100μgL(-1)) for 56days. Various endpoints were studied, from the individual level (e.g., gametogenesis and tissue alterations) to the molecular level (mRNA quantification), including biochemical endpoints such as glutathione-S-transferase (GST) and catalase activities and malondialdehyde content. No mortality and growth occurred during the experiment, and individual biomarkers revealed only slight effects. The levels of gene expression significantly increased in oysters exposed to the highest glyphosate concentration (GST and metallothioneins) or to all concentrations (multi-xenobiotic resistance). These results suggested an activation of defence mechanisms at the molecular level.


The alcohol harm paradox: using a national survey to explore how alcohol may disproportionately impact health in deprived individuals.
Internationally, studies show that similar levels of alcohol consumption in deprived communities (vs. more affluent) result in higher levels of alcohol-related ill health. Hypotheses to explain this alcohol harm paradox include deprived drinkers: suffering greater combined health challenges (e.g. smoking, obesity) which exacerbate effects of alcohol harms; exhibiting more harmful consumption patterns (e.g. bingeing); having a history of more harmful consumption; and disproportionately under-reporting consumption. We use a bespoke national survey to assess each of these hypotheses. A national telephone survey designed to test this alcohol harm paradox was undertaken (May 2013 to April 2014) with English adults (n = 6015). Deprivation was assigned by area of residence. Questions examined factors including: current and historic drinking patterns; combined health challenges (smoking, diet, exercise and body mass); and under-reported consumption (enhanced questioning on atypical/special occasion drinking). For each factor, analyses examined differences between deprived and more affluent individuals controlled for total alcohol consumption. Independent of total consumption, deprived drinkers were more likely to smoke, be overweight and report poor diet and exercise. Consequently, deprived increased risk drinkers (male >168-400 g, female >112-280 g alcohol/week) were >10 times more likely than non-deprived counterparts to drink in a behavioural syndrome combining smoking, excess weight and poor diet/exercise. Differences by deprivation were significant but less marked in higher risk drinkers (male >400 g, female >280 g alcohol/week). Current binge drinking was associated with deprivation independently of total consumption and a history of bingeing was also associated with deprivation in lower and increased risk drinkers. Deprived increased/higher drinkers are more likely than affluent counterparts to consume alcohol as part of a suite of health challenging behaviours including smoking, excess weight and poor diet/exercise. Together these can have multiplicative effects on risks of wholly (e.g. alcoholic liver disease) and partly (e.g. cancers) alcohol-related conditions. More binge drinking in deprived individuals will also increase risks of injury and heart disease despite total alcohol consumption not differing from affluent counterparts. Public health messages on how smoking, poor diet/exercise and bingeing escalate health risks associated with alcohol are needed, especially in deprived communities, as their absence will contribute to health inequalities.