Giant intracranial aneurysms: evolution of management in a contemporary surgical series.
Many significant microsurgical series of patients with giant aneurysms predate changes in practice during the endovascular era. A contemporary surgical experience is presented to examine changes in management relative to earlier reports, to establish the role of open microsurgery in the management strategy, and to quantify results for comparison with evolving endovascular therapies. During a 13-year period, 140 patients with 141 giant aneurysms were treated surgically. One hundred aneurysms (71%) were located in the anterior circulation, and 41 aneurysms were located in the posterior circulation. One hundred eight aneurysms (77%) were completely occluded, 14 aneurysms (10%) had minimal residual aneurysm, and 16 aneurysms (11%) were incompletely occluded with reversed or diminished flow. Three patients with calcified aneurysms were coiled after unsuccessful clipping attempts. Eighteen patients died in the perioperative period (surgical mortality, 13%). Bypass-related complications resulted from bypass occlusion (7 patients), aneurysm hemorrhage due to incomplete aneurysm occlusion (4 patients), or aneurysm thrombosis with perforator or branch artery occlusion (4 patients). Thirteen patients were worse at late follow-up (permanent neurological morbidity, 9%; mean length of follow-up, 23 ± 1.9 months). Overall, good outcomes (Glasgow Outcome Score 5 or 4) were observed in 114 patients (81%), and 109 patients (78%) were improved or unchanged after therapy. A heavy reliance on bypass techniques plus indirect giant aneurysm occlusion distinguishes this contemporary surgical experience from earlier ones, and obviates the need for hypothermic circulatory arrest. Experienced neurosurgeons can achieve excellent results with surgery as the "first-line" management approach and endovascular techniques as adjuncts to surgery.


Comparative and population mitogenomic analyses of Madagascar's extinct, giant 'subfossil' lemurs.
Humans first arrived on Madagascar only a few thousand years ago. Subsequent habitat destruction and hunting activities have had significant impacts on the island's biodiversity, including the extinction of megafauna. For example, we know of 17 recently extinct 'subfossil' lemur species, all of which were substantially larger (body mass ∼11-160 kg) than any living population of the ∼100 extant lemur species (largest body mass ∼6.8 kg). We used ancient DNA and genomic methods to study subfossil lemur extinction biology and update our understanding of extant lemur conservation risk factors by i) reconstructing a comprehensive phylogeny of extinct and extant lemurs, and ii) testing whether low genetic diversity is associated with body size and extinction risk. We recovered complete or near-complete mitochondrial genomes from five subfossil lemur taxa, and generated sequence data from population samples of two extinct and eight extant lemur species. Phylogenetic comparisons resolved prior taxonomic uncertainties and confirmed that the extinct subfossil species did not comprise a single clade. Genetic diversity estimates for the two sampled extinct species were relatively low, suggesting small historical population sizes. Low genetic diversity and small population sizes are both risk factors that would have rendered giant lemurs especially susceptible to extinction. Surprisingly, among the extant lemurs, we did not observe a relationship between body size and genetic diversity. The decoupling of these variables suggests that risk factors other than body size may have as much or more meaning for establishing future lemur conservation priorities.


Peer effects, fast food consumption and adolescent weight gain.
This paper aims at opening the black box of peer effects in adolescent weight gain. Using Add Health data on secondary schools in the U.S., we investigate whether these effects partly flow through the eating habits channel. Adolescents are assumed to interact through a friendship social network. We propose a two-equation model. The first equation provides a social interaction model of fast food consumption. To estimate this equation we use a quasi maximum likelihood approach that allows us to control for common environment at the network level and to solve the simultaneity (reflection) problem. Our second equation is a panel dynamic weight production function relating an individual's Body Mass Index z-score (zBMI) to his fast food consumption and his lagged zBMI, and allowing for irregular intervals in the data. Results show that there are positive but small peer effects in fast food consumption among adolescents belonging to a same friendship school network. Based on our preferred specification, the estimated social multiplier is 1.15. Our results also suggest that, in the long run, an extra day of weekly fast food restaurant visits increases zBMI by 4.45% when ignoring peer effects and by 5.11%, when they are taken into account.


Disruption of cerebral cortex MET signaling in autism spectrum disorder.
Multiple genes contribute to autism spectrum disorder (ASD) susceptibility. One particularly promising candidate is the MET gene, which encodes a receptor tyrosine kinase that mediates hepatocyte growth factor (HGF) signaling in brain circuit formation, immune function, and gastrointestinal repair. The MET promoter variant rs1858830 allele "C" is strongly associated with ASD and results in reduced gene transcription. Here we examined expression levels of MET and members of the MET signaling pathway in postmortem cerebral cortex from ASD cases and healthy control subjects. Protein, total RNA, and DNA were extracted from postmortem temporal cortex gray matter samples (BA 41/42, 52, or 22) belonging to eight pairs of ASD cases and matched control subjects. MET protein expression was determined by Western blotting; messenger RNA expression of MET and other related transcripts was assayed by microarray and quantitative reverse transcriptase polymerase chain reaction. MET protein levels were significantly decreased in ASD cases compared with control subjects. This was accompanied in ASD brains by increased messenger RNA expression for proteins involved in regulating MET signaling activity. Analyses of coexpression of MET and HGF demonstrated a positive correlation in control subjects that was disrupted in ASD cases. Altered expression of MET and related molecules suggests dysregulation of signaling that may contribute to altered circuit formation and function in ASD. The complement of genes that encode proteins involved in MET activation appears to undergo long-term compensatory changes in expression that may be a hallmark contribution to the pathophysiology of ASD.


Maternal dioxin exposure combined with a diet high in fat increases mammary cancer incidence in mice.
RESULTS from previous studies have suggested that breast cancer risk correlates with total lifetime exposure to estrogens and that early-life 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or diets high in fat can also increase cancer risk. Because both TCDD and diet affect the estrogen pathway, we examined how TCDD and a high-fat diet (HFD) interact to alter breast cancer susceptibility. We exposed pregnant female FVB/NJ mice (12.5 days postcoitus) to 1 microg/kg TCDD or vehicle; at parturition, the dams were randomly assigned to a low-fat diet (LFD) or a high-fat diet (HFD). Female offspring were maintained on the same diets after weaning and were exposed to 7,12-dimethylbenz[a]anthracene on postnatal days (PNDs) 35, 49, and 63 to initiate mammary tumors. A second cohort of females was treated identically until PND35 or PND49, when mammary gland morphology was examined, or PND50, when mammary gland mRNA was analyzed. We found that maternal TCDD exposure doubled mammary tumor incidence only in mice fed the HFD. Among HFD-fed mice, maternal TCDD exposure caused rapid mammary development with increased Cyp1b1 (cytochrome P450 1B1) expression and decreased Comt (catechol-O-methyltransferase) expression in mammary tissue. Maternal TCDD exposure also increased mammary tumor Cyp1b1 expression. Our data suggest that the HFD increases sensitivity to maternal TCDD exposure, resulting in increased breast cancer incidence, by changing metabolism capability. These results provide a mechanism to explain epidemiological data linking early-life TCDD exposure and diets high in fat to increased risk for breast cancer in humans.


Supporting the Implementation of Connected Care Technologies in the Veterans Health Administration: Cross-Sectional Survey Findings from the Veterans Engagement with Technology Collaborative (VET-C) Cohort.
Widespread adoption, use, and integration of patient-facing technologies into the workflow of health care systems has been slow, thus limiting the realization of their potential. A growing body of work has focused on how best to promote adoption and use of these technologies and measure their impacts on processes of care and outcomes. This body of work currently suffers from limitations (eg, cross-sectional analyses, limited patient-generated data linked with clinical records) and would benefit from institutional infrastructure to enhance available data and integrate the voice of the patient into implementation and evaluation efforts. The Veterans Health Administration (VHA) has launched an initiative called the Veterans Engagement with Technology Collaborative cohort to directly address these challenges. This paper reports the process by which the cohort was developed and describes the baseline data being collected from cohort members. The overarching goal of the Veterans Engagement with Technology Collaborative cohort is to directly engage veterans in the evaluation of new VHA patient-facing technologies and in so doing, to create new infrastructure to support related quality improvement and evaluation activities. Inclusion criteria for veterans to be eligible for membership in the cohort included being an active user of VHA health care services, having a mobile phone, and being an established user of existing VHA patient-facing technologies as represented by use of the secure messaging feature of VHA's patient portal. Between 2017 and 2018, we recruited veterans who met these criteria and administered a survey to them over the telephone. The majority of participants (N=2727) were male (2268/2727, 83.2%), White (2226/2727, 81.6%), living in their own apartment or house (2519/2696, 93.4%), and had completed some college (1176/2701, 43.5%) or an advanced degree (1178/2701, 43.6%). Cohort members were 59.9 years old, on average. The majority self-reported their health status as being good (1055/2725, 38.7%) or very good (524/2725, 19.2%). Most cohort members owned a personal computer (2609/2725, 95.7%), tablet computer (1616/2716, 59.5%), and/or smartphone (2438/2722, 89.6%). The Veterans Engagement with Technology Collaborative cohort is an example of a VHA learning health care system initiative designed to support the data-driven implementation of patient-facing technologies into practice and measurement of their impacts. With this initiative, VHA is building capacity for future, rapid, rigorous evaluation and quality improvement efforts to enhance understanding of the adoption, use, and impact of patient-facing technologies.


Combined isometric and vibration training does not enhance strength beyond that of isometric training alone.
Research considering combined vibration and strength training is extensive yet results are equivocal. However, to date there appears no research which has considered the combination of both direct vibration and whole-body vibration when used in an isometric deadlift position. The aim of this study was to compare groups performing isometric training with and without direct and whole-body vibration. Twenty four participants (19-24 years) were randomly divided into: isometric training with vibration (ST+VT: N.=8), isometric training without vibration (ST: N.=8), and control (CON: N.=8). Within the training groups participants trained twice per week, for 6 weeks, performing 6-sets of maximal isometric deadlift contractions, increasing in duration from 30 seconds to 40 seconds (weeks 1-6). Hip and knee angle was maintained at 60° and 110°, respectively for both testing and training. Training sessions for ST+VT were identical to ST with the addition of a direct vibratory stimulus through hand-held straps and whole-body vibration via standing on vibration a platform. The amplitude remained constant (2 mm) throughout the intervention whilst the frequency increased from 35Hz to 50Hz. Pre- and post-test isometric strength was measured using an isometric deadlift dynamometer. Results revealed significant increases in isometric strength for both ST+VT (P<0.001, 23.8%) and ST (P<0.001, 32.5%) compared to CON, with no significant differences between ST+VT and ST training groups. The present study provides evidence to suggest that there are no greater gains to be incurred by the addition of a vibratory stimulus to traditional strength training.


A supramolecular approach to construct a hydrolase mimic with photo-switchable catalytic activity.
In this study, a peptide-based artificial hydrolase with photo-switchable activity was fabricated by the introduction of a catalytic histidine residue and a photo-responsive azobenzene group into the peptide chain. The peptide exhibits a structural transition from an antiparallel β-sheet to a random coil upon photo-irradiation, leading to the assembly/disassembly of the peptide fibril. An enhanced catalytic activity on p-nitrophenyl acetate was observed due to the proximity effect of the histidine residues and the hydrophobic microenvironment in the supramolecular assemblies. Under UV irradiation, this supramolecular system was destroyed together with a decline in the catalytic activity. Based on these photo-responsive properties, the activity of the hydrolase mimic can be reversibly controlled using UV and visible light. This study provides a new approach for constructing a switchable artificial enzyme based on a peptide material platform.


Intraoperative measurement of intraventricular pressure in dogs with communicating internal hydrocephalus.
Collapse of the lateral cerebral ventricles after ventriculo-peritoneal drainage is a fatal complication in dogs with internal hydrocephalus. It occurs due to excessive outflow of cerebrospinal fluid into the peritoneal cavity (overshunting). In most shunt systems, one-way valves with different pressure settings regulate flow into the distal catheter to avoid overshunting. The rationale for the choice of an appropriate opening pressure is a setting at the upper limit of normal intracranial pressure in dogs. However, physiological intraventricular pressure in normal dogs vary between 5 and 12 mm Hg. Furthermore, we hypothesise that intraventricular pressure in hydrocephalic dogs might differ from pressure in normal dogs and we also consider that normotensive hydrocephalus exists in dogs, as in humans. In order to evaluate intraventricular pressure in hydrocephalic dogs, twenty-three client owned dogs with newly diagnosed communicating internal hydrocephalus were examined before implantation of a ventriculo-peritoneal shunt using a single use piezo-resistive strain-gauge sensor (MicroSensor ICP probe). Ventricular volume and brain volume were measured before surgery, based on magnetic resonance images. Total ventricular volume was calculated and expressed in relation to the total volume of the brain, including the cerebrum, cerebellum, and brainstem (ventricle-brain index). Multiple logistic regression analysis was performed to assess the influence of the covariates "age", "gender", "duration of clinical signs", "body weight", and "ventricle-brain index" on intraventricular pressure. The mean cerebrospinal fluid pressure in the hydrocephalic dogs was 8.8 mm Hg (standard deviation 4.22), ranging from 3-18 mm Hg. The covariates "age", (P = 0.782), "gender" (P = 0.162), "body weight", (P = 0.065), or ventricle-brain index (P = 0.27)" were not correlated with intraventricular pressure. The duration of clinical signs before surgery, however, was correlated with intraventricular pressure (P< 0.0001). Dogs with internal hydrocephalus do not necessarily have increased intraventricular pressure. Normotensive communicating hydrocephalus exists in dogs.


Deoxynivalenol exposure assessment in a cohort of pregnant women from Bradford, UK.
Deoxynivalenol (DON) is a ubiquitous contaminant of cereal crops in temperate regions of the world. It causes growth faltering and immune suppression in animals. Limited information is available on DON exposure in UK subpopulations. The objective of this study was to provide DON exposure assessment in a subset of pregnant women scheduled for an elective caesarean in a large multi-ethnic mother/infant birth cohort from Bradford, UK. Women aged 16-44 years (n = 85) provided a urine sample for DON analysis in the last trimester of pregnancy, and concurrently completed a food-frequency questionnaire (FFQ). The urinary DON biomarker was detected in all measured samples (geometric mean (GM) = 10.3 ng DON mg(-1) creatinine, range = 0.5-116.7 ng mg(-1)). Levels were higher in women classified as South Asian in origin (GM: 15.2 ng mg(-1); 95% CI = 10.7-21.5 ng mg(-1)) compared with non-South Asians (GM = 8.6 ng mg(-1); 95% CI = 6.6-11.8 ng mg(-1)), p = 0.02). Estimated DON intake from FFQ data and typical levels of DON contamination of food suggest that this was mainly due to higher levels of exposure from bread, particularly daily intake of DON from chapattis in South Asians (estimated mean = 2.4 µg day(-1); 95% CI = 1.2, 3.7 µg day(-1)) compared with non-South Asians (estimated mean = 0.2 µg day(-1); 95% CI = 0-0.4 µg day(-1)), p < 0.001. This is the first biomarker demonstration of DON exposure in pregnant women, and several urinary DON levels were the highest ever recorded in any study. A larger survey within this birth cohort is warranted to investigate any potential risk to mothers and their babies, from DON exposure during pregnancy.


Aldosterone as a renal growth factor.
Aldosterone regulates blood pressure through its effects on the cardiovascular system and kidney. Aldosterone can also contribute to the development of hypertension that leads to chronic pathologies such as nephropathy and renal fibrosis. Aldosterone directly modulates renal cell proliferation and differentiation as part of normal kidney development. The stimulation of rapidly activated protein kinase cascades is one facet of how aldosterone regulates renal cell growth. These cascades may also contribute to myofibroblastic transformation and cell proliferation observed in pathological conditions of the kidney. Polycystic kidney disease is a genetic disorder that is accelerated by hypertension. EGFR-dependent proliferation of the renal epithelium is a factor in cyst development and trans-activation of EGFR is a key feature in initiating aldosterone-induced signalling cascades. Delineating the components of aldosterone-induced signalling cascades may identify novel therapeutic targets for proliferative diseases of the kidney.


Being in a critical illness-recovery process: a phenomenological hermeneutical study.
The aim of this study was to describe and interpret the essential meaning of the lived experiences of being in a critical illness-recovery process after a life-threatening condition. The critical illness-recovery process after a life-threatening condition takes several years and does not only include patients' experiences during intensive care. Previous research has mainly focused on what critically ill patients recall. However, from a phenomenological point of view, experiences are more than memories alone. To plan and perform relevant health care and social support for patients who have survived a life-threatening condition, a more profound understanding about their lived experiences is needed. In this qualitative study, a phenomenological hermeneutical approach was used. Interviews were conducted with seven patients, two to four years after they had received care in an intensive care unit in Sweden. The comprehensive understanding of the results shows that the critical illness-recovery process after a life-threatening condition means an existential struggle to reconcile with an unfamiliar body and with ordinary life. This can be understood as an 'unhomelikeness' implying a struggle to create meaning and coherence from scary and fragmented memories. The previous life projects, such as work and social life become unfamiliar when the patient's fragile and weak body is disobedient and brings on altered sensations. Patients who survive a life-threatening condition have an immense need for care and support during the entire critical illness-recovery process, and also after the initial acute phase. They need a coherent understanding of what happened, and support to be able to perform their changed life projects. Supporting and caring for patients' recovery from a life- threatening condition involves recognising the patients' struggle and responding to their existential concerns.


Diagnostics of tissue involved injury occurrence of top-level judokas during the competition: suggestion for prevention.
Judo, as a high-intensity contact sport, may lead to the occurrence of injuries, especially in competitions. This work aims to assess the likelihood of soft and hard tissue injuries in top-level judokas during competition with defining factors that determine the probability of injury occurrence. The injuries that occurred in 123 official international competitions from 2005-2019 were recorded by the European Judo Union (EJU) Medical Commission as a survey that was a part of the EJU Injury Registration form with internal consistency shown by a Crombach Alpha of 0.69. This survey data identified factors such as: sex, anatomical localisation of injury, type of injury, tissue involved and mechanisms of the injury. A total of 650 tissue injuries were reported correctly in terms of tissue injury definition. The most frequent soft tissue injury (STI) reported was a ligament STI (48.15%), closely followed by skin STI (12.15%) and muscles STI (11.38%). In turn, the most frequent hard tissue injury occurred in bones (8.56%). The highest rates of injuries occurred during the fight in the standing position (78%). Injuries in the standing position mainly occurred while executing a throw (25.85%) and followed by the attempt to throw, i.e., the action of reaching the throwing position (22.30%), grip fighting (15.07%), and during falls (14.77%). Opposite to this, fight in groundwork reached only 18.30% soft and hard tissue injuries combined. The ongoing registration of injuries during judo combat and training and the early diagnosis of risk factors for injuries are the basis for the development of effective strategies for injury prevention and further treatment.


Prognostic Value of High-sensitivity Troponin I in Patients with Septic Shock: A Prospective Observational Study.
Myocardial dysfunction is one of the mechanisms involved in the pathophysiology of septic shock. The role of troponin as a surrogate of myocardial injury in septic shock is still debated. The aim of this study was to assess the prognostic value of high-sensitivity cardiac troponin I (hs-cTnI) assay in predicting 28-day mortality in patients with septic shock. Prospective study including 75 patients with septic shock admitted to a medico-surgical ICU from January to December 2017. Patients under the age of 18 years, known pregnancy and patients in post-cardiac arrest were excluded. Clinical and demographic data including age, gender, comorbidities, SAPS II and SOFA scores were collected. Hs-cTnI was measured soon after admission and 12, 24, 48 and 72 after. Receiver operating characteristic (ROC) analysis was performed to identify the most useful troponin I cut-off level for the prediction of 28-day mortality. A p <0.05 was considered significant. Seventy-five (M/F = 53/22) patients with septic shock were included in the study. The median SOFA and SAPS II scores were 10 and 42, respectively. The median duration of mechanical ventilation was 8 days and the median length of ICU stay was 11 days. The 28-day mortality was 54.6%. We found a high prevalence (47%) of elevated hs-cTnI in patients with septic shock. Median hs-cTnI on admission in the whole group was 36 ng/L. The 28-day mortality was found to be related to age (p <0.001), SAPS II score (p = 0.001), mean arterial pressure (p = 0.038), lactate (p <0.001) and glomerular filtration rate (p <0.001).Hs-cTnI levels were significantly higher in non-survival group than survival one at all time points: H12 (p = 0.006), H24 (p = 0.003), H48 (p = 0.005) and H72 (p=0.001). In multivariate analysis, hs-cTnI at H72 was independently associated with 28-day mortality. Hs-cTnI elevation at 72 hours was associated with 28-day mortality in septic shock patients. Jendoubi A, Jerbi S, Maamar E, Abbess A, Samoud Z, Kanzari L, et al. Prognostic Value of High-Sensitivity Troponin I in Patients with Septic Shock: A Prospective Observational Study. Indian J Crit Care Med 2019;23(7):320-325.


Rubisco activase is required for optimal photosynthesis in the green alga Chlamydomonas reinhardtii in a low-CO(2) atmosphere.
This report describes a Chlamydomonas reinhardtii mutant that lacks Rubisco activase (Rca). Using the BleR (bleomycin resistance) gene as a positive selectable marker for nuclear transformation, an insertional mutagenesis screen was performed to select for cells that required a high-CO2 atmosphere for optimal growth. The DNA flanking the BleR insert of one of the high-CO2-requiring strains was cloned using thermal asymmetric interlaced-polymerase chain reaction and inverse polymerase chain reaction and sequenced. The flanking sequence matched the C. reinhardtii Rca cDNA sequence previously deposited in the National Center for Biotechnology Information database. The loss of a functional Rca in the strain was confirmed by the absence of Rca mRNA and protein. The open reading frame for Rca was cloned and expressed in pSL18, a C. reinhardtii expression vector conferring paromomycin resistance. This construct partially complemented the mutant phenotype, supporting the hypothesis that the loss of Rca was the reason the mutant grew poorly in a low-CO2 atmosphere. Sequencing of the C. reinhardtii Rca gene revealed that it contains 10 exons ranging in size from 18 to 470 bp. Low-CO2-grown rca1 cultures had a growth rate and maximum rate of photosynthesis 60% of wild-type cells. Results obtained from experiments on a cia5 rca1 double mutant also suggest that the CO2-concentrating mechanism partially compensates for the absence of an active Rca in the green alga C. reinhardtii.


A multi-scale time-resolved study of photoactivated dynamics in 5-benzyl uracil, a model for DNA/protein interactions.
We combine fluorescence up-conversion and time correlated single photon counting experiments to investigate the 5-benzyl uracil excited state dynamics in methanol from 100 fs up to several ns. This molecule has been proposed as a model for DNA/protein interactions. Our results show emission bands at about 310 and 350 nm that exhibit bi-exponential sub-ps decays. Calculations, including solvent effects by a mixed discrete-continuum model, indicate that the Franck Condon region is characterized by significant coupling between the excited states of the benzyl and the uracil moieties, mirrored by the short-lived emission at 310 nm. Two main ground state recovery pathways are identified, both contributing to the 350 nm emission. The first 'photophysical' decay path involves a ππ* excited state localized on the uracil and is connected to the ground electronic state by an easily accessible crossing with S0, accounting for the short lifetime component. Simulations indicate that a possible second pathway is characterized by exciplex formation, with partial benzene → uracil charge transfer character, that may lead instead to photocyclization. The relevance of our results is discussed in view of the photoactivated dynamics of DNA/protein complexes, with implications on their interaction mechanisms.


Proteome analysis for pathogenicity and new diagnostic markers for Aspergillus fumigatus.
With the completion of the Aspergillus fumigatus genome it is now possible to study protein regulation on a global scale. One of the most suitable protein separation techniques is based on 2D-gel electrophoresis, which allows the separation of proteins based on their charge and size in a gel matrix. In addition, gel-free proteomics techniques based on liquid-chromatography coupled with mass spectrometry have gained importance. With the application of proteomic tools a comprehensive overview about the proteins of A. fumigatus present or induced during environmental changes and stress conditions can be obtained. For A. fumigatus, several proteomic studies have already been published including the response of the fungus to oxidative stress that induced the up-regulation of many proteins including catalases and thioredoxin peroxidase. Since many of the identified proteins/genes were apparently regulated by a putative Saccharomyces cerevisiae Yap1 homolog, the corresponding gene of A. fumigatus was identified, designated Afyap1 and further characterized. In addition, some of the gene products expressed under stress conditions are also known fungal antigens, such as the thioredoxin peroxidase AspF3. Thus, besides pathogenicity studies, proteomics also delivers the tools to screen for new antigens which could improve the diagnosis of diseases caused by A. fumigatus.


Intraosseous mucoepidermoid carcinoma of maxilla: a rare entity.
Mucoepidermoid carcinoma (MEC) is the malignant salivary gland neoplasm chiefly occurred in minor salivary gland. One of the rare variant of MEC is intra-osseous variant found in the jaws known as central mucoepidermoid carcinoma. Presently in this case report, we described a 28-year-old male diagnosed with central low grade mucoepidermoid carcinoma subsequently with the presence of asymptomatic swelling with a history of trauma. Clinically mimicking a cystic lesion and radiographically gives an idea of mixed radio-opaque radiolucent lesion which creates a confusion to render a final diagnosis. The site, duration and history of the case are uncommon for the occurrence of intra-osseous malignant lesion of salivary glands. Present case adds new dimensions to the present knowledge about the clinical and radiographical picture that a central mucoepidermoid carcinoma can mimic.


Forest insects and climate change: long-term trends in herbivore damage.
Long-term data sets, covering several decades, could help to reveal the effects of observed climate change on herbivore damage to plants. However, sufficiently long time series in ecology are scarce. The research presented here analyzes a long-term data set collected by the Hungarian Forest Research Institute over the period 1961-2009. The number of hectares with visible defoliation was estimated and documented for several forest insect pest species. This resulted in a unique time series that provides us with the opportunity to compare insect damage trends with trends in weather patterns. Data were analyzed for six lepidopteran species: Thaumetopoea processionea, Tortrix viridana, Rhyacionia buoliana, Malacosoma neustria, Euproctis chrysorrhoea, and Lymantria dispar. All these species exhibit outbreak dynamics in Hungary. Five of these species prefer deciduous tree species as their host plants, whereas R. buoliana is a specialist on Pinus spp. The data were analyzed using general linear models and generalized least squares regression in relation to mean monthly temperature and precipitation. Temperature increased considerably, especially over the last 25 years (+1.6°C), whereas precipitation exhibited no trend over the period. No change in weather variability over time was observed. There was increased damage caused by two species on deciduous trees. The area of damage attributed to R. buoliana decreased over the study period. There was no evidence of increased variability in damage. We conclude that species exhibiting a trend toward outbreak-level damage over a greater geographical area may be positively affected by changes in weather conditions coinciding with important life stages. Strong associations between the geographical extent of severe damage and monthly temperature and precipitation are difficult to confirm, studying the life-history traits of species could help to increase understanding of responses to climate change.


The Goals of Treating Obstructive Sleep Apnea.
Obstructive sleep apnea (OSA) syndrome is a destructive and insidious entity mostly underdiagnosed and undertreated. It affects not only individuals but the society as a whole. The costs to the populations can be measured not only in morbidity and mortality but also in the financial wellbeing of a society. Financial burden of this disease is staggering. The social fabric of society is also greatly impacted. Physiologic effects of OSA are far reaching. It has been shown that early intervention with treatment of OSA can often prevent and/or reverse many of the negative outcomes associated with this condition.


Hypoglycaemia and hyperglycaemia are associated with unfavourable outcome in infants with hypoxic ischaemic encephalopathy: a post hoc analysis of the CoolCap Study.
To investigate the association of neonatal hypoglycaemia and hyperglycaemia with outcomes in infants with hypoxic ischaemic encephalopathy (HIE). Post hoc analysis of the CoolCap Study. 25 perinatal centres in the UK, the USA and New Zealand during 1999-2002. 234 infants at ≥36 weeks' gestation with moderate-to-severe HIE enrolled in the CoolCap Study. 214 (91%) infants had documented plasma glucose and follow-up outcome data. Infants were randomised to head cooling for 72 h starting within 6 h of birth, or standard care. Plasma glucose levels were measured at predetermined time intervals after randomisation. The unfavourable primary outcome of the study was death and/or severe neurodevelopmental disability at 18 months. Hypoglycaemia (≤40 mg/dL, ≤2.2 mmol/L) and hyperglycaemia (>150 mg/dL, >8.3 mmol/L) during the first 12 h after randomisation were investigated for univariable and multivariable associations with unfavourable primary outcome. 121 (57%) infants had abnormal plasma glucose values within 12 h of randomisation. Unfavourable outcome was observed in 126 (60%) infants and was more common among subjects with hypoglycaemia (81%, p=0.004), hyperglycaemia (67%, p=0.01) and any glucose derangement within the first 12 h (67%, p=0.002) compared with normoglycaemic infants (48%) in univariable analysis. These associations remained significant after adjusting for birth weight, Apgar score, pH, Sarnat stage and hypothermia therapy. Both hypoglycaemia and hyperglycaemia in infants with moderate-to-severe HIE were independently associated with unfavourable outcome. Future studies are needed to investigate the prognostic significance of these associations and their role as biomarkers of brain injury. (ClinicalTrials.gov NCT00383305).


Average beta burst duration profiles provide a signature of dynamical changes between the ON and OFF medication states in Parkinson's disease.
Parkinson's disease motor symptoms are associated with an increase in subthalamic nucleus beta band oscillatory power. However, these oscillations are phasic, and there is a growing body of evidence suggesting that beta burst duration may be of critical importance to motor symptoms. This makes insights into the dynamics of beta bursting generation valuable, in particular to refine closed-loop deep brain stimulation in Parkinson's disease. In this study, we ask the question "Can average burst duration reveal how dynamics change between the ON and OFF medication states?". Our analysis of local field potentials from the subthalamic nucleus demonstrates using linear surrogates that the system generating beta oscillations is more likely to act in a non-linear regime OFF medication and that the change in a non-linearity measure is correlated with motor impairment. In addition, we pinpoint the simplest dynamical changes that could be responsible for changes in the temporal patterning of beta oscillations between medication states by fitting to data biologically inspired models, and simpler beta envelope models. Finally, we show that the non-linearity can be directly extracted from average burst duration profiles under the assumption of constant noise in envelope models. This reveals that average burst duration profiles provide a window into burst dynamics, which may underlie the success of burst duration as a biomarker. In summary, we demonstrate a relationship between average burst duration profiles, dynamics of the system generating beta oscillations, and motor impairment, which puts us in a better position to understand the pathology and improve therapies such as deep brain stimulation.


Imitation dynamics of vaccination behaviour on social networks.
The problem of achieving widespread immunity to infectious diseases by voluntary vaccination is often presented as a public-goods dilemma, as an individual's vaccination contributes to herd immunity, protecting those who forgo vaccination. The temptation to free-ride brings the equilibrium vaccination level below the social optimum. Here, we present an evolutionary game-theoretic approach to this problem, exploring the roles of individual imitation behaviour and population structure in vaccination. To this end, we integrate an epidemiological process into a simple agent-based model of adaptive learning, where individuals use anecdotal evidence to estimate costs and benefits of vaccination. In our simulations, we focus on parameter values that are realistic for a flu-like infection. Paradoxically, as agents become more adept at imitating successful strategies, the equilibrium level of vaccination falls below the rational individual optimum. In structured populations, the picture is only somewhat more optimistic: vaccination is widespread over a range of low vaccination costs, but coverage plummets after cost exceeds a critical threshold. This result suggests parallels to historical scenarios in which vaccination coverage provided herd immunity for some time, but then rapidly dropped. Our work sheds light on how imitation of peers shapes individual vaccination choices in social networks.


The HUPO initiative on Model Organism Proteomes, iMOP.
The community working on model organisms is growing steadily and the number of model organisms for which proteome data are being generated is continuously increasing. To standardize efforts and to make optimal use of proteomics data acquired from model organisms, a new Human Proteome Organisation (HUPO) initiative on model organism proteomes (iMOP) was approved at the HUPO Ninth Annual World Congress in Sydney, 2010. iMOP will seek to stimulate scientific exchange and disseminate HUPO best practices. The needs of model organism researchers for central databases will be better represented, catalyzing the integration of proteomics and organism-specific databases. Full details of iMOP activities, members, tools and resources can be found at our website http://www.imop.uzh.ch/ and new members are invited to join us.


Can you hear me now? Range-testing a submerged passive acoustic receiver array in a Caribbean coral reef habitat.
Submerged passive acoustic technology allows researchers to investigate spatial and temporal movement patterns of many marine and freshwater species. The technology uses receivers to detect and record acoustic transmissions emitted from tags attached to an individual. Acoustic signal strength naturally attenuates over distance, but numerous environmental variables also affect the probability a tag is detected. Knowledge of receiver range is crucial for designing acoustic arrays and analyzing telemetry data. Here, we present a method for testing a relatively large-scale receiver array in a dynamic Caribbean coastal environment intended for long-term monitoring of multiple species. The U.S. Geological Survey and several academic institutions in collaboration with resource management at Buck Island Reef National Monument (BIRNM), off the coast of St. Croix, recently deployed a 52 passive acoustic receiver array. We targeted 19 array-representative receivers for range-testing by submersing fixed delay interval range-testing tags at various distance intervals in each cardinal direction from a receiver for a minimum of an hour. Using a generalized linear mixed model (GLMM), we estimated the probability of detection across the array and assessed the effect of water depth, habitat, wind, temperature, and time of day on the probability of detection. The predicted probability of detection across the entire array at 100 m distance from a receiver was 58.2% (95% CI: 44.0-73.0%) and dropped to 26.0% (95% CI: 11.4-39.3%) 200 m from a receiver indicating a somewhat constrained effective detection range. Detection probability varied across habitat classes with the greatest effective detection range occurring in homogenous sand substrate and the smallest in high rugosity reef. Predicted probability of detection across BIRNM highlights potential gaps in coverage using the current array as well as limitations of passive acoustic technology within a complex coral reef environment.


Activated sludge model (ASM) based modelling of membrane bioreactor (MBR) processes: a critical review with special regard to MBR specificities.
Membrane bioreactors (MBRs) have been increasingly employed for municipal and industrial wastewater treatment in the last decade. The efforts for modelling of such wastewater treatment systems have always targeted either the biological processes (treatment quality target) as well as the various aspects of engineering (cost effective design and operation). The development of Activated Sludge Models (ASM) was an important evolution in the modelling of Conventional Activated Sludge (CAS) processes and their use is now very well established. However, although they were initially developed to describe CAS processes, they have simply been transferred and applied to MBR processes. Recent studies on MBR biological processes have reported several crucial specificities: medium to very high sludge retention times, high mixed liquor concentration, accumulation of soluble microbial products (SMP) rejected by the membrane filtration step, and high aeration rates for scouring purposes. These aspects raise the question as to what extent the ASM framework is applicable to MBR processes. Several studies highlighting some of the aforementioned issues are scattered through the literature. Hence, through a concise and structured overview of the past developments and current state-of-the-art in biological modelling of MBR, this review explores ASM-based modelling applied to MBR processes. The work aims to synthesize previous studies and differentiates between unmodified and modified applications of ASM to MBR. Particular emphasis is placed on influent fractionation, biokinetics, and soluble microbial products (SMPs)/exo-polymeric substances (EPS) modelling, and suggestions are put forward as to good modelling practice with regard to MBR modelling both for end-users and academia. A last section highlights shortcomings and future needs for improved biological modelling of MBR processes.


1H, 13C and 15N backbone chemical shift assignments of SARS-CoV-2 nsp3a.
The non-structural protein nsp3 from SARS-CoV-2 plays an essential role in the viral replication transcription complex. Nsp3a constitutes the N-terminal domain of nsp3, comprising a ubiquitin-like folded domain and a disordered acidic chain. This region of nsp3a has been linked to interactions with the viral nucleoprotein and the structure of double membrane vesicles. Here, we report the backbone resonance assignment of both domains of nsp3a. The study is carried out in the context of the international covid19-nmr consortium, which aims to characterize SARS-CoV-2 proteins and RNAs, providing for example NMR chemical shift assignments of the different viral components. Our assignment will provide the basis for the identification of inhibitors and further functional and interaction studies of this essential protein.


The G gamma / T-15 transgenic mouse model of androgen-independent prostate cancer: target cells of carcinogenesis and the effect of the vitamin D analogue EB 1089.
Transgenic mouse models of prostate cancer provide unique opportunities to understand the molecular events in prostate carcinogenesis and for the preclinical testing of new therapies. We studied the G gamma T-15 transgenic mouse line, which contains the human fetal globin promoter linked to SV40 T antigen (Tag) and which develops androgen-independent prostate cancer. Using the immunohistochemistry of normal mouse prostates before tumor formation, we showed that the target cells of carcinogenesis in G gamma T-15 mice are located in the basal epithelial layer. We tested the efficacy of the 1,25(OH)(2)D(3) analogue, EB 1089, to chemoprevent prostate cancer in these transgenic mice. Compared with treatment with placebo, treatment with EB 1089 at three different time points before the onset of prostate tumors in mice did not prevent or delay tumor onset. However, EB 1089 significantly inhibited prostate tumor growth. At the highest dose, EB 1089 inhibited prostate tumor growth by 60% (P = 0.0003) and the growth in the number of metastases, although this dose also caused significant hypercalcemia and weight loss. We conducted several in vitro experiments to explore why EB 1089 did not prevent the occurrence of the primary tumors. EB 1089 significantly inhibited the growth of a Tag-expressing human prostate epithelial cell line, BPH-1, and an androgen-insensitive subline of LNCaP cells [which was not inhibited by 1,25(OH)(2)D(3)]. Thus, neither Tag expression nor androgen insensitivity explain the absence of chemopreventive effect. Conversely, neither 1,25(OH)(2)D(3) nor EB 1089 inhibited the growth of the normal rat prostate basal epithelial cell line NRP-152. It is likely that EB 1089 was not effective in delaying the growth of the primary tumor in G gamma T-15 transgenic mice because the target cells of carcinogenesis in these mice are located in the basal epithelial layer. We conclude that G gamma T-15 transgenic mice are a useful model for testing vitamin D-based therapies in androgen-insensitive prostate cancer but are not suitable for studies of vitamin D-based chemoprevention. The superiority of EB 1089 over 1,25(OH)(2)D(3) in the growth suppression of androgen-insensitive prostate cancer cells supports the use of EB 1089 in androgen-insensitive prostate cancer.


Quantitative magnetic resonance imaging of the lumbar intervertebral discs.
Human lumbar spine is composed of multiple tissue components that serve to provide structural stability and proper nutrition. Conventional magnetic resonance (MR) imaging techniques have been useful for evaluation of IVD, but inadequate at imaging the discovertebral junction and ligamentous tissues due primarily to their short T2 nature. Ultrashort time to echo (UTE) MR techniques acquire sufficient MR signal from these short T2 tissues, thereby allowing direct and quantitative evaluation. This article discusses the anatomy of the lumbar spine, MR techniques available for morphologic and quantitative MR evaluation of long and short T2 tissues of the lumbar spine, considerations for T2 relaxation modeling and fitting, and existing and new techniques for spine image post-processing, focusing on segmentation. This article will be of interest to radiologic and orthopaedic researchers performing lumbar spine imaging.


Two new grape cultivars, bud sports of Cabernet Sauvignon bearing pale-coloured berries, are the result of deletion of two regulatory genes of the berry colour locus.
Bud sports are infrequent changes in phenotype affecting shoots of woody perennials but the molecular basis of these mutations has rarely been identified. In this report, we show that the bronze-coloured berries of the Malian cultivar, a documented bud sport of the wine grape Cabernet Sauvignon (Vitis vinifera L.), lack anthocyanins in the subepidermal cells compared to the red/black berried Cabernet Sauvignon in which both the epidermis and several subepidermal cell layers contain anthocyanin. The Malian phenotype is correlated with an alteration in the genome indicated by a reduction of hybridisation signal using a MYBA probe. In Shalistin, a white-berried bud sport of Malian, the red allele at the berry colour locus appears to have been deleted completely. These data suggest that Malian could be a L1/L2 periclinal chimera, which gave rise to Shalistin by an invasion of epidermal cells (L1) by the mutated subepidermal cells (L2). The red grape Pinot Noir has given rise to a number of pale coloured sports, although the provenance of the extant sports is not known. We show that a clone of Pinot Blanc (white-berried) does not have a deletion of the red allele of the same dimensions as that in Shalistin, though a small deletion is a likely explanation for the altered phenotype. However, the mechanism of deletion of the red allele of the berry colour locus is a possible means by which other red to white clonal mutations of grapevines have occurred.


Selenium and bladder cancer risk: a meta-analysis.
Selenium is considered to be an antioxidant, and its high levels have been inversely associated with cancer risk of several sites. This meta-analysis examined the relationship between levels of selenium measured in serum and toenails, and the risk of bladder cancer. A meta-analysis using data from seven published epidemiologic studies (three case-control, three nested case-control, one case-cohort) published before March 2010 was done to examine the association between levels of selenium and bladder cancer. Fixed and random effects analyses were done to calculate meta-odds ratio (mOR) and 95% confidence intervals (CI). Heterogeneity among studies was measured by the I(2) statistic. Overall, the risk of bladder cancer was inversely associated with elevated levels of selenium according to a random-effects model (mOR = 0.61; 95% CI, 0.42-0.87). The mORs were 0.95 (95% CI, 0.69-1.27) and 0.55 (95% CI, 0.32-0.95) among men and women, respectively. Sex, type of sample specimen, smoking status, and study design were found to be potential sources of heterogeneity. A significant protective effect of selenium, observed mainly among women, may result from gender-specific differences in its accumulation and excretion. The heterogeneity found among studies was mainly linked to the different biological sample specimens used to measure the selenium concentrations and the small size of the studies. Although these results suggest a protective effect of selenium for bladder cancer risk, additional large studies are warranted to support these preliminary evidence. The present results suggest a beneficial effect of high selenium intake for bladder cancer risk.


Prospective Predictions of Human Pharmacokinetics for Eighteen Compounds.
Quantitative predictions of pharmacokinetics (PKs) and concentration-time profiles using in vitro and in vivo preclinical data are critical to estimate systemic exposures for first-in-human studies. Prospective prediction accuracies of human PKs for 18 compounds across all Biopharmaceutics Classification System/Biopharmaceutics Drug Disposition Classification System classes were evaluated. The a priori predicted profiles were then compared with clinical profiles. Predictions were conducted using advanced compartmental absorption and transit (ACAT) physiology based PK models. Human intravenous profiles were predicted with in vivo preclinical intravenous data using Wajima formulas. Human oral profiles were generated by combining intravenous PKs together with either physiologically based oral ACAT models utilizing solubility and permeability data or by using the average bioavailability (F) and absorption rate constant (ka ) from preclinical species. Key PK parameters evaluated were the maximum plasma concentration (Cmax ), the area under the plasma concentration-time curve (AUC), CL/F, and Vdss /F. A decision tree was provided to guide human PK and ACAT predictions. Our prospective human PK prediction methods yielded good prediction results. The predictions were within a twofold error for 80% (Cmax ), 65% (AUC), 65% (CL/F), and 80% (Vz /F) of the compounds. The methods described can be readily implemented with available in vitro and in vivo data during early drug development.


Investigating adolescents' sources of information concerning tobacco and the resulting impact on attitudes toward public policy.
In this study, we investigated different sources of information concerning the use of tobacco and the impact that these sources may have on attitudes toward tobacco policies. We surveyed 4336 high school students gathered from 5 high schools in the Southeastern United States. The results indicate that just over half of these youth are supportive of public policies targeting bans on smoking in public places and having a minimum age to purchase tobacco products. Race is significant in impacting both age restriction and prohibition of smoking in public places, with African American youth being less supportive of both dependent variables. However, holding this variable constant in an ordinal logistic regression, we found that attitudes toward policy are impacted by the environment related to smoking in which the youth lives; the extent to which the youth believes he/she is well informed; and more important, the amount of correct and accurate information on smoking the youth possess. Communicating accurate information is vital in increasing youth support for pending or already existing tobacco policies.


The potential of optical proteomic technologies to individualize prognosis and guide rational treatment for cancer patients.
Genomics and proteomics will improve outcome prediction in cancer and have great potential to help in the discovery of unknown mechanisms of metastasis, ripe for therapeutic exploitation. Current methods of prognosis estimation rely on clinical data, anatomical staging and histopathological features. It is hoped that translational genomic and proteomic research will discriminate more accurately than is possible at present between patients with a good prognosis and those who carry a high risk of recurrence. Rational treatments, targeted to the specific molecular pathways of an individual's high-risk tumor, are at the core of tailored therapy. The aim of targeted oncology is to select the right patient for the right drug at precisely the right point in their cancer journey. Optical proteomics uses advanced optical imaging technologies to quantify the activity states of and associations between signaling proteins by measuring energy transfer between fluorophores attached to specific proteins. Förster resonance energy transfer (FRET) and fluorescence lifetime imaging microscopy (FLIM) assays are suitable for use in cell line models of cancer, fresh human tissues and formalin-fixed paraffin-embedded tissue (FFPE). In animal models, dynamic deep tissue FLIM/FRET imaging of cancer cells in vivo is now also feasible. Analysis of protein expression and post-translational modifications such as phosphorylation and ubiquitination can be performed in cell lines and are remarkably efficiently in cancer tissue samples using tissue microarrays (TMAs). FRET assays can be performed to quantify protein-protein interactions within FFPE tissue, far beyond the spatial resolution conventionally associated with light or confocal laser microscopy. Multivariate optical parameters can be correlated with disease relapse for individual patients. FRET-FLIM assays allow rapid screening of target modifiers using high content drug screens. Specific protein-protein interactions conferring a poor prognosis identified by high content tissue screening will be perturbed with targeted therapeutics. Future targeted drugs will be identified using high content/throughput drug screens that are based on multivariate proteomic assays. Response to therapy at a molecular level can be monitored using these assays while the patient receives treatment: utilizing re-biopsy tumor tissue samples in the neoadjuvant setting or by examining surrogate tissues. These technologies will prove to be both prognostic of risk for individuals when applied to tumor tissue at first diagnosis and predictive of response to specifically selected targeted anticancer drugs. Advanced optical assays have great potential to be translated into real-life benefit for cancer patients.


An overview of 37 randomised trials of blood pressure lowering agents among 270,000 individuals. World Health Organization-International Society of Hypertension Blood Pressure Lowering Treatment Trialists' Collaboration.
Overviews (meta-analyses) of the major ongoing randomized trials of blood pressure lowering drugs will be conducted to determine the effects of: first, newer versus older classes of blood pressure lowering drugs in patients with hypertension; and second, blood pressure lowering treatments versus untreated or less treated control conditions in patient groups at high risk of cardiovascular events. The principal study outcomes are stroke, coronary heart disease, total cardiovascular events and total cardiovascular deaths. The overviews have been prospectively designed and will be conducted on individual patient data. The analyses will be conducted as a collaboration between the principal investigators of participating trials involving about 270,000 patients. Full data should be available in 2003, with the first round of analyses performed in 1999-2000. The combination of trial results should provide good statistical power to detect even modest differences between the effects on the main study outcomes.


Mesenchymal lineage stem cells have pronounced anti-inflammatory effects in the twitcher mouse model of Krabbe's disease.
The twitcher mouse is an animal model of Krabbe's disease (KD), which is a neurodegenerative lysosomal storage disorder resulting from the absence of functional lysosomal enzyme galactocerebrosidase (GALC). This disease affects the central and peripheral nervous systems and in its most severe form results in death before the age of 2 in humans and approximately 30-40 days in mice. This study evaluates the effect of intracerebroventricular administration of mesenchymal stem cells derived from adipose tissue (ASCs) and bone marrow (BMSCs) on the pathology of KD. Subsequent to the intracerebroventricular injection of ASCs or BMSCs on postnatal day (PND) 3-4, body weight, lifespan, and neuromotor function were evaluated longitudinally beginning on PND15. At sacrifice, tissues were harvested for analysis of GALC activity, presence of myelin, infiltration of macrophages, microglial activation, inflammatory markers, and cellular persistence. Survival analysis curves indicate a statistically significant increase in lifespan in stem cell-treated twitcher mice as compared with control twitcher mice. Body weight and motor function were also improved compared with controls. The stem cells may mediate some of these benefits through an anti-inflammatory mechanism because the expression of numerous proinflammatory markers was downregulated at both transcriptional and translational levels. A marked decrease in the levels of macrophage infiltration and microglial activation was also noted. These data indicate that mesenchymal lineage stem cells are potent inhibitors of inflammation associated with KD progression and offer potential benefits as a component of a combination approach for in vivo treatment by reducing the levels of inflammation.


Chlordiazepoxide-induced expression of c-Fos in the central extended amygdala and other brain regions of the C57BL/6J and DBA/2J inbred mouse strains: relationships to mechanisms of ethanol action.
Previous studies have established an association between the ethanol-induced locomotor response and activation of the central nucleus of the amygdala (CeA) as determined by changes in the number of Fos-like immunoreactive (Fos-li) neurons. The purpose of the current study was to determine if the benzodiazepine chlordiazepoxide (CDP) would produce similar effects to ethanol on behavior and the CeA. In experiment 1, C57BL/6J (B6) and DBA/2J (D2) mice were administered CDP over a dose range of 3 to 30 mg/kg and the effects on locomotor behavior and the number of Fos-li neurons in the extended CeA determined. For experiment 2, B6D2 F2 intercross animals were phenotyped for their locomotor response to ethanol using a test-retest design. The activity responsive and nonresponsive extreme phenotypes were then tested in the same fashion as the inbred strains. Similar to ethanol, CDP increased locomotor activity in the D2 strain but not the B6 strain; furthermore, the D2 strain was 3 to 10 times more sensitive than the B6 strain in terms of CDP activating the CeA and the associated lateral posterior aspect of the bed nucleus of the stria terminalis (BSTLP). In the shell of the nucleus accumbens (NAc), CDP inhibited the number of Fos-positive neurons in both strains. CDP also discriminated between the responsive and nonresponsive extremes both in terms of behavior and activation of the CeA. Overall, these data point to the importance of GABA(A) mediated mechanisms in the ethanol-induced locomotor response. It is suggested that both drugs block the feed-forward inhibition in the CeA, resulting in activation of the GABAergic projection neurons. The overall net effect of CDP or ethanol administration on the output from the CeA will be inhibitory, from which it follows that the locomotor activation response must be associated with the selective inhibition of some behavior or ensembles of behaviors that are known to be mediated by the CeA and reduce locomotor activity (i.e., the "freezing" response).


A preliminary study for the development of indices and the current state of surgical site infections (SSIs) in Korea: the Korean Surgical Site Infection Surveillance (KOSSIS) program.
We aimed to develop an effective system for surgical site infection (SSI) surveillance and examine the current domestic state of SSIs for common abdominal surgeries in Korea. The Korean Surgical Site Infection Surveillance (KOSSIS) program was developed as an SSI surveillance system. A prospective multicenter study in nine university-affiliated or general hospitals was conducted for patients who underwent gastrectomy, cholecystectomy, appendectomy, colectomy, or proctectomy between August 16 and September 30 in 2012. Patients were monitored for up to 30 days by combining direct observation and a postdischarge surgeon survey. Data on SSIs were prospectively collected with KOSSIS secretarial support according to a common protocol. Operation-specific SSI rates were stratified according to risk factors and compared with data from the Korean Nosocomial Infections Surveillance System (KONIS) and National Healthcare Safety Network. A focus group interview was conducted with participating hospitals for feedback. A total of 1,088 operations were monitored: 207 gastrectomies, 318 cholecystectomies, 270 appendectomies, 197 colectomies, and 96 proctectomies. Operation-specific SSI rates determined by the KOSSIS program were substantially higher than those found in KONIS (7.73% [95% confidence interval, 4.5%-12.3%] vs. 3.4% for gastrectomies, 10.15% [95% confidence interval, 6.1%-15.2%] vs. 4.0% for colectomy, and 13.5% [95% confidence interval, 7.4%-22.0%] vs. 4.2% for proctectomy). Despite a short surveillance period and heterogenous group of hospitals, our results suggest that KOSSIS could be a useful program to enhance SSI surveillance in Korea.


A mixed-methods study of the Care Needs of individuals with idiopathic Pulmonary fibrosis and their carers--CaNoPy: a study protocol.
Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening illness of unknown aetiology, with no proven pharmacological treatments. There is a limited evidence base indicating that the disease negatively affects quality of life, leading to increased dependence, restrictions on daily activities and fatigue. However, there is a paucity of in-depth information on disease impact across its trajectory, particularly in relation to unmet needs, outcomes of importance to patients and the experiences of carers. Furthermore, little is known about the support and information needs of individuals and their carers, or at what point individual need should trigger a referral to palliative care services. A mixed-methods study is proposed recruiting individuals with IPF at different stages of the disease and their carers from three respiratory centres in England and Wales. In-depth interviews will be undertaken with participants, adopting an Interpretative Phenomenological Analysis approach. The study will also use validated questionnaires to explore quality of life (EQ-5D), depression (Hospital Anxiety and Depression Scale), breathlessness (Borg dyspnoea scale) and cough (Leicester Cough Questionnaire, Cough Symptom Score). Ethical approvals were gained in April 2012. Palliative care research is a developing field, but there has been limited focus on IPF. We anticipate that the results of the study will enable healthcare professionals to provide appropriate palliative care across the trajectory for individuals with the disease, and their carers, and we therefore aim to disseminate via relevant respiratory and palliative care journals and conferences. We will also support the lay representative involved in the project to disseminate the findings to patient groups.


Out-of-hospital medication errors among young children in the United States, 2002-2012.
To investigate out-of-hospital medication errors among young children in the United States. Using data from the National Poison Database System, a retrospective analysis of out-of-hospital medication errors among children <6 years old from 2002 through 2012 was conducted. During 2002-2012, 696,937 children <6 years experienced out-of-hospital medication errors, averaging 63,358 episodes per year, or 1 child every 8 minutes. The average annual rate of medication errors was 26.42 per 10,000 population. Cough and cold medication errors decreased significantly, whereas the number (42.9% increase) and rate (37.2% increase) of all other medication errors rose significantly during the 11-year study period. The number and rate of medication error events decreased with increasing child age, with children <1 year accounting for 25.2% of episodes. Analgesics (25.2%) were most commonly involved in medication errors, followed by cough and cold preparations (24.6%). Ingestion accounted for 96.2% of events, and 27.0% of medication errors were attributed to inadvertently taking or being given medication twice. Most (93.5%) cases were managed outside of a health care facility; 4.4% were treated and released from a health care facility; 0.4% were admitted to a non-critical care unit; 0.3% were admitted to a critical care unit; and 25 children died. This is the first comprehensive study to evaluate the epidemiologic characteristics of out-of-hospital medication errors among children <6 years of age on a national level. Increased efforts are needed to prevent medication errors, especially those involving non-cough and cold preparations, among young children.


Placental malaria is associated with reduced early life weight development of affected children independent of low birth weight.
Infection with Plasmodium falciparum during pregnancy contributes substantially to the disease burden in both mothers and offspring. Placental malaria may lead to intrauterine growth restriction or preterm delivery resulting in low birth weight (LBW), which, in general, is associated with increased infant morbidity and mortality. However, little is known about the possible direct impact of the specific disease processes occurring in PM on longer term outcomes such as subsequent retarded growth development independent of LBW. In an existing West-African cohort, 783 healthy infants with a birth weight of at least 2,000 g were followed up during their first year of life. The aim of the study was to investigate if Plasmodium falciparum infection of the placenta, assessed by placental histology, has an impact on several anthropometric parameters, measured at birth and after three, six and 12 months using generalized estimating equations models adjusting for moderate low birth weight. Independent of LBW, first to third born infants who were exposed to either past, chronic or acute placental malaria during pregnancy had significantly lower weight-for-age (-0.43, 95% CI: -0.80;-0.07), weight-for-length (-0.47, 95% CI: -0.84; -0.10) and BMI-for-age z-scores (-0.57, 95% CI: -0.84; -0.10) compared to infants born to mothers who were not diagnosed with placental malaria (p = 0.019, 0.013, and 0.012, respectively). Interestingly, the longitudinal data on histology-based diagnosis of PM also document a sharp decline of PM prevalence in the Sukuta cohort from 16.5% in 2002 to 5.4% in 2004. It was demonstrated that PM has a negative impact on the infant's subsequent weight development that is independent of LBW, suggesting that the longer term effects of PM have been underestimated, even in areas where malaria transmission is declining.


Creation of an antibody-based subcellular protein atlas.
An important part for understanding the complex machinery of living cells is to know the spatial distribution of proteins all the way from organ to organelle levels. An equally important part of proteomics is to map the subcellular distribution of all human proteins. Here, we discuss methodologies for systematic subcellular profiling with emphasis on the antibody-based approach performed as a part of the Human Protein Atlas project. The considerations made when creating the subcellular protein atlas and critical parameters of this approach are discussed.


Iron therapy in maintenance haemodialysis.
1. Marrow-iron stores were absent or reduced in twenty-three of thirty-nine patients studied within 52 months of starting maintenance haemodialysis. 2. Oral iron was given to twelve patients (group I) with absent or reduced, and to eleven patients (group II) with normal or increased marrow-iron stores. 3. A significant increase in mean haemoglobin concentration and marrow iron was observed in group I. No significant change in mean haemoglobin concentration or marrow iron occurred in group II. Mean haemoglogin concentration after treatment was significantly higher in group I than in group II. 4. The four patients who had normal or increased marrow iron and who received no oral iron all suffered a fall in haemoglobin concentration, and three of them showed a reduction in marrow iron. 5. These findings indicate that continuous oral iron therapy should be given to all patients on maintenance dialysis to correct or prevent iron deficiency.


Nonlocal rheology of dense granular flow in annular shear experiments.
The flow of dense granular materials at low inertial numbers cannot be fully characterized by local rheological models; several nonlocal rheologies have recently been developed to address these shortcomings. To test the efficacy of these models across different packing fractions and shear rates, we perform experiments in a quasi-2D annular shear cell with a fixed outer wall and a rotating inner wall, using photoelastic particles. The apparatus is designed to measure both the stress ratio μ (the ratio of shear to normal stress) and the inertial number I through the use of a torque sensor, laser-cut leaf springs, and particle-tracking. We obtain μ(I) curves for several different packing fractions and rotation rates, and successfully find that a single set of model parameters is able to capture the full range of data collected once we account for frictional drag with the bottom plate. Our measurements confirm the prediction that there is a growing lengthscale at a finite value μs, associated with a frictional yield criterion. Finally, we newly identify the physical mechanism behind this transition at μs by observing that it corresponds to a drop in the susceptibility to force chain fluctuations.


Lung function 8-18 years after intermittent positive pressure ventilation for hyaline membrane disease.
Lung function and respiratory symptoms were studied in 40 children aged 8-18 years who had been ventilated for hyaline membrane disease after birth; 11 had had bronchopulmonary dysplasia. Also studied were 38 age matched children who had had hyaline membrane disease but had not required ventilation, 25 unmatched children who were born prematurely but did not develop hyaline membrane disease, and 39 randomly selected pupils of similar age. There was no difference in thoracic gas volume, total lung capacity, inspiratory vital capacity, residual volume, or transfer factor for carbon monoxide between the groups. Respiratory symptoms during the three years before the study and the frequency of clinically diagnosed asthma in patients and their family were similar in all the children with hyaline membrane disease irrespective of whether they had been ventilated or had had bronchopulmonary dysplasia. The children with bronchopulmonary dysplasia, however, had a lower forced expiratory volume in one second (FEV1) before bronchodilator (73% predicted) than the other groups (88-95% predicted). Children who had required ventilation had lower values for specific airways conductance (sGaw) and a greater increase in FEV1 (delta FEV1) after salbutamol (13%) than non-ventilated children (6%); delta FEV1 was associated with the peak pressure of intermittent positive pressure ventilation, a family history of asthma and a history of wheezing, recurrent respiratory illnesses, and a doctor's diagnosis of asthma during the three years before the study. These findings indicate that after eight years of age patients with bronchopulmonary dysplasia have more reversible airways obstruction, compatible with increased bronchial smooth muscle tone.


Agonists of epoxyeicosatrienoic acids reduce infarct size and ameliorate cardiac dysfunction via activation of HO-1 and Wnt1 canonical pathway.
Myocardial infarction (MI) is complicated by ventricular fibrosis and associated diastolic and systolic failure. Emerging studies implicate Wnt1 signaling in the formation of new blood vessels. Epoxyeicosatrienoic acids (EETs)-mediated up-regulation of heme oxygenase-1 (HO-1) protects against the detrimental consequences of MI in several animal models, however, the mechanism(s) by which this occurs remains unclear. The aim of this study was to examine these mechanisms in the LAD ligation animal model of post infarcted heart failure. Specifically, we sought to clarify the mechanistic basis of the interactions of the Wnt1 canonical pathway, HO-1 and associated angiogenesis. Human microvascular endothelial cells (HMECs) were exposed to anoxia and treated with the EET agonist, NUDSA, in the presence and absence of tin mesoporphyrin (SnMP). Increased capillary density, and Wnt1 and HO-1 expression occurred in cells treated with NUDSA. Anoxic HMECs treated with NUDSA and Wnt1 siRNA, exhibited decreased in the expression of β-catenin and the Wnt1 target gene, PPARδ (p<0.05 vs. NUDSA). Furthermore, blocking the Wnt 1 antagonist, Dickkopf 1, by siRNA increased β-catenin and PPARδ expression, and this effect was further enhanced by the concurrent administration of NUDSA. In in vivo experiments, C57B16 mice were divided into 4 groups: sham, mice with MI via LAD ligation and mice with MI treated with NUDSA, with and without SnMP. Increased fractional area change (FAC) and myocardial angiogenesis were observed in mice treated with NUDSA (p<0.05 vs. MI). Increased expression of HO-1, Wnt1, β-catenin, adiponectin, and phospho-endothelial nitric oxide synthetase (p-eNOS), and a decrease in the glycosylated subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, gp91(phox) expression occurred in cardiac tissue of mice treated with NUDSA (p<0.05 vs. MI). SnMP reversed these effects. This novel study demonstrates that increasing the canonical Wnt1 signaling cascade with the subsequent increase in HO-1, adiponectin and angiogenesis ameliorates fibrosis and cardiac dysfunction in a mouse model of MI and supports the hypothesis that HO-1 is an integral component of the EETs-adiponectin axis and is central for the control of resistance to fibrosis and vascular dysfunction and in part determine how they influence the cellular/vascular homeostasis and provides insight into the mechanisms involved in vascular dysfunction as well as potential targets for the treatment of CVD.


Macromolecular trafficking indicated by localization and turnover of sucrose transporters in enucleate sieve elements.
The leaf sucrose transporter SUT1 is essential for phloem loading and long-distance transport of assimilates. Both SUT1 messenger RNA (mRNA) and protein were shown to be diurnally regulated and to have high turnover rates. SUT1 protein was detected by immunolocalization in plasma membranes of enucleate sieve elements (SEs) in tobacco, potato, and tomato. Analysis by in situ hybridization showed that SUT1 mRNA localizes mainly to the SE and is preferentially associated with plasmodesmata. Antisense inhibition of SUT1 expression under control of a companion cell (CC)-specific promoter indicated synthesis of SUT1 mRNA in the CC. These results provide evidence for targeting of plant endogenous mRNA and potentially SUT1 protein through phloem plasmodesmata and for sucrose loading at the plasma membrane of SE.


Solution structures of beta peptide and its constituent fragments: relation to amyloid deposition.
The secondary structures in solution of the synthetic, naturally occurring, amyloid beta peptides, residues 1 to 42 [beta (1-42)] and beta (1-39), and related fragments, beta (1-28) and beta (29-42), have been studied by circular dichroism and two-dimensional nuclear magnetic resonance spectroscopy. In patients with Alzheimer's disease, extracellular amyloid plaque core is primarily composed of beta (1-42), whereas cerebrovascular amyloid contains the more soluble beta (1-39). In aqueous trifluoroethanol solution, the beta (1-28), beta (1-39), and beta (1-42) peptides adopt monomeric alpha-helical structures at both low and high pH, whereas at intermediate pH (4 to 7) an oligomeric beta structure (the probable structure in plaques) predominates. Thus, beta peptide is not by itself an insoluble protein (as originally thought), and localized or normal age-related alterations of pH may be necessary for the self-assembly and deposition of beta peptide. The hydrophobic carboxyl-terminal segment, beta(29-42), exists exclusively as an oligomeric beta sheet in solution, regardless of differences in solvent, pH, or temperature, suggesting that this segment directs the folding of the complete beta (1-42) peptide to produce the beta-pleated sheet found in amyloid plaques.


Behavioral economic analysis of cue-elicited craving for alcohol.
Craving as a motivational determinant of drug use remains controversial because of ambiguous empirical findings. A behavioral economic approach may clarify the nature of craving, theorizing that subjective craving functionally reflects an acute increase in a drug's value. The current study tested this hypothesis via a multidimensional assessment of alcohol demand over the course of an alcohol cue reactivity procedure. One-way within-subjects design. Human laboratory environment. Heavy drinkers (n = 92) underwent exposures to neutral (water) cues followed by personalized alcohol cues. Participants were assessed for craving, alcohol demand, affect, and salivation following each exposure. Alcohol versus neutral cues significantly increased craving and multiple behavioral economic measures of the relative value of alcohol, including alcohol consumption under conditions of zero cost (intensity), maximum expenditure on alcohol (O(max)), persistence in drinking to higher prices (breakpoint) and proportionate price insensitivity (normalized P(max)). Craving was significantly correlated with demand measures at levels ranging from 0.21-0.43. These findings support the potential utility of a behavioral economic approach to understanding the role of environmental stimuli in alcohol-related decision making. Specifically, they suggest that the behavioral economic indices of demand may provide complementary motivational information that is related to though not entirely redundant with measures of subjective craving.


CD84 is a regulator of the immunosuppressive microenvironment in multiple myeloma.
Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) within the BM. The BM microenvironment supports survival of the malignant cells and is composed of cellular fractions that foster myeloma development and progression by suppression of the immune response. Despite major progress in understanding the biology and pathophysiology of MM, this disease is still incurable and requires aggressive treatment with significant side effects. CD84 is a self-binding immunoreceptor belonging to the signaling lymphocyte activation molecule (SLAM) family. Previously, we showed that CD84 bridges between chronic lymphocytic leukemia cells and their microenvironment, and it regulates T cell function. In the current study, we investigated the role of CD84 in MM. Our results show that MM cells express low levels of CD84. However, these cells secrete the cytokine macrophage migration inhibitory factor (MIF), which induces CD84 expression on cells in their microenvironment. Its activation leads to an elevation of expression of genes regulating differentiation to monocytic/granulocytic-myeloid-derived suppressor cells (M-MDSCs and G-MDSCs, respectively) and upregulation of PD-L1 expression on MDSCs, which together suppress T cell function. Downregulation of CD84 or its blocking reduce MDSC accumulation, resulting in elevated T cell activity and reduced tumor load. Our data suggest that CD84 might serve as a novel therapeutic target in MM.


Identification of a stereotypic molecular arrangement of endogenous glycine receptors at spinal cord synapses.
Precise quantitative information about the molecular architecture of synapses is essential to understanding the functional specificity and downstream signaling processes at specific populations of synapses. Glycine receptors (GlyRs) are the primary fast inhibitory neurotransmitter receptors in the spinal cord and brainstem. These inhibitory glycinergic networks crucially regulate motor and sensory processes. Thus far, the nanoscale organization of GlyRs underlying the different network specificities has not been defined. Here, we have quantitatively characterized the molecular arrangement and ultra-structure of glycinergic synapses in spinal cord tissue using quantitative super-resolution correlative light and electron microscopy. We show that endogenous GlyRs exhibit equal receptor-scaffold occupancy and constant packing densities of about 2000 GlyRs µm-2 at synapses across the spinal cord and throughout adulthood, even though ventral horn synapses have twice the total copy numbers, larger postsynaptic domains, and more convoluted morphologies than dorsal horn synapses. We demonstrate that this stereotypic molecular arrangement is maintained at glycinergic synapses in the oscillator mouse model of the neuromotor disease hyperekplexia despite a decrease in synapse size, indicating that the molecular organization of GlyRs is preserved in this hypomorph. We thus conclude that the morphology and size of inhibitory postsynaptic specializations rather than differences in GlyR packing determine the postsynaptic strength of glycinergic neurotransmission in motor and sensory spinal cord networks.


The influence of Surelease and sodium alginate on the in-vitro release of tamsulosin hydrochloride in pellet dosage form.
The objective of this study was to prepare controlled-release pellets containing 0.2 mg tamsulosin hydrochloride using a pelletizer-equipped piston extruder and double-arm counter-rotating rollers with Surelease and sodium alginate. The release of tamsulosin HCl from pellets coated with the commercial aqueous ethylcellulose dispersion (Surelease) was investigated at different coating loads. In addition, the effect of sodium alginate on drug release was investigated by varying the ratio of sodium alginate to microcrystalline cellulose (MCC). Dissolution studies were first performed in 500 mL simulated gastric fluid (pH 1.2) containing 0.003% (w/w) polysorbate 80 and then in simulated intestinal fluids (pH 7.2). The morphology of pellet surfaces and cross sections were examined by scanning electron microscopy (SEM). Apparently, the spherical pellets were prepared using a pelletizer-equipped piston extruder and double-arm counter-rotating rollers. The release profiles of tamsulosin HCl from Surelease-coated pellets were significantly affected by changing the content of Surelease, the pH of the dissolution medium and the ratio of sodium alginate to MCC. The drug release rates not only decreased with increase in the coating load, but also increased when the pH of the dissolution medium was increased from 1.2 to 7.2 regardless of the sodium alginate-to-MCC ratio. Moreover, the drug release rate at pH 7.2 was gradually increased by increasing the ratio of sodium alginate to MCC. SEM showed smooth surfaces of Surelease-coated pellets. These results suggest that Surelease and sodium alginate would be useful excipients in the preparation of controlled-release pellets with the desired release profiles.


Preparation of biofunctionalized quantum dots using microfluidic chips for bioimaging.
Biofunctionalized quantum dots (QDs), especially protein-coated QDs, are known to be useful targeted fluorescent labels for cellular and deep-tissue imaging. These nanoparticles can also serve as efficient energy donors in fluorescence resonance energy transfer (FRET) binding assays for the multiplexed sensing of tumor markers. However, current preparation processes for protein-functionalized QDs are laborious and require multiple synthesis steps (e.g. preparing them in high temperature, making them dispersible in water, and functionalizing them with surface ligands) to obtain a high quality and quantity of QD formulations, significantly impeding the progress of employing QDs for clinical diagnostics use such as a QD-based immunohistofluorescence assay. Herein, we demonstrate a one-step synthesis approach for preparing protein-functionalized QDs using a microfluidic (MF) chip setup. Using bovine serum albumin (BSA) molecules as the surface ligand model, we first studied and optimized the MF reaction synthesis parameters (e.g. reaction temperature, and channel width and length) for making protein-functionalized QDs using COMSOL simulation modeling, followed by experimental verification. Moreover, in comparison with the BSA-functionalized QDs synthesized using the conventional bench-top method, BSA-QDs prepared using the MF approach exhibit a significantly higher protein-functionalization efficiency, photostability and colloidal stability. The proposed one-step MF synthesis approach provides a rapid, cost effective, and a small-scale production of nanocrystals platform for developing new QD formulations in applications ranging from cell labeling to biomolecular sensing. Most importantly, this approach will considerably reduce the amount of chemical waste generated during the trial-and-error stage of developing and perfecting the desired physical and optical properties of new QD materials.


Net effects of multiple stressors in freshwater ecosystems: a meta-analysis.
The accelerating rate of global change has focused attention on the cumulative impacts of novel and extreme environmental changes (i.e. stressors), especially in marine ecosystems. As integrators of local catchment and regional processes, freshwater ecosystems are also ranked highly sensitive to the net effects of multiple stressors, yet there has not been a large-scale quantitative synthesis. We analysed data from 88 papers including 286 responses of freshwater ecosystems to paired stressors and discovered that overall, their cumulative mean effect size was less than the sum of their single effects (i.e. an antagonistic interaction). Net effects of dual stressors on diversity and functional performance response metrics were additive and antagonistic, respectively. Across individual studies, a simple vote-counting method revealed that the net effects of stressor pairs were frequently more antagonistic (41%) than synergistic (28%), additive (16%) or reversed (15%). Here, we define a reversal as occurring when the net impact of two stressors is in the opposite direction (negative or positive) from that of the sum of their single effects. While warming paired with nutrification resulted in additive net effects, the overall mean net effect of warming combined with a second stressor was antagonistic. Most importantly, the mean net effects across all stressor pairs and response metrics were consistently antagonistic or additive, contrasting the greater prevalence of reported synergies in marine systems. Here, a possible explanation for more antagonistic responses by freshwater biota to stressors is that the inherent greater environmental variability of smaller aquatic ecosystems fosters greater potential for acclimation and co-adaptation to multiple stressors.


Characterization of shifts of koala (Phascolarctos cinereus) intestinal microbial communities associated with antibiotic treatment.
Koalas (Phascolarctos cinereus) are arboreal marsupials native to Australia that eat a specialized diet of almost exclusively eucalyptus leaves. Microbes in koala intestines are known to break down otherwise toxic compounds, such as tannins, in eucalyptus leaves. Infections by Chlamydia, obligate intracellular bacterial pathogens, are highly prevalent in koala populations. If animals with Chlamydia infections are received by wildlife hospitals, a range of antibiotics can be used to treat them. However, previous studies suggested that koalas can suffer adverse side effects during antibiotic treatment. This study aimed to use 16S rRNA gene sequences derived from koala feces to characterize the intestinal microbiome of koalas throughout antibiotic treatment and identify specific taxa associated with koala health after treatment. Although differences in the alpha diversity were observed in the intestinal flora between treated and untreated koalas and between koalas treated with different antibiotics, these differences were not statistically significant. The alpha diversity of microbial communities from koalas that lived through antibiotic treatment versus those who did not was significantly greater, however. Beta diversity analysis largely confirmed the latter observation, revealing that the overall communities were different between koalas on antibiotics that died versus those that survived or never received antibiotics. Using both machine learning and OTU (operational taxonomic unit) co-occurrence network analyses, we found that OTUs that are very closely related to Lonepinella koalarum, a known tannin degrader found by culture-based methods to be present in koala intestines, was correlated with a koala's health status. This is the first study to characterize the time course of effects of antibiotics on koala intestinal microbiomes. Our results suggest it may be useful to pursue alternative treatments for Chlamydia infections without the use of antibiotics or the development of Chlamydia-specific antimicrobial compounds that do not broadly affect microbial communities.


Medicine 2.0: social networking, collaboration, participation, apomediation, and openness.
In a very significant development for eHealth, broad adoption of Web 2.0 technologies and approaches coincides with the more recent emergence of Personal Health Application Platforms and Personally Controlled Health Records such as Google Health, Microsoft HealthVault, and Dossia. "Medicine 2.0" applications, services and tools are defined as Web-based services for health care consumers, caregivers, patients, health professionals, and biomedical researchers, that use Web 2.0 technologies and/or semantic web and virtual reality approaches to enable and facilitate specifically 1) social networking, 2) participation, 3) apomediation, 4) openness and 5) collaboration, within and between these user groups. The Journal of Medical Internet Research (JMIR) publishes a Medicine 2.0 theme issue and sponsors a conference on "How Social Networking and Web 2.0 changes Health, Health Care, Medicine and Biomedical Research", to stimulate and encourage research in these five areas.


Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers.
Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1-master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility.


Turnover of amyloid precursor protein family members determines their nuclear signaling capability.
The amyloid precursor protein (APP) as well as its homologues, APP-like protein 1 and 2 (APLP1 and APLP2), are cleaved by α-, β-, and γ-secretases, resulting in the release of their intracellular domains (ICDs). We have shown that the APP intracellular domain (AICD) is transported to the nucleus by Fe65 where they jointly bind the histone acetyltransferase Tip60 and localize to spherical nuclear complexes (AFT complexes), which are thought to be sites of transcription. We have now analyzed the subcellular localization and turnover of the APP family members. Similarly to AICD, the ICD of APLP2 localizes to spherical nuclear complexes together with Fe65 and Tip60. In contrast, the ICD of APLP1, despite binding to Fe65, does not translocate to the nucleus. In addition, APLP1 predominantly localizes to the plasma membrane, whereas APP and APLP2 are detected in vesicular structures. APLP1 also demonstrates a much slower turnover of the full-length protein compared to APP and APLP2. We further show that the ICDs of all APP family members are degraded by the proteasome and that the N-terminal amino acids of ICDs determine ICD degradation rate. Together, our results suggest that different nuclear signaling capabilities of APP family members are due to different rates of full-length protein processing and ICD proteasomal degradation. Our results provide evidence in support of a common nuclear signaling function for APP and APLP2 that is absent in APLP1, but suggest that APLP1 has a regulatory role in the nuclear translocation of APP family ICDs due to the sequestration of Fe65.


Cognitive reserve and Alzheimer disease.
Epidemiologic evidence suggests that individuals with higher IQ, education, occupational attainment, or participation in leisure activities have a reduced risk of developing Alzheimer disease (AD). The concept of cognitive reserve (CR) posits that individual differences in how tasks are processed provide differential reserve against brain pathology or age-related changes. This may take 2 forms. In neural reserve, preexisting brain networks that are more efficient or have greater capacity may be less susceptible to disruption. In neural compensation, alternate networks may compensate for pathology's disruption of preexisting networks. Imaging studies have begun to identify the neural substrate of CR. Because CR may modulate the clinical expression of AD pathology, it is an important consideration in studies of "preclinical" AD and treatment studies. There is also the possibility that directly enhancing CR may help forestall the diagnosis of AD.


Dynamic micro- and macrovascular remodeling in coronary circulation of obese Ossabaw pigs with metabolic syndrome.
Previous studies from our laboratory showed that coronary arterioles from type 2 diabetic mice undergo inward hypertrophic remodeling and reduced stiffness. The aim of the current study was to determine if coronary resistance microvessels (CRMs) in Ossabaw swine with metabolic syndrome (MetS) undergo remodeling distinct from coronary conduit arteries. Male Ossabaw swine were fed normal (n = 7, Lean) or hypercaloric high-fat (n = 7, MetS) diets for 6 mo, and then CRMs were isolated and mounted on a pressure myograph. CRMs isolated from MetS swine exhibited decreased luminal diameters (126 ± 5 and 105 ± 9 μm in Lean and MetS, respectively, P < 0.05) with thicker walls (18 ± 3 and 31 ± 3 μm in Lean and MetS, respectively, P < 0.05), which doubled the wall-to-lumen ratio (14 ± 2 and 30 ± 2 in Lean and MetS, respectively, P < 0.01). Incremental modulus of elasticity (IME) and beta stiffness index (BSI) were reduced in CRMs isolated from MetS pigs (IME: 3.6 × 10(6) ± 0.7 × 10(6) and 1.1 × 10(6) ± 0.2 × 10(6) dyn/cm(2) in Lean and MetS, respectively, P < 0.001; BSI: 10.3 ± 0.4 and 7.3 ± 1.8 in Lean and MetS, respectively, P < 0.001). BSI in the left anterior descending coronary artery was augmented in pigs with MetS. Structural changes were associated with capillary rarefaction, decreased hyperemic-to-basal coronary flow velocity ratio, and augmented myogenic tone. MetS CRMs showed a reduced collagen-to-elastin ratio, while immunostaining for the receptor for advanced glycation end products was selectively increased in the left anterior descending coronary artery. These data suggest that MetS causes hypertrophic inward remodeling of CRMs and capillary rarefaction, which contribute to decreased coronary flow and myocardial ischemia. Moreover, our data demonstrate novel differential remodeling between coronary micro- and macrovessels in a clinically relevant model of MetS.