Incidence and management of metabolic acidosis with sodium bicarbonate in the ICU: An international observational study.
Metabolic acidosis is a major complication of critical illness. However, its current epidemiology and its treatment with sodium bicarbonate given to correct metabolic acidosis in the ICU are poorly understood. This was an international retrospective observational study in 18 ICUs in Australia, Japan, and Taiwan. Adult patients were consecutively screened, and those with early metabolic acidosis (pH < 7.3 and a Base Excess < -4 mEq/L, within 24-h of ICU admission) were included. Screening continued until 10 patients who received and 10 patients who did not receive sodium bicarbonate in the first 24 h (early bicarbonate therapy) were included at each site. The primary outcome was ICU mortality, and the association between sodium bicarbonate and the clinical outcomes were assessed using regression analysis with generalized linear mixed model. We screened 9437 patients. Of these, 1292 had early metabolic acidosis (14.0%). Early sodium bicarbonate was given to 18.0% (233/1292) of these patients. Dosing, physiological, and clinical outcome data were assessed in 360 patients. The median dose of sodium bicarbonate in the first 24 h was 110 mmol, which was not correlated with bodyweight or the severity of metabolic acidosis. Patients who received early sodium bicarbonate had higher APACHE III scores, lower pH, lower base excess, lower PaCO2, and a higher lactate and received higher doses of vasopressors. After adjusting for confounders, the early administration of sodium bicarbonate was associated with an adjusted odds ratio (aOR) of 0.85 (95% CI, 0.44 to 1.62) for ICU mortality. In patients with vasopressor dependency, early sodium bicarbonate was associated with higher mean arterial pressure at 6 h and an aOR of 0.52 (95% CI, 0.22 to 1.19) for ICU mortality. Early metabolic acidosis is common in critically ill patients. Early sodium bicarbonate is administered by clinicians to more severely ill patients but without correction for weight or acidosis severity. Bicarbonate therapy in acidotic vasopressor-dependent patients may be beneficial and warrants further investigation.


Prioritizing the health education needs based on community participation: AHP method.
The identification of health education needs through the community results in targeted services and health promotion. Prioritizing these needs, in addition to identifying the desired health system based on the needs of the community, is required for the optimal allocation of resources. Therefore, this study was conducted with the aim prioritizing the health educational needs of Sabzevar-Iran community. This study was a two-step mix study. In the first stage, the qualitative method of the main themes of health educational needs of Sabzevar society was determined. Then, the questionnaire was prepared by a paired scale (36 questions) and quantitative method was used to prioritize the main themes with Analytic Hierarchy Process (AHP) software. The random sampling method was used in this study and data analysis was performed using Expert Choice software using AHP method. Social problems with 0.206, contagious diseases with 0.205, nutrition with 0.161, and public health with 0.132 were in the first to fourth grades of health educational needs in Sabzevar city and environmental health, health management, noncontagion diseases, elderly, and occupational health were in the fifth to ninth grades. The consistency index in this study was 0.08, although the adjustment index is <0.1 good and acceptable. Social problems are the first priority of Sabzevar society, which require appropriate training.


Structure of the streptococcal endopeptidase IdeS, a cysteine proteinase with strict specificity for IgG.
Pathogenic bacteria have developed complex and diverse virulence mechanisms that weaken or disable the host immune defense system. IdeS (IgG-degrading enzyme of Streptococcus pyogenes) is a secreted cysteine endopeptidase from the human pathogen S. pyogenes with an extraordinarily high degree of substrate specificity, catalyzing a single proteolytic cleavage at the lower hinge of human IgG. This proteolytic degradation promotes inhibition of opsonophagocytosis and interferes with the killing of group A Streptococcus. We have determined the crystal structure of the catalytically inactive mutant IdeS-C94S by x-ray crystallography at 1.9-A resolution. Despite negligible sequence homology to known proteinases, the core of the structure resembles the canonical papain fold although with major insertions and a distinct substrate-binding site. Therefore IdeS belongs to a unique family within the CA clan of cysteine proteinases. Based on analogy with inhibitor complexes of papain-like proteinases, we propose a model for substrate binding by IdeS.


Core antigen mutations of human hepatitis B virus in hepatomas accumulate in MHC class II-restricted T cell epitopes.
Despite the extensive molecular information on serum-derived human hepatitis B viruses (HBV), liver-derived replicative HBV genomes have remained largely uninvestigated. We have examined the sequences of the entire core antigen (nucleocapsid) of liver-derived HBVs in 15 different hepatoma patients. Bona fide mutations, rather than subtype polymorphism, have been identified based on the high-frequency occurrence of structural differences from wild type at the highly evolutionarily conserved positions, instead of at the positions known to contain genetic heterogeneity among different isolates from different geographic locations. The distribution of these naturally occurring mutations of HBV core gene appears to be nonrandom and is found predominantly within three major (I, IV, and V) and four minor domains (II, III, VI, and VII). In general, domain IV mutations correlate with domain V mutations. The replicative HBV DNAs tend to accumulate a higher number of mutated core domains than the integrated HBV DNAs. At the domain level, there is no significant difference in HBV core mutation frequencies between the liver tumors and the adjacent nontumorous livers. Strikingly, domains I, III, and V coincide with three major known T cell epitopes within the core protein in acute and chronic hepatitis B patients. Furthermore, these domains coincide with HLA class II-restricted T cell epitopes, rather than with the conventional HLA class I-restricted epitopes of cytotoxic T lymphocytes. Our results support the hypothesis that HBV core antigen variants can accomplish immunoevasion via accumulated escape mutations. In addition, they also provide a potential molecular explanation for the maintenance of persistent infection of human hepatitis B virus in chronic carriers.


On the evolution of sexual reproduction in hosts coevolving with multiple parasites.
Host-parasite coevolution has been studied extensively in the context of the evolution of sex. Although hosts typically coevolve with several parasites, most studies considered one-host/one-parasite interactions. Here, we study population-genetic models in which hosts interact with two parasites. We find that host/multiple-parasite models differ nontrivially from host/single-parasite models. Selection for sex resulting from interactions with a single parasite is often outweighed by detrimental effects due to the interaction between parasites if coinfection affects the host more severely than expected based on single infections, and/or if double infections are more common than expected based on single infections. The resulting selection against sex is caused by strong linkage-disequilibria of constant sign that arise between host loci interacting with different parasites. In contrast, if coinfection affects hosts less severely than expected and double infections are less common than expected, selection for sex due to interactions with individual parasites can now be reinforced by additional rapid linkage-disequilibrium oscillations with changing sign. Thus, our findings indicate that the presence of an additional parasite can strongly affect the evolution of sex in ways that cannot be predicted from single-parasite models, and that thus host/multiparasite models are an important extension of the Red Queen Hypothesis.


Protective effects of the urocortin homologues stresscopin (SCP) and stresscopin-related peptide (SRP) against hypoxia/reoxygenation injury in rat neonatal cardiomyocytes.
Urocortin (UCN), a member of the Corticotropin-Releasing Factor (CRF) family of peptides is a well described cardioprotective agent. UCN is able to bind to two types of G-protein coupled receptors: CRF receptor type 1 (CRFR1) and CRF receptor type 2 (CRFR2), whereas, two homologues of UCN, stresscopin (SCP) or also known as urocortin III (UCNIII) and stresscopin related peptide (SRP), or urocortin II (UCNII), bind exclusively and with high affinity to CRFR2, we hypothesised that they will exhibit more pronounced cardioprotective effects than UCN. We show for the first time that SCP is expressed in rat cardiomyocytes and that the levels of SRP and SCP are increased by hypoxic stress. All three peptides have potent cardioprotective effects in cells exposed to hypoxia/reoxygenation. When used at 10(-8) M they increased the amount of live cells by 25% when added prior to hypoxia, and by 20% when UCN and SCP were added at the onset of reoxygenation. In addition, the peptides are equally are more potent antiapoptotic factors than UCN. The antiapoptotic effects of SCP were more pronounced than SRP and UCN at a concentration of 10(-10) M. Furthermore, SCP and SRP protect cardiomyocytes better than UCN at concentrations up to and including 10(-10) M and reduced the amount of TUNEL positive cells almost by half at concentrations of 10(-12) to 10(-10) M. More importantly, we demonstrate that SCP and SRP are able to protect cardiomyocytes even if they are administered after the hypoxic insult and prior to reoxygenation. In this case SCP was more potent than UCN and SRP at 10(-12) M and both SCP and SRP exhibited higher protection at 10(-8) M compared to UCN. Cardioprotection of cardiomyocytes by 10(-8) M of peptides was abolished when treated with 50 microM LY294002 or 100 microM PD98059, but not by 10 microM SB203580 prior to the hypoxic insult. Transfection of dominant negative Akt and MEK1 also blocked protection by the peptides, whereas dominant negative MEKK6 had no effects, demonstrating that SCP and SRP, like UCN, require activation of p42/44 Mitogen activated protein kinase and Akt/Protein Kinase B in order to produce their cardioprotective effects. In addition, we showed that SCP and UCN are potent activators of the p42/44 MAPK pathway, with SRP able to induce phosphorylation of p42/44 MAPK as well, albeit not as pronounced.


Interpersonal Counseling for College Students: Pilot Feasibility and Acceptability Study.
University counseling centers struggle to meet the growing demand for mental health treatment by students in distress. More acutely distressed students typically receive priority, whereas those with mild to moderate depression often face longer wait times and fewer available therapy sessions. For this reason, interpersonal counseling for college students (IPC-C) was created as a brief manualized psychotherapy, suitable for students with mild to moderate depression, that maintains the core components of interpersonal counseling and integrates components from interpersonal psychotherapy for adolescents and other developmentally appropriate techniques. This article describes a pilot trial of IPC-C. IPC-C is delivered in three to six psychotherapy sessions focused on alleviating depressive symptoms and increasing social support. Ten participants from two university counseling centers were recruited to receive IPC-C. The inclusion criterion was a Patient Health Questionnaire-9 (PHQ-9) score of 5-14, indicating mild to moderate depression. Participants completed the PHQ-9 at each session, the College Adjustment Test at baseline and termination, and the IPC Satisfaction Scale at termination. Nine of the 10 participants completed the study, attending an average of five therapy sessions each. Participants agreed that the number of sessions was appropriate and indicated satisfaction with the IPC-C intervention. Participants exhibited significantly reduced depression severity (Cohen's d=2.45) and significantly improved college adjustment (d=0.92). In this pilot trial, IPC-C was found to be a feasible and acceptable intervention for university-based treatment of young adults with mild to moderate depressive symptoms. IPC-C holds promise as a potentially effective intervention for this population and warrants further study in a randomized trial.


Rhabdomyolysis in Severe COVID-19: Male Sex, High Body Mass Index, and Prone Positioning Confer High Risk.
Bedside experience and studies of critically ill patients with coronavirus disease 2019 (COVID-19) indicate COVID-19 to be a devastating multisystem disease. We aim to describe the incidence, associated variables, and outcomes of rhabdomyolysis in critically ill COVID-19 patients. Data for all critically ill adult patients (≥18 years old) admitted to the ICU at a large academic medical center with confirmed COVID-19 between March 13, 2020 and April 18, 2020 were prospectively collected. Patients with serum creatine kinase (CK) concentrations greater than 1000 U/L were diagnosed with rhabdomyolysis. Patients were further stratified as having moderate (serum CK concentration 1000-4999 U/L) or severe (serum CK concentration ≥5000 U/L) rhabdomyolysis. Univariate and multivariate analyses were performed to identify outcomes and variables associated with the development of rhabdomyolysis. Of 235 critically ill COVID-19 patients, 114 (48.5%) met diagnostic criteria for rhabdomyolysis. Patients with rhabdomyolysis more often required mechanical ventilation (P < 0.001), prone positioning (P < 0.001), pharmacological paralysis (P < 0.001), renal replacement therapy (P = 0.010), and extracorporeal membrane oxygenation (ECMO) (P = 0.025). They also had longer median ICU length of stay (LOS) (P < 0.001) and hospital LOS (P < 0.001). No difference in mortality was observed. Male sex, patients with morbid obesity, SOFA score, and prone positioning were independently associated with rhabdomyolysis. Nearly half of critically ill COVID-19 patients in our cohort met diagnostic criteria for rhabdomyolysis. Male sex, morbid obesity, SOFA score, and prone position were independently associated with rhabdomyolysis.


Effect of the thin-film limit on the measurable optical properties of graphene.
The fundamental sheet conductance of graphene can be directly related to the product of its absorption coefficient, thickness and refractive index. The same can be done for graphene's fundamental opacity if the so-called thin-film limit is considered. Here, we test mathematically and experimentally the validity of this limit on graphene, as well as on thin metal and semiconductor layers. Notably, within this limit, all measurable properties depend only on the product of the absorption coefficient, thickness, and refractive index. As a direct consequence, the absorptance of graphene depends on the refractive indices of the surrounding media. This explains the difficulty in determining separately the optical constants of graphene and their widely varying values found in literature so far. Finally, our results allow an accurate estimation of the potential optical losses or gains when graphene is used for various optoelectronic applications.


Complaints with encounters in healthcare - men's experiences.
Good encounters within healthcare are important for the manner in which ill people facilitate their health and their perception of quality of care. Research about quality of care are important, but point out that dissatisfaction with healthcare may in the future be even more common regarding the demands for a more effective healthcare. The aim of this study was therefore to describe experiences of dissatisfaction with encounters in healthcare among men who personally filed a complaint to the Patients' Advisory Committee in the county council. Qualitative data were collected in semi-structured interviews with a purposive sample of nine men who have filed a complaint to the Patients' Advisory Committee. The analysis resulted in two categories: being met with a disrespectful manner and not receiving a personal apology. The results in the first category describe that the men were treated with disrespect and suspicions by healthcare professionals. This was related to lack of communication which made the men sensitive to negative attitudes on the part of professionals. The results in the second category show that the men expected amends to be made in form of a personal apology about the dissatisfaction. The men were given no opportunities to influence the encounters and the professionals were unconscious of their behaviour in form of bad treatment. In conclusion, the results indicate the importance of meeting patients and their relatives with respect and dignity, listening to their experiences and proceeding with the treatment without insulting anyone as a person.


Fluid supplementation accelerates epithelial repair during chemical colitis.
The dextran sulfate sodium (DSS) model of colitis is a common animal model of inflammatory bowel disease that causes pain and distress. In this study, we aimed to determine whether fluid supplementation can be used as a welfare-based intervention to minimize animal suffering. C57Bl/6 females undergoing acute colitis by administration of 3% DSS in drinking water were supplemented with 1 mL intraperitoneal injections of NaCl and compared to non-supplemented control mice. Mouse behavior and locomotive activity were assessed on days 5-6 after DSS initiation by means of tail suspension, novel object recognition and open field activity tests. Mice were euthanized after either the acute (day 7) or the recovery phase (day 12) of colitis and inflammation, epithelial proliferation, and differentiation were assessed by means of histology, immunohistochemistry, quantitative PCR, and western blot. We found that fluid-supplemented mice had reduced signs of colitis with no alterations in behavior or locomotive activity. Furthermore, we observed an accelerated epithelial repair response after fluid hydration during the acute phase of colitis, characterized by increased crypt proliferation, activation of ERK1/2, and modulation of TGF-β1 expression. Consistent with these findings, fluid-supplemented mice had increased numbers of goblet cells, upregulated expression of differentiation markers for absorptive enterocytes, and reduced inflammation during the recovery phase. Our results show that fluid hydration does not reduce stress in DSS-treated mice but alters colitis evolution by reducing clinical signs and accelerating epithelial repair. These results argue against the routine use of fluid supplementation in DSS-treated mice.


Clinical Efficacy of Intracoronary Papaverine After Nicorandil Administration for Safe and Optimal Fractional Flow Reserve Measurement.
Fractional flow reserve (FFR) is considered the standard for assessment of the physiological significance of coronary artery stenosis. Intracoronary papaverine (PAP) is the most potent vasodilator used for the achievement of maximal hyperemia. However, its use can provoke ventricular tachycardia (VT) due to excessive QT prolongation. We evaluated the clinical efficacy and safety of the administration of PAP after nicorandil (NIC), a potassium channel opener that prevents VT, for optimal FFR measurement.A total of 127 patients with 178 stenoses were enrolled. The FFR values were measured using NIC (NIC-FFR) and PAP (PAP-FFR). We administered PAP following NIC (NIC-PAP). Changes in the FFR and electrogram parameters (baseline versus NIC versus PAP) were assessed and the incidence of arrhythmias after PAP was evaluated. In addition, we analyzed another 41 patients with 51 stenoses by assessing the FFR using PAP before NIC (PAP-NIC). After propensity score matching, the electrogram parameters between 2 groups were compared.The mean PAP-FFR was significantly lower than the mean NIC-FFR (0.82 ± 0.11 versus 0.81 ± 0.11, P < 0.05). The mean baseline-QTc, NIC-QTc, and PAP-QTc values were 425 ± 37 ms1/2, 424 ± 41 ms1/2, and 483 ± 54 ms1/2, respectively. VT occurred in only 1 patient (0.6%). Although PAP induced QTc prolongation (P < 0.05), the PAP-QTc duration was significantly shorter in NIC-PAP compared to PAP-NIC (P < 0.05).The administration of PAP with NIC may induce sufficient hyperemia and prevent fatal arrhythmia through reductions in the PAP-induced QTc prolongation during FFR measurement.


A novel function of apolipoprotein E: upregulation of ATP-binding cassette transporter A1 expression.
Despite the well known importance of apolipoprotein (Apo) E in cholesterol efflux, the effect of ApoE on the expression of ATP-binding cassette transporter A1 (ABCA1) has never been investigated. The objective of this study was to determine the effect of ApoE on ApoB-carrying lipoprotein-induced expression of ABCA1, a protein that mediates cholesterol efflux. Our data demonstrate that ApoB-carrying lipoproteins obtained from both wild-type and ApoE knockout mice induced ApoAI-mediated cholesterol efflux in mouse macrophages, which was associated with an enhanced ABCA1 promoter activity, and an increased ABCA1 mRNA and protein expression. In addition, these lipoproteins increased the level of phosphorylated specificity protein 1 (Sp1) and the amount of Sp1 bound to the ABCA1 promoter. However, all these inductions were significantly diminished in cells treated with ApoE-free lipoproteins, when compared to those treated with wild-type lipoproteins. Enrichment with human ApoE3 reversed the reduced inducibility of ApoE-free lipoproteins. Moreover, we observed that inhibition of Sp1 DNA-binding by mithramycin A diminished ABCA1 expression and ApoAI-mediated cholesterol efflux induced by ApoB-carrying lipoproteins, and that mutation of the Sp1-binding motif in the ABCA1 promoter region diminished ApoB-carrying lipoprotein-induced ABCA1 promoter activity. Collectively, these data suggest that ApoE associated with ApoB-carrying lipoproteins has an upregulatory role on ABCA1 expression, and that induction of Sp1 phosphorylation is a mechanism by which ApoE upregulates ABCA1 expression.


RPL39L is an example of a recently evolved ribosomal protein paralog that shows highly specific tissue expression patterns and is upregulated in ESCs and HCC tumors.
Ribosomal proteins (RPs) have been shown to be able to impart selectivity on the translating ribosome implicating them in gene expression control. Many ribosomal proteins are highly conserved and recently a number of ribosomal protein paralogs have been described in mammals. We examined the expression pattern of RPs in differentiating mouse Embryonic Stem Cells (ESCs), paying particular attention to the RP paralogs. We find the RP paralog Rpl39l is highly expressed in ESC and its expression strongly correlates with hepatocellular carcinoma tumor (HCC) samples with high tumor grading and alpha-fetoprotein level giving it diagnostic potential. We further screen the expression pattern of all RPs and their paralogs across 22 different tissues. We find that the more recently evolved RP paralogs show a much greater level of tissue-specific expression. We propose that these RP paralogs evolved more recently to provide a greater level of gene expression control to higher eukaryotes.


The brian simulator.
"Brian" is a simulator for spiking neural networks (http://www.briansimulator.org). The focus is on making the writing of simulation code as quick and easy as possible for the user, and on flexibility: new and non-standard models are no more difficult to define than standard ones. This allows scientists to spend more time on the details of their models, and less on their implementation. Neuron models are defined by writing differential equations in standard mathematical notation, facilitating scientific communication. Brian is written in the Python programming language, and uses vector-based computation to allow for efficient simulations. It is particularly useful for neuroscientific modelling at the systems level, and for teaching computational neuroscience.


Life cycle energy use and greenhouse gas emission analysis for a water resource recovery facility in India.
This paper quantifies life cycle energy use and greenhouse gas (GHG) emissions associated with water resource recovery facilities (WRRFs) in India versus water quality improvements achieved from infrastructure investments. A first such analysis is conducted using operating data for a WRRF, which employs upflow anaerobic sludge blanket (UASB) reactors and oxidation. On-site operations energy use, process GHG emissions, and embodied energy in infrastructure were quantified. The analysis showed energy use and GHG emissions of 0.2 watt-hours (Wh) and 0.3 gram carbon dioxide (CO2) equivalents per liter (gCO2e/L) wastewater treated, and 1.3 Wh and 2.1 gCO2e/gBOD removed, achieving 81% biochemical oxygen demand (BOD) and 999% fecal coliform removal annually. Process emissions of WRRFs contributed 44% of life cycle GHG emissions, similar in magnitude to those from electricity (46%), whereas infrastructure contributed 10%. Average WRRF-associated GHG emissions (0.9gCO2e/L) were lower than those expected if untreated wastewater was released to the river. Investments made by WRRFs in developing world cities improve water quality and may mitigate overall GHG emissions.


Oxidative stress in blood in Alzheimer's disease and mild cognitive impairment: a meta-analysis.
Abnormal oxidative stress is an established feature of Alzheimer's disease, but clinical trials aiming to reduce oxidative stress have not yet proven an effective therapy for dementia patients. The purpose of this review is to systematically analyze available data describing markers of oxidative stress and antioxidants in blood from subjects with Alzheimer's disease or those with mild cognitive impairment to highlight potential interactions between peripheral redox changes and central nervous system pathology and contribute to the design of future clinical study. PubMed, SCOPUS and Web of Science were systematically queried to collect studies which have evaluated markers of oxidative stress, levels of antioxidants, copper, transferrin and ceruloplasmin levels in blood from subjects with Alzheimer's disease and matched controls. After application of quality measures, results were aggregated in a random effects analysis. We found that markers of lipid peroxidation are elevated in blood in Alzheimer's disease and in mild cognitive impairment, copper metabolism is dysregulated and total antioxidant capacity is decreased. While surprisingly none of the major antioxidative enzymes are significantly decreased, non-enzymatic antioxidants in blood (particularly uric acid, vitamins A, E and C, α- and β-carotene) are significantly decreased. There is significant oxidative damage in peripheral blood early in the process of neurodegeneration. We propose that clinical studies assessing cognitive outcomes after antioxidant therapy tailor interventions to individual patients' deficiencies and confirm an improvement in an appropriate serological marker of oxidative stress. This strategy may be most effectively applied in a clinical trial of primary prevention.


Intelligent monitoring networks--transformation of data into information for water management.
The EU-WFD requires certain monitoring tasks, which yet cannot be fulfilled by automated monitoring devices. Nevertheless, the technical progress of recent years allows monitoring station designs, which enable long-term field application under reasonable maintenance demand. State-of-the-art monitoring stations allow the setup and operation of intelligent monitoring networks, which deliver quality proved and utilisable information to the end-user as opposed to a collection of time-series. Based on a full-scale example monitoring station design, long-term observations and possible ways of (automated) data interpretation are discussed.


The impact of Coronavirus disease 2019 (COVID-19) pandemic on migraine disorder.
To evaluate the impact of the Coronavirus disease of 2019 (COVID-19) pandemic on patients with migraine. Self-reported data from a migraine tracking smartphone application, Migraine Buddy, were used. Data were collected from users who reported at least one attack in the Jan, Feb, Mar and Apr of 2018, 2019 and 2020. In addition, a survey was conducted to evaluate the impact of COVID-19 on migraine management. On average, data from 124,717 users per month (mean age 36.3 ± 10.9 years and 89% female) were collected. Overall, the mean frequency of migraine headache was higher in 2020 than in 2019 and higher in 2019 than in 2018. The four commonest headache triggers in 2018, 2019 and 2020 were stress in 39.7, 38.4 and 36.1%, lack of sleep in 25, 25 and 22.8%, neck pain, 20, 20.4 and 19.3 and anxiety in 19, 18.4 and 18.4% of participants, respectively. 1689 users participated in the survey and they reported that they preferred face-to-face (54.29%) to telehealth (11.9%) consultations. An increase in migraine frequency from 2018 to 2020 was reported by the users of the mobile phone. This could reflect a real increase or change in reporting habits. Stress, lack of sleep, neck pain and anxiety were the commonest attack triggers. The frequency of these triggers decreased slightly in 2020 compared to 2019 and 2018. An increase in telehealth consultations with specialists was reported in the survey but migraine patients preferred face-to-face consultations.


Idiopathic sclerosing encapsulating peritonitis (or abdominal cocoon).
Idiopathic sclerosing encapsulating peritonitis (or abdominal cocoon) is a rare cause of small bowel obstruction, especially in adult population. Diagnosis is usually incidental at laparotomy. We discuss one such rare case, outlining the fact that an intra-operative surprise diagnosis could have been facilitated by previous investigations. A 56 year-old man presented in A&E department with small bowel ileus. He had a history of 6 similar episodes of small bowel obstruction in the past 4 years, which resolved with conservative treatment. Pre-operative work-up did not reveal any specific etiology. At laparotomy, a fibrous capsule was revealed, in which small bowel loops were encased, with the presence of interloop adhesions. A diagnosis of abdominal cocoon was established and extensive adhesiolysis was performed. The patient had an uneventful recovery and follow-up. Idiopathic sclerosing encapsulating peritonitis, although rare, may be the cause of a common surgical emergency such as small bowel ileus, especially in cases with attacks of non-strangulating obstruction in the same individual. A high index of clinical suspicion may be generated by the recurrent character of small bowel ileus combined with relevant imaging findings and lack of other plausible etiologies. Clinicians must rigorously pursue a preoperative diagnosis, as it may prevent a "surprise" upon laparotomy and result in proper management.


Volunteer revegetation of waste rock surfaces at the Bingham Canyon Mine, Utah.
Voluntary recolonization of sulfide-bearing waste rock dumps by native vegetation is inhibited by the harsh chemical and physical conditions. The success of volunteer vegetation on the waste rock surfaces at the Bingham Canyon (Utah) porphyry copper deposit is most strongly dependent on the soil pH and salinity, and to a lesser extent on physical characteristics such as compaction and distance from seed source. Vegetation cover and richness both decline below a paste pH of about 6 and above a paste conductivity of about 0.7 dS/m (for a 1:1 soil to water mixture). No significant vegetation establishment occurs below a soil pH of about 4.5. Young sulfide-bearing waste rock surfaces at Bingham Canyon have high salinity, but as reactive pyrite is depleted and salts are flushed from the soil, the salinity eventually declines, allowing volunteer native vegetation to become established on surfaces with a circumneutral pH. Under natural conditions, the pH of older acidic weathered surfaces will recover very slowly, but it can be rapidly raised by adding relatively small amounts of limestone because there are few intact reactive sulfides. For uncompacted waste rock surfaces with favorable chemical conditions, less than 90% gravel content, and that are located near a native seed source, the arithmetic mean volunteer vegetation cover was 56 +/- 24% and the mean species richness was 17 +/- 5. These data indicate that with adequate surface preparation and limestone addition, direct planting of older, acidic, but low salinity waste rock surfaces can greatly accelerate natural revegetation.


An allele of microtubule-associated protein 1A (Mtap1a) reduces photoreceptor degeneration in Tulp1 and Tub Mutant Mice.
To identify genes that modify photoreceptor cell loss in the retinas of homozygous Tulp1(tm1Pjn) and Tub(tub) mice, which exhibit juvenile retinitis pigmentosa. Modifier loci were identified by genetic quantitative trait locus analysis. F2 Tulp1(tm1Pjn/tm1Pjn) mutant mice from a B6-Tulp1(tm1Pjn/tm1Pjn) × AKR/J intercross were genotyped with a panel of single nucleotide polymorphism markers and phenotyped by histology for photoreceptor nuclei remaining at 9 weeks of age. Genotype and phenotype data were correlated and examined with Pseudomarker 2.02 using 128 imputations to map modifier loci. Thresholds for the 63%, 10%, 5%, and 1% significance levels were obtained from 100 permutations. A significant, protective candidate modifier was identified by bioinformatic analysis and confirmed by crossing transgenic mice bearing a protective allele of this gene with Tulp1- and Tub-deficient mice. A significant, protective modifier locus on chromosome 2 and a suggestive locus on chromosome 13 that increases photoreceptor loss were identified in a B6-Tulp1(tm1Pjn/tm1Pjn) × AKR/J intercross. The chromosome 2 locus mapped near Mtap1a, which encodes a protein associated with microtubule-based intracellular transport and synapse function. The protective Mtap1a(129P2/OlaHsd) allele was shown to reduce photoreceptor loss in both Tulp1(tm1Pjn/tm1Pjn) and Tub(tub/tub) mice. It was demonstrated that the gene Mtap1a, which modifies hearing loss in Tub(tub/tub) mice, also modifies retinal degeneration in Tub(tub/tub) and Tulp1(tm1Pjn/tm1Pjn) mice. These results suggest that functionally nonredundant members of the TULP family (TUB and TULP1) share a common functional interaction with MTAP1A.


Tracking post-hibernation behavior and early migration does not reveal the expected sex-differences in a "female-migrating" bat.
Long-distance migration is a rare phenomenon in European bats. Genetic analyses and banding studies show that females can cover distances of up to 1,600 km, whereas males are sedentary or migrate only short distances. The onset of this sex-biased migration is supposed to occur shortly after rousing from hibernation and when the females are already pregnant. We therefore predicted that the sexes are exposed to different energetic pressures in early spring, and this should be reflected in their behavior and physiology. We investigated this in one of the three Central European long-distance migrants, the common noctule (Nyctalus noctula) in Southern Germany recording the first individual partial migration tracks of this species. In contrast to our predictions, we found no difference between male and female home range size, activity, habitat use or diet. Males and females emerged from hibernation in similar body condition and mass increase rate was the same in males and females. We followed the first migration steps, up to 475 km, of radio-tagged individuals from an airplane. All females, as well as some of the males, migrated away from the wintering area in the same northeasterly direction. Sex differences in long-distance migratory behavior were confirmed through stable isotope analysis of hair, which showed greater variation in females than in males. We hypothesize that both sexes faced similarly good conditions after hibernation and fattened at maximum rates, thus showing no differences in their local behavior. Interesting results that warrant further investigation are the better initial condition of the females and the highly consistent direction of the first migratory step in this population as summering habitats of the common noctule occur at a broad range in Northern Europe. Only research focused on individual strategies will allow us to fully understand the migratory behavior of European bats.


The DegU orphan response regulator of Listeria monocytogenes autorepresses its own synthesis and is required for bacterial motility, virulence and biofilm formation.
The Gram-positive intracellular pathogen Listeria monocytogenes is endowed with 17 sets of genes encoding two-component systems. L. monocytogenes is closely related to the Gram-positive model bacterium Bacillus subtilis, in which we have shown previously that the DegS/DegU system plays a central role in controlling stationary phase adaptive responses, including degradative enzyme synthesis and competence. Although an orthologue of the DegU response regulator is present in L. monocytogenes, the gene encoding the cognate DegS kinase is conspicuously absent. We have inactivated the degU gene of L. monocytogenes and shown that DegU negatively regulates its own synthesis. Direct binding of L. monocytogenes DegU to its own promoter region was shown in vitro by gel mobility shift and DNase I footprinting experiments. DegU was also shown to bind upstream from the motB operon, which also encodes the GmaR anti-repressor of flagellar synthesis. In contrast to the situation in B. subtilis, DegU was shown to be essential for flagellar synthesis and bacterial motility in L. monocytogenes and is cotranscribed with the yviA gene located downstream. We also show that DegU is required for growth at high temperatures, adherence to plastic surfaces and the formation of efficient biofilms by L. monocytogenes. DegU plays a role in virulence of L. monocytogenes as well: in a murine intravenous infection model, an 11-fold increase in LD(50) was observed for the degU mutant. Taken together, our results indicate that despite the lack of the DegS kinase, DegU is fully functional as an orphan response regulator, and plays a central role in controlling several crucial adaptive responses in L. monocytogenes.


Fructose 2,6-bisphosphate and its phosphorothioate analogue. Comparison of their hydrolysis and action on glycolytic and gluconeogenic enzymes.
Purified chicken liver 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase was phosphorylated either from fructose 2,6-bis[2-32P]phosphate or fructose 2-phosphoro[35S]thioate 6-phosphate. The turnover of the thiophosphorylated enzyme intermediate as well as the overall phosphatase reaction was four times faster than with authentic fructose 2,6-bisphosphate. Fructose 2-phosphorothioate 6-phosphate was 10-100-fold less potent than authentic fructose 2,6-bisphosphate in stimulating 6-phosphofructo-1-kinase and pyrophosphate:fructose 6-phosphate phosphotransferase, but about 10 times more potent in inhibiting fructose 1,6-bisphosphatase. The analogue was twice as effective as authentic fructose 2,6-bisphosphate in stimulating pyruvate kinase from trypanosomes.


Divergence between adolescent and parental perceptions of conflict in relationship to adolescent empathy development.
Adolescents' developing empathy may be associated with the frequency of conflict with parents, as well as the level of agreement between adolescent and parental perceptions of the frequency of such conflicts. This 6-year longitudinal study investigated the link between adolescent empathy development and perceptions of the frequency of parent-child conflict, as reported by 467 adolescents (43% female, from age 13) and both parents. First, we investigated heterogeneity in empathy development by identifying classes of individuals with similar developmental trajectories. Adolescents were categorized into high-, average-, and low-empathy classes. Initial differences between these classes further increased from age 13 to 16, particularly for cognitive empathy. To assess the association between empathy and the frequency of conflict, we compared these empathy classes in terms of initial levels and over-time changes in the frequency of adolescent- and parent-reported conflict. Compared to the average- and high-empathy classes, the low-empathy class evidenced elevated conflict throughout adolescence. Furthermore, the low- and average-empathy classes demonstrated temporary divergence between adolescent- and parent-reported conflict from early- to mid-adolescence, with adolescents underreporting conflict compared to both parents. Adolescents' agreement with parents was moderated by empathy class, while parents were always in agreement with one another. This may suggest that these discrepancies are related to distortions in adolescents' perceptions, as opposed to biased parental reports. These findings highlight the potential importance of early detection and intervention in empathy deficiencies, and suggest that lower adolescent empathy may indicate elevated family conflict, even if a failure to consider parents' perspective leads adolescents to underreport it.


The variable natural history of idiopathic dilated cardiomyopathy.
Determining the prognosis of patients with heart failure is essential for patient management and clinical trial conduct. The relative value of traditional prognostic criteria remains unclear and the assessment of long-term prognosis for individual patients is problematic. To determine the ability of clinical, hemodynamic and echocardiographic parameters to predict the long-term prognosis of patients with idiopathic dilated cardiomyopathy. We investigated the ability of clinical, hemodynamic and echocardiographic parameters to predict the long-term prognosis of individual patients in a large, representative, contemporary cohort of idiopathic dilated cardiomyopathy (IDCM) patients referred to Johns Hopkins from 1997 to 2004 for evaluation of cardiomyopathy. In all patients a baseline history was taken, and physical examination, laboratory studies, echocardiogram, right heart catheterization and endomyocardial biopsy were performed. In 171 IDCM patients followed for a median 3.5 years, there were 50 long-term event-free survivors (LTS) (median survival 6.4 years) and 34 patients died or underwent ventricular assist device placement or transplantation within 5 years (NLTS; non-long-term survivors) (median time to event 1.83 years. Established risk factors (gender, race, presence of diabetes, serum creatinine, sodium) and the use of accepted heart failure medications (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers) were similar between the two groups. Although LTS had younger age, higher ejection fraction (EF) and lower New York Heart Association (NYHA) class at presentation, the positive predictive value of an EF < 25% was 64% (95% CI 41%-79%) and that of NYHA class > 2 was 53% (95% CI 36-69%). A logistic model incorporating these three variables incorrectly classified 29% of patients. IDCM exhibits a highly variable natural history and standard clinical predictors have limited ability to classify IDCM patients into broad prognostic categories. These findings suggest that there are important host-environmental factors still unappreciated in the biology of IDCM.


High-Resolution Genomic Comparisons within Salmonella enterica Serotypes Derived from Beef Feedlot Cattle: Parsing the Roles of Cattle Source, Pen, Animal, Sample Type, and Production Period.
Salmonella enterica is a major foodborne pathogen, and contaminated beef products have been identified as one of the primary sources of Salmonella-related outbreaks. Pathogenicity and antibiotic resistance of Salmonella are highly serotype and subpopulation specific, which makes it essential to understand high-resolution Salmonella population dynamics in cattle. Time of year, source of cattle, pen, and sample type (i.e., feces, hide, or lymph nodes) have previously been identified as important factors influencing the serotype distribution of Salmonella (e.g., Anatum, Lubbock, Cerro, Montevideo, Kentucky, Newport, and Norwich) that were isolated from a longitudinal sampling design in a research feedlot. In this study, we performed high-resolution genomic comparisons of Salmonella isolates within each serotype using both single-nucleotide polymorphism-based maximum-likelihood phylogeny and hierarchical clustering of core-genome multilocus sequence typing. The importance of the aforementioned features in clonal Salmonella expansion was further explored using a supervised machine learning algorithm. In addition, we identified and compared the resistance genes, plasmids, and pathogenicity island profiles of the isolates within each subpopulation. Our findings indicate that clonal expansion of Salmonella strains in cattle was mainly influenced by the randomization of block and pen, as well as the origin/source of the cattle, i.e., regardless of sampling time and sample type (i.e., feces, lymph node, or hide). Further research is needed concerning the role of the feedlot pen environment prior to cattle placement to better understand carryover contributions of existing strains of Salmonella and their bacteriophages. IMPORTANCESalmonella serotypes isolated from outbreaks in humans can also be found in beef cattle and feedlots. Virulence factors and antibiotic resistance are among the primary defense mechanisms of Salmonella, and are often associated with clonal expansion. This makes understanding the subpopulation dynamics of Salmonella in cattle critical for effective mitigation. There remains a gap in the literature concerning subpopulation dynamics within Salmonella serotypes in feedlot cattle from the beginning of feeding up until slaughter. Here, we explore Salmonella population dynamics within each serotype using core-genome phylogeny and hierarchical classifications. We used machine learning to quantitatively parse the relative importance of both hierarchical and longitudinal clustering among cattle host samples. Our results reveal that Salmonella populations in cattle are highly clonal over a 6-month study period and that clonal dissemination of Salmonella in cattle is mainly influenced spatially by experimental block and pen, as well by the geographical origin of the cattle.


Associations of erosive arthritis with anti-cyclic citrullinated peptide antibodies and MHC Class II alleles in systemic lupus erythematosus.
To determine the associations of erosive arthritis (EA) with anti-cyclic citrullinated peptide (anti-CCP) antibodies and major histocompatibility class (MHC) II alleles in systemic lupus erythematosus (SLE). One hundred four patients with SLE were evaluated for arthritis and classified as EA, nonerosive arthritis, or no arthritis. EA was further classified as major or minor erosions. Sera from patients and 130 serum controls were tested for anti-CCP2 and rheumatoid factor (RF). Patients and 117 genetic controls were genotyped for HLA-DRB1 and HLA-DQB1. Statistical associations were tested using chi-square tests and odds ratios (OR) with 95% confidence intervals (CI). Eight patients (8%) were anti-CCP+ and they accounted for 11% (8/71) of patients with synovitis. Twelve patients (11%) had EA. Among patients with synovitis, EA was associated with anti-CCP (OR 28.5, 95% CI 4.7-173.8, p = 0.001), with a weaker association for RF (p = 0.3). Six patients with EA had major erosions and also met criteria for rheumatoid arthritis (RA). Four of these patients (67%) were anti-CCP+. HLA-DQB1*0302 was associated with EA (p = 0.01), with similar trends for HLA-DRB1*0401 and 2 copies of the shared epitope (SE). There were trends for associations of HLA-DQB1*0302 and 2 SE copies with anti-CCP production. The frequency of EA in SLE is likely to be higher than previously reported. Anti-CCP+ patients with SLE are more likely to have EA. Anti-CCP may be a useful serological marker for EA for patients presenting with synovitis. Anti-citrulline antibodies may have a pathogenic role in the development of major erosions, resulting in clinical features that overlap SLE with RA (rhupus).


Alternative, complementary, energy-based medicine for spinal cord injury.
This paper provides an overview on various alternative, complementary, or energy-based therapies that expand the healing spectrum of individuals with spinal cord injury (SCI). Not only do they have the capability to help a variety of secondary conditions, they have the ability in some people, for certain injuries, to restore function, sometimes dramatically. After providing an overall contextual rationale for the use of alternative medicine, this paper briefly summarizes various Eastern-medicine healing modalities, laser-based therapies, nutritional and homeopathic approaches, and pulsed electromagnetic therapies.


Small cell osteosarcoma. A clinicopathologic study of 27 cases.
We report a study of 27 patients with small cell osteosarcoma (SCO), 17 from the M. D. Anderson Cancer Center (MDAH) and ten from the Pediatric Oncology Group (POG). There were 12 male patients and 15 female patients; 19 were white, five were black, and three were Hispanic. They ranged from 6 to 28 years of age with a median of 14 years. Histologically there were three patterns: Ewing's-like, lymphoma-like, and spindle cell. All cases showed osteoid formation and a few had chondroid areas. There was cytoplasmic glycogen in ten cases. Initial treatment for MDAH patients included intraarterial infusion of cisplatin in ten, amputation in four, partial mandibulectomies in two, and biopsy with local radiotherapy and systemic chemotherapy in one. All POG patients had resection or amputation followed by adjuvant chemotherapy. Twelve patients are alive, of whom nine have had significant follow-ups for 25 to 90 months. Fourteen patients are dead of lung, spine, and brain metastases from 1 to 23 months after initial diagnosis. One patient is alive with lung relapse at 4 months. In summary, SCO is a high-grade variant of osteosarcoma, with an incidence of up to 4% of all osteosarcomas, that affects patients of the same age group and has the same anatomic location as conventional osteosarcoma. Currently, SCO appears to have a prognosis that is the same as or slightly worse than that of conventional osteosarcoma. Furthermore, although intraarterial infusion is effective for the primary tumors in the bone, distant metastases are difficult to control.


Few Plasmodium falciparum merozoite ligand and erythrocyte receptor pairs show evidence of balancing selection.
Erythrocyte surface proteins have been identified as receptors of Plasmodium falciparum merozoite proteins. The ligand-receptor interactions enable the parasite to invade human erythrocytes, initiating the clinical symptoms of malaria. These interactions are likely to have had an evolutionary impact on the genes that encode the ligand and receptor proteins. We used sequence data from Kilifi, Kenya to detect departures from neutrality in a paired analysis of P. falciparum merozoite ligands and their erythrocyte receptor genes from the same population. We genotyped parasite and human DNA obtained from 93 individuals with severe malaria. We examined six merozoite ligands EBA175, EBL1, EBA140, MSP1, Rh4 and Rh5, and their corresponding erythrocyte receptors, glycophorin (Gyp) A, GypB, GypC, band 3, complement receptor (CR) 1 and basigin, focusing on the regions involved in the ligand-receptor interactions. Positive Tajima's D values (>1) were observed only in the MSP1 C-terminal region and EBA175 region II, while negative values (<-1) were observed in EBL-1 region II, Rh4, basigin exons 3 and 5, CR1 exon 5, Gyp B exons 2, 3 and 4 and Gyp C exon 2. Additionally, ebl-1 region II and basigin exon 3 showed extreme negative values in all three tests, Tajima's D, Fu & Li D* and F*, ≤ - 2. A large majority of the erythrocyte receptor and merozoite genes have a negative Tajima's D even when compared with previously published whole genome data. Thus, highlighting EBA175 region II and MSP1-33, as outlier genes with a positive Tajima's D (>1). Both these genes contain multiple polymorphisms, which in the case of EBA175 may counteract receptor polymorphisms and/or evade host immune responses and in MSP1 the polymorphisms may primarily evade host immune responses.


High-multiplicity HIV-1 infection and neutralizing antibody evasion mediated by the macrophage-T cell virological synapse.
Macrophage infection is considered to play an important role in HIV-1 pathogenesis and persistence. Using a primary cell-based coculture model, we show that monocyte-derived macrophages (MDM) efficiently transmit a high-multiplicity HIV-1 infection to autologous CD4(+) T cells through a viral envelope glycoprotein (Env) receptor- and actin-dependent virological synapse (VS), facilitated by interactions between ICAM-1 and LFA-1. Virological synapse (VS)-mediated transmission by MDM results in high levels of T cell HIV-1 integration and is 1 to 2 orders of magnitude more efficient than cell-free infection. This mode of cell-to-cell transmission is broadly susceptible to the activity of CD4 binding site (CD4bs) and glycan or glycopeptide epitope-specific broadly neutralizing monoclonal antibodies (bNMAbs) but shows resistance to bNMAbs targeting the Env gp41 subunit membrane-proximal external region (MPER). These data define for the first time the structure and function of the macrophage-to-T cell VS and have important implications for bNMAb activity in HIV-1 prophylaxis and therapy. IMPORTANCE The ability of HIV-1 to move directly between contacting immune cells allows efficient viral dissemination with the potential to evade antibody attack. Here, we show that HIV-1 spreads from infected macrophages to T cells via a structure called a virological synapse that maintains extended contact between the two cell types, allowing transfer of multiple infectious events to the T cell. This process allows the virus to avoid neutralization by a class of antibody targeting the gp41 subunit of the envelope glycoproteins. These results have implications for viral spread in vivo and the specificities of neutralizing antibody elicited by antibody-based vaccines.


Mechanisms of sustained high firing rates in two classes of vestibular nucleus neurons: differential contributions of resurgent Na, Kv3, and BK currents.
To fire at high rates, neurons express ionic currents that work together to minimize refractory periods by ensuring that sodium channels are available for activation shortly after each action potential. Vestibular nucleus neurons operate around high baseline firing rates and encode information with bidirectional modulation of firing rates up to several hundred Hz. To determine the mechanisms that enable these neurons to sustain firing at high rates, ionic currents were measured during firing by using the action potential clamp technique in vestibular nucleus neurons acutely dissociated from transgenic mice. Although neurons from the YFP-16 line fire at rates higher than those from the GIN line, both classes of neurons express Kv3 and BK currents as well as both transient and resurgent Na currents. In the fastest firing neurons, Kv3 currents dominated repolarization at all firing rates and minimized Na channel inactivation by rapidly transitioning Na channels from the open to the closed state. In slower firing neurons, BK currents dominated repolarization at the highest firing rates and sodium channel availability was protected by a resurgent blocking mechanism. Quantitative differences in Kv3 current density across neurons and qualitative differences in immunohistochemically detected expression of Kv3 subunits could account for the difference in firing range within and across cell classes. These results demonstrate how divergent firing properties of two neuronal populations arise through the interplay of at least three ionic currents.


Time- and concentration-dependent effects of exogenous serotonin and inflammatory cytokines on mast cell function.
Mast cells play a significant role in both the innate and adaptive immune response; however, the tissue-bound nature of mast cells presents an experimental roadblock to performing physiologically relevant mast cell experiments. In this work, a heterogeneous cell culture containing primary culture murine peritoneal mast cells (MPMCs) was studied to characterize the time-dependence of mast cell response to allergen stimulation and the time- and concentration-dependence of the ability of the heterogeneous MPMC culture to uptake and degranulate exogenous serotonin using high performance liquid chromatography (HPLC) coupled to an electrochemical detector. Additionally, because mast cells play a central role in asthma, MPMCs were exposed to CXCL10 and CCL5, two important asthma-related inflammatory cytokines that have recently been shown to induce mast cell degranulation. MPMC response to both allergen exposure and cytokine exposure was evaluated for 5-HT secretion and bioactive lipid formation using ultraperformance liquid chromatography coupled to an electrospray ionization triple quadrupole mass spectrometer (UPLC-MS/MS). In this work, MPMC response was shown to be highly regulated and responsive to subtle alterations in a complex environment through time- and concentration-dependent degranulation and bioactive lipid formation. These results highlight the importance of selecting an appropriate mast cell model when studying mast cell involvement in allergic response and inflammation.


Anthropometric profile and body composition of Irish adolescent rugby union players aged 16-18.
The literature suggests that one of the key determinants of success at rugby union international competitions is the anthropometric profile of players. The Irish Rugby Football Union (IRFU) long-term player development (LTPD) model is a framework designed to guide the development of the tactical, physical, and psychological domains of sporting participation. In Ireland, the Train-to-Train stage of the IRFU model is a critical stage, whereby the next developmental progression would include the transition of players into professional academies. To date, no previously published studies have examined the anthropometric profile of Irish Schools' rugby union players at the Train-to-Train stage of the IRFU model. The anthropometric profile of 136 male adolescent rugby union players at the Train-to-Train stage of the IRFU model was assessed using total-body dual-energy x-ray absorptiometry. Significant differences in height, body mass, body fat percentage, fat mass, lean mass, and fat-free mass were observed between players assigned to the forward and back units, and for specific position categorizations within each unit. Direct logistic regression revealed that body mass was a statistically significant (p < 0.01) predictor of unit position classification, with an odds ratio of 2.35, indicating that the players with a higher body mass were twice as likely to be classified as forwards. The results of this study indicate that at the Train-to-Train stage of the IRFU model, forward and back units have distinctly different anthropometric profiles. Furthermore, anthropometric differentiation also exists within specific position categorizations within each of these playing units. Thus, anthropometric profiling should be carried out on a systematic and periodic basis, because this will allow for the evaluation of the effectiveness of the implementation strategies of the IRFU model on a national basis.


Association Between Type 2 Diabetes and Changes in Myocardial Structure, Contractile Function, Energetics, and Blood Flow Before and After Aortic Valve Replacement in Patients With Severe Aortic Stenosis.
Type 2 diabetes (T2D) is associated with an increased risk of left ventricular dysfunction after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Persistent impairments in myocardial energetics and myocardial blood flow (MBF) may underpin this observation. Using phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance, this study tested the hypothesis that patients with severe AS and T2D (AS-T2D) would have impaired myocardial energetics as reflected by the phosphocreatine to ATP ratio (PCr/ATP) and vasodilator stress MBF compared with patients with AS without T2D (AS-noT2D), and that these differences would persist after AVR. Ninety-five patients with severe AS without coronary artery disease awaiting AVR (30 AS-T2D and 65 AS-noT2D) were recruited (mean, 71 years of age [95% CI, 69, 73]; 34 [37%] women). Thirty demographically matched healthy volunteers (HVs) and 30 patients with T2D without AS (T2D controls) were controls. One month before and 6 months after AVR, cardiac PCr/ATP, adenosine stress MBF, global longitudinal strain, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and 6-minute walk distance were assessed in patients with AS. T2D controls underwent identical assessments at baseline and 6-month follow-up. HVs were assessed once and did not undergo 6-minute walk testing. Compared with HVs, patients with AS (AS-T2D and AS-noT2D combined) showed impairment in PCr/ATP (mean [95% CI]; HVs, 2.15 [1.89, 2.34]; AS, 1.66 [1.56, 1.75]; P<0.0001) and vasodilator stress MBF (HVs, 2.11 mL min g [1.89, 2.34]; AS, 1.54 mL min g [1.41, 1.66]; P<0.0001) before AVR. Before AVR, within the AS group, patients with AS-T2D had worse PCr/ATP (AS-noT2D, 1.74 [1.62, 1.86]; AS-T2D, 1.44 [1.32, 1.56]; P=0.002) and vasodilator stress MBF (AS-noT2D, 1.67 mL min g [1.5, 1.84]; AS-T2D, 1.25 mL min g [1.22, 1.38]; P=0.001) compared with patients with AS-noT2D. Before AVR, patients with AS-T2D also had worse PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.66 [1.56, 1.75]; P=0.04) and vasodilator stress MBF (AS-T2D, 1.25 mL min g [1.10, 1.41]; T2D controls, 1.54 mL min g [1.41, 1.66]; P=0.001) compared with T2D controls at baseline. After AVR, PCr/ATP normalized in patients with AS-noT2D, whereas patients with AS-T2D showed no improvements (AS-noT2D, 2.11 [1.79, 2.43]; AS-T2D, 1.30 [1.07, 1.53]; P=0.0006). Vasodilator stress MBF improved in both AS groups after AVR, but this remained lower in patients with AS-T2D (AS-noT2D, 1.80 mL min g [1.59, 2.0]; AS-T2D, 1.48 mL min g [1.29, 1.66]; P=0.03). There were no longer differences in PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.51 [1.34, 1.53]; P=0.12) or vasodilator stress MBF (AS-T2D, 1.48 mL min g [1.29, 1.66]; T2D controls, 1.60 mL min g [1.34, 1.86]; P=0.82) between patients with AS-T2D after AVR and T2D controls at follow-up. Whereas global longitudinal strain, 6-minute walk distance, and NT-proBNP all improved after AVR in patients with AS-noT2D, no improvement in these assessments was observed in patients with AS-T2D. Among patients with severe AS, those with T2D demonstrate persistent abnormalities in myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function after AVR; AVR effectively normalizes myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function in patients without T2D.


A competitive protein interaction network buffers Oct4-mediated differentiation to promote pluripotency in embryonic stem cells.
Pluripotency in embryonic stem cells is maintained through the activity of a small set of transcription factors centred around Oct4 and Nanog, which control the expression of 'self-renewal' and 'differentiation' genes. Here, we combine single-cell quantitative immunofluorescence microscopy and gene expression analysis, together with theoretical modelling, to investigate how the activity of those factors is regulated. We uncover a key role for post-translational regulation in the maintenance of pluripotency, which complements the well-established transcriptional regulatory layer. Specifically, we find that the activity of a network of protein complexes involving Nanog, Oct4, Tcf3, and β-catenin suffices to account for the behavior of ES cells under different conditions. Our results suggest that the function of the network is to buffer the transcriptional activity of Oct4, which appears to be the main determinant to exit pluripotency. The protein network explains the mechanisms underlying the gain and loss of function in different mutants, and brings us closer to a full understanding of the molecular basis of pluripotency.


A genome-wide association study of DSM-IV cannabis dependence.
Despite twin studies showing that 50-70% of variation in DSM-IV cannabis dependence is attributable to heritable influences, little is known of specific genotypes that influence vulnerability to cannabis dependence. We conducted a genome-wide association study of DSM-IV cannabis dependence. Association analyses of 708 DSM-IV cannabis-dependent cases with 2346 cannabis-exposed non-dependent controls was conducted using logistic regression in PLINK. None of the 948 142 single nucleotide polymorphisms met genome-wide significance (P at E-8). The lowest P values were obtained for polymorphisms on chromosome 17 (rs1019238 and rs1431318, P values at E-7) in the ANKFN1 gene. While replication is required, this study represents an important first step toward clarifying the biological underpinnings of cannabis dependence.


Radionuclide cerebral blood flow and carotid angiogram. Correlation in internal carotid artery disease.
Radionuclide cerebral blood flow (CBF) examinations of 48 patients with atherosclerosis, 18 with occlusion and 30 with stenosis of the internal carotid artery (ICA) were correlated with their respective cerebral angiograms. The following results were obtained. Flow was visually unilaterally diminished in 29 (60%) of 48 patients, including 14 (78%) with occlusion and 15 (50%) with stenosis. Sixty-two percent of the subjects with severe stenoses and 46% of the patients with mild stenoses had a positive flow study. Diminished flow was evident in the neck in 80% of the patients, intracranially in 20%. Positive radionuclide angiograms always pointed to the side with occlusion or the greater degree of stenosis even though bilateral interanl carotid disease was frequently found (54%). The data leading to the differentiation between major and minor ICA stenosis are not sufficient to justify any conclusion.


The usefulness of laparoscopy and hysteroscopy in the diagnostics and treatment of infertility.
The aim of the study was to analyze the use of endoscopic procedures in the group of infertile patients. The study material consisted of 636 patients, aged 20-41. They all had endoscopic procedures performed (laparoscopy and/or hysteroscopy) due to infertility, and were qualified for the procedure after a gynecological examination and ultrasound scan. The study group was divided into subgroups of primary and secondary sterility and endoscopic procedures were then analyzed. A total of 724 endoscopic procedures were performed on 636 patients. Eighty eight women had both hysteroscopy and laparoscopy performed, 476 had only laparoscopy, while 72--only hysteroscopy. Women diagnosed due to primary sterility more often had no visible abnormalities in the pelvic region (30%) and patent oviducts than those with secondary sterility. The remaining 70% more often had ovaries typical for polycystic ovarian syndrome and endometriosis. However, periadnexal adhesions and tubal impotency were more common in the group of secondary sterility. As to hysteroscopy, women with primary sterility more often had congenital uterine malformations, while submucosal myomas and intrauterine adhesions were less common in that group. All the surgical procedures performed during laparoscopies were analyzed. Tubal patency assessment and ovarian drilling were significantly more often performed in the subgroup of primary sterility. All intrauterine pathologies were treated during hysteroscopy. Laparoscopy and hysteroscopy play an important role as both diagnostic and therapeutic tools in the infertility treatment centers.


Strong interplay between the electron spin lifetime in chemically synthesized graphene multilayers and surface-bound oxygen.
The electron spin lifetime in an assembly of chemically synthesized graphene sheets was found to be extremely sensitive to oxygen. Introducing small concentrations of physisorbed O2 onto the graphene surface reduced the exceptionally long 140 ns electron spin lifetime by an order of magnitude. This effect was completely reversible: Removing the O2 by using a dynamic vacuum restored the spin lifetime. The presence of covalently bound oxygen also decreased the electron spin lifetime in graphene, although to a far lesser extent compared to physisorbed O2 . The conduction electrons in graphene were found to play a significant role by counter-balancing the spin depolarization caused by oxygen molecules. Our results highlight the importance of chemical environment control and device packing in practical graphene-based spintronic applications.


Comparison of the efficacy of nifedipine and hydralazine in hypertensive crisis in pregnancy.
Intravenous hydralazine is a commonly administered arteriolar vasodilator that is effective for hypertensive emergencies associated with pregnancy. Oral nifedipine is an alternative in management of these patients. In this study the efficacy of nifedipine and hydralazine in pregnancy was compared in a group of Iranian patients. Fifty hypertensive pregnant women were enrolled in the study. A randomized clinical trial was performed, in which patients in two groups received intravenus hydralazine or oral nifedipine to achieve target blood pressure reduction. The primary outcomes measured were the time and doses required for desired blood pressure achievement. Secondary measures included urinary output and maternal and neonatal side effects. The time required for reduction in systolic and diastolic blood pressure was shorter for oral nifedipine group (24.0 ± 10.0 min) than intravenus Hydralazine group (34.8 ± 18.8 min) (P ≤ 0.016). Less frequent doses were required with oral nifedipine (1.2 ± 0.5) compared to intravenus hydralazine (2.1 ± 1.0) (P ≤ 0.0005). There were no episodes of hypotension after hydralazine and one after nifedipine. Nifedipine and hydralazine are safe and effective antihypertensive drugs, showing a controlled and comparable blood pressure reduction in women with hypertensive emergencies in pregnancy. Both drugs reduce episodes of persistent severe hypertension. Considering pharmacokinetic properties of nifedipine such as rapid onset and long duration of action, the good oral bioavailability and less frequent side effects, it looks more preferable in hypertension emergencies of pregnancy than hydralazine.


Acclimation of the Global Transcriptome of the Cyanobacterium Synechococcus sp. Strain PCC 7002 to Nutrient Limitations and Different Nitrogen Sources.
The unicellular, euryhaline cyanobacterium Synechococcus sp. strain PCC 7002 is a model organism for laboratory-based studies of cyanobacterial metabolism and is a potential platform for biotechnological applications. Two of its most notable properties are its exceptional tolerance of high-light intensity and very rapid growth under optimal conditions. In this study, transcription profiling by RNAseq has been used to perform an integrated study of global changes in transcript levels in cells subjected to limitation for the major nutrients CO(2), nitrogen, sulfate, phosphate, and iron. Transcriptional patterns for cells grown on nitrate, ammonia, and urea were also studied. Nutrient limitation caused strong decreases of transcript levels of the genes encoding major metabolic pathways, especially for components of the photosynthetic apparatus, CO(2) fixation, and protein biosynthesis. Uptake mechanisms for the respective nutrients were strongly up-regulated. The transcription data further suggest that major changes in the composition of the NADH dehydrogenase complex occur upon nutrient limitation. Transcripts for flavoproteins increased strongly when CO(2) was limiting. Genes involved in protection from oxidative stress generally showed high, constitutive transcript levels, which possibly explains the high-light tolerance of this organism. The transcriptomes of cells grown with ammonia or urea as nitrogen source showed increased transcript levels for components of the CO(2) fixation machinery compared to cells grown with nitrate, but in general transcription differences in cells grown on different N-sources exhibited surprisingly minor differences.


Puerperal development of ewes following dystocia: a retrospective analysis of two approaches to caesarean section.
The objective of this study was to retrospectively analyse the puerperal development of ewes referred to a veterinary teaching hospital following caesarean section in comparison with assisted parturition. Laparotomy was performed either via left flank incision (group 1, n=86) or ventral mid-line approach (group 2, n=33). Both groups were compared with ewes following non-surgical intervention (group 3, n=73). The overall fetal death rate was 41 per cent. There was no significant difference in fetal deaths between groups 1 and 2, but assisted delivery led to a higher number of liveborn lambs compared with caesarean section (P<0.05). Seven ewes (3.6 per cent) died or were euthanased on welfare grounds during caesarean surgery, and the overall maternal mortality rate following dystocia in the postpartum period was 10.9 per cent. While there was no significant difference between groups 1 and 2 in the percentage of ewes developing healing disorders, the complications that occurred were more severe after the left flank approach (P=0.04), and the mean hospitalisation period was significantly longer in group 1 than in group 2 (P<0.05), leading to the conclusion that ventral mid-line laparotomy has some advantages over a left flank approach.


Breast MRI segmentation for density estimation: Do different methods give the same results and how much do differences matter?
To compare two methods of automatic breast segmentation with each other and with manual segmentation in a large subject cohort. To discuss the factors involved in selecting the most appropriate algorithm for automatic segmentation and, in particular, to investigate the appropriateness of overlap measures (e.g., Dice and Jaccard coefficients) as the primary determinant in algorithm selection. Two methods of breast segmentation were applied to the task of calculating MRI breast density in 200 subjects drawn from the Avon Longitudinal Study of Parents and Children, a large cohort study with an MRI component. A semiautomated, bias-corrected, fuzzy C-means (BC-FCM) method was combined with morphological operations to segment the overall breast volume from in-phase Dixon images. The method makes use of novel, problem-specific insights. The resulting segmentation mask was then applied to the corresponding Dixon water and fat images, which were combined to give Dixon MRI density values. Contemporaneously acquired T1 - and T2 -weighted image datasets were analyzed using a novel and fully automated algorithm involving image filtering, landmark identification, and explicit location of the pectoral muscle boundary. Within the region found, fat-water discrimination was performed using an Expectation Maximization-Markov Random Field technique, yielding a second independent estimate of MRI density. Images are presented for two individual women, demonstrating how the difficulty of the problem is highly subject-specific. Dice and Jaccard coefficients comparing the semiautomated BC-FCM method, operating on Dixon source data, with expert manual segmentation are presented. The corresponding results for the method based on T1 - and T2 -weighted data are slightly lower in the individual cases shown, but scatter plots and interclass correlations for the cohort as a whole show that both methods do an excellent job in segmenting and classifying breast tissue. Epidemiological results demonstrate that both methods of automated segmentation are suitable for the chosen application and that it is important to consider a range of factors when choosing a segmentation algorithm, rather than focus narrowly on a single metric such as the Dice coefficient.


What is peripersonal space? An examination of unresolved empirical issues and emerging findings.
Findings from diverse fields of study, including neuroscience, psychology, zoology, and sociology, demonstrate that human and non-human primates maintain a representation of the space immediately surrounding the body, known as peripersonal space (PPS). However, progress in this field has been hampered by the lack of an agreed upon definition of PPS. Since the beginning of its formal study, scientists have argued that PPS plays a crucial role in both defensive and non-defensive actions. Yet consensus is lacking about the cognitive and neural instantiation of these functions. In particular, researchers have begun to ask whether a single, unified system of spatial-attentional resources supports both the defensive and non-defensive functions of PPS or, rather, whether there are multiple, independent systems. Moreover, there are open questions about the specificity of PPS. For example: Does PPS dissociate from other well-known phenomena such as personal space and the body schema? Finally, emerging research has brought attention to important questions about individual differences in the flexibility of PPS and the distribution of PPS in front compared to behind the body. In this advanced review, we shed light on questions about the nature of PPS, offering answers when the research permits or providing recommendations for achieving answers in future research. In so doing, we lay the groundwork for a comprehensive definition of PPS. This article is categorized under: Cognitive Biology > Evolutionary Roots of Cognition Psychology > Attention Psychology > Perception and Psychophysics Neuroscience > Plasticity.


Survival of Escherichia coli under lethal heat stress by L-form conversion.
Transition of bacteria to cell wall deficient L-forms in response to stress factors has been assumed as a potential mechanism for survival of microbes under unfavorable conditions. In this article, we provide evidence of paradoxal survival through L-form conversion of E. coli high cell density population after lethal treatments (boiling or autoclaving). Light and transmission electron microscopy demonstrated conversion from classical rod to polymorphic L-form shape morphology and atypical growths of E. coli. Microcrystal formations observed at this stage were interpreted as being closely linked to the processes of L-form conversion and probably involved in the general phenomenon of protection against lethal environment. Identity of the morphologically modified L-forms as E. coli was verified by species specific DNA-based test. Our study might contribute to a better understanding of the L-form phenomenon and its importance for bacterial survival, as well as provoke reexamination of the traditional view of killing strategies against bacteria.


Delivery of mobile clinic services to migrant and seasonal farmworkers: a review of practice models for community-academic partnerships.
Farmworkers in the US are a medically underserved group, who are largely uninsured, foreign-born, and working in a hazardous industry. This review addresses the challenges of providing health services for this priority population to study the numerous health access barriers that face migrant and seasonal farmworkers (MSFW), evaluates the services provided at mobile clinics, summarizes practice models for community-academic partnerships, and synthesizes the literature on effective partnership approaches to deliver these services. Because MSFW are a difficult group to reach and access, mobile farmworker clinics provide an opportunity for unique student training experiences, in addition to small survey and feasibility studies. A literature search was conducted to identify articles for the review. Out of 196 articles identified by the article databases and manual search techniques, 18 articles were finally selected for the review based on predetermined inclusion and exclusion criteria. Half of the articles were classified as case studies or descriptive studies with lessons learned. Only three articles were classified as research studies, and six articles were not classified as research studies, but rather descriptions of the clinics only. Many of the partnership models were structured with the lead agency as either the academic partner or an Area Health Education Center. The academic partner was usually a nursing school, and less frequently a medical school. Other service partners frequently mentioned were federally-qualified Community Health Centers, Migrant Health Centers, and health departments. The review found that service partnerships were characterized by collaboration between academic institutions and community organizations, with a lead agency driving sustainability efforts.


Plain language summary of a study looking at heart muscle thickness and kidney function in women with Fabry disease who received agalsidase beta treatment.
Fabry disease is a rare genetic condition that affects many different cells and organs in the body. People have Fabry disease when they inherit a GLA gene containing an error from one or both of their parents. This causes an enzyme in their body called alpha-galactosidase (also called α-Gal) to not work properly. In people without Fabry disease, a-Gal breaks down fats called glycolipids. In people with Fabry disease, as a-Gal does not work properly, glycolipids build up in the body, particularly in the cells of the kidney, heart, nerves, and the cells that line blood vessels. People who have Fabry disease can receive an enzyme replacement therapy (ERT for short) called agalsidase beta, which acts as a substitute for a-Gal. Although both males and females can have Fabry disease, it generally affects males more severely than females, and symptoms in females can vary significantly. Several researchers have studied the long-term effects of agalsidase beta ERT in males, but there have been fewer studies in females. This study looked at women with Fabry disease who started receiving agalsidase beta treatment when they were at least 18 years old, using information from the Fabry Registry (the largest worldwide database that collects and stores information about people with Fabry disease). The researchers evaluated heart muscle thickness (thickening can be a sign of poor heart health) and kidney function from 5 years before women with Fabry disease started agalsidase beta treatment to 5 years after they started treatment. Before women with Fabry disease started treatment, their heart muscle tended to thicken over time. After starting treatment, their heart muscle thickening slowed. Kidney function was similar to that of unaffected people both before and after treatment. This study provides a unique insight into the effects of agalsidase beta in women with Fabry disease. The findings suggest that agalsidase beta may slow heart muscle thickening and maintain normal kidney function in women with Fabry disease. Clinical Trial Registration: NCT00196742 (ClinicalTrials.gov).


In the absence of phosphate shuttling, exercise reveals the in vivo importance of creatine-independent mitochondrial ADP transport.
The transport of cytosolic adenosine diphosphate (ADP) into the mitochondria is a major control point in metabolic homeostasis, as ADP concentrations directly affect glycolytic flux and oxidative phosphorylation rates within mitochondria. A large contributor to the efficiency of this process is thought to involve phosphocreatine (PCr)/Creatine (Cr) shuttling through mitochondrial creatine kinase (Mi-CK), whereas the biological importance of alterations in Cr-independent ADP transport during exercise remains unknown. Therefore, we utilized an Mi-CK knockout (KO) model to determine whether in vivo Cr-independent mechanisms are biologically important for sustaining energy homeostasis during exercise. Ablating Mi-CK did not alter exercise tolerance, as the time to volitional fatigue was similar between wild-type (WT) and KO mice at various exercise intensities. In addition, skeletal muscle metabolic profiles after exercise, including glycogen, PCr/Cr ratios, free ADP/adenosine monophosphate (AMP), and lactate, were similar between genotypes. While these data suggest that the absence of PCr/Cr shuttling is not detrimental to maintaining energy homeostasis during exercise, KO mice displayed a dramatic increase in Cr-independent mitochondrial ADP sensitivity after exercise. Specifically, whereas mitochondrial ADP sensitivity decreased with exercise in WT mice, in stark contrast, exercise increased mitochondrial Cr-independent ADP sensitivity in KO mice. As a result, the apparent ADP Km was 50% lower in KO mice after exercise, suggesting that in vivo activation of voltage-dependent anion channel (VDAC)/adenine nucleotide translocase (ANT) can support mitochondrial ADP transport. Altogether, we provide insight that Cr-independent ADP transport mechanisms are biologically important for regulating ADP sensitivity during exercise, while highlighting complex regulation and the plasticity of the VDAC/ANT axis to support adenosine triphosphate demand.


Screening of target-specific stress-responsive genes for the development of cell-based biosensors using a DNA microarray.
In this study, we describe a straightforward strategy to develop whole cell-based biosensors using fusions of the bacterial bioluminescence genes and the promoters from chemically responsive genes within Escherichia coli, in which chemical target-responsive genes were screened by using the information of gene expression data obtained from DNA microarray analysis. Paraquat was used as a model chemical to trigger gene expression changes of E. coli and to show the DNA microarray-assisted development of whole cell-based biosensors. Gene expression data from the DNA microarray were obtained by time course analysis (10, 30, and 60 min) after exposure to paraquat. After clustering gene expression data obtained by time course analysis, a group of highly expressed genes over the all time courses could be classified. Within this group, three genes expressed highly for overall time points were selected and promoters of these genes were used as fusion partners with reporter genes, lux CDABE, to construct whole cell-based biosensors. The constructed biosensors recognized the presence of model inducer, paraquat, and structural analogue chemicals of paraquat with a high specificity, and the results were reconfirmed by using DNA microarray experiments for those structural analogues. This strategy to develop whole cell-based biosensors assisted by DNA microarray information should be useful in general for constructing chemical-specific or stress-specific biosensors with a high-throughput manner.


Analysis of pigmented inkjet printer inks and printed documents by laser desorption/mass spectrometry.
Anyone with a computer, scanner, and color printer has the capability for creating documents such as identification cards, passports, and counterfeit currency. Laser desorption mass spectrometry (LDMS) has been demonstrated as a powerful tool for colorant analysis. Inkjet printers are now moving largely toward the use of pigments as colorants; their insolubility makes analysis by simpler methods such as thin-layer chromatography no longer an option. Recent developments in pigmented inkjet printer inks, such as gloss optimizers that coat pigment particles, may prohibit colorant analysis by LDMS. We demonstrate here that pigments used in inks from two Epson printers can be detected and analyzed by LDMS. Also, LDMS spectra of various colors created using a 4-cartridge (cyan/magenta/yellow/black, CMYK) inkset are evaluated, to begin to develop an approach for unraveling LDMS data from real samples, to determine the number of inks used by a printer, and the chemical composition of the colorants.


Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia.
Cancer onset and progression involves the accumulation of multiple oncogenic hits, which are thought to dominate or bypass the physiologic regulatory mechanisms in tissue development and homeostasis. We demonstrate in T-cell acute lymphoblastic leukemia (T-ALL) that, irrespective of the complex oncogenic abnormalities underlying tumor progression, experimentally induced, persistent T-cell receptor (TCR) signaling has antileukemic properties and enforces a molecular program resembling thymic negative selection, a major developmental event in normal T-cell development. Using mouse models of T-ALL, we show that induction of TCR signaling by high-affinity self-peptide/MHC or treatment with monoclonal antibodies to the CD3ε chain (anti-CD3) causes massive leukemic cell death. Importantly, anti-CD3 treatment hampered leukemogenesis in mice transplanted with either mouse- or patient-derived T-ALLs. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of patients with TCR-expressing T-ALL and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells. T-ALLs are aggressive malignant lymphoid proliferations of T-cell precursors characterized by high relapse rates and poor prognosis, calling for the search for novel therapeutic options. Here, we report that the lineage-specific TCR/CD3 developmental checkpoint controlling cell death in normal T-cell progenitors remains switchable to induce massive tumor cell apoptosis in T-ALL and is amenable to preclinical therapeutic intervention. Cancer Discov; 6(9); 972-85. ©2016 AACR.See related commentary by Lemonnier and Mak, p. 946This article is highlighted in the In This Issue feature, p. 932.


Inferring 3D chromatin structure using a multiscale approach based on quaternions.
The knowledge of the spatial organisation of the chromatin fibre in cell nuclei helps researchers to understand the nuclear machinery that regulates DNA activity. Recent experimental techniques of the type Chromosome Conformation Capture (3C, or similar) provide high-resolution, high-throughput data consisting in the number of times any possible pair of DNA fragments is found to be in contact, in a certain population of cells. As these data carry information on the structure of the chromatin fibre, several attempts have been made to use them to obtain high-resolution 3D reconstructions of entire chromosomes, or even an entire genome. The techniques proposed treat the data in different ways, possibly exploiting physical-geometric chromatin models. One popular strategy is to transform contact data into Euclidean distances between pairs of fragments, and then solve a classical distance-to-geometry problem. We developed and tested a reconstruction technique that does not require translating contacts into distances, thus avoiding a number of related drawbacks. Also, we introduce a geometrical chromatin chain model that allows us to include sound biochemical and biological constraints in the problem. This model can be scaled at different genomic resolutions, where the structures of the coarser models are influenced by the reconstructions at finer resolutions. The search in the solution space is then performed by a classical simulated annealing, where the model is evolved efficiently through quaternion operators. The presence of appropriate constraints permits the less reliable data to be overlooked, so the result is a set of plausible chromatin configurations compatible with both the data and the prior knowledge. To test our method, we obtained a number of 3D chromatin configurations from Hi-C data available in the literature for the long arm of human chromosome 1, and validated their features against known properties of gene density and transcriptional activity. Our results are compatible with biological features not introduced a priori in the problem: structurally different regions in our reconstructions highly correlate with functionally different regions as known from literature and genomic repositories.


De Novo assembly of the complete genome of an enhanced electricity-producing variant of Geobacter sulfurreducens using only short reads.
State-of-the-art DNA sequencing technologies are transforming the life sciences due to their ability to generate nucleotide sequence information with a speed and quantity that is unapproachable with traditional Sanger sequencing. Genome sequencing is a principal application of this technology, where the ultimate goal is the full and complete sequence of the organism of interest. Due to the nature of the raw data produced by these technologies, a full genomic sequence attained without the aid of Sanger sequencing has yet to be demonstrated.We have successfully developed a four-phase strategy for using only next-generation sequencing technologies (Illumina and 454) to assemble a complete microbial genome de novo. We applied this approach to completely assemble the 3.7 Mb genome of a rare Geobacter variant (KN400) that is capable of unprecedented current production at an electrode. Two key components of our strategy enabled us to achieve this result. First, we integrated the two data types early in the process to maximally leverage their complementary characteristics. And second, we used the output of different short read assembly programs in such a way so as to leverage the complementary nature of their different underlying algorithms or of their different implementations of the same underlying algorithm.The significance of our result is that it demonstrates a general approach for maximizing the efficiency and success of genome assembly projects as new sequencing technologies and new assembly algorithms are introduced. The general approach is a meta strategy, wherein sequencing data are integrated as early as possible and in particular ways and wherein multiple assembly algorithms are judiciously applied such that the deficiencies in one are complemented by another.


Patterns of use of a free nicotine patch program for Medicaid and uninsured patients.
This study assessed the use and effectiveness of a free nicotine patch program among Medicaid and uninsured smokers. Patterns of patch use, associated behaviors with quit attempt, side effects, and self-reported abstinence from smoking for 6 months were evaluated prospectively among patients from five urban family practice offices and a nicotine dependence clinic located in a comprehensive cancer center in Western New York. Results indicated that the majority of participants used the program as intended, and 90% of the participants found the patch useful in their quit attempt. Fourteen percent of participants were abstinent for 6 months or more. We found no support for inappropriate use of transdermal nicotine patches among patients with no health insurance or those on Medicaid. Transdermal nicotine patches are an effective cessation aid for smokers. Given the tall of the consequences of smoking on health costs, barriers to access to effective treatment for smoking cessation among individuals covered by Medicaid for health insurance need to be eliminated.


The contribution of non-malarial febrile illness co-infections to Plasmodium falciparum case counts in health facilities in sub-Saharan Africa.
The disease burden of Plasmodium falciparum malaria illness is generally estimated using one of two distinct approaches: either by transforming P. falciparum infection prevalence estimates into incidence estimates using conversion formulae; or through adjustment of counts of recorded P. falciparum-positive fever cases from clinics. Whilst both ostensibly seek to evaluate P. falciparum disease burden, there is an implicit and problematic difference in the metric being estimated. The first enumerates only symptomatic malaria cases, while the second enumerates all febrile episodes coincident with a P. falciparum infection, regardless of the fever's underlying cause. Here, a novel approach was used to triangulate community-based data sources capturing P. falciparum infection, fever, and care-seeking to estimate the fraction of P. falciparum-positive fevers amongst children under 5 years of age presenting at health facilities that are attributable to P. falciparum infection versus other non-malarial causes. A Bayesian hierarchical model was used to assign probabilities of malaria-attributable fever (MAF) and non-malarial febrile illness (NMFI) to children under five from a dataset of 41 surveys from 21 countries in sub-Saharan Africa conducted between 2006 and 2016. Using subsequent treatment-seeking outcomes, the proportion of MAF and NMFI amongst P. falciparum-positive febrile children presenting at public clinics was estimated. Across all surveyed malaria-positive febrile children who sought care at public clinics across 41 country-years in sub-Saharan Africa, P. falciparum infection was estimated to be the underlying cause of only 37.7% (31.1-45.4, 95% CrI) of P. falciparum-positive fevers, with significant geographical and temporal heterogeneity between surveys. These findings highlight the complex nature of the P. falciparum burden amongst children under 5 years of age and indicate that for many children presenting at health clinics, a positive P. falciparum diagnosis and a fever does not necessarily mean P. falciparum is the underlying cause of the child's symptoms, and thus other causes of illness should always be investigated, in addition to prescribing an effective anti-malarial medication. In addition to providing new large-scale estimates of malaria-attributable fever prevalence, the results presented here improve comparability between different methods for calculating P. falciparum disease burden, with significant implications for national and global estimation of malaria burden.