Who goes to sexually transmitted disease clinics? Results from a national population survey.
To examine the pattern of attendance at sexually transmitted disease (STD) clinics in Britain. To compare the demographic characteristics, behaviours and attitudes of STD clinic attenders with those of non-attenders, and to assess the extent to which STD clinics are used by those with high-risk sexual lifestyles. Random sample general population survey of sexual attitudes and lifestyle. 18,876 randomly selected men and women resident in Britain aged 16-59 years. Demographic characteristics, pattern of homosexual partnerships, heterosexual partnerships, payment for sex, abortion, drug injection in the last five years, and attitudes to sexual behaviours amongst 512 respondents who had attended STD clinic in the last five years compared with those who had not. 8.3% of men and 5.6% of women had attended a clinic in their lifetime and 3.4% and 2.6% respectively in the last five years. Attendance rates varied substantially with area of residence. 11% of Inner London residents had attended in the last five years. In multivariate analysis, STD clinic attendance for men was most strongly associated with increased numbers of heterosexual partners, (OR = 6.01 (4.44-8.15) and homosexual partnerships (OR = 9.59 (5.83-15.8)) and more weakly associated with payment for sex, non-manual social class, age 25-44, unmarried status and smoking. Clinic attendance for women was most strongly associated with numbers of heterosexual partners (OR = 3.74 (2.76-5.08) and injecting drug use (OR = 4.39 (1.73-11.1)). A weaker independent association was found with a history of abortion, anal sex, non-manual social class, non-married status and age 16-24. From the total population, 1 in 6 men and 1 in 7 women in the top 5% of the distribution for numbers of heterosexual partners and 1 in 5 men paying for sex and 1 in 4 of those with a homosexual partner had attended a clinic in the last five years. The probability of attendance increased with multiple risk behaviours. Of women 64.2% and of men 69.7% attending clinics reported major risk markers for STD transmission. STD clinics in Britain are used by a wide demographic spectrum of the population. The behaviours, but not the attitudes, of attenders differed markedly from those of non-attenders. Clinics are relatively efficient in attracting only those with high-risk lifestyles, but, at a population level, the minority of those reporting risk-markers for STD transmission attend clinics. These findings suggest that STD clinics are an important focus for sexual health promotion, but that community programmes are also important for reaching non-attenders.


Predictive factors of an incomplete examination and inadequate small-bowel cleanliness during capsule endoscopy.
the aim of this study was to determine predictive factors for an incomplete capsule endoscopy and an inadequate small-bowel preparation in capsule endoscopy. predictive factors for an incomplete capsule endoscopy were evaluated. Therefore, all patients with incomplete examinations performed between June 2009 and February 2016 were retrospectively included and compared with all patients with complete procedures performed between January 2014 and February 2016. Predictive factors of an inadequate small-bowel cleanliness were assessed. Therefore, the subset of patients that underwent capsule endoscopy between January 2014 and February 2016, including incomplete examinations, were evaluated. Small-bowel cleanliness was evaluated according to a quantitative index and a qualitative evaluation scale. Data with regard to patient and capsule endoscopy was analyzed. 31 incomplete and 122 complete capsule endoscopies were included in the analysis of predictive factors for an incomplete capsule endoscopy. The degree of dependency (OR = 4.67; p = 0.028), performance of a capsule endoscopy in hospitalized patients (OR = 4.04; p = 0.006) and prior abdominal surgery (OR = 3.45; p = 0.012) were independent predictive factors of an incomplete procedure. 130 patients were included in the analysis of predictive factors for an inadequate small-bowel cleanliness. The mean quantitative index value was 7.3 (s.d. ± 2.3); 41.6% and 58.5% of capsule endoscopies were classified as poor-fair and good/excellent respectively, according to the qualitative evaluation. Independent predictive factors for an inadequate preparation according to the quantitative index included male gender (Beta = -0.79; p = 0.028), small-bowel transit time (Beta = -0.007; p < 0.0001) and cardiac disease (Beta = -1.29; p = 0.001). Associated factors according to the qualitative evaluation included male gender (OR = 0.406; p = 0.027) and small-bowel transit time (SBTT) (OR = 0.993; p < 0.0001). inpatient status, higher degrees of dependency and abdominal surgery are predictive factors for an incomplete capsule endoscopy; male gender and higher small-bowel transit time are predictive factors for an inadequate cleanliness.


Reference interval for albumin-adjusted calcium based on a large UK population.
Primary hyperparathyroidism is a common condition and results in hypercalcaemia, especially in older women. Thus, it is critical to obtain a robust estimate for the upper limit of the reference interval for albumin-adjusted serum calcium in the general population. The current reference interval in use in the UK (Pathology Harmony range, 2.20 to 2.60 mmol/L) was based on a consensus. To establish a reference interval for albumin-adjusted serum calcium in men and women. Cross-sectional study of men and women who did not have chronic kidney disease or vitamin D deficiency; outliers were identified statistically and then rejected and then a 99% reference interval was calculated. 502 524 men and women aged 40 to 69 years from the UK Biobank Study. Serum total calcium, albumin, 25-hydroxyvitamin D, estimated glomerular function (eGFR). We developed an equation for albumin-adjusted serum calcium and applied it to 178 377 men and women who did not have chronic kidney disease or vitamin D deficiency. We identified 2962 (1.7%) as outliers, and when excluded, we report a 99% reference interval of 2.19 to 2.56 mmol/L (8.76 to 10.24 mg/dL). We found that for older (55-69 years) and younger women (40-55 years) the upper limits were 2.59 mmol/L and 2.57 mmol/L and that for all men, the upper limit was 2.55 mmol/L. We have established an upper limit of the reference range for older women that would identify all high outliers (2.60 mmol/L and above). The upper limit for young women and for men is lower, at 2.57 and 2.55 mmol/L respectively. The current reference interval in use has to be updated and improved based on these findings. These upper limits may prove helpful for identifying hypercalcaemic disorders like primary hyperparathyroidism in clinical practice.


Rapid and sensitive glycan targeting by lectin-SERS assay.
Glycosylation is an important part of cell signalling that is implicated in many disease states in which glycans play an essential role. Therefore rapid and sensitive differentiation of glycans on proteins is highly desirable. Current technologies for glycan structural analysis normally involve the isolation of glycans from proteins, or enrichment of glycopeptides, and detection by mass spectrometry, which requires relatively large amounts of sample and is not able to be used by non-specialist laboratories. Herein we present a simple and new strategy for targeting the glycans on a protein (with IgG as a model glycoprotein) using surface-enhanced Raman scattering (SERS) coupled to glycan-binding WGA (wheat germ agglutinin) lectin, in a lectin-SERS assay. With one drop (1 μL) of glycoprotein solution, our lectin-SERS assay can detect as low as 10 ng IgG within two hours with high glycan specificity. We extend our technique to examine the surface glycan profiles on two human colorectal cancer cell lines, which show different and unique glycan signatures specific to the target cell lines. Thus, we believe that this method could be potentially used for the real-time and in situ monitoring of glycans on the surface of cells or tissue or in body fluids, and is thus a powerful tool for glycomics research.


In utero gene therapy: prospect and future.
Many genetic disorders are reported to cause irreversible damage to the fetus before birth. In utero gene therapy may be an effective tool for correction of genetic disorders by replacing defective gene with normal one. There are many reasons for moving forward with in utero gene therapy. The most important reason is to provide early intervention as to prevent or slow dysfunction and morbidity. This approach may prove to be advantageous in rapidly replicating fetal cells, and less sensitive to immune response to vector or transgene product due to underdeveloped immune system. In addition, the developing fetus may be a better candidate for gene therapy than the adult because gene engraftment may be more feasible in early fetal life, where stem cells or pleuripotent progenitor cells are more accessible to vectors. Some reports are available on successful in utero gene transfer in animal models but many questions remain to be answered before in utero gene therapy can be considered a viable solution to human. The real moral challenge facing in utero gene therapy is finding ways to insure that the review of protocols is adequate, and that those undertaking trials are competent to do so. Present review article analyzes the overall progress of the field, and the research that still needs to be performed before it can be considered to human clinical trials.


Free Boomerang-shaped Extended Rectus Abdominis Myocutaneous flap: The longest possible skin/myocutaneous free flap for soft tissue reconstruction of extremities.
A soft tissue defect requiring flap cover which is longer than that provided by the conventional "long" free flaps like latissimus dorsi (LD) and anterolateral thigh (ALT) flap is a challenging problem. Often, in such a situation, a combination of flaps is required. Over the last 3 years, we have managed nine such defects successfully with a free "Boomerang-shaped" Extended Rectus Abdominis Myocutaneous (BERAM) flap. This flap is the slightly modified and "free" version of a similar flap described by Ian Taylor in 1983. This is a retrospective study of patients who underwent free BERAM flap reconstruction of soft tissue defects of extremity over the last 3 years. We also did a clinical study on 30 volunteers to compare the length of flap available using our design of BERAM flap with the maximum available flap length of LD and ALT flaps, using standard markings. Our clinical experience of nine cases combined with the results of our clinical study has confirmed that our design of BERAM flap consistently provides a flap length which is 32.6% longer than the standard LD flap and 42.2% longer than the standard ALT flap in adults. The difference is even more marked in children. The BERAM flap is consistently reliable as long as the distal end is not extended beyond the mid-axillary line. BERAM flap is simple in design, easy to harvest, reliable and provides the longest possible free skin/myocutaneous flap in the body. It is a useful new alternative for covering long soft tissue defects in the limbs.


Intestinal metaplasia surveillance: searching for the road-map.
Atrophic gastritis and intestinal metaplasia (IM) of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, a pragmatic management has been performed in Western countries in patients with these premalignant conditions. Recently, formal European guidelines have been delivered on this topic. Basically, it has been recommended that patients with extensive atrophic gastritis (AG) and/or extensive IM should be offered endoscopic surveillance every 3 years. On the contrary, no scheduled endoscopic/histological control has been advised for those patients with precancerous conditions confined to the antrum. In this commentary, we highlighted some potential weaknesses in the management formally recommended by the new guidelines. In detail, we discussed that AG and IM patients do not share the same gastric cancer risk, at least in Western countries, deserving a different approach. Some factors significantly associated with gastric cancer risk, such as IM type, first-degree family history of gastric cancer, and smoking habit have not been considered in tailoring the endoscopic follow-up. Finally, some data would suggest that a 3-year follow-up in patients with extensive gastric precancerous conditions could result in an inadequate secondary prevention.


Meckel's Diverticulum Causing Small Bowel Intussusception in Third Trimester Pregnancy, a Case Report.
Intestinal obstruction complicating pregnancy is a surgical emergency associated with a high incidence of morbidity and mortality for both the mother and fetus. This case report discusses the presentation and treatment of a young female in her third trimester of pregnancy at a repeat visit to the emergency department (ED) with right-sided abdominal pain. She was diagnosed with ileal intussusception secondary to a Meckel's diverticulum with associated small bowel obstruction (SBO) seen on computerized tomography (CT) imaging. She underwent surgical reduction of the invaginated bowel and diverticulectomy. Making a diagnosis of intestinal intussusception during pregnancy is particularly difficult because common symptoms of intestinal obstruction such as anorexia, nausea, vomiting and abdominal pain are encountered frequently during a normal pregnancy.1 Diagnosis is often delayed during pregnancy due to physician hesitancy over the radiation risk to the fetus. While the gold standard for diagnosis is a barium enema, it is often identified on CT scan in adults, and it is regularly managed with surgery.2. Intussusception, small bowel obstruction, pregnancy, Meckel's diverticulum.


Impaired transit and tolerance of intestinal gas in the irritable bowel syndrome.
Patients with irritable bowel syndrome (IBS) frequently complain of excessive gas but their fasting volume of intestinal gas is apparently normal. We hypothesised that the pathophysiological mechanism involved may be impairment of intestinal gas transit. To investigate intestinal gas transit and tolerance in IBS patients compared with healthy subjects. A gas mixture (N(2), O(2), and CO(2) in venous proportions) was infused into the jejunum of 20 patients with IBS and 20 healthy controls at 12 ml/min for four hours. Gas evacuation, initially flatus from the anus (two hours) and then intrarectally (two hours), was continuously recorded. Symptom perception (0-6 scale) and abdominal distension were measured at 10 minute intervals. After two hours of external gas (flatus) collection, 18 of 20 IBS patients had developed gas retention (>400 ml), increased gastrointestinal symptoms (score >3), or abdominal distension (>3 mm girth increment) compared with only four of 20 control subjects. During intrarectal gas collection, 13 of 17 patients still exhibited abnormal responses. A large proportion of patients with IBS can be shown to have impaired transit and tolerance of intestinal gas loads. This anomaly may represent a possible mechanism of IBS symptoms, specifically pain and bloating.


More support for mothers: a qualitative study on factors affecting immunisation behaviour in Kampala, Uganda.
The proportion of Ugandan children who are fully vaccinated has varied over the years. Understanding vaccination behaviour is important for the success of the immunisation programme. This study examined influences on immunisation behaviour using the attitude-social influence-self efficacy model. We conducted nine focus group discussions (FGDs) with mothers and fathers. Eight key informant interviews (KIIs) were held with those in charge of community mobilisation for immunisation, fathers and mothers. Data was analysed using content analysis. Influences on the mother's immunisation behaviour ranged from the non-supportive role of male partners sometimes resulting into intimate partner violence, lack of presentable clothing which made mothers vulnerable to bullying, inconvenient schedules and time constraints, to suspicion against immunisation such as vaccines cause physical disability and/or death. Immunisation programmes should position themselves to address social contexts. A community programme that empowers women economically and helps men recognise the role of women in decision making for child health is needed. Increasing male involvement and knowledge of immunisation concepts among caretakers could improve immunisation.


Oxidative stress is fundamental to hyperbaric oxygen therapy.
The goal of this review is to outline advances addressing the role that reactive species of oxygen and nitrogen play in therapeutic mechanisms of hyperbaric oxygen. The review will be organized around major categories of problems or processes where controlled clinical trials have demonstrated clinical efficacy for hyperbaric oxygen therapy. Reactive species are now recognized to play a major role in cell signal transduction cascades, and the discussion will focus on how hyperbaric oxygen acts through these pathways to mediate wound healing and ameliorate postischemic and inflammatory injuries.


15,16-Dihydrotanshinone I, a Compound of Salvia miltiorrhiza Bunge, Induces Apoptosis through Inducing Endoplasmic Reticular Stress in Human Prostate Carcinoma Cells.
5,16-dihydrotanshinone I (DHTS) is extracted from Salvia miltiorrhiza Bunge (tanshen root) and was found to be the most effective compound of tanshen extracts against breast cancer cells in our previous studies. However, whether DHTS can induce apoptosis through an endoplasmic reticular (ER) stress pathway was examined herein. In this study, we found that DHTS significantly inhibited the proliferation of human prostate DU145 carcinoma cells and induced apoptosis. DHTS was able to induce ER stress as evidenced by the upregulation of glucose regulation protein 78 (GRP78/Bip) and CAAT/enhancer binding protein homologous protein/growth arrest- and DNA damage-inducible gene 153 (CHOP/GADD153), as well as increases in phosphorylated eukaryotic initiation factor 2α (eIF2α), c-jun N-terminal kinase (JNK), and X-box-binding protein 1 (XBP1) mRNA splicing forms. DHTS treatment also caused significant accumulation of polyubiquitinated proteins and hypoxia-inducible factor (HIF)-1α, indicating that DHTS might be a proteasome inhibitor that is known to induce ER stress or enhance apoptosis caused by the classic ER stress-dependent mechanism. Moreover, DHTS-induced apoptosis was reversed by salubrinal, an ER stress inhibitor. Results suggest that DHTS can induce apoptosis of prostate carcinoma cells via induction of ER stress and/or inhibition of proteasome activity, and may have therapeutic potential for prostate cancer patients.


An Overview on Citrus aurantium L.: Its Functions as Food Ingredient and Therapeutic Agent.
Citrus aurantium L. (Rutaceae), commonly known as bitter orange, possesses multiple therapeutic potentials. These biological credentials include anticancer, antianxiety, antiobesity, antibacterial, antioxidant, pesticidal, and antidiabetic activities. The essential oil of C. aurantium was reported to display marked pharmacological effects and great variation in chemical composition depending on growing locations but mostly contained limonene, linalool, and β-myrcene. Phytochemically, C. aurantium is rich in p-synephrine, an alkaloid, and many health-giving secondary metabolites such as flavonoids. Animal studies have demonstrated a low affinity of p-synephrine for adrenergic receptors and an even lower affinity in human models. The present review focuses on the different biological activities of the C. aurantium in animal and human models in the form of extract and its pure secondary metabolites. Finally, it is concluded that both the extract and isolated compounds have no unwanted effects in human at therapeutic doses and, therefore, can confidently be used in various dietary formulations.


Postnatal overfeeding causes early shifts in gene expression in the heart and long-term alterations in cardiometabolic and oxidative parameters.
Postnatal overfeeding (OF) in rodents induces a permanent moderate increase in body weight in adulthood. However, the repercussions of postnatal OF on cardiac gene expression, cardiac metabolism and nitro-oxidative stress are less well known. Immediately after birth, litters of C57BL/6 mice were either maintained at 10 (normal-fed group, NF), or reduced to 3 in order to induce OF. At weaning, mice of both groups received a standard diet. The cardiac gene expression profile was determined at weaning and cardiac metabolism and oxidative stress were assessed at 7 months. The cardiac expression of several genes, including members of the extracellular matrix and apelin pathway, was modified in juvenile OF mice. In adult mice, OF led to an increase in body weight (+30%) and to significant increases in plasma cholesterol, insulin and leptin levels. Myocardial oxidative stress, SOD and catalase activity and mRNA expression were increased in OF mice. In vivo, diastolic and systolic blood pressures were significantly higher and LV shortening and ejection fraction were decreased in OF mice. Ex vivo, after 30 min of ischemia, hearts isolated from OF mice showed lower functional recovery and larger infarct size (31% vs. 54%, p<0.05). Increases in collagen deposition and expression/activity of matrix-metalloproteinase-2 were observed in adult OF mouse hearts. Moreover, an increase in the expression of SOCS-3 and a decrease in STAT-3 phosphorylation were observed in ventricular tissues from OF mice. Our study emphasizes that over-nutrition during the immediate postnatal period in mice leads to early changes in cardiac gene expression, which may permanently modify the heart's structural organization and metabolism and could contribute to a greater susceptibility to myocardial ischemia-reperfusion injury.


Milankovitch hypothesis supported by precise dating of coral reefs and deep-sea sediments.
Barbados provides a possibly unique opportunity for reconstruction of the times and elevations of late-Pleistocene high stands of the sea. The island appears to be rising from the sea at a uniform rate that is fast enough to separate in elevation coral-reef tracts formed at successive high stands of the sea. Unaltered coral found in the lower terraces enables high-precision Th(230): U(234) and Pa(231): U(235) dating. Three distinct high stands of the sea are found about 122,000, 103,000, and 82,000 years ago. New Pa(231) and Th(230) dates from a deep-sea core also indicate that Ericson's W-X cold-to-warm climatic change occurred close to 126,000 years ago. These data show a parallelism over the last 150,000 years between changes in Earth's climate and changes in the summer insolation predicted from cycles in the tilt and precession of Earth's axis.


Identification of the ADP-glucose pyrophosphorylase isoforms essential for starch synthesis in the leaf and seed endosperm of rice (Oryza sativa L.).
ADP-glucose pyrophosphorylase (AGP) catalyzes the first committed step of starch biosynthesis in higher plants. To identify AGP isoforms essential for this biosynthetic process in sink and source tissues of rice plants, we analyzed the rice AGP gene family which consists of two genes, OsAGPS1 and OsAGPS2, encoding small subunits (SSU) and four genes, OsAGPL1, OsAGPL2, OsAGPL3 and OsAGPL4, encoding large subunits (LSU) of this enzyme heterotetrameric complex. Subcellular localization studies using green fluorescent protein (GFP) fusion constructs indicate that OsAGPS2a, the product of the leaf-preferential transcript of OsAGPS2, and OsAGPS1, OsAGPL1, OsAGPL3, and OsAGPL4 are plastid-targeted isoforms. In contrast, two isoforms, SSU OsAGPS2b which is a product of a seed-specific transcript of OsAGPS2, and LSU OsAGPL2, are localized in the cytosol. Analysis of osagps2 and osagpl2 mutants revealed that a lesion of one of the two cytosolic isoforms, OsAGPL2 and OsAGPS2b, causes a shrunken endosperm due to a remarkable reduction in starch synthesis. In leaves, however, only the osagps2 mutant appears to severely reduce the transitory starch content. Interestingly, the osagps2 mutant was indistinguishable from wild type during vegetative plant growth. Western blot analysis of the osagp mutants and wild type plants demonstrated that OsAGPS2a is an SSU isoform mainly present in leaves, and that OsAGPS2b and OsAGPL2 are the major SSU and LSU isoforms, respectively, in the endosperm. Finally, we propose a spatiotemporal complex model of OsAGP SSU and LSU isoforms in leaves and in developing endosperm of rice plants.


Acute Activation of Metabolic Syndrome Components in Pediatric Acute Lymphoblastic Leukemia Patients Treated with Dexamethasone.
Although dexamethasone is highly effective in the treatment of pediatric acute lymphoblastic leukemia (ALL), it can cause serious metabolic side effects. Because studies regarding the effects of dexamethasone are limited by their small scale, we prospectively studied the direct effects of treating pediatric ALL with dexamethasone administration with respect to activation of components of metabolic syndrome (MetS); in addition, we investigated whether these side effects were correlated with the level of dexamethasone. Fifty pediatric patients (3-16 years of age) with ALL were studied during a 5-day dexamethasone course during the maintenance phase of the Dutch Childhood Oncology Group ALL-10 and ALL-11 protocols. Fasting insulin, glucose, total cholesterol, HDL, LDL, and triglycerides levels were measured at baseline (before the start of dexamethasone; T1) and on the fifth day of treatment (T2). Dexamethasone trough levels were measured at T2. We found that dexamethasone treatment significantly increased the following fasting serum levels (P<0.05): HDL, LDL, total cholesterol, triglycerides, glucose, and insulin. In addition, dexamethasone increased insulin resistance (HOMA-IR>3.4) from 8% to 85% (P<0.01). Dexamethasone treatment also significantly increased the diastolic and systolic blood pressure. Lastly, dexamethasone trough levels (N = 24) were directly correlated with high glucose levels at T2, but not with other parameters. These results indicate that dexamethasone treatment acutely induces three components of the MetS. Together with the weight gain typically associated with dexamethasone treatment, these factors may contribute to the higher prevalence of MetS and cardiovascular risk among survivors of childhood leukemia who received dexamethasone treatment.


Characterisation of the conformational changes in platelet factor 4 induced by polyanions: towards in vitro prediction of antigenicity.
Heparin-induced thrombocytopenia (HIT) is the most frequent drug-induced immune reaction affecting blood cells. Its antigen is formed when the chemokine platelet factor 4 (PF4) complexes with polyanions. By assessing polyanions of varying length and degree of sulfation using immunoassay and circular dichroism (CD)-spectroscopy, we show that PF4 structural changes resulting in antiparallel β-sheet content >30% make PF4/polyanion complexes antigenic. Further, we found that polyphosphates (polyP-55) induce antigenic changes on PF4, whereas fondaparinux does not. We provide a model suggesting that conformational changes exposing antigens on PF4/polyanion complexes occur in the hairpin involving AA 32-38, which form together with C-terminal AA (66-70) of the adjacent PF4 monomer a continuous patch on the PF4 tetramer surface, explaining why only tetrameric PF4 molecules express "HIT antigens". The correlation of antibody binding in immunoassays with PF4 structural changes provides the intriguing possibility that CD-spectroscopy could become the first antibody-independent, in vitro method to predict potential immunogenicity of drugs. CD-spectroscopy could identify compounds during preclinical drug development that induce PF4 structural changes correlated with antigenicity. The clinical relevance can then be specifically addressed during clinical trials. Whether these findings can be transferred to other endogenous proteins requires further studies.


Using Boolean Logic Modeling of Gene Regulatory Networks to Exploit the Links Between Cancer and Metabolism for Therapeutic Purposes.
The uncontrolled cell proliferation that is characteristically associated with cancer is usually accompanied by alterations in the genome and cell metabolism. Indeed, the phenomenon of cancer cells metabolizing glucose using a less efficient anaerobic process even in the presence of normal oxygen levels, termed the Warburg effect, is currently considered to be one of the hallmarks of cancer. Diabetes, much like cancer, is defined by significant metabolic changes. Recent epidemiological studies have shown that diabetes patients treated with the antidiabetic drug Metformin have significantly lowered risk of cancer as compared to patients treated with other antidiabetic drugs. We utilize a Boolean logic model of the pathways commonly mutated in cancer to not only investigate the efficacy of Metformin for cancer therapeutic purposes but also demonstrate how Metformin in concert with other cancer drugs could provide better and less toxic clinical outcomes as compared to using cancer drugs alone.


The prevalence, severity, and distribution of childhood food allergy in the United States.
The goal of this study was to better estimate the prevalence and severity of childhood food allergy in the United States. A randomized, cross-sectional survey was administered electronically to a representative sample of US households with children from June 2009 to February 2010. Eligible participants included adults (aged 18 years or older) able to complete the survey in Spanish or English who resided in a household with at least 1 child younger than 18 years. Data were adjusted using both base and poststratification weights to account for potential biases from sampling design and nonresponse. Data were analyzed as weighted proportions to estimate prevalence and severity of food allergy. Multiple logistic regression models were constructed to identify characteristics significantly associated with outcomes. Data were collected for 40 104 children; incomplete responses for 1624 children were excluded, which yielded a final sample of 38 480. Food allergy prevalence was 8.0% (95% confidence interval [CI]: 7.6-8.3). Among children with food allergy, 38.7% had a history of severe reactions, and 30.4% had multiple food allergies. Prevalence according to allergen among food-allergic children was highest for peanut (25.2% [95% CI: 23.3-27.1]), followed by milk (21.1% [95% CI: 19.4-22.8]) and shellfish (17.2% [95% CI: 15.6-18.9]). Odds of food allergy were significantly associated with race, age, income, and geographic region. Disparities in food allergy diagnosis according to race and income were observed. Findings suggest that the prevalence and severity of childhood food allergy is greater than previously reported. Data suggest that disparities exist in the clinical diagnosis of disease.


Effect of acetate on molecular and physiological aspects of Clostridium beijerinckii NCIMB 8052 solvent production and strain degeneration.
The addition of sodium acetate to chemically defined MP2 medium was found to increase and stabilize solvent production and also increase glucose utilization by Clostridium beijerinckii NCIMB 8052. RNA and enzyme analyses indicated that coenzyme A (CoA) transferase was highly expressed and has higher activity in C. beijerinckii NCIMB 8052 grown in MP2 medium containing added sodium acetate than in the microorganism grown without sodium acetate. RNA analysis suggested the existence of a sol operon and confirmed the presence of a ptb-buk operon in C. beijerinckii NCIMB 8052. In addition to CoA transferase, C. beijerinckii NCIMB 8052 grown in MP2 medium containing added acetate demonstrated higher acetate kinase- and butyrate kinase-specific activity than when the culture was grown in MP2 medium containing no added acetate. Southern blot analysis with chromosomal DNA isolated from solventogenic and degenerated C. beijerinckii NCIMB 8052 indicated that C. beijerinckii NCIMB 8052 strain degeneration does not involve loss of the CoA transferase genes. The addition of acetate to MP2 medium may induce the expression of the sol operon, which ensures solvent production and prevents strain degeneration in C. beijerinckii NCIMB 8052.


Unlocking the forest inventory data: relating individual tree performance to unmeasured environmental factors.
Geographically extensive forest inventories, such as the USDA Forest Service's Forest Inventory and Analysis (FIA) program, contain millions of individual tree growth and mortality records that could be used to develop broad-scale models of forest dynamics. A limitation of inventory data, however, is that individual-level measurements of light (L) and other environmental factors are typically absent. Thus, inventory data alone cannot be used to parameterize mechanistic models of forest dynamics in which individual performance depends on light, water, nutrients, etc. To overcome this limitation, we developed methods to estimate species-specific parameters (thetaG) relating sapling growth (G) to L using data sets in which G, but not L, is observed for each sapling. Our approach involves: (1) using calibration data that we collected in both eastern and western North America to quantify the probability that saplings receive different amounts of light, conditional on covariates x that can be obtained from inventory data (e.g., sapling crown class and neighborhood crowding); and (2) combining these probability distributions with observed G and x to estimate thetaG using Bayesian computational methods. Here, we present a test case using a data set in which G, L, and x were observed for saplings of nine species. This test data set allowed us to compare estimates of thetaG obtained from the standard approach (where G and L are observed for each sapling) to our method (where G and x, but not L, are observed). For all species, estimates of thetaG obtained from analyses with and without observed L were similar. This suggests that our approach should be useful for estimating light-dependent growth functions from inventory data that lack direct measurements of L. Our approach could be extended to estimate parameters relating sapling mortality to L from inventory data, as well as to deal with uncertainty in other resources (e.g., water or nutrients) or environmental factors (e.g., temperature).


Remapping of border ownership in the visual cortex.
We see objects as having continuity although the retinal image changes frequently. How such continuity is achieved is hard to understand, because neurons in the visual cortex have small receptive fields that are fixed on the retina, which means that a different set of neurons is activated every time the eyes move. Neurons in areas V1 and V2 of the visual cortex signal the local features that are currently in their receptive fields and do not show "remapping" when the image moves. However, subsets of neurons in these areas also carry information about global aspects, such as figure-ground organization. Here we performed experiments to find out whether figure-ground organization is remapped. We recorded single neurons in macaque V1 and V2 in which figure-ground organization is represented by assignment of contours to regions (border ownership). We found previously that border-ownership signals persist when a figure edge is switched to an ambiguous edge by removing the context. We now used this paradigm to see whether border ownership transfers when the ambiguous edge is moved across the retina. In the new position, the edge activated a different set of neurons at a different location in cortex. We found that border ownership was transferred to the newly activated neurons. The transfer occurred whether the edge was moved by a saccade or by moving the visual display. Thus, although the contours are coded in retinal coordinates, their assignment to objects is maintained across movements of the retinal image.


Accumulation of point mutations and reassortment of genomic RNA segments are involved in the microevolution of Puumala hantavirus in a bank vole (Myodes glareolus) population.
The genetic diversity of Puumala hantavirus (PUUV) was studied in a local population of its natural host, the bank vole (Myodes glareolus). The trapping area (2.5 x 2.5 km) at Konnevesi, Central Finland, included 14 trapping sites, at least 500 m apart; altogether, 147 voles were captured during May and October 2005. Partial sequences of the S, M and L viral genome segments were recovered from 40 animals. Seven, 12 and 17 variants were detected for the S, M and L sequences, respectively; these represent new wild-type PUUV strains that belong to the Finnish genetic lineage. The genetic diversity of PUUV strains from Konnevesi was 0.2-4.9 % for the S segment, 0.2-4.8 % for the M segment and 0.2-9.7 % for the L segment. Most nucleotide substitutions were synonymous and most deduced amino acid substitutions were conservative, probably due to strong stabilizing selection operating at the protein level. Based on both sequence markers and phylogenetic clustering, the S, M and L sequences could be assigned to two groups, 'A' and 'B'. Notably, not all bank voles carried S, M and L sequences belonging to the same group, i.e. S(A)M(A)L(A) or S(B)M(B)L(B). A substantial proportion (8/40, 20 %) of the newly characterized PUUV strains possessed reassortant genomes such as S(B)M(A)L(A), S(A)M(B)L(B) or S(B)M(A)L(B). These results suggest that at least some of the PUUV reassortants are viable and can survive in the presence of their parental strains.


Practical Treatments Considering the Role of Sociocultural Factors on Problem Gambling.
Reviews of problem gambling (PG) literature increasingly recognize the ways in which different ethnic groups are affected by gambling behaviors, yet discourse, which considers sociocultural factors within PG, remains limited. Literature on this topic is influenced by large inconsistencies amongst research studies, overlapping terminology, and variability in the validity of research studies, making conclusions difficult to draw. Despite these discrepancies, this paper explores how sociocultural factors influence PG among diverse cultural groups and provides specific practical implications for treating PG disorders in culturally diverse populations. Notable factors that exacerbate PG behavior cross-culturally include substance abuse, low socioeconomic status, lack of social activities, and geographic location. Culturally sensitive treatment options such as Motivational Interviewing and Cognitive Behavioral Therapy have been identified as effective treatments for PG with culturally diverse populations. This paper extends current thought by providing practical treatment recommendations that consider the subtle nuances of diverse populations. It explains how treatment providers and behavioral addiction professionals can increase their understanding and skills when conceptualizing PG clients from a diverse background.


Communicating with biobank participants: preferences for receiving and providing updates to researchers.
Research biobanks collect biologic samples and health information. Previous work shows that biobank participants desire general study updates, but preferences about the method or frequency of these communications have not been explored. Thus, we surveyed participants in a long-standing research biobank. Eligible participants were drawn from a study of patients with personal/family history suggestive of Cowden syndrome, a poorly recognized inherited cancer syndrome. Participants gave blood samples and access to medical records and received individual results but had no other study interactions. The biobank had 3,618 participants at sampling. Survey eligibility included age ≥18 years, enrollment within the biobank's first 5 years, normal PTEN analysis, and contiguous U.S. address. Multivariate logistic regression analyses identified predictors of participant interest in Internet-based versus offline methods and methods allowing participant-researcher interaction versus one-way communication. Independent variables were narrowed by independent Pearson correlations by cutoff P < 0.2, with P < 0.02 considered significant. Surveys were returned from 840 of 1,267 (66%) eligible subjects. Most (97%) wanted study updates, with 92% wanting updates at least once a year. Participants preferred paper (66%) or emailed (62%) newsletter methods, with 95% selecting one of these. Older, less-educated, and lower-income respondents strongly preferred offline approaches (P < 0.001). Most (93%) had no concerns about receiving updates and 97% were willing to provide health updates to researchers. Most participants were comfortable receiving and providing updated information. Demographic factors predicted communication preferences. Researchers should make plans for ongoing communication early in study development and funders should support the necessary infrastructure for these efforts.


A quadruple blind, randomised controlled trial of gargling agents in reducing intraoral viral load among hospitalised COVID-19 patients: A structured summary of a study protocol for a randomised controlled trial.
1- To compare the effectiveness of 1% Hydrogen peroxide, 0.2% Povidone-Iodine, 2% hypertonic saline and a novel solution Neem extract (Azardirachta indica) in reducing intra-oral viral load in COVID-19 positive patients. 2- To determine the salivary cytokine profiles of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ and IL- 17 among COVID-19 patients subjected to 1% Hydrogen peroxide, 0.2% Povidone-Iodine, 2% hypertonic saline or Neem extract (Azardirachta indica) based gargles. This will be a parallel group, quadruple blind-randomised controlled pilot trial with an add on laboratory based study. A non-probability, purposive sampling technique will be followed to identify participants for this study. The clinical trial will be carried out at the Aga Khan University Hospital (AKUH), Karachi, Pakistan. The viral PCR tests will be done at main AKUH clinical laboratories whereas the immunological tests (cytokine analysis) will be done at the Juma research laboratory of AKUH. The inclusion criteria are laboratory-confirmed COVID-19 positive patients, male or female, in the age range of 18-65 years, with mild to moderate disease, already admitted to the AKUH. Subjects with low Glasgow coma score, with a history of radiotherapy or chemotherapy, who are more than 7 days past the onset of COVID- 19 symptoms, or intubated or edentulous patients will be excluded. Patients who are being treated with any form of oral or parenteral antiviral therapy will be excluded, as well as patients with known pre-existing chronic mucosal lesions such as lichen planus. Group A (n=10) patients on 10 ml gargle and nasal lavage using 0.2% Povidone-Iodine (Betadiene® by Aviro Health Inc./ Pyodine® by Brooks Pharma Inc.) for 20-30 seconds, thrice daily for 6 days. Group B (n=10) patients will be subjected to 10 ml gargle and nasal lavage using 1% Hydrogen peroxide (HP® by Karachi Chemicals Products Inc./ ActiveOxy® by Boumatic Inc.) for 20-30 seconds, thrice daily for 6 days. Group C will comprised of (n=10) subjects on 10ml gargle and nasal lavage using Neem extract solution (Azardirachta indica) formulated by Karachi University (chemistry department laboratories) for 20-30 seconds, thrice daily for 6 days. Group D (n=10) patients will use 2% hypertonic saline (Plabottle® by Otsuka Inc.) gargle and nasal lavage for a similar time period. Group E (n=10) will serve as positive controls. These will be given simple distilled water gargles and nasal lavage for 20-30 seconds, thrice daily for six days. For nasal lavage, a special douche syringe will be provided to each participant. Its use will be thoroughly explained by the data collection officer. After each use, the patient is asked not to eat, drink, or rinse their mouth for the next 30 minutes. The primary outcome is the reduction in the intra-oral viral load confirmed with real time quantitative PCR. The assignment to the study group/ allocation will be done using the sealed envelope method under the supervision of Clinical Trial Unit (CTU) of Aga Khan University, Karachi, Pakistan. The patients will be randomised to their respective study group (1:1:1:1:1 allocation ratio) immediately after the eligibility assessment and consent administration is done. The study will be quadruple-blinded. Patients, intervention provider, outcome assessor and the data collection officer will be blinded. The groups will be labelled as A, B, C, D or E. The codes of the intervention will be kept in lock & key at the CTU and will only be revealed at the end of study or if the study is terminated prematurely. As there is no prior work on this research question, so no assumptions for the sample size calculation could be made. The present study will serve as a pilot trial. We intend to study 50 patients in five study groups with 10 patients in each study group. For details, please refer to Fig. 1 for details. Protocol version is 7.0, approved by the department and institutional ethics committees and clinical trial unit of the university hospital. Recruitment is planned to start as soon as the funding is sanctioned. The total duration of the study is expected to be 6 months i.e. August 2020-January 2021. This study protocol was registered at www.clinicaltrials.gov on 10 April 2020 NCT04341688 . The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2). Fig. 1 Flow diagram of study-participants' timeline.


Rabies and rabies-related viruses: a modern perspective on an ancient disease.
Rabies is a worldwide zoonosis caused by a lyssavirus, with many host species acting as reservoirs for infection. The epidemiology of rabies has changed over recent years, as this disease has been brought under control or eliminated in many terrestrial animal species in Europe and North America. A large number of Lyssavirus variants have now been characterised, and their distribution and animal hosts have become known. However, new lyssaviruses have been isolated from bats, prompting scientists to question the efficacy of the existing human and veterinary vaccines against these new strains. The epidemiology of bat rabies should be fully explored, so that the precise risks to the health of humans and domestic and wild carnivores may be determined and methods of preventing the disease among people who handle bats can be discovered. Rabies is still a significant public health problem, particularly in areas where canine rabies is still endemic, such as countries in Africa and Asia.


Leucine-rich repeat containing 8A contributes to the expansion of brain ventricles in zebrafish embryos.
The sodium osmotic gradient is necessary for the initiation of brain ventricle inflation, but a previous study predicted that organic and inorganic osmolytes play equivalently important roles in osmotic homeostasis in astrocytes. To test whether organic osmoregulation also plays a role in brain ventricle inflation, the core component for volume-regulated anion and organic osmolyte channel, lrrc8a, was investigated in the zebrafish model. RT-PCR and whole-mount in situ hybridization indicated that both genes were ubiquitously expressed through to 12 hpf, and around the ventricular layer of neural tubes and the cardiogenic region at 24 hpf. Knocking down either one lrrc8a paralog with morpholino oligos resulted in abnormalities in circulation at 32 hpf. Morpholino oligos or CRISPR interference against either paralog led to smaller brain ventricles at 24 hpf. Either lrrc8aa or lrrc8ab mRNA rescued the phenotypic penetrance in both lrrc8aa and lrrc8ab morphants. Supplementation of taurine in the E3 medium and overexpression csad mRNA also rescued lrrc8aa and lrrc8ab morphants. Our results indicate that the two zebrafish lrrc8a paralogs are maternal message genes and are ubiquitously expressed in early embryos. The two genes play redundant roles in the expansion of brain ventricles and the circulatory system and taurine contributes to brain ventricle expansion via the volume-regulated anion and organic osmolyte channels.


Screening of transporters to improve xylodextrin utilization in the yeast Saccharomyces cerevisiae.
The economic production of cellulosic biofuel requires efficient and full utilization of all abundant carbohydrates naturally released from plant biomass by enzyme cocktails. Recently, we reconstituted the Neurospora crassa xylodextrin transport and consumption system in Saccharomyces cerevisiae, enabling growth of yeast on xylodextrins aerobically. However, the consumption rate of xylodextrin requires improvement for industrial applications, including consumption in anaerobic conditions. As a first step in this improvement, we report analysis of orthologues of the N. crassa transporters CDT-1 and CDT-2. Transporter ST16 from Trichoderma virens enables faster aerobic growth of S. cerevisiae on xylodextrins compared to CDT-2. ST16 is a xylodextrin-specific transporter, and the xylobiose transport activity of ST16 is not inhibited by cellobiose. Other transporters identified in the screen also enable growth on xylodextrins including xylotriose. Taken together, these results indicate that multiple transporters might prove useful to improve xylodextrin utilization in S. cerevisiae. Efforts to use directed evolution to improve ST16 from a chromosomally-integrated copy were not successful, due to background growth of yeast on other carbon sources present in the selection medium. Future experiments will require increasing the baseline growth rate of the yeast population on xylodextrins, to ensure that the selective pressure exerted on xylodextrin transport can lead to isolation of improved xylodextrin transporters.


[Biological role of a neurotrophic factor fragment from pigment epithelium: structure-functional homology with a differentiation factor for the HL-60 cell line].
It was shown that the full-size neurotrophic factor from pigment epithelium (PEDF) induces the cell differentiation of the human promyelocyte leukemia cell line HL-60. A structural analysis of PEDF revealed in its C-terminal region a six-membered peptide fragment PEDF-(352-357) (PEDF-6) whose sequence is highly homologous to the 41-46 fragment of the active site of the human leukocyte differentiation factor HLDF (HLDF-6). The biological effect of PEDF and synthetic peptides PEDF-6 and HLDF-6 on the HL-60 cells and the early gastrula ectoderm of Xenopus laevis embryos was studied. On the basis of the structural and functional homologies of HLDF, PEDF, and their homologous peptides and the computer models of the spatial structures of the full-size PEDF and the PEDF with the C-terminal fragment split off tby the cleavage of the Leu380-Thr381 bond in the serpin loop, a hypothesis on the functional role of the serpin loop in PEDF was put forward.


PconsFold: improved contact predictions improve protein models.
Recently it has been shown that the quality of protein contact prediction from evolutionary information can be improved significantly if direct and indirect information is separated. Given sufficiently large protein families, the contact predictions contain sufficient information to predict the structure of many protein families. However, since the first studies contact prediction methods have improved. Here, we ask how much the final models are improved if improved contact predictions are used. In a small benchmark of 15 proteins, we show that the TM-scores of top-ranked models are improved by on average 33% using PconsFold compared with the original version of EVfold. In a larger benchmark, we find that the quality is improved with 15-30% when using PconsC in comparison with earlier contact prediction methods. Further, using Rosetta instead of CNS does not significantly improve global model accuracy, but the chemistry of models generated with Rosetta is improved. PconsFold is a fully automated pipeline for ab initio protein structure prediction based on evolutionary information. PconsFold is based on PconsC contact prediction and uses the Rosetta folding protocol. Due to its modularity, the contact prediction tool can be easily exchanged. The source code of PconsFold is available on GitHub at https://www.github.com/ElofssonLab/pcons-fold under the MIT license. PconsC is available from http://c.pcons.net/. Supplementary data are available at Bioinformatics online.


Early recruitment of neutrophils determines subsequent T1/T2 host responses in a murine model of Legionella pneumophila pneumonia.
The contribution of neutrophils to lethal sensitivity and cytokine balance governing T1 and T2 host responses was assessed in a murine model of Legionella pneumophila pneumonia. Neutrophil depletion by administration of granulocyte-specific mAb RB6-8C5 at 1 day before infection rendered mice approximately 100-fold more susceptible to lethal pneumonia induced by L. pneumophila. However, this treatment did not alter early bacterial clearance, despite a substantial decrease in neutrophil influx at this time point. Cytokine profiles in the lungs of control mice demonstrated strong T1 responses, characterized by an increase of IFN-gamma and IL-12. In contrast, neutrophil-depleted mice exhibited significantly lower levels of IFN-gamma and IL-12, and elevation of T2 cytokines, IL-4 and IL-10. Immunohistochemistry of bronchoalveolar lavage cells demonstrated the presence of IL-12 in neutrophils, but not alveolar macrophages. Moreover, IL-12 was detected in lavage cell lysates by ELISA, which was paralleled to neutrophil number. However, intratracheal administration of recombinant murine IL-12 did not restore resistance, whereas reconstitution of IFN-gamma drastically improved bacterial clearance and survival in neutrophil-depleted mice. Taken together, these data demonstrated that neutrophils play crucial roles in primary L. pneumophila infection, not via direct killing but more immunomodulatory effects. Our results suggest that the early recruitment of neutrophils may contribute to T1 polarization in a murine model of L. pneumophila pneumonia.


Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.
Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.


Preparation and Observation of Thick Biological Samples by Scanning Transmission Electron Tomography.
This report describes a protocol for preparing thick biological specimens for further observation using a scanning transmission electron microscope. It also describes an imaging method for studying the 3D structure of thick biological specimens by scanning transmission electron tomography. The sample preparation protocol is based on conventional methods in which the sample is fixed using chemical agents, treated with a heavy atom salt contrasting agent, dehydrated in a series of ethanol baths, and embedded in resin. The specific imaging conditions for observing thick samples by scanning transmission electron microscopy are then described. Sections of the sample are observed using a through-focus method involving the collection of several images at various focal planes. This enables the recovery of in-focus information at various heights throughout the sample. This particular collection pattern is performed at each tilt angle during tomography data collection. A single image is then generated, merging the in-focus information from all the different focal planes. A classic tilt-series dataset is then generated. The advantage of the method is that the tilt-series alignment and reconstruction can be performed using standard tools. The collection of through-focal images allows the reconstruction of a 3D volume that contains all of the structural details of the sample in focus.


Feasibility of salivary DNA collection in a population-based case-control study: a pilot study of pediatric Crohn's disease.
Epidemiologic studies combining exposure and outcome data with the collection of biosamples are needed to study gene-environment interactions that might contribute to the etiology of complex diseases such as pediatric Crohn's disease (CD). Nationwide registries, including those in Denmark and other Scandinavian countries, provide efficient and reliable sources of data for epidemiological studies evaluating the environmental determinants of disease. We performed a pilot study to test the feasibility of collecting salivary DNA to augment registry data in established cases of pediatric CD and randomly selected, population-based controls. Cases of CD born after 1995 and residing in the central region of Denmark were identified through the Danish National Patient Registry and confirmed by using standard diagnostic criteria. Age- and gender-matched controls were selected at random through the civil registration system. Cases and controls were contacted by mail and telephone and invited to submit a saliva sample. DNA was extracted and genotyped for six CD-associated single-nucleotide polymorphisms (SNPs). A total of 53 cases of pediatric CD were invited, and 40 contributed a saliva sample (75% response rate). A total of 126 controls were invited, and 54 contributed a saliva sample (44% response rate). As expected, demographic characteristics did not differ between cases and controls. DNA was successfully isolated from 93 of 94 samples. Genotyping was performed with only 2% undetermined genotypes. For five of six SNPs known to be associated with CD, risk allele frequencies were higher in cases than controls. This pilot study strongly supports the feasibility of augmenting traditional epidemiological data from Danish population-based registries with the de novo collection of genetic information from population-based cases and controls. This will facilitate rigorous studies of gene-environment interactions in complex chronic conditions such as CD.


Rhodomollanol A, a Highly Oxygenated Diterpenoid with a 5/7/5/5 Tetracyclic Carbon Skeleton from the Leaves of Rhododendron molle.
A novel diterpenoid with an unprecedented carbon skeleton, rhodomollanol A (1), and a new grayanane diterpenoid, rhodomollein XXXI (2), were isolated from the leaves of Rhododendron molle. Their structures were elucidated using comprehensive spectroscopic methods and single-crystal X-ray diffraction. Compound 1 possesses a unique cis/trans/trans/cis/cis-fused 3/5/7/5/5/5 hexacyclic ring system featuring a rare 7-oxabicyclo[4.2.1]nonane core decorated with three cyclopentane units. The plausible biosynthetic pathway for 1 was proposed. Compound 1 exhibited moderate PTP1B inhibitory activity.


The Krüppel-associated box repressor domain can induce reversible heterochromatization of a mouse locus in vivo.
The study of chromatin and its regulators is key to understanding and manipulating transcription. We previously exploited the Krüppel-associated box (KRAB) transcriptional repressor domain, present in hundreds of vertebrate-specific zinc finger proteins, to assess the effect of its binding to gene bodies. These experiments revealed that the ectopic and doxycycline (dox)-controlled tet repressor KRAB fusion protein (tTRKRAB) can induce reversible and long-range silencing of cellular promoters. Here, we extend this system to in vivo applications and use tTRKRAB to achieve externally controllable repression of an endogenous mouse locus. We employed lentiviral-mediated transgenesis with promoterless TetO-containing gene traps to engineer a mouse line where the endogenous kinesin family member 2A (Kif2A) promoter drives a YFP reporter gene. When these mice were crossed to animals expressing the TetO-binding tTRKRAB repressor, this regulator was recruited to the Kif2A locus, and YFP expression was reduced. This effect was reversed when dox was given to embryos or adult mice, demonstrating that the cellular Kif2A promoter was only silenced upon repressor binding. Molecular analyses confirmed that tTRKRAB induced transcriptional repression through the spread of H3K9me3-containing heterochromatin, without DNA methylation of the trapped Kif2A promoter. Therefore, we demonstrate that targeting of tTRKRAB to a gene body in vivo results in reversible transcriptional repression through the spreading of facultative heterochromatin. This finding not only sheds light on KRAB-mediated transcriptional processes, but also suggests approaches for the externally controllable and reversible modulation of chromatin and transcription in vivo.


Subtotal peritonectomy with chemohyperthermic peritoneal perfusion for peritonitis carcinomatosa in gastrointestinal cancer.
Treatment for peritonitis carcinomatosa in gastrointestinal cancer remains to be established though it is one of the commonest causes of cancer death. Subtotal peritonectomy (SP) with chemohyperthermic peritoneal perfusion (CHPP) was developed for the new therapeutic strategy for peritoneal dissemination in gastrointestinal cancer in our department. SP includes resection of stomach, colon, small bowel, spleen, gall bladder, and parietal peritoneum. CHPP was carried out by heated saline containing 25 mg/l cisplatin, 10 mg/l mitomycin C, and 20 mg/l etoposide. Intraperitoneal temperature was maintained at 42 degrees C for 60 min. Fifteen gastric cancer and three colon cancer patients with severe peritoneal dissemination underwent these procedures. The averages of operating time, intraoperative bleeding volume, and total perioperative transfused blood volume were 9 h, 4400 ml, and 5600 ml, respectively. The patients estimated as complete resection and residual disease by histopathological study numbered 11 and 7. There was no treatment-related deaths though bleeding occurred in 5 patients; perforation in 2 patients; and abscesses in 2 patients. The 1-year survival rate (1ysr) and the 2-year survival rate (2-ysr) of all the patients were 57% and 21%, respectively. The 1-ysr and the 2-ysr of the patients who underwent complete resection were 67% and 40% significantly greater than the 43% and 0% of the patients who had residual tumors (p=0.02). The combination therapy of SP and CHPP is feasible in spite of its morbidity and has great possibilities in complete resection of peritoneal dissemination and prolongation of patient's survival.


A Natural Combination Extract of Viscum album L. Containing Both Triterpene Acids and Lectins Is Highly Effective against AML In Vivo.
Aqueous Viscum album L. extracts are widely used in complementary cancer medicine. Hydrophobic triterpene acids also possess anti-cancer properties, but due to their low solubility they do not occur in significant amounts in aqueous extracts. Using cyclodextrins we solubilised mistletoe triterpenes (mainly oleanolic acid) and investigated the effect of a mistletoe whole plant extract on human acute myeloid leukaemia cells in vitro, ex vivo and in vivo. Single Viscum album L. extracts containing only solubilised triterpene acids (TT) or lectins (viscum) inhibited cell proliferation and induced apoptosis in a dose-dependent manner in vitro and ex vivo. The combination of viscum and TT extracts (viscumTT) enhanced the induction of apoptosis synergistically. The experiments demonstrated that all three extracts are able to induce apoptosis via caspase-8 and -9 dependent pathways with down-regulation of members of the inhibitor of apoptosis and Bcl-2 families of proteins. Finally, the acute myeloid leukaemia mouse model experiment confirmed the therapeutic effectiveness of viscumTT-treatment resulting in significant tumour weight reduction, comparable to the effect in cytarabine-treated mice. These results suggest that the combination viscumTT may have a potential therapeutic value for the treatment AML.


A Zebrafish Model for a Human Myopathy Associated with Mutation of the Unconventional Myosin MYO18B.
Myosin 18B is an unconventional myosin that has been implicated in tumor progression in humans. In addition, loss-of-function mutations of the MYO18B gene have recently been identified in several patients exhibiting symptoms of nemaline myopathy. In mouse, mutation of Myo18B results in early developmental arrest associated with cardiomyopathy, precluding analysis of its effects on skeletal muscle development. The zebrafish, frozen (fro) mutant was identified as one of a group of immotile mutants in the 1996 Tübingen genetic screen. Mutant embryos display a loss of birefringency in their skeletal muscle, indicative of disrupted sarcomeric organization. Using meiotic mapping, we localized the fro locus to the previously unannotated zebrafish myo18b gene, the product of which shares close to 50% identity with its human ortholog. Transcription of myo18b is restricted to fast-twitch myocytes in the zebrafish embryo; consistent with this, fro mutant embryos exhibit defects specifically in their fast-twitch skeletal muscles. We show that sarcomeric assembly is blocked at an early stage in fro mutants, leading to the disorganized accumulation of actin, myosin, and α-actinin and a complete loss of myofibrillar organization in fast-twitch muscles.


Substance use management: a harm reduction-principled approach to assisting the relief of drug-related problems.
Disease (particularly HIV) has increased our motivation to reconsider how the current help system deals with drug-related problems. A more concrete focus on disease prevention as an additional goal has, for many, lead to a reevaluation of the goals of drug help work. Such a critical examination shows how much there is to improve within the system even in the absence of blood borne disease. Integrating the heart of harm reduction--respecting work on any positive change as a person defines it for his/herself--into treatment fashions a health sensitive alternative to the predominant practice of abstinence-only assistance for the relief of drug problems. This new approach is called substance use management (SUM), as it no longer requires abstinence but instead focuses on a range of options for improvements while still including abstinence among the possible self-selected outcomes. SUM is suggested as a framework for change within the treatment system that would maximize treatment's constructive impact, cost-effectiveness and maturation as a distinct discipline that can appropriately attract support and gain stature for making society healthier. This article describes a formalized system for applying some of the main principles of harm reduction within the treatment system. Viable options for a SUM treatment focus are suggested herein as well as a critical process, based on respect and collaboration, for use with these options.


Climate change: essential knowledge for developing holistic solutions to our climate crisis.
Understanding anthropogenic climate change is essential for anyone working in the life sciences. Firstly because climate change has already started to impact the Earth biosphere and human health and these changes need to be documented and acknowledged. Secondly, many of the solutions to climate change, both mitigation and adaptation, will be through the life sciences, everything from massive reforestation and sustainable agriculture to preventing the spread of disease and protecting individual human health. Anthropogenic climate change is, therefore, one of the defining challenges of the 21st century, along with poverty alleviation, environmental degradation and global security. Climate change is no longer just a scientific concern but encompasses economics, sociology, geopolitics, national and local politics, law and health to name a few. Hence, to understand climate change fully then not only does one have to review the science but also the politics and geopolitics, which have created the issue and can provide the solutions. Climate change ultimately makes us examine the whole basis of modern society and ultimately asks questions about humanity's relationship with the rest of the planet.


A Component-Based Extension Framework for Large-Scale Parallel Simulations in NEURON.
As neuronal simulations approach larger scales with increasing levels of detail, the neurosimulator software represents only a part of a chain of tools ranging from setup, simulation, interaction with virtual environments to analysis and visualizations. Previously published approaches to abstracting simulator engines have not received wide-spread acceptance, which in part may be to the fact that they tried to address the challenge of solving the model specification problem. Here, we present an approach that uses a neurosimulator, in this case NEURON, to describe and instantiate the network model in the simulator's native model language but then replaces the main integration loop with its own. Existing parallel network models are easily adopted to run in the presented framework. The presented approach is thus an extension to NEURON but uses a component-based architecture to allow for replaceable spike exchange components and pluggable components for monitoring, analysis, or control that can run in this framework alongside with the simulation.


Improving the relational aspects of trauma care through translational simulation.
Major trauma care is complex and requires individuals and teams to perform together in time critical, high-stakes situations. Scenario-based simulation is well established as a strategy for trauma teamwork improvement, but its role in the relational and cultural aspects of trauma care is less well understood. Relational coordination theory offers a framework through which we aimed to understand the impact of an established trauma simulation programme. We studied simulation activities using a narrative survey of trauma providers from anaesthesia, emergency medicine, medical imaging, surgery, trauma service, intensive care, and pre-hospital providers at Gold Coast University Hospital, in conjunction with data from an ethnography. Data analysis was performed using a recursive approach-a simultaneous deductive approach using the relational coordination framework and an inductive analysis. Ninety-five of 480 (19.8%) staff completed free-text survey questions on simulation. Deductive analysis of data from these narrative survey results using the RC framework domains identified examples of shared goals, shared knowledge, communication and mutual respect. Two major themes from the inductive analysis-"Behaviour, process and system change" and "Culture and relationships"-aligned closely with findings from the RC analysis, with additional themes of "Personal and team learning" and the "Impact of the simulation experience" identified. Our findings suggest that an established trauma simulation programme can have a profound impact on the relational aspects of care and the development of a collaborative culture, with perceived tangible impacts on teamwork behaviours and institutional systems and processes. The RC framework-shared knowledge, shared goals and mutual respect in the context of communication that is timely, accurate, frequent and problem-solving based-can provide a common language for simulation educators to design and debrief simulation exercises that aim to have a translational impact.


Molecular Evolution of PvMSP3α Block II in Plasmodium vivax from Diverse Geographic Origins.
Block II of Plasmodium vivax merozoite surface protein 3α (PvMSP3α) is conserved and has been proposed as a potential candidate for a malaria vaccine. The present study aimed to compare sequence diversity in PvMSP3a block II at a local microgeographic scale in a village as well as from larger geographic regions (countries and worldwide). Blood samples were collected from asymptomatic carriers of P. vivax in a village at the western border of Thailand and PvMSP3α was amplified and sequenced. For population genetic analysis, 237 PvMSP3α block II sequences from eleven P. vivax endemic countries were analyzed. PvMSP3α sequences from 20 village-level samples revealed two length variant types with one type containing a large deletion in block I. In contrast, block II was relatively conserved; especially, some non-synonymous mutations were extensively shared among 11 parasite populations. However, the majority of the low-frequency synonymous variations were population specific. The conserved pattern of nucleotide diversity in block II sequences was probably due to functional/structural constraints, which were further supported by the tests of neutrality. Notably, a small region in block II that encodes a predicted B cell epitope was highly polymorphic and showed signs of balancing selection, signifying that this region might be influenced by the immune selection and may serve as a starting point for designing multi-antigen/stage epitope based vaccines against this parasite.


Living with Inflammatory Bowel Disease: A review of qualitative research studies.
Inflammatory Bowel Disease is a chronic, untreatable condition represented by two illnesses, Crohn's and Ulcerative Colitis. Despite high incidence in well-developed industrialised countries, and the significant impact of symptoms on patient's quality of life, little is known about living with Inflammatory Bowel Disease. To explore the patients' experiences of living with Inflammatory Bowel Disease. A qualitative systematic review. CINAHL, Medline, British Nursing Index and PsycINFO were searched using the following keywords: Inflammatory Bowel Disease AND experiences. We have limited the search to studies published in English from 2000 to 2017. Thematic synthesis. Data from 23 studies, identified that fatigue, incontinence and uncertainty about future, body image, and lack of information from healthcare professionals dominated the experiences of those living with Inflammatory Bowel Disease. Also, patients living with Inflammatory Bowel Disease were reluctant to disclose their illness due to lack of public awareness and stigma surrounding symptoms. From these, an overarching theme has been identified: Living in isolation and exclusion. Patients with Inflammatory Bowel Disease face a variety of problems, often their priorities and those of healthcare professionals differ greatly. Healthcare professionals have little evidence needed to provide adequate, holistic care to this group. With a rise in the Inflammatory Bowel Disease population in newly industrialised countries it is estimated that the condition is turning into a global disease, potentially making long term care unsustainable. More evidence is needed to understand the concerns of this group.


Folate concentrations during pregnancy and autistic traits in the offspring. The Generation R Study.
In a population-based study, we examined the associations of maternal plasma folate concentrations at 13 weeks of gestation and prenatal folic acid supplement use with autistic traits in the offspring at the age of six years. Parent-reported autistic traits were assessed using the Social Responsiveness Scale short form. Maternal folate was not associated with autistic traits in the offspring. In contrast, prenatal folic acid use was associated with less child autistic traits. Future research should focus on the timing of the potential effect of prenatal folate on the development of autistic traits in combination with clinical diagnosis of autism in the offspring.


Management of the dry ejaculate: a systematic review of aspermia and retrograde ejaculation.
A dry ejaculate (aspermia), may occur either because of an inability to transport semen (anejaculation) or because of an inability to ejaculate in an antegrade direction (retrograde ejaculation). The treatment of aspermia varies with underlying etiology and includes medical therapy with sympathomimetics, urinary sperm retrieval, bladder neck reconstruction, prostatic massage, penile vibratory stimulation, electroejaculation, and surgical sperm retrieval. A systematic review of the current literature was performed for articles on ejaculatory dysfunction related to dry ejaculate. However, the data are insufficient to allow firm comparisons between treatment options. Treatments must be tailored to the individual patient, and treatment decisions should involve consideration of ease of administration, degree of invasiveness, and anticipated success.


Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel.
Rosacea is currently diagnosed by consensus-defined primary and secondary features and managed by subtype. However, individual features (phenotypes) can span multiple subtypes, which has implications for clinical practice and research. Adopting a phenotype-led approach may facilitate patient-centred management. To advance clinical practice by obtaining international consensus to establish a phenotype-led rosacea diagnosis and classification scheme with global representation. Seventeen dermatologists and three ophthalmologists used a modified Delphi approach to reach consensus on statements pertaining to critical aspects of rosacea diagnosis, classification and severity evaluation. All voting was electronic and blinded. Consensus was achieved for transitioning to a phenotype-based approach to rosacea diagnosis and classification. The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes. Flushing, telangiectasia, inflammatory lesions and ocular manifestations were not considered to be individually diagnostic. The panel reached agreement on dimensions for phenotype severity measures and established the importance of assessing the patient burden of rosacea. The panel recommended an approach for diagnosis and classification of rosacea based on disease phenotype.


Brevetoxins cause acute excitotoxicity in primary cultures of rat cerebellar granule neurons.
Brevetoxins (designated PbTx-1 to -10) are potent lipid-soluble polyether compounds that are known to bind to and modulate voltage-gated sodium channel activity. To investigate whether brevetoxins produce direct central nervous system neurotoxic effects, cultured rat cerebellar granule neurons were exposed to brevetoxins in Locke's buffer for 2 h at 22 degrees C. Neuronal injury was quantified by assaying lactate dehydrogenase activity in the exposure buffer and in conditioned growth media collected at 22 h after brevetoxin exposure. Brevetoxins produced acute neuronal injury and death in neurons with a rank order potency of PbTx-1 (EC50 = 9.31 +/- 0.45 nM) > PbTx-3 (EC50 = 53.9 +/- 2.8 nM) > PbTx-2 (EC50 = 80.5 +/- 5.9 nM) > PbTx-6 (EC50 = 1417 +/- 32 nM), which is similar to their previously determined rank order potency for brevetoxin-induced icthyotoxicity and binding to [3H]PbTx-3-labeled sodium channels on synaptosomes. The neurotoxic response could be prevented by coapplication of the sodium channel antagonist tetrodotoxin or by the competitive or noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists D-AP5 and MK-801, ketamine, dextromethorphan, and dextrorphan, respectively. NMDA receptor antagonists afforded neuroprotection with rank order potencies comparable to those measured previously for protection against glutamate-induced excitotoxic responses. Further analysis revealed that brevetoxins induced a concentration-dependent release of L-glutamate and L-aspartate into the exposure buffer. These data indicate that brevetoxin-induced injury in cultured rat cerebellar granule neurons is mediated by NMDA receptors that are activated indirectly as a consequence of PbTx-induced sodium channel activation and attendant excitatory amino acid release.


Alcohol consumption and the risk of alcohol related cirrhosis in women.
The risks in women of cirrhosis with a likely primary alcohol aetiology were estimated for various levels of alcohol consumption in a case-control study. Data were obtained from 41 women with a first diagnosis of cirrhosis who had no evidence of non-alcohol-related cirrhosis; three matched controls were interviewed for each case. Significant increases in the risk of cirrhosis were detected at levels of consumption between 41 and 60 g daily; above this level a dose-response relation was observed. The risk of cirrhosis did not appear to be influenced by other nutritional factors or history of liver disease or use of hepatotoxic drugs. One per cent of Australian women consume more than 40 g alcohol daily, yet more than 90% of women identified with cirrhosis consumed alcohol at this level. Preventive interventions to reduce alcohol consumption in the small group of women who consume more than 40 g daily have the potential to reduce substantially the incidence of alcohol related cirrhosis.


Evidence of stable high-temperature D(x)-CO intermediates on the Ru(0001) surface.
We demonstrate the formation of complexes involving attractive interactions between D and CO on Ru(0001) that are stable at significantly higher temperatures than have previously been reported for such intermediate species on this surface. These complexes are evident by the appearance of new desorption features upon heating of the sample. They decompose in stages as the sample temperature is increased, with the most stable component desorbing at >500 K. The D:CO ratio remaining on the surface during the final stages of desorption tends towards 1:1. The new features are populated during normally incident molecular beam dosing of D(2) on to CO pre-covered Ru(0001) surfaces (180 K) when the CO coverage exceeds 50% of the saturation value. The amount of complex formed decreases somewhat with increasing CO pre-coverage. It is almost absent in the case of dosing on to the fully saturated surface. The results are interpreted in terms of both local and long-range rearrangements of the overlayer that give rise to the observed CO coverage dependence and limit the amount of complex that can be formed.


Life-threatening hyponatremia after krait bite envenoming - a new syndrome.
Bites by kraits are a major cause of snake bite death in South Asia, mainly because of their venom is paralytic causing respiratory failure. We describe another life-threatening effect of the venom of some Bungarus species. We report the death of a young woman due to severe hyponatremia-induced brain damage after envenoming attributed to a Bungarus multicinctus. Her serum sodium of 137 mmol/l on admission dropped to 104 mmol/l within 48 h. The patient suddenly deteriorated with seizures and coma and showed signs of severe cerebral edema. The osmolality and sodium concentration in her urine were high. She died 18 days after the bite. Since this case, a retrospective study and a prospective trial have confirmed the high risk of hyponatremia after envenoming by B. multicinctus. In addition, a recent study in southern Vietnam has shown that envenoming by the Malayan krait (Bungarus candidus) also commonly causes profound hyponatremia. Hyponatremia is a potential serious complication in patients envenomed by B. multicinctus or B. candidus, and appropriate monitoring and management is necessary.


Antiangiogenic therapies in epithelial ovarian cancer.
Angiogenesis is a critical component of tumor development and proliferation, and increased angiogenesis has been associated with a worse clinical outcome in a number of solid tumors, including ovarian cancer. Therefore, agents that target the angiogenic process are of considerable interest in the treatment of ovarian cancer. Studies evaluating the efficacy of antiangiogenic agents in ovarian cancer are reported. Antiangiogenic agents examined include vascular endothelial growth factor (VEGF) pathway inhibitors, including monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and a soluble receptor decoy, as well as inhibitors of other angiogenic factors and vascular disrupting agents. The VEGF inhibitor bevacizumab has been shown to have efficacy in ovarian cancer in phase II trials and a progression-free survival advantage in one phase III trial. TKIs block the VEGF receptors and secondary angiogenic pathways and have shown activity in phase I and II trials. Alternative angiogenesis inhibitors include EphA2 inhibitors and a selective angiopoietin 1/2-neutralizing peptibody. Another strategy is to destroy the existing tumor vasculature, and a number of vascular disrupting agents are being studied in preclinical and phase I trials. Antiangiogenic agents have a unique side effect profile, likely due to inhibition of normal physiologic angiogenesis. Phase II and early phase III trials have demonstrated that antiangiogenic therapies have significant activity in ovarian cancer. The results of phase III trials in the front-line and recurrent settings will determine the extent of clinical benefit of antiangiogenic therapies in combination with chemotherapy. Antiangiogenic agents have a distinct side effect profile, and further studies are necessary to evaluate how to minimize the incidence of these events and to identify women most likely to benefit from these therapies.


End-of-life care in intensive care units: family routines and environmental factors.
The purpose of this study was to describe family care routines and to explore environmental factors when patients die in Swedish intensive care units (ICUs). The main research questions were: what are the physical environmental circumstances and facilities when caring for patients in end-of-life and are there any routines or guidelines when caring for dying patients and their families? A questionnaire was sent to 79 eligible Swedish ICUs in December 2003, addressed to the unit managers. The response rate was 94% (n = 74 units). The findings show that, despite recommendations highlighting the importance of privacy for dying ICU patients and their families, only 11% of the respondents stated that patients never died in shared rooms in their ICU. If a patient dies in a shared room, nurses strive to ensure a dignified goodbye by moving the body to an empty room or to one specially designated for this purpose. The majority (76%) of the units had waiting rooms within the ICU. The study also revealed that there is a need for improvements in the follow-up routines for bereaved families. Many units reported (51%) that they often or almost always offer a follow-up visit, although in most cases the bereaved family had to initiate the follow-up by contacting the ICU. Guidelines in the area of end-of-life care were used by 25% of the ICUs. Further research is necessary to acquire a deeper knowledge of the circumstances under which patients die in ICUs and what impact the ICU environment has on bereaved families.


Epigenome-based splicing prediction using a recurrent neural network.
Alternative RNA splicing provides an important means to expand metazoan transcriptome diversity. Contrary to what was accepted previously, splicing is now thought to predominantly take place during transcription. Motivated by emerging data showing the physical proximity of the spliceosome to Pol II, we surveyed the effect of epigenetic context on co-transcriptional splicing. In particular, we observed that splicing factors were not necessarily enriched at exon junctions and that most epigenetic signatures had a distinctly asymmetric profile around known splice sites. Given this, we tried to build an interpretable model that mimics the physical layout of splicing regulation where the chromatin context progressively changes as the Pol II moves along the guide DNA. We used a recurrent-neural-network architecture to predict the inclusion of a spliced exon based on adjacent epigenetic signals, and we showed that distinct spatio-temporal features of these signals were key determinants of model outcome, in addition to the actual nucleotide sequence of the guide DNA strand. After the model had been trained and tested (with >80% precision-recall curve metric), we explored the derived weights of the latent factors, finding they highlight the importance of the asymmetric time-direction of chromatin context during transcription.


Late presentation to hospital services necessitates greater community-based care for malnourished children.
The records for all paediatric deaths (ages 0-14) in a large hospital in urban Southern Africa were examined for a 3 year period (January 2007 to February 2010), to explore the role of malnutrition in paediatric mortality in this region. A total of 516 records were obtained, demonstrating that malnutrition was the primary or secondary cause of death in 35% of cases. It was also found that children presented very late to hospital services, with an average length of final admission of only 0-3 days. The rate of human immunodeficiency virus (HIV) infection was found to be very high, although low testing rates limits the analysis of these figures. Malnutrition remains an important factor in paediatric mortality in southern Africa, contributing to approximately 35% of deaths. Furthermore, fatal cases presented very late to hospital services. In light of this, increased community-based therapy would be beneficial. Implementation of universal HIV testing would also be valuable.


Tracing the molecular pathogenesis of antiphospholipid syndrome.
Fetal loss induced by antiphospholipid antibodies (aPLs) in mice is a complement-driven inflammatory condition. Engagement of the complement receptor C5aR on neutrophils induces expression of the principal initiator of the blood clotting mechanism, tissue factor (TF), and blocking this downstream event of complement activation prevents antibody-induced fetal loss. In this issue of the JCI, the study by Redecha et al. clarifies that in mice, the contribution of TF to this pathogenic mechanism is independent of its role in coagulation and thrombosis, but involves inflammatory signaling through the receptor PAR2 (see the related article beginning on page 3453). The study not only sheds light on a critical effector mechanism of aPL-induced fetal loss, but also suggests that treatment with statins, which decrease TF and PAR2 expression, may hold promise as a therapeutic approach to antiphospholipid syndrome-associated pregnancy complications.


Transcriptional profiling of macrophages derived from monocytes and iPS cells identifies a conserved response to LPS and novel alternative transcription.
Macrophages differentiated from human induced pluripotent stem cells (IPSDMs) are a potentially valuable new tool for linking genotype to phenotype in functional studies. However, at a genome-wide level these cells have remained largely uncharacterised. Here, we compared the transcriptomes of naïve and lipopolysaccharide (LPS) stimulated monocyte-derived macrophages (MDMs) and IPSDMs using RNA-Seq. The IPSDM and MDM transcriptomes were broadly similar and exhibited a highly conserved response to LPS. However, there were also significant differences in the expression of genes associated with antigen presentation and tissue remodelling. Furthermore, genes coding for multiple chemokines involved in neutrophil recruitment were more highly expressed in IPSDMs upon LPS stimulation. Additionally, analysing individual transcript expression identified hundreds of genes undergoing alternative promoter and 3' untranslated region usage following LPS treatment representing a previously under-appreciated level of regulation in the LPS response.


Delays without mistakes: response time and error distributions in dual-task.
When two tasks are presented within a short interval, a delay in the execution of the second task has been systematically observed. Psychological theorizing has argued that while sensory and motor operations can proceed in parallel, the coordination between these modules establishes a processing bottleneck. This model predicts that the timing but not the characteristics (duration, precision, variability...) of each processing stage are affected by interference. Thus, a critical test to this hypothesis is to explore whether the quality of the decision is unaffected by a concurrent task. In number comparison--as in most decision comparison tasks with a scalar measure of the evidence--the extent to which two stimuli can be discriminated is determined by their ratio, referred as the Weber fraction. We investigated performance in a rapid succession of two non-symbolic comparison tasks (number comparison and tone discrimination) in which error rates in both tasks could be manipulated parametrically from chance to almost perfect. We observed that dual-task interference has a massive effect on RT but does not affect the error rates, or the distribution of errors as a function of the evidence. Our results imply that while the decision process itself is delayed during multiple task execution, its workings are unaffected by task interference, providing strong evidence in favor of a sequential model of task execution.


A Structural and Dynamic Analysis of the Partially Disordered Polymerase-Binding Domain in RSV Phosphoprotein.
The phosphoprotein P of Mononegavirales (MNV) is an essential co-factor of the viral RNA polymerase L. Its prime function is to recruit L to the ribonucleocapsid composed of the viral genome encapsidated by the nucleoprotein N. MNV phosphoproteins often contain a high degree of disorder. In Pneumoviridae phosphoproteins, the only domain with well-defined structure is a small oligomerization domain (POD). We previously characterized the differential disorder in respiratory syncytial virus (RSV) phosphoprotein by NMR. We showed that outside of RSV POD, the intrinsically disordered N-and C-terminal regions displayed a structural and dynamic diversity ranging from random coil to high helical propensity. Here we provide additional insight into the dynamic behavior of PCα, a domain that is C-terminal to POD and constitutes the RSV L-binding region together with POD. By using small phosphoprotein fragments centered on or adjacent to POD, we obtained a structural picture of the POD-PCα region in solution, at the single residue level by NMR and at lower resolution by complementary biophysical methods. We probed POD-PCα inter-domain contacts and showed that small molecules were able to modify the dynamics of PCα. These structural properties are fundamental to the peculiar binding mode of RSV phosphoprotein to L, where each of the four protomers binds to L in a different way.


Between- and within-sex variation in hormonal responses to psychological stress in a large sample of college students.
This study investigated (1) sex differences in hormonal responses to psychosocial stress; (2) the relation between variability in pre-test hormone concentrations and stress-induced hormonal changes; and (3) some possible sources of within-sex variation in pre-test hormone concentrations and in hormonal responses to the test in a large human subject population. To this end, changes in salivary concentrations of testosterone and cortisol in response to a mild psychosocial stressor (a set of computerized economic decision-making tests) were measured in a sample of over 500 MBA students. Males had higher concentrations of testosterone and cortisol than females both before and after the test. After taking effects of time of testing on hormone concentrations into account, testosterone showed a post-test decrease in males but not in females. Cortisol level increased in both sexes but the post-test increase was larger in females than in males. At the individual level, the pre-test concentrations of testosterone and cortisol predicted both the direction and the magnitude of the post-test hormone change, so that low pre-test hormone concentrations showed large post-test increases whereas high pre-test concentrations showed large post-test decreases. Within-sex variation in hormone concentrations was not accounted for by variation in 2D:4D digit length ratio, a marker of prenatal androgen exposure, but by social variables. Single males without a stable romantic partner had higher testosterone level than males with stable partners, and both males and females without a partner showed a greater cortisol response to the test than married individuals with or without children. Studies conducted with large sample sizes such as this one can help understand normative patterns of hormonal responses to psychosocial stimuli as well as identify the sources of interindividual variation in endocrine function.