Nuclear DNA content by cytofluorometry of stage I adenocarcinoma of the lung in relation to postoperative recurrence.
Forty-six cases of adenocarcinoma of the lung, categorized as stage I (T1N0M0, T2N0M0) pathologically, were studied in terms of nuclear DNA content (NDC) determined by cytofluorometry. They comprised 23 cases each with and without tumor recurrence within five years postoperatively, and the NDC was compared in 23 pairs in which the tumor size and the degree of histologic differentiation were completely matched. The NDC was larger in the recurrent group than in the nonrecurrent group in terms of mean nuclear DNA content (MNDC), DNA histogram pattern, and occurrence of the aneuploid stem cell line, of which the difference in MNDC was statistically significant (p less than 0.05). When the comparison of NDC was made between the nonrecurrent and recurrent groups in the well differentiated (W/D), moderately to poorly differentiated (M.P/D), T1, and T2 subgroups, the NDC of the recurrent group was significantly larger than that of the nonrecurrent group in the W/D (MNDC, p less than 0.01 and DNA histogram pattern, p less than 0.005) and T1 subgroups (MNDC, p less than 0.05), but not in the M.P/D and T2 subgroups. The results indicate that the NDC is a good predictor of prognosis in stage I adenocarcinoma of the lung and its prognostic importance increases in more differentiated and smaller tumors, compared to less differentiated and larger tumors.


Retrospective multicenter study concerning electrocautery forceps with soft coagulation for nonmalignant gastroduodenal ulcer bleeding in Japan.
Electrocautery forceps with soft coagulation are actively used for treatment of bleeding and nonbleeding visible vessels during endoscopic submucosal dissection, but the usefulness of gastroduodenal ulcer bleeding has not been elucidated so far. The purpose of this paper is to elucidate the outcomes of electrocautery forceps with soft coagulation for peptic and artificial gastroduodenal ulcer bleeding. A retrospective multicenter study of consecutive case series during one year involved nine departments of high-volume hospitals in Japan. The study included 128 consecutive patients (62 with peptic ulcers and 66 with artificial ulcers) with bleeding nonmalignant gastroduodenal ulcers that were revealed using emergency endoscopy between January 2008 and December 2008. Hemostasis was carried out using electrocautery forceps with soft coagulation. Rates of successful initial hemostasis, rebleeding, transfer to surgery, and death according to peptic and artificial ulcer bleeding were recorded. Successful initial endoscopic hemostasis was obtained in 61 peptic ulcer patients (98.4%) and 66 artificial ulcer patients (100%). Rebleeding was observed in seven peptic ulcer patients (11.5%) and five artificial ulcer patients (7.6%). Rates of successful management with endoscopic methods alone were 96.8% (60/62) and 100% (66/66) in peptic ulcer patients and artificial ulcer patients, respectively. There were no severe complications or deaths related to the management of gastroduodenal ulcer bleeding. The novel endoscopic method using electrocautery forceps with soft coagulation for gastroduodenal ulcer bleeding seems to provide safety and efficacy that is comparable with that of endoscopic hemostasis with other established hemostatic techniques.


Identification of differences in human and great ape phytanic acid metabolism that could influence gene expression profiles and physiological functions.
It has been proposed that anatomical differences in human and great ape guts arose in response to species-specific diets and energy demands. To investigate functional genomic consequences of these differences, we compared their physiological levels of phytanic acid, a branched chain fatty acid that can be derived from the microbial degradation of chlorophyll in ruminant guts. Humans who accumulate large stores of phytanic acid commonly develop cerebellar ataxia, peripheral polyneuropathy, and retinitis pigmentosa in addition to other medical conditions. Furthermore, phytanic acid is an activator of the PPAR-alpha transcription factor that influences the expression of genes relevant to lipid metabolism. Despite their trace dietary phytanic acid intake, all great ape species had elevated red blood cell (RBC) phytanic acid levels relative to humans on diverse diets. Unlike humans, chimpanzees showed sexual dimorphism in RBC phytanic acid levels, which were higher in males relative to females. Cultured skin fibroblasts from all species had a robust capacity to degrade phytanic acid. We provide indirect evidence that great apes, in contrast to humans, derive significant amounts of phytanic acid from the hindgut fermentation of plant materials. This would represent a novel reduction of metabolic activity in humans relative to the great apes. We identified differences in the physiological levels of phytanic acid in humans and great apes and propose this is causally related to their gut anatomies and microbiomes. Phytanic acid levels could contribute to cross-species and sex-specific differences in human and great ape transcriptomes, especially those related to lipid metabolism. Based on the medical conditions caused by phytanic acid accumulation, we suggest that differences in phytanic acid metabolism could influence the functions of human and great ape nervous, cardiovascular, and skeletal systems.


Persistent infection in Neotoma fuscipes (Muridae: Sigmodontinae) with Ehrlichia phagocytophila sensu lato.
Dusky-footed wood rats (Neotoma fuscipes Baird) and two species of Peromyscus mice (P. maniculatus Wagner and P. truei Shufeldt) were collected over a 16-month period from three sites in Sonoma County, California. Blood was collected from 93 wood rats and 177 mice and serum or plasma was tested for seroreactivity with Ehrlichia phagocytophila sensu lato (also known as the human granulocytic ehrlichiosis agent). Thirty-five (37.6%) wood rats and 15 (8.5%) mice were seropositive. Positive Neotoma serology by site ranged from 9.4% to 62.1%. Polymerase chain reaction (PCR) testing for the Ehrlichia groESL heat shock operon was performed on all the seropositive and selected seronegative wood rats; 24 (68.6%) seropositive animals were PCR positive. Two seroconversions and no seroreversions were detected among 18 of the seropositive wood rats that were recaptured and tested multiple times (range = 2-6). Fourteen (77.8%) of the 18 were also PCR positive with six of these positive at every testing point (range = 2-6). One wood rat remained serologically and PCR positive in six specimens collected over a 14-month period. One male of 84 questing adult Ixodes pacificus Cooley & Kohls collected was PCR-positive for E. phagocytophila. Borrelia burgdorferi, the agent of Lyme disease, was cultured from ear punch biopsies from six of seven E. phagocytophila seropositive and one of four seronegative wood rats.


First trimester serum angiogenic/anti-angiogenic status in twin pregnancies: relationship with assisted reproduction technology.
The risk of pre-eclampsia (PE) increases in twin pregnancies, especially when assisted reproduction technologies (ART) are used. The aim of this study was to assess angiogenic/anti-angiogenic factors in maternal serum in the first trimester of twin pregnancies and establish if the mode of conception influences angiogenic status. This prospective study enrolled women with twin (n = 61) and singleton (n = 50) pregnancies. Dichorionic twin pregnancies were divided into two groups according to their mode of conception. Singleton pregnancies were used as the control group. Soluble fms-like tyrosine kinase (sFlt-1), free placental growth factor (PlGF) and soluble endoglin (sEng) concentrations were measured in the first trimester maternal serum. In the first trimester, women with twin pregnancies had higher serum concentrations of the anti-angiogenic factor sFlt-1 than that with singleton pregnancies (3924 ± 250 versus 2426 ± 162 pg/ml, respectively; P < 0.001). Maternal serum PlGF concentrations were lower in singleton pregnancies than those in twin pregnancies (37 ± 3.7 versus 59 ± 5.6, respectively; P < 0.001). Serum concentrations of sFlt-1 were higher in twin pregnancies conceived by ART than those in spontaneous twin pregnancies (4313 ± 389 versus 3522 ± 300 pg/ml, respectively; P < 0.05). No differences between groups were observed for sEng. In the first trimester, twin pregnancies conceived using ART showed a heightened anti-angiogenic status that could explain the increased risk of PE in these cases.


Carbon-14 dates at grande pile: correlation of land and sea chronologies.
Sixteen radiocarbon dates extending back to 70,000 years provide a chronology for the continuous continental pollen record of Grande Pile. This record reflects climatic changes over the last 140,000 years in northeastern France. The cold period initiating the Middle Weichselian, dated previously at 55,000 years, is dated at 70,000 years before the present (B.P.) at Grande Pile. This event is marked by the disappearance of deciduous forests at this site. The Early Weichselian is placed before 70,000 years B.P. A correlation with the oxygen isotope stages from oceanic records is demonstrated until 70,000 years B.P. and attempted beyond.


Metabolic syndrome and sleep apnea.
Metabolic syndrome is a disorder characterized by abdominal obesity, hypertension, increased triglycerides, decreased HDL cholesterol and increased blood glucose. Accumulating evidence strongly indicates that insulin resistance and an increased amount of abdominal fat are the pathogenic factors for the characteristics of metabolic syndrome. The metabolic syndrome is characterized by an increased risk for the development of cardiovascular disease and type 2 diabetes mellitus. Studies indicate that sleep apnea may be a manifestation of the metabolic syndrome. It has also been suggested that the metabolic syndrome or "syndrome X" should also comprise obstructive sleep apnea and should then be called syndrome "Z". It appears that obstructive sleep apnea and the metabolic syndrome are characterized by the same pathophysiologic environment, which increases the risk for the development of cardiovascular disease. The increased amount of visceral fat and the accompanying insulin resistance seem to be the main characteristics responsible for the development of obstructive sleep apnea and the metabolic syndrome.


Genes for Adult-Plant Resistance to Leaf Rust in Soft Red Winter Wheat.
Host plant resistance in wheat (Triticum aestivum) has been the principal means of managing leaf rust caused by Puccinia triticina. The need for durable resistance has changed the focus from the use of seedling resistance to adult-plant resistance. The objectives of this study were to determine the genetic basis for adult-plant resistance and to determine the most effective method to identify adult-plant resistance genes Lr12, 13, and 34 among 116 contemporary soft red winter wheat cultivars and breeding lines. Adult-plant resistance was detected by inoculating flag leaves with a race that was virulent on seedlings. Approximately 90% of the lines expressed resistance under controlled conditions. It was postulated that the adult-plant resistance in 67 lines was due in part to either Lr12, 13, or 34; the adult-plant resistance detected in 17 lines was attributed to Lr12 based on a distinctive low infection type very similar to that on the isoline TcLr12; the adult-plant resistance in 27 lines was attributed to Lr34, as all of these lines expressed a "leaf tip necrosis" in the field (a phenotype controlled by a gene known to be tightly linked with Lr34); and the adult-plant resistance in 23 lines was attributed to Lr13 based on a high infection type at 18.1°C and low infection type at 25.5°C with one or more pathogen isolates that were virulent on Lr13 at 18.1°C and avirulent on Lr13 at 25.5°C. The adult-plant resistance detected in the remaining 40% of the lines was due to one or more unidentified genes for adult-plant resistance. In a 4-year field study at several locations, nearly 29% of the lines were resistant at all locations, no line was susceptible at all locations, and only 30% of the lines were susceptible at one or more locations. Given that many of the lines in this study were resistant to all known races of P. triticina before being released as cultivars, the high frequency of adult-plant resistance in this study demonstrates that adult-plant resistance can be incorporated even in the presence of highly effective seedling resistance.


The needs of health promoters on a health promotion programme for families with adolescents orphaned by HIV and AIDS.
The South African communities has shown to have a challenge in accessing health services especially in rural areas; hence the national strategic objective 1.7 aimed at strengthening community systems to expand access to services using the community-based care programmes (NSP 2012-2016). The programmes enhance access to health services whilst promoting health and educating the community to improve health knowledge and work towards attaining a healthy living (NSP 2012-2016). However, the health promoters from the rural Hammanskraal region in the North West Province of South Africa often found themselves rendering the health promotion services in their communities with limited resources. This study aimed at exploring and describing the challenges faced by health promoters in implementing health promotion programmes for families with adolescents orphaned by HIV and AIDS. The study followed a qualitative design. Data was collected using focus group interviews. Participants were purposely selected by the social worker and the health promotion coordinator working at Hammanskraal. The process of data analysis was adapted from the eight steps of Tesch method of data analysis where categories, sub-categories and themes were isolated. The following categories emerged as the needs of health promoters on health promotion programmes for families with adolescents orphaned by HIV and AIDS, (1) financial needs, (2) resources, (3) basic life needs, (4) educational needs and (5) health promoter's needs. It is therefore recommended that equal distribution of resources: including medicine, equipment and finances, should be maintained in order to ensure non-interrupted services.


Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity.
Glucosamine (Glmn), a product of glucose metabolism via the hexosamine pathway, causes insulin resistance in isolated adipocytes by impairing insulin-induced GLUT 4 glucose transporter translocation to the plasma membrane. We hypothesized that Glmn causes insulin resistance in vivo by a similar mechanism in skeletal muscle. We performed euglycemic hyperinsulinemic clamps (12 mU/kg/min + 3H-3-glucose) in awake male Sprague-Dawley rats with and without Glmn infusion at rates ranging from 0.1 to 6.5 mg/kg/min. After 4h of euglycemic clamping, hindquarter muscles were quick-frozen and homogenized, and membranes were subfractionated by differential centrifugation and separated on a discontinuous sucrose gradient (25, 30, and 35% sucrose). Membrane proteins were solubilized and immunoblotted for GLUT 4. With Glmn, glucose uptake (GU) was maximally reduced by 33 +/- 1%, P < 0.001. The apparent Glmn dose to reduce maximal GU by 50% was 0.1 mg/kg/min or 1/70th the rate of GU on a molar basis. Control galactosamine and mannosamine infusions had no effect on GU. Relative to baseline, insulin caused a 2.6-fold increase in GLUT 4 in the 25% membrane fraction (f), P < 0.01, and a 40% reduction in the 35%f, P < 0.05, but had no effect on GLUT 4 in the 30% f, P= NS. Addition of Glmn to insulin caused a 41% reduction of GLUT 4 in the 25%f, P < 0.05, a 29% fall in the 30%f, and prevented the reduction of GLUT 4 in the 35% f. The 30%f membranes were subjected to a second separation with a 27 and 30% sucrose gradient. Insulin mobilized GLUT 4 away from the 30%f, P < 0.05, but not the 27% f. In contrast, Glmn reduced GLUT 4 in the 27%f, P < 0.05, but not the 30%f. Thus Glmn appears to alter translocation of an insulin-insensitive GLUT 4 pool. Coinfusion of Glmn did not alter enrichment of the sarcolemmal markers 5'-nucleotidase, Na+/K+ATPase, and phospholemman in either 25, 30, or 35% f. Thus Glmn completely blocked movement of Glut 4 induced by insulin. Glmn is a potent inducer of insulin resistance in vivo by causing (at least in part) a defect intrinsic to GLUT 4 translocation and/or trafficking. These data support a potential role for Glmn to cause glucose-induced insulin resistance (glucose toxicity).


Fetal and Perinatal Brain Autopsy: Useful Macroscopic Techniques Including Agar In-situ and Pre-Embedding Methods.
Fragile perinatal and fetal brains are the rule rather than the exception for developmental neuropathologists. Retrieving the fresh brain from the skull and examining early fetal, macerated or severely hydrocephalic brains after fixation can be a challenge. Textbooks on neurodevelopmental pathology mention these challenges to macroscopic examination of the developing central nervous system only in passing, but many perinatal pathologists recognize this diagnostic problem. We reviewed protocols and publications on the removal, fixation, slicing and sampling of these fetal- and perinatal brains. In addition, we describe a technique to facilitate the removal of severely hydrocephalic brains with very thin cerebral walls from the skull by replacing the intraventricular fluid with agar in-situ. Furthermore, we present a method for post-fixation pre-embedding in agar to facilitate slicing, macroscopic examination and sampling of fragile and macerated brains.


HER 2 Expression in Gastric and Gastro-esophageal Junction (GEJ) Adenocarcinomas.
Gastric cancer is one of the leading causes of cancer mortality in the world/India with majority being diagnosed at an advanced stage. Various chemotherapeutic regimens have modestly improved overall survival leading to quest for novel therapeutic agents. Overexpression of HER2 in many gastric cancers has lead to the advent of targeted therapy with anti HER2 antibody like Trastusumab which has improved the overall survival. Sixty cases of gastric adenocarcinomas (44 biopsies and 16 gastrectomies) over the past five years ( June 2009 to June 2014),were included in the study. Diagnosis was confirmed by review of slides and IHC with anti HER2 antibodies was performed using Dako Real Envision Detection system and scoring was done by Hoffmann et al., scoring system. Of the 60 cases, majority were males (60%),with a mean age of 65.65 yrs. Tumours in antrum (76.7%) formed the major bulk. HER2 expression was observed in 26.7% of Tumours, predominantly in males (p=0.006) and intestinal type (p= 0.054). HER2 expression correlated with Tumour grade (moderately differentiated and well differentiated, p= 0.042). Tumours of gastro-esophageal junction (GEJ) showed HER2 expression in 45.5% as opposed to 22.4% in gastric location. Poorly differentiated and diffuse type of adenocarcinomas did not express HER2. Two of three Tumours from patients in the age group 31-40 y expressed HER2. Male gender, intestinal-type and moderately differentiated gastric cancers may be the ones that can be targeted for therapy using Herceptin. Though trastusumab is approved for advanced gastric and GEJ cancers, it's role in adjuvant / neo-adjuvant setting in early stages needs to be evaluated with newer agents like Pertuzumab, Bevacizumab, especially in young patients.


Studies of interferon as a regulator of hematopoietic cell proliferation.
The presence of interferon (IFN) in normal bone marrow and its abnormal production in aplastic anemia suggest that IFN may have normal regulatory roles and implicates them in the pathophysiology of bone marrow failure. We studied the effects of recombinant IFN (r-IFN) on hematopoietic colony formation in methylcellulose cultures of human bone marrow. Both recombinant IFN-gamma (r-IFN-gamma) and recombinant IFN-alpha (r-IFN-alpha) were potent suppressors of myeloid (CFU-C-derived) colony formation, with 50% inhibition occurring at 291 u/ml for r-IFN-gamma and 275 U/ml for r-IFN-alpha. Small amounts of r-IFN-gamma acted synergistically with r-IFN-alpha; as little as 5 U/ml of r-IFN-gamma increased inhibition of CFU-C-derived colony formation by r-IFN-alpha over threefold. Conversely, small amounts of r-IFN-alpha did not affect inhibition by r-IFN-gamma. Inhibition by r-IFN was highly dependent on culture conditions: reduction of the fetal calf serum concentration from 30% to 20%, a change that did not alter the plating efficiency of control cultures, significantly enhanced the action of r-IFN-gamma. Competition between positive hematopoietic factors and r-IFN was further demonstrated as increasing amounts of human placenta-conditioned media, used as a source of colony-stimulating activity, also partially blocked r-IFN inhibition. To determine if r-IFN could directly inhibit the proliferation of a progenitor cell, cells isolated from immature BFU-E-derived colonies, a population enriched for late erythroid progenitors and free of auxiliary cells, were tested; similar inhibition by r-IFN-gamma was observed with these isolated erythroid progenitors as with total bone marrow CFU-E. Although small amounts of r-IFN-gamma also increased inhibition of bone marrow CFU-E-derived colony formation by r-IFN-alpha, no synergy was demonstrable with isolated erythroid progenitor cells. Therefore, even though r-IFN can directly inhibit proliferation of a progenitor cell, auxiliary cells may be required for synergy between r-IFN-gamma and r-IFN-alpha.


ED administration of thienopyridines in non-ST-segment elevation myocardial infarction: results from the NCDR.
American Heart Association/American College of Cardiology guidelines recommend that patients with definite unstable angina or non-ST-segment elevation myocardial infarction (NSTEMI) receive dual antiplatelet therapy on presentation to the hospital when undergoing early invasive management or "as soon as possible" after admission when being managed conservatively. The guidelines do not specify whether these medications should be administered in the emergency department (ED). Our aim was to determine whether ED administration of a thienopyridine was associated with clinical outcomes among patients with NSTEMI. We examined thienopyridine use in 39454 patients with NSTEMI who received a thienopyridine within 24 hours of presentation in the National Cardiovascular Data Registry's Acute Coronary Treatment and Intervention Outcomes Network-Get With The Guidelines Registry from January 2007 to June 2010. Patients who were not seen initially in the ED, were transferred in, or were missing time data were excluded. We analyzed the association between ED administration of thienopyridines and outcomes and patient demographics. Of the cohort receiving a thienopyridine within 24 hours, 9534 (24.2%) received it in the ED. Emergency department administration of a thienopyridine was not associated with in-hospital major bleeding (multivariable adjusted odds ratio, 0.99; 95% confidence interval, 0.91-1.09) or in-hospital mortality (adjusted 1.02; 95% confidence interval, 0.86-1.20). Independent predictors most strongly associated with ED thienopyridine administration were elevated troponin, ED length of stay, prior percutaneous coronary intervention, and initial electrocardiogram showing ischemic changes. There was no association between ED thienopyridine administration and in-hospital major bleeding or mortality. Emergency department length of stay, electrocardiographic changes, and elevated troponin were associated with ED thienopyridine administration.


Trafficking of matrix collagens through bone-resorbing osteoclasts.
An intracellular pathway for proteins liberated from mineralized matrix during resorption was identified in osteoclasts. Analysis by confocal microscopy of sites of active bone resorption showed that released matrix proteins, including degraded type I collagen, were endocytosed along the ruffled border within the resorption compartment and transcytosed through the osteoclast to the basolateral membrane. Intracellular trafficking of degraded collagen, as typified by the resorbing osteoclast, may provide the cell with a regulatory mechanism for the control of tissue degradation.


Calretinin is differentially localized in magnocellular oxytocin neurons of the rat hypothalamus. A double-labeling immunofluorescence study.
By use of a double-labeling immunofluorescence method with a confocal laser scanning microscope, we have examined whether a calcium-binding protein, calretinin, is localized in magnocellular oxytocin and vasopressin neurons of the rat hypothalamus. In the supraoptic nucleus, all oxytocin-labeled cells were stained for calretinin. However, in the magnocellular part of the paraventricular nucleus, almost all oxytocin-stained cells were devoid of calretinin immunoreactivity. All vasopressin-positive cells of both the supraoptic nucleus and the magnocellular part of the paraventricular nucleus lacked calretinin immunoreactivity. No calretinin immunoreactivity was found in oxytocin-labeled cells of the the anterior commissural nucleus or in vasopressin-labeled cells of the suprachiasmatic nucleus. We previously showed that another calcium-binding protein, calbindin-D28k, was localized in magnocellular oxytocin neurons of the supraoptic nucleus but not in those of the paraventricular nucleus. These findings suggest that, in general, magnocellular oxytocin neurons of the supraoptic nucleus and those of the paraventricular nucleus can be chemically distinguished, that is, the former contain both calretinin and calbindin-D28k but the latter lack the two calcium-binding proteins.


Phytic acid as a potential treatment for alzheimer's pathology: evidence from animal and in vitro models.
Alzheimer's disease (AD) causes progressive, age-dependent cortical and hippocampal dysfunction leading to abnormal intellectual capacity and memory. We propose a novel protective treatment for AD pathology with phytic acid (inositol hexakisphosphate), a phytochemical found in food grains and a key signaling molecule in mammalian cells. We evaluated the protective and beneficial effects of phytic acid against amyloid-β (Aβ) pathology in MC65 cells and the Tg2576 mouse model. In MC65 cells, 48-72-hour treatment with phytic acid provided complete protection against amyloid precursor protein-C-terminal fragment-induced cytotoxicity by attenuating levels of increased intracellular calcium, hydrogen peroxide, superoxide, Aβ oligomers, and moderately upregulated the expression of autophagy (beclin-1) protein. In a tolerance paradigm, wild type mice were treated with 2% phytic acid in drinking water for 70 days. Phytic acid was well tolerated. Ceruloplasmin activity, brain copper and iron levels, and brain superoxide dismutase and ATP levels were unaffected by the treatment. There was a significant increase in brain levels of cytochrome oxidase and a decrease in lipid peroxidation with phytic acid administration. In a treatment paradigm, 12-month old Tg2576 and wild type mice were treated with 2% phytic acid or vehicle for 6 months. Brain levels of copper, iron, and zinc were unaffected. The effects of phytic acid were modest on the expression of AβPP trafficking-associated protein AP180, autophagy-associated proteins (beclin-1, LC3B), sirtuin 1, the ratio of phosphorylated AMP-activated protein kinase (PAMPK) to AMPK, soluble Aβ1-40, and insoluble Aβ1-42. These results suggest that phytic acid may provide a viable treatment option for AD.


Microbiota and Pathogen Proteases Modulate Type III Secretion Activity in Enterohemorrhagic Escherichia coli.
Enteric pathogens have complex interactions with the gut microbiota. Most of what is known about them has focused on microbiota-derived metabolites or small molecules that serve as nutrients and/or signals to aid in growth or transcriptionally regulate virulence gene expression. A common virulence strategy is to express a type III secretion system (T3SS), which is a molecular syringe deployed by many Gram-negative pathogens to hijack host cell function. Enterohemorrhagic Escherichiacoli (EHEC) requires its T3SS to colonize the intestinal tract and cause disease. Here we report that a prominent member of the intestinal microbiota, Bacteroides thetaiotamicron (Bt), secretes proteases that cleave the translocon of the T3SS of EHEC to enhance effector translocation into host cells. This is in contrast from an endogenous protease from EHEC itself (namely, EspP) that cleaves the translocon protein EspB in a different site to limit effector translocation. The EspB protein forms the T3SS pore in mammalian cells, and pore proteins are conserved in the T3SSs from several pathogens. This is the first demonstration of a commensal species directly processing a pathogen's T3SS, posing a new paradigm for how the microbiota can influence the severity of disease caused by bacterial pathogens. Because T3SSs are employed by many pathogens, this phenomenon has broad implications to commensal-pathogen relationships.IMPORTANCE The gut microbiota is usually regarded as providing colonization resistance against enteric pathogens. However, some pathogens evolved to thrive with the aid of certain members of the microbiota. Several Gram-negative bacteria employ type three secretion systems (T3SSs), which are molecular syringes that deliver effector proteins to host cells, hijacking host cell function. Here we show that the T3SS of enterohemorrhagic E. coli (EHEC) is cleaved by self and microbiota-derived proteases. Self-cleavage limits effector translocation, while cleavage by the microbiota member Bacteroides thetaiotamicron (Bt) exacerbates effector translocation and lesion formation on epithelial cells.


Involvement of 5-HT2 receptors in chronic endothelial dysfunction after balloon injury of porcine coronary arteries.
Endothelium-dependent, pertussis toxin-sensitive relaxation to 5-hydroxytryptamine (5-HT) is impaired selectively after balloon injury of porcine coronary artery, followed by regeneration of the endothelial cells. The present study was designed to test the hypothesis that 5-HT, released from aggregating platelets, affects the progression of the endothelial dysfunction. Yorkshire pigs were assigned randomly to three groups: control group (standard diet), denudation group (high-cholesterol diet plus balloon denudation of the endothelium of coronary artery under fluoroscopy), and DV-7028-treated group (denudation group plus chronic treatment with the selective 5-HT2 receptor antagonist DV-7028, given from the first day on after balloon denudation). Four weeks after the denudation, quantitative angiography revealed that 5-HT injected into the coronary artery decreased the luminal diameter of the left anterior descending coronary artery at the denuded site in the denudation group but not in the control or the DV-7028-treated group. Then, animals were killed so we could study the endothelium-dependent responses of their coronary arteries in conventional organ chambers. The arteries from the denudation group exhibited less relaxation to 5-HT and sodium fluoride (a stimulant of G proteins) than those of the control group. Relaxations to 5-HT and sodium fluoride were greater in arteries from the DV-7028-treated group than in those from the denudation group. In contrast, the endothelium-dependent, pertussis toxin-insensitive relaxations to bradykinin and thrombin and the endothelium-independent relaxations to sodium nitroprusside and isoproterenol were not affected significantly by chronic treatment with DV-7028. These results suggest that 5-HT2 receptors are involved in the chronic progression of endothelial dysfunction after balloon denudation in the porcine coronary artery.


Surgical management of Graves disease in childhood and adolescence: an institutional experience.
Graves disease is the most common cause of hyperthyroidism in children. Medical therapy, radioiodine ablation, and thyroidectomy are all treatment options. To evaluate the safety and efficacy of operative therapy, we updated our operative experience with pediatric Graves disease at a single tertiary care center. The medical records of children <18 years old who underwent thyroidectomy for Graves disease between 1986-2003 were reviewed. We identified 78 patients (median age, 13.8 years; 87% female). The most common presenting signs and symptoms included heat intolerance (61%), decreased academic performance (50%), tremor (49%), and ophthalmopathy (43%). All patients had clinical and laboratory evidence of autoimmune thyrotoxicosis. Sixty-nine percent chose operative therapy because of failure of medical therapy or adverse drug reactions. Near-total thyroidectomy was the most common surgical procedure performed (65%). Pathology demonstrated previously unrecognized thyroid malignancies in 4 (5%) patients. Operative morbidities were transient and included hypoparathyroidism (6%) and recurrent laryngeal nerve neuropraxia (1%). Three (4%) patients who underwent subtotal thyroidectomy developed recurrent hyperthyroidism; all were treated successfully with radioiodine ablation. Of patients presenting with ophthalmopathy, 85% noted improvement postoperatively, while 1 (3%) patient experienced worsening of symptoms. Only 5% developed new-onset Graves ophthalmopathy after operation. Near-total thyroidectomy for Graves disease in children is safe and effective when performed by experienced thyroid surgeons. In addition to relief of systemic symptoms, the majority of patients presenting with Graves ophthalmopathy experienced improvement of their ocular disease after operation. In 5% of patients, surgical management allowed for detection and treatment of clinically occult thyroid malignancies.


Oral triiodothyronine for the prevention of thyroid hormone reduction in adult valvular cardiac surgery.
Treatment of non-thyroidal illness by intravenous triiodothyronine (T3) after cardiac surgery causes a disproportional elevation of hormone levels. The administration of oral T3, which has never been studied in this context, could cause physiological hormone levels. The aim of this study was to test oral T3 for the prevention of T3 reduction during the postoperative period of valvular cardiac surgery in adults. Eighteen patients who underwent cardiac surgery for valvular disease with invasive hemodynamic monitoring were randomly assigned to 2 groups: the T group received oral T3 (N = 8), 25 microg three times/day, initiated 24 h before surgery and maintained for 48 h and the NT group (N = 10) received placebo. Serum T3, thyroxine and thyrotropin were determined at baseline, 1 h before surgery, within 30 min of cardiopulmonary bypass and 6, 12, 24, and 48 h after removal of the aortic cross-clamp. Baseline T3 was similar in both groups (T: 119 +/- 13; NT: 131 +/- 9 ng/dL). Serum T3 increased during the first 24 h in the T group compared to the NT group (232 +/- 18 vs 151 +/- 13 ng/dL; P < 0.001). In the NT group, T3 was reduced by 24% (P = 0.007) 6 h after removal of the aortic cross-clamp, confirming the non-thyroidal illness syndrome. There were no differences in clinical or hemodynamic parameters between groups. Administration of oral T3 prevented its serum reduction after valvular cardiac surgery in adults, with normal serum levels for 48 h without disproportional elevations.


Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.


RETRACTED: Ras-ERK1/2 signaling accelerates the progression of colorectal cancer via mediation of H2BK5ac.
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Given the comments of Dr Elisabeth Bik regarding this article "… the Western blot bands in all 400+ papers are all very regularly spaced and have a smooth appearance in the shape of a dumbbell or tadpole, without any of the usual smudges or stains. All bands are placed on similar looking backgrounds, suggesting they were copy/pasted from other sources, or computer generated", the journal requested the authors to provide the raw data. However, the authors were not able to fulfil this request and therefore the Editor-in-Chief decided to retract the article.


Psychological and family factors associated with suicidal ideation in pre-adolescents.
To assess the psychological and family factors associated with suicidal ideation in pre-adolescent children, we studied a sample of 361 students, average age 9 years old. Two groups were formed, on the basis of the presence (n = 34) or absence (n = 44) of suicidal ideation. Suicidal ideation was assessed with the Children's Depression Inventory and the Children's Depression Rating Scale-Revised. Depression, hopelessness, self-esteem, and perceived family environment were compared in both the suicidal ideation and the control groups. Students with suicidal ideation generally presented greater depressive symptoms and hopelessness, and lower self-esteem and family expressiveness, although there were differences both between sexes, and when the variable depression was controlled. Identifying these risk factors in pre-adolescents may have an impact on prevention of suicidal behavior at higher risk ages.


Immune regulation by intralymphatic immunotherapy with modular allergen translocation MAT vaccine.
Allergen-specific immunotherapy (SIT) faces problems related to side effects and limited efficacy. Direct administration of allergen extracts into lymph nodes induces increased specific IgG production and T-cell responses using significantly lower allergen doses. In this study, mechanisms of immune regulation by MAT vaccines in vitro and in allergen-SIT of cat-allergic rhinitis patients, who received 3 inguinal intra-lymph node injections of MAT-Fel d 1 vaccine, were investigated in PBMC and cell cultures for specific T-cell proliferation, Fel d 1-tetramer-specific responses, and multiple immune regulatory molecules. MAT-Fel d 1 vaccine was efficiently internalized by antigen-presenting cells. This was followed by precaspase 1 cleavage to caspase 1 and secretion of IL-1β, indicating inflammasome activation. Mat-Fel d 1 induced specific T-cell proliferation and an IL-10- and IFN-γ-dominated T-cell responses with decreased Th2 cytokines at 100 times lower doses than Fel d 1. Induction of immune tolerance by MAT-Fel d 1-ILIT involved multiple mechanisms of immune suppression. Early Fel d 1-specific T-cell activation was followed by full T-cell unresponsiveness to allergen after 1 year in the MAT-Fel d 1 group, characterized by increased allergen-specific T regulatory cells, decreased circulating Fel d 1 tetramer-positive cells, increased IL-10 and FOXP3 expression, and change in the HR2/HR1 ratio toward HR2. This study demonstrates the induction of allergen tolerance after 3 intra-lymph node injections of MAT-Fel d 1 vaccine, mediated by increased cellular internalization of the allergen, activation of inflammasome, and generation of allergen-specific peripheral T-cell tolerance.


Modeling the airborne survival of influenza virus in a residential setting: the impacts of home humidification.
Laboratory research studies indicate that aerosolized influenza viruses survive for longer periods at low relative humidity (RH) conditions. Further analysis has shown that absolute humidity (AH) may be an improved predictor of virus survival in the environment. Maintaining airborne moisture levels that reduce survival of the virus in the air and on surfaces could be another tool for managing public health risks of influenza. A multi-zone indoor air quality model was used to evaluate the ability of portable humidifiers to control moisture content of the air and the potential related benefit of decreasing survival of influenza viruses in single-family residences. We modeled indoor AH and influenza virus concentrations during winter months (Northeast US) using the CONTAM multi-zone indoor air quality model. A two-story residential template was used under two different ventilation conditions - forced hot air and radiant heating. Humidity was evaluated on a room-specific and whole house basis. Estimates of emission rates for influenza virus were particle-size specific and derived from published studies and included emissions during both tidal breathing and coughing events. The survival of the influenza virus was determined based on the established relationship between AH and virus survival. The presence of a portable humidifier with an output of 0.16 kg water per hour in the bedroom resulted in an increase in median sleeping hours AH/RH levels of 11 to 19% compared to periods without a humidifier present. The associated percent decrease in influenza virus survival was 17.5 - 31.6%. Distribution of water vapor through a residence was estimated to yield 3 to 12% increases in AH/RH and 7.8-13.9% reductions in influenza virus survival. This modeling analysis demonstrates the potential benefit of portable residential humidifiers in reducing the survival of aerosolized influenza virus by controlling humidity indoors.


Causes of death among stillbirths.
Stillbirth affects 1 in 160 pregnancies in the United States, equal to the number of infant deaths each year. Rates are higher than those of other developed countries and have stagnated over the past decade. There is significant racial disparity in the rate of stillbirth that is unexplained. To ascertain the causes of stillbirth in a population that is diverse by race/ethnicity and geography. A population-based study from March 2006 to September 2008 with surveillance for all stillbirths at 20 weeks or later in 59 tertiary care and community hospitals in 5 catchment areas defined by state and county boundaries to ensure access to at least 90% of all deliveries. Termination of a live fetus was excluded. Standardized evaluations were performed at delivery. Medical history, fetal postmortem and placental pathology, karyotype, other laboratory tests, systematic assignment of causes of death. Of 663 women with stillbirth enrolled, 500 women consented to complete postmortem examinations of 512 neonates. A probable cause of death was found in 312 stillbirths (60.9%; 95% CI, 56.5%-65.2%) and possible or probable cause in 390 (76.2%; 95% CI, 72.2%-79.8%). The most common causes were obstetric conditions (150 [29.3%; 95% CI, 25.4%-33.5%]), placental abnormalities (121 [23.6%; 95% CI, 20.1%-27.6%]), fetal genetic/structural abnormalities (70 [13.7%; 95% CI, 10.9%-17.0%]), infection (66 [12.9%; 95% CI, 10.2%-16.2%]), umbilical cord abnormalities (53 [10.4%; 95% CI, 7.9%-13.4%]), hypertensive disorders (47 [9.2%; 95% CI, 6.9%-12.1%]), and other maternal medical conditions (40 [7.8%; 95% CI, 5.7%-10.6%]). A higher proportion of stillbirths in non-Hispanic black women compared with non-Hispanic white and Hispanic ones was associated with obstetric complications (43.5% [50] vs 23.7% [85]; difference, 19.8%; 95% CI, 9.7%-29.9%; P < .001) and infections (25.2% [29] vs 7.8% [28]; difference, 17.4%; 95% CI, 9.0%-25.8%; P < .001). Stillbirths occurring intrapartum and early in gestation were more common in non-Hispanic black women. Sources most likely to provide positive information regarding cause of death were placental histology (268 [52.3%; 95% CI, 47.9%-56.7%]), perinatal postmortem examination (161 [31.4%; 95% CI, 27.5%-35.7%]), and karyotype (32 of 357 with definitive results [9%; 95% CI, 6.3%-12.5%]). A systematic evaluation led to a probable or possible cause in the majority of stillbirths. Obstetric conditions and placental abnormalities were the most common causes of stillbirth, although the distribution differed by race/ethnicity.


Early biomarkers of stroke.
The diagnosis and management of acute ischemic stroke are limited by the lack of rapid diagnostic assays for use in an emergency setting. Computed tomography (CT) scanning is used to diagnose hemorrhagic stroke but is relatively ineffective (<33% sensitive) in detecting ischemic stroke. The ability to correlate blood-borne protein biomarkers with stroke phenotypes would aid in the development of such rapid tests. ELISAs for >50 protein biomarkers were developed for use on a high-throughput robotic workstation. These assays were used to screen plasma samples from 214 healthy donors and 223 patients diagnosed with stroke, including 82 patients diagnosed with acute ischemic stroke. Marker assay values were first compared by univariate analysis, and then the top markers were subjected to multivariate analysis to derive a marker panel algorithm for the prediction of stroke. The top markers from this analysis were S-100b (a marker of astrocytic activation), B-type neurotrophic growth factor, von Willebrand factor, matrix metalloproteinase-9, and monocyte chemotactic protein-1. In a panel algorithm in which three or more marker values above their respective cutoffs were scored as positive, these five markers provided a sensitivity of 92% at 93% specificity for ischemic stroke samples taken within 6 h from symptom onset. A marker panel approach to the diagnosis of stroke may provide a useful adjunct to CT scanning in the emergency setting.


Predictors and moderators of outcomes of HIV/STD sex risk reduction interventions in substance abuse treatment programs: a pooled analysis of two randomized controlled trials.
The objective of the current study was to examine predictors and moderators of response to two HIV sexual risk interventions of different content and duration for individuals in substance abuse treatment programs. Participants were recruited from community drug treatment programs participating in the National Institute on Drug Abuse Clinical Trials Network (CTN). Data were pooled from two parallel randomized controlled CTN studies (one with men and one with women) each examining the impact of a multi-session motivational and skills training program, in comparison to a single-session HIV education intervention, on the degree of reduction in unprotected sex from baseline to 3- and 6- month follow-ups. The findings were analyzed using a zero-inflated negative binomial (ZINB) model. Severity of drug use (p < .01), gender (p < .001), and age (p < .001) were significant main effect predictors of number of unprotected sexual occasions (USOs) at follow-up in the non-zero portion of the ZINB model (men, younger participants, and those with greater severity of drug/alcohol abuse have more USOs). Monogamous relationship status (p < .001) and race/ethnicity (p < .001) were significant predictors of having at least one USO vs. none (monogamous individuals and African Americans were more likely to have at least one USO). Significant moderators of intervention effectiveness included recent sex under the influence of drugs/alcohol (p < .01 in non-zero portion of model), duration of abuse of primary drug (p < .05 in non-zero portion of model), and Hispanic ethnicity (p < .01 in the zero portion, p < .05 in the non-zero portion of model). These predictor and moderator findings point to ways in which patients may be selected for the different HIV sexual risk reduction interventions and suggest potential avenues for further development of the interventions for increasing their effectiveness within certain subgroups.


Systematic discovery of genetic modulation by Jumonji histone demethylases in Drosophila.
Jumonji (JmjC) domain proteins influence gene expression and chromatin organization by way of histone demethylation, which provides a means to regulate the activity of genes across the genome. JmjC proteins have been associated with many human diseases including various cancers, developmental and neurological disorders, however, the shared biology and possible common contribution to organismal development and tissue homeostasis of all JmjC proteins remains unclear. Here, we systematically tested the function of all 13 Drosophila JmjC genes. Generation of molecularly defined null mutants revealed that loss of 8 out of 13 JmjC genes modify position effect variegation (PEV) phenotypes, consistent with their ascribed role in regulating chromatin organization. However, most JmjC genes do not critically regulate development, as 10 members are viable and fertile with no obvious developmental defects. Rather, we find that different JmjC mutants specifically alter the phenotypic outcomes in various sensitized genetic backgrounds. Our data demonstrate that, rather than controlling essential gene expression programs, Drosophila JmjC proteins generally act to "fine-tune" different biological processes.


Cerebrovascular Autoregulation Monitoring in the Management of Adult Severe Traumatic Brain Injury: A Delphi Consensus of Clinicians.
Several methods have been proposed to measure cerebrovascular autoregulation (CA) in traumatic brain injury (TBI), but the lack of a gold standard and the absence of prospective clinical data on risks, impact on care and outcomes of implementation of CA-guided management lead to uncertainty. To formulate statements using a Delphi consensus approach employing a group of expert clinicians, that reflect current knowledge of CA, aspects that can be implemented in TBI management and CA research priorities. A group of 25 international academic experts with clinical expertise in the management of adult severe TBI patients participated in this consensus process. Seventy-seven statements and multiple-choice questions were submitted to the group in two online surveys, followed by a face-to-face meeting and a third online survey. Participants received feedback on average scores and the rationale for resubmission or rephrasing of statements. Consensus on a statement was defined as agreement of more than 75% of participants. Consensus amongst participants was achieved on the importance of CA status in adult severe TBI pathophysiology, the dynamic non-binary nature of CA impairment, its association with outcome and the inadvisability of employing universal and absolute cerebral perfusion pressure targets. Consensus could not be reached on the accuracy, reliability and validation of any current CA assessment method. There was also no consensus on how to implement CA information in clinical management protocols, reflecting insufficient clinical evidence. The Delphi process resulted in 25 consensus statements addressing the pathophysiology of impaired CA, and its impact on cerebral perfusion pressure targets and outcome. A research agenda was proposed emphasizing the need for better validated CA assessment methods as well as the focused investigation of the application of CA-guided management in clinical care using prospective safety, feasibility and efficacy studies.


A computational framework to explore large-scale biosynthetic diversity.
Genome mining has become a key technology to exploit natural product diversity. Although initially performed on a single-genome basis, the process is now being scaled up to mine entire genera, strain collections and microbiomes. However, no bioinformatic framework is currently available for effectively analyzing datasets of this size and complexity. In the present study, a streamlined computational workflow is provided, consisting of two new software tools: the 'biosynthetic gene similarity clustering and prospecting engine' (BiG-SCAPE), which facilitates fast and interactive sequence similarity network analysis of biosynthetic gene clusters and gene cluster families; and the 'core analysis of syntenic orthologues to prioritize natural product gene clusters' (CORASON), which elucidates phylogenetic relationships within and across these families. BiG-SCAPE is validated by correlating its output to metabolomic data across 363 actinobacterial strains and the discovery potential of CORASON is demonstrated by comprehensively mapping biosynthetic diversity across a range of detoxin/rimosamide-related gene cluster families, culminating in the characterization of seven detoxin analogues.


The Effectiveness of Mindfulness-Based Interventions in the Perinatal Period: A Systematic Review and Meta-Analysis.
Perinatal mental health difficulties are associated with adverse consequences for parents and infants. However, the potential risks associated with the use of psychotropic medication for pregnant and breastfeeding women and the preferences expressed by women for non-pharmacological interventions mean it is important to ensure that effective psychological interventions are available. It has been argued that mindfulness-based interventions may offer a novel approach to treating perinatal mental health difficulties, but relatively little is known about their effectiveness with perinatal populations. This paper therefore presents a systematic review and meta-analysis of the effectiveness of mindfulness-based interventions for reducing depression, anxiety and stress and improving mindfulness skills in the perinatal period. A systematic review identified seventeen studies of mindfulness-based interventions in the perinatal period, including both controlled trials (n = 9) and pre-post uncontrolled studies (n = 8). Eight of these studies also included qualitative data. Hedge's g was used to assess uncontrolled and controlled effect sizes in separate meta-analyses, and a narrative synthesis of qualitative data was produced. Pre- to post-analyses showed significant reductions in depression, anxiety and stress and significant increases in mindfulness skills post intervention, each with small to medium effect sizes. Completion of the mindfulness-based interventions was reasonable with around three quarters of participants meeting study-defined criteria for engagement or completion where this was recorded. Qualitative data suggested that participants viewed mindfulness interventions positively. However, between-group analyses failed to find any significant post-intervention benefits for depression, anxiety or stress of mindfulness-based interventions in comparison to control conditions: effect sizes were negligible and it was conspicuous that intervention group participants did not appear to improve significantly more than controls in their mindfulness skills. The interventions offered often deviated from traditional mindfulness-based cognitive therapy or mindfulness-based stress reduction programmes, and there was also a tendency for studies to focus on healthy rather than clinical populations, and on antenatal rather than postnatal populations. It is argued that these and other limitations with the included studies and their interventions may have been partly responsible for the lack of significant between-group effects. The implications of the findings and recommendations for future research are discussed.


Immunomodulatory action of dietary fish oil and targeted deletion of intestinal epithelial cell PPARδ in inflammation-induced colon carcinogenesis.
The ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR)-δ is highly expressed in colonic epithelial cells; however, the role of PPARδ ligands, such as fatty acids, in mucosal inflammation and malignant transformation has not been clarified. Recent evidence suggests that the anti-inflammatory/chemoprotective properties of fish oil (FO)-derived n-3 polyunsaturated fatty acids (PUFAs) may be partly mediated by PPARδ. Therefore, we assessed the role of PPARδ in modulating the effects of dietary n-3 PUFAs by targeted deletion of intestinal epithelial cell PPARδ (PPARδ(ΔIEpC)). Subsequently, we documented changes in colon tumorigenesis and the inflammatory microenvironment, i.e., local [mesenteric lymph node (MLN)] and systemic (spleen) T cell activation. Animals were fed chemopromotive [corn oil (CO)] or chemoprotective (FO) diets during the induction of chronic inflammation/carcinogenesis. Tumor incidence was similar in control and PPARδ(ΔIEpC) mice. FO reduced mucosal injury, tumor incidence, colonic STAT3 activation, and inflammatory cytokine gene expression, independent of PPARδ genotype. CD8(+) T cell recruitment into MLNs was suppressed in PPARδ(ΔIEpC) mice. Similarly, FO reduced CD8(+) T cell numbers in the MLN. Dietary FO independently modulated MLN CD4(+) T cell activation status by decreasing CD44 expression. CD11a expression by MLN CD4(+) T cells was downregulated in PPARδ(ΔIEpC) mice. Lastly, splenic CD62L expression was downregulated in PPARδ(ΔIEpC) CD4(+) and CD8(+) T cells. These data demonstrate that expression of intestinal epithelial cell PPARδ does not influence azoxymethane/dextran sodium sulfate-induced colon tumor incidence. Moreover, we provide new evidence that dietary n-3 PUFAs attenuate intestinal inflammation in an intestinal epithelial cell PPARδ-independent manner.


Discontinuity of human presence at Atapuerca during the early Middle Pleistocene: a matter of ecological competition?
Increasing evidence suggests that the European human settlement is older than 1.2 Ma. However, there is a fierce debate about the continuity or discontinuity of the early human settlement of Europe. In particular, evidence of human presence in the interval 0.7-0.5 Ma is scarce in comparison with evidence for the previous and later periods. Here, we present a case study in which the environmental conditions at Sierra de Atapuerca in the early Middle Pleistocene, a period without evidence of human presence, are compared with the conditions in the previous period, for which a relatively intense human occupation is documented. With this objective in mind, the available resources for a human population and the intensity of competition between secondary consumers during the two periods are compared using a mathematical model. The Gran Dolina site TD8 level, dated to 0.7-0.6 Ma, is taken as representative of the period during which Atapuerca was apparently not occupied by humans. Conditions at TD8 are compared with those of the previous period, represented by the TD6-2 level, which has yielded abundant evidence of intense human occupation. The results show that survival opportunities for a hypothetical human population were lower at TD8 than they were at TD6-2. Increased resource competition between secondary consumers arises as a possible explanation for the absence of human occupation at Atapuerca in the early Middle Pleistocene.


Effectiveness of six core strategies based on trauma informed care in reducing seclusions and restraints at a child and adolescent psychiatric hospital.
The purpose of the study was to determine the effectiveness of six core strategies based on trauma informed care in reducing the use of seclusion and restraints with hospitalized youth. The hospital staff received training in March 2005 in six core strategies that are based on trauma informed care. Medical records were reviewed for youth admitted between July 2004 and March 2007. Data were collected on demographics, including age, gender, ethnicity, number of admissions, type of admissions, length of stay, psychiatric diagnosis, number of seclusions, and restraints. Four hundred fifty-eight youth (females 276/males 182) were admitted between July 2004 and March 2007. Seventy-nine patients or 17.2% (females 44/males 35) required 278 seclusions/restraints (159 seclusions/119 restraints), with average number of episodes 3.5/patient (range 1-28). Thirty-seven children and adolescents placed in seclusion and/or restraints had three or more episodes. In the first six months of study, the number of seclusions/restraints episodes were 93 (73 seclusions/20 restraints), involving 22 children and adolescents (females 11/males 11). Comparatively, in final six months of study following the training program, there were 31 episodes (6 seclusions/25 restraints) involving 11 children and adolescents (females 7/males 4). The major diagnoses of the youth placed in seclusion and/or restraints were disruptive behavior disorders (61%) and mood disorders (52%). This study shows downward trend in seclusions/restraints among hospitalized youth after implementation of National Association of State Mental Health Program Directors six core strategies based on trauma informed care.


Using Standardized Patients to Assess Hospitalist Communication Skills.
Standardized patients (SPs) have been used to assess communication skills in undergraduate medical education, but no published studies describe the use of SPs in assessing practicing physicians on their communication skills. In this study, done with 23 hospitalists at a large urban academic hospital, 3 SP scenarios, daily rounding, discharge, and interacting with a difficult patient, were created. After each encounter, each hospitalist reviewed their videotape and received feedback from their SP based on a checklist that had 3 core domains: Listen, Courtesy and Respect, and Explain. These domains correlated with the 3 questions in the Hospital Consumer Assessment of Healthcare Providers and Systems survey that relate to doctors. Hospitalists performed significantly better in the Listen domain, with a mean percent adequate score of 90.2% (95% confidence interval [CI], 72.2%-100%; 𝑃 < 0.05), and significantly worse in the Explain domain, with a mean percent adequate score of 65.0% (95% CI, 49.2%-83.6%; 𝑃 < 0.05). Checklist items in the Explain domain that were most commonly not performed adequately were summarizing information at the end of the encounter, teach back, encouraging additional questions, managing team and self-up, setting expectations about length of stay, and timing of tests. After the SP encounters, hospitalists felt more confident in their communication skills. SPs can be used to assess and give feedback to hospitalists and increase confidence in several aspects of communication.


Chronic benign neutropenia among Chinese children.
To delineate the clinical behaviour of chronic benign neutropenia in Chinese children in Hong Kong. Retrospective study. University teaching hospital, Hong Kong. All infants and children with absolute neutrophil count of 1.5 x 10(9) /L or lower for more than 3 months. Development of significant infection, and achievement of remission. Twenty-four children with chronic benign neutropenia were identified between 1992 and 2001. Their median age of diagnosis was 9 months. The mean (standard deviation) initial absolute neutrophil count was 0.28 x 10(9) /L (0.24 x 10(9) /L). Twenty-three patients presented with infection. Of the 19 patients tested, four (21%) were positive for anti-neutrophil antibodies. Bone marrow examination was performed in 17 patients: nine had normal results, but six showed evidence of peripheral consumption, one showed late maturation arrest at band stage, and one showed phagocytosis of myeloid cells by histiocytes. The overall hospitalised infection rate was 51.6 episodes per 1000 patient-months. Ten percent of cases were considered 'significant' infections and required hospital admission with either surgical intervention or intravenous therapy (antibiotics or fluid replacement). In the first year of diagnosis, more than 80% of patients had their lowest absolute neutrophil count (mean, 0.16 x 10(9) /L; standard deviation, 0.11 x 10(9) /L). Granulocyte-colony stimulating factor was used to treat three patients and induced transient elevation of absolute neutrophil count in all three. The projected remission rate was 55.4% at 3 years. Even for those with persistent disease, there was significant recovery in absolute neutrophil count to a mean of 0.5 x 10(9) /L (P<0.01). Patients with chronic benign neutropenia experienced a relatively benign clinical course regardless of their remission status. Only a small proportion of patients developed significant infections. A multi-centre prospective study may help identify predictive factors of remission.


Genotype calling in tetraploid species from bi-allelic marker data using mixture models.
Automated genotype calling in tetraploid species was until recently not possible, which hampered genetic analysis. Modern genotyping assays often produce two signals, one for each allele of a bi-allelic marker. While ample software is available to obtain genotypes (homozygous for either allele, or heterozygous) for diploid species from these signals, such software is not available for tetraploid species which may be scored as five alternative genotypes (aaaa, baaa, bbaa, bbba and bbbb; nulliplex to quadruplex). We present a novel algorithm, implemented in the R package fitTetra, to assign genotypes for bi-allelic markers to tetraploid samples from genotyping assays that produce intensity signals for both alleles. The algorithm is based on the fitting of several mixture models with five components, one for each of the five possible genotypes. The models have different numbers of parameters specifying the relation between the five component means, and some of them impose a constraint on the mixing proportions to conform to Hardy-Weinberg equilibrium (HWE) ratios. The software rejects markers that do not allow a reliable genotyping for the majority of the samples, and it assigns a missing score to samples that cannot be scored into one of the five possible genotypes with sufficient confidence. We have validated the software with data of a collection of 224 potato varieties assayed with an Illumina GoldenGate™ 384 SNP array and shown that all SNPs with informative ratio distributions are fitted. Almost all fitted models appear to be correct based on visual inspection and comparison with diploid samples. When the collection of potato varieties is analyzed as if it were a population, almost all markers seem to be in Hardy-Weinberg equilibrium. The R package fitTetra is freely available under the GNU Public License from http://www.plantbreeding.wur.nl/UK/software_fitTetra.html and as Additional files with this article.


Superior underwater vision in a human population of sea gypsies.
Humans are poorly adapted for underwater vision. In air, the curved corneal surface accounts for two-thirds of the eye's refractive power, and this is lost when air is replaced by water. Despite this, some tribes of sea gypsies in Southeast Asia live off the sea, and the children collect food from the sea floor without the use of visual aids. This is a remarkable feat when one considers that the human eye is not focused underwater and small objects should remain unresolved. We have measured the visual acuity of children in a sea gypsy population, the Moken, and found that the children see much better underwater than one might expect. Their underwater acuity (6.06 cycles/degree) is more than twice as good as that of European children (2.95 cycles/degree). Our investigations show that the Moken children achieve their superior underwater vision by maximally constricting the pupil (1.96 mm compared to 2.50 mm in European children) and by accommodating to the known limit of human performance (15-16 D). This extreme reaction-which is routine in Moken children-is completely absent in European children. Because they are completely dependent on the sea, the Moken are very likely to derive great benefit from this strategy.


Effects upon metabolic pathways and energy production by Sb(III) and As(III)/Sb(III)-oxidase gene aioA in Agrobacterium tumefaciens GW4.
Agrobacterium tumefaciens GW4 is a heterotrophic arsenite [As(III)]/antimonite [Sb(III)]-oxidizing strain. The As(III) oxidase AioAB is responsible for As(III) oxidation in the periplasm and it is also involved in Sb(III) oxidation in Agrobacterium tumefaciens 5A. In addition, Sb(III) oxidase AnoA and cellular H2O2 are also responsible for Sb(III) oxidation in strain GW4. However, the deletion of aioA increased the Sb(III) oxidation efficiency in strain GW4. In the present study, we found that the cell mobility to Sb(III), ATP and NADH contents and heat release were also increased by Sb(III) and more significantly in the aioA mutant. Proteomics and transcriptional analyses showed that proteins/genes involved in Sb(III) oxidation and resistance, stress responses, carbon metabolism, cell mobility, phosphonate and phosphinate metabolism, and amino acid and nucleotide metabolism were induced by Sb(III) and were more significantly induced in the aioA mutant. The results suggested that Sb(III) oxidation may produce energy. In addition, without periplasmic AioAB, more Sb(III) would enter bacterial cells, however, the cytoplasmic AnoA and the oxidative stress response proteins were significantly up-regulated, which may contribute to the increased Sb(III) oxidation efficiency. Moreover, the carbon metabolism was also activated to generate more energy against Sb(III) stress. The generated energy may be used in Sb transportation, DNA repair, amino acid synthesis, and cell mobility, and may be released in the form of heat.


Longterm changes of silicon photodiodes and their use for photometric standardization.
A secondary standard silicon photodiode matched with a V-lambda filter was calibrated against primary standard, self-calibrated inversion layer silicon photodiodes, to achieve a high accuracy photometer, according to the new definition of the canadela (the photometric base unit). The measured several percent/year specular spectral reflectance change of the windowless primary standard photodiodes was eliminated by their repeated self-calibration. This self-calibration also eliminated the measured several tenth of a percent/year spectral response change of the secondary standard silicon photodiode. The secondary standard detector could be a nonunity quantum efficiency light detector. The spectral response calibration of the V-lambda matched detector of medium spectral mismatch (f(1)= 3.0%) against the absolute spectral responses of three self-calibrated photodiodes resulted in a standard deviation of 0.17% in luminous flux (lumen) calibration. Also illuminance (lux) and light intensity (candela) calibrations were derived from the above primary photometric calibration. It is shown that the V-lambda matched photometer with the above spectral calibration can be used for accurate photometric measurements for all kinds of light sources of known spectral power distribution.


PDGF-BB, IGF-I and mechanical load stimulate DNA synthesis in avian tendon fibroblasts in vitro.
Resident cells in the surface epitenon and internal compartment of flexor tendons are subjected to cyclic mechanical load as muscle contracts to move limbs or digits. Tendons are largely tensile load bearing tissues and are highly matrix intensive with nondividing cells providing maintenance functions. However, when an injury occurs, tendon cells are stimulated to divide by activated endogenous growth factors and those from platelets and plasma. We hypothesize that tendon cells detect mechanical load signals but do not interpret such signals as mitogenic unless an active growth factor is present. We have used an in vitro mechanical load model, application of cyclic strain to cells cultured on flexible bottomed culture plates, to test the hypothesis that tendon cells require platelet-derived growth factor (PDGF-BB) and insulin-like growth factor-I (IGF-I) in addition to mechanical load to stimulate DNA synthesis. In addition, we demonstrate that in avian tendon cells, load and growth factors stimulate phosphorylation of tyrosine residues in multiple proteins, including pp60src, a protein kinase that phosphorylates receptor protein tyrosine kinases. A lack of mitogenic responsiveness to mechanical load alone by tendon cells may be a characteristic of a regulatory pathway that modulates cell division.


Cyclic dominance in evolutionary games: a review.
Rock is wrapped by paper, paper is cut by scissors and scissors are crushed by rock. This simple game is popular among children and adults to decide on trivial disputes that have no obvious winner, but cyclic dominance is also at the heart of predator-prey interactions, the mating strategy of side-blotched lizards, the overgrowth of marine sessile organisms and competition in microbial populations. Cyclical interactions also emerge spontaneously in evolutionary games entailing volunteering, reward, punishment, and in fact are common when the competing strategies are three or more, regardless of the particularities of the game. Here, we review recent advances on the rock-paper-scissors (RPS) and related evolutionary games, focusing, in particular, on pattern formation, the impact of mobility and the spontaneous emergence of cyclic dominance. We also review mean-field and zero-dimensional RPS models and the application of the complex Ginzburg-Landau equation, and we highlight the importance and usefulness of statistical physics for the successful study of large-scale ecological systems. Directions for future research, related, for example, to dynamical effects of coevolutionary rules and invasion reversals owing to multi-point interactions, are also outlined.


LPATH: A semi-automated Python tool for clustering molecular pathways.
The pathways by which a molecular process transitions to a target state are highly sought-after as direct views of a transition mechanism. While great strides have been made in the physics-based simulation of such pathways, the analysis of these pathways can be a major challenge due to their diversity and variable lengths. Here we present the LPATH Python tool, which implements a semi-automated method for linguistics-assisted clustering of pathways into distinct classes (or routes). This method involves three steps: 1) discretizing the configurational space into key states, 2) extracting a text-string sequence of key visited states for each pathway, and 3) pairwise matching of pathways based on a text-string similarity score. To circumvent the prohibitive memory requirements of the first step, we have implemented a general two-stage method for clustering conformational states that exploits machine learning. LPATH is primarily designed for use with the WESTPA software for weighted ensemble simulations; however, the tool can also be applied to conventional simulations. As demonstrated for the C7eq to C7ax conformational transition of alanine dipeptide, LPATH provides physically reasonable classes of pathways and corresponding probabilities.


Two regression methods for estimation of a two-parameter Weibull distribution for reliability of dental materials.
Comparison of estimation of the two-parameter Weibull distribution by two least squares (LS) methods with interchanged axes. Investigation of the influence of plotting positions and sample size. Derivation of 95% confidence intervals (95%CI) for Weibull parameters applicable in the context of LS estimation. Preparation of a free available Excel template for computation of point estimates and 95%CI for Weibull modulus (m) and characteristic strength (s). Monte Carlo simulation covering a wide range of Weibull parameters and sample sizes. Mathematical derivation of formulae for computation of 95%CI according to a Menon-type approach for both m and s. Empirical proof that the practically observed coverage agrees with the nominal one of 95%. Relative and absolute performance of LS estimators depended on sample size, plotting positions and parameter to be estimated. For most situations they outperformed the corresponding Maximum Likelihood (ML) estimator in terms of bias, while precision was almost the same. Naïve Wald-type 95%CI based on standard errors of LS regression coefficients did not reach targeted coverage. An easy-to-apply alternative based on asymptotic standard errors (Menon 95%CI) resulted in excellent coverage. Accuracy of the LS methods for Weibull modulus and characteristic strength essentially depend on plotting position and sample size. Large sample sizes (n≥30) support a credible Weibull parameters estimation. An important complement of the point estimates of Weibull parameters is provided by the Menon 95%CI. A free available Excel template considerably facilitating computation of point and interval estimates of Weibull parameters is provided.


Bacterial Biosensors for in Vivo Spatiotemporal Mapping of Root Secretion.
Plants engineer the rhizosphere to their advantage by secreting various nutrients and secondary metabolites. Coupling transcriptomic and metabolomic analyses of the pea (Pisum sativum) rhizosphere, a suite of bioreporters has been developed in Rhizobium leguminosarum bv viciae strain 3841, and these detect metabolites secreted by roots in space and time. Fourteen bacterial lux fusion bioreporters, specific for sugars, polyols, amino acids, organic acids, or flavonoids, have been validated in vitro and in vivo. Using different bacterial mutants (nodC and nifH), the process of colonization and symbiosis has been analyzed, revealing compounds important in the different steps of the rhizobium-legume association. Dicarboxylates and sucrose are the main carbon sources within the nodules; in ineffective (nifH) nodules, particularly low levels of sucrose were observed, suggesting that plant sanctions affect carbon supply to nodules. In contrast, high myo-inositol levels were observed prior to nodule formation and also in nifH senescent nodules. Amino acid biosensors showed different patterns: a γ-aminobutyrate biosensor was active only inside nodules, whereas the phenylalanine bioreporter showed a high signal also in the rhizosphere. The bioreporters were further validated in vetch (Vicia hirsuta), producing similar results. In addition, vetch exhibited a local increase of nod gene-inducing flavonoids at sites where nodules developed subsequently. These bioreporters will be particularly helpful in understanding the dynamics of root exudation and the role of different molecules secreted into the rhizosphere.


Sleep-wake disorders in Alzheimer's disease: further genetic analyses in relation to objective sleep measures.
This paper presents updated analyses on the genetic associations of sleep disruption in individuals with Alzheimer's disease (AD). We published previously a study of the association between single nucleotide polymorphisms (SNPs) found in eight genes related to circadian rhythms and objective measures of sleep-wake disturbances in 124 individuals with AD. Here, we present new relevant analyses using polygenic risk scores (PRS) and variable number tandem repeats (VNTRs) enumerations. PRS were calculated using the genetic data from the original participants and relevant genome wide association studies (GWAS). VNTRs for the same circadian rhythm genes studied with SNPs were obtained from a separate cohort of participants using whole genome sequencing (WGS). Objectively (wrist actigraphy) determined wake after sleep onset (WASO) was used as a measure of sleep disruption. None of the PRS were associated with sleep disturbance. Computer analyses using VNTRseek software generated a total of 30 VNTRs for the circadian-related genes but none appear relevant to our objective sleep measure. In addition, of 71 neurotransmitter function-related genes, 29 genes had VNTRs that differed from the reference VNTR, but it was not clear if any of these might affect circadian function in AD patients. Although we have not found in either the current analyses or in our previous published analyses of SNPs any direct linkages between identified genetic factors and WASO, research in this area remains in its infancy.


Real-time observation of aortic vessel dilation through delivery of sodium nitroprusside via slow release mesoporous nanoparticles.
Spherical mesoporous nanoparticles (MNPs) with a diameter of ∼100nm were synthesised via a sol-gel method in the presences of organic template (with and without fluorescein dye encapsulation). The template molecules were removed by acidic extraction to form a regular pore lattice structure. The nanoparticle size and morphology were analysed using transmission electron microscopy and dynamic light scattering analysis. The MNPs were further characterised by zeta potential, nitrogen adsorption measurements and infra-red spectroscopy. The interior pores had an average diameter of ∼3nm and were loaded with an endothelial-independent vasodilator, sodium nitroprusside (SNP). The optimal drug loading and drug release was determined in high potassium physiological salt solution using dialysis and atomic absorption spectroscopy. We demonstrate that the initial instantaneous release is due to the surface desorption of the drug followed by diffusion from the pores. Furthermore, these drug loaded MNPs (with and without fluorescein dye encapsulation) were added to viable aortic vessels and release in real-time was observed, ex vivo. MNPs and loaded with and without SNP were incubated with the vessel (at 1.96×10(12)NPmL(-1)) over a 3h time period. The real-time exposure to unloaded MNPs resulted in a small attenuation in constriction that occurred after approximately 1h. In contrast, MNPs loaded with SNP led to a rapid relaxation of aortic vessels that was sustained over the 3h period (p<0.001).


Structural transformation of h-BN overlayers on Pt(111) in oxidative atmospheres.
Interaction of hexagonal boron nitride (h-BN) with gases is of great importance for its properties and applications. In the present work, the structural changes of h-BN overlayers on Pt(111) in oxidative atmospheres including O2 and NO2 have been investigated by using low energy electron microscopy, Auger electron spectroscopy, X-ray photoelectron spectroscopy (XPS), and near ambient pressure XPS. We find that h-BN islands can be intercalated by oxygen in 10-6 Torr O2 at 200 °C, while oxygen intercalation of full layer h-BN around 200 °C requires near ambient pressure O2 (0.1 Torr) or such a strong oxidant as NO2 (10-6 Torr). h-BN overlayers can be etched away in the gases at much high temperatures, e.g. 800 °C. Upon mild oxidation in O2 or NO2 at temperatures of 400-450 °C, h-BN is transformed to boron oxide (BOx) overlayers, which can be converted back to h-BN by heating in NH3 at 800 °C.


Adhesion of Pseudomonas fluorescens onto nanophase materials.
Nanobiotechnology is a growing area of research, primarily due to the potentially numerous applications of new synthetic nanomaterials in engineering/science. Although various definitions have been given for the word 'nanomaterials' by many different experts, the commonly accepted one refers to nanomaterials as those materials which possess grains, particles, fibres, or other constituent components that have one dimension specifically less than 100 nm. In biological applications, most of the research to date has focused on the interactions between mammalian cells and synthetic nanophase surfaces for the creation of better tissue engineering materials. Although mammalian cells have shown a definite positive response to nanophase materials, information on bacterial interactions with nanophase materials remains elusive. For this reason, this study was designed to assess the adhesion of Pseudomonas fluorescens on nanophase compared to conventional grain size alumina substrates. Results provide the first evidence of increased adhesion of Pseudomonas fluorescens on alumina with nanometre compared to conventional grain sizes. To understand more about the process, polymer (specifically, poly-lactic-co-glycolic acid or PLGA) casts were made of the conventional and nanostructured alumina surfaces. Results showed similar increased Pseudomonas fluorescens capture on PLGA casts of nanostructured compared to conventional alumina as on the alumina itself. For these reasons, a key material property shown to enhance bacterial adhesion was elucidated in this study for both polymers and ceramics: nanostructured surface features.


Importance and process of feedback in undergraduate medical education in Saudi Arabia.
Feedback is an essential element in the process of students' learning and development. This study aimed to explore the views of medical students regarding the importance and process of feedback in their medical education. A cross-sectional questionnaire-based study was conducted in our college of medicine. The questionnaire included questions to assess the students' views about the importance and the need of feedback in the learning process and whether feed-back should follow certain or all forms of assessment. In addition, the questionnaire contained questions that aimed to explore students' views about the contents and process of feedback. One hundred and eighty-six male medical students participated in this study. While the majority of students (85%) indicated that feedback was important for their learning and expressed their need for regular feedback during their study, only about 20% of them indicated receiving regular feed-back. Senior students perceived that they received feedback less frequently than their junior colleagues' (P <0.05). The majority of the participants expressed their interest into receiving an immediate feedback after their summative and formative assessment. Students think that feedback should be balanced and include a suggested plan for their future learning process. Senior students showed a higher preference to have feedback that also contained points related to their strengths more than juniors. Students also indicated their preference to have one-to-one and written feed-back more than feedback that was conveyed in groups and verbally. These issues are of high importance and should be considered for planning and implementing an effective feedback system.


Chocolate Under Threat from Old and New Cacao Diseases.
Theobroma cacao, the source of chocolate, is affected by destructive diseases wherever it is grown. Some diseases are endemic; however, as cacao was disseminated from the Amazon rain forest to new cultivation sites it encountered new pathogens. Two well-established diseases cause the greatest losses: black pod rot, caused by several species of Phytophthora, and witches' broom of cacao, caused by Moniliophthora perniciosa. Phytophthora megakarya causes the severest damage in the main cacao producing countries in West Africa, while P. palmivora causes significant losses globally. M. perniciosa is related to a sister basidiomycete species, M. roreri which causes frosty pod rot. These Moniliophthora species only occur in South and Central America, where they have significantly limited production since the beginnings of cacao cultivation. The basidiomycete Ceratobasidium theobromae causing vascular-streak dieback occurs only in South-East Asia and remains poorly understood. Cacao swollen shoot disease caused by Cacao swollen shoot virus is rapidly spreading in West Africa. This review presents contemporary research on the biology, taxonomy and genomics of what are often new-encounter pathogens, as well as the management of the diseases they cause.


Stabilization of the prevalence of childhood obesity in Switzerland.
The prevalence of childhood obesity is increasing rapidly in most industrialised countries, but several countries, including Switzerland, have recently reported a levelling off or even a reversal of this alarming trend. Our aim was to evaluate the prevalence of childhood obesity in a national sample of Swiss school children recruited to assess iodine nutrition and with this to reconfirm a recently shown stabilising trend. Using a probability-proportionate-to-size cluster sampling, 6 to 12 year old children (n = 907) were recruited in a study of iodine status in Switzerland. Height and weight were measured and body mass index calculated in all children. The prevalence of overweight detected was 12.5% (SE = 1.6) in boys and 12.8% (1.6) in girls while 6.2% (1.1) of boys and 4.2% (0.9) of girls were classified as obese. The highest prevalence of overweight and obesity were found in the Southern region and in bigger cities (>100000 inhabitants). Compared to the most recent national study in 2007, the prevalence was slightly higher, but the differences were not significant, suggesting negative sampling bias does not strongly affect surveys of paediatric adiposity in Switzerland. This present study clearly confirms the stabilisation of the prevalence of childhood overweight and obesity in Switzerland.


Lithium-assisted plastic deformation of silicon electrodes in lithium-ion batteries: a first-principles theoretical study.
Silicon can host a large amount of lithium, making it a promising electrode for high-capacity lithium-ion batteries. Recent experiments indicate that silicon experiences large plastic deformation upon Li absorption, which can significantly decrease the stresses induced by lithiation and thus mitigate fracture failure of electrodes. These issues become especially relevant in nanostructured electrodes with confined geometries. On the basis of first-principles calculations, we present a study of the microscopic deformation mechanism of lithiated silicon at relatively low Li concentration, which captures the onset of plasticity induced by lithiation. We find that lithium insertion leads to breaking of Si-Si bonds and formation of weaker bonds between neighboring Si and Li atoms, which results in a decrease in Young's modulus, a reduction in strength, and a brittle-to-ductile transition with increasing Li concentration. The microscopic mechanism of large plastic deformation is attributed to continuous lithium-assisted breaking and re-forming of Si-Si bonds and the creation of nanopores.


Immune defenses against Batrachochytrium dendrobatidis, a fungus linked to global amphibian declines, in the South African clawed frog, Xenopus laevis.
Batrachochytrium dendrobatidis is a chytrid fungus that causes the lethal skin disease chytridiomycosis in amphibians. It is regarded as an emerging infectious disease affecting diverse amphibian populations in many parts of the world. Because there are few model amphibian species for immunological studies, little is known about immune defenses against B. dendrobatidis. We show here that the South African clawed frog, Xenopus laevis, is a suitable model for investigating immunity to this pathogen. After an experimental exposure, a mild infection developed over 20 to 30 days and declined by 45 days postexposure. Either purified antimicrobial peptides or mixtures of peptides in the skin mucus inhibited B. dendrobatidis growth in vitro. Skin peptide secretion was maximally induced by injection of norepinephrine, and this treatment resulted in sustained skin peptide depletion and increased susceptibility to infection. Sublethal X-irradiation of frogs decreased leukocyte numbers in the spleen and resulted in greater susceptibility to infection. Immunization against B. dendrobatidis induced elevated pathogen-specific IgM and IgY serum antibodies. Mucus secretions from X. laevis previously exposed to B. dendrobatidis contained significant amounts of IgM, IgY, and IgX antibodies that bind to B. dendrobatidis. These data strongly suggest that both innate and adaptive immune defenses are involved in the resistance of X. laevis to lethal B. dendrobatidis infections.


Lovastatin decreases coenzyme Q levels in rats.
Lovastatin is used for the treatment of hypercholesterolemia. It functions by inhibiting the enzyme, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (EC 220.127.116.11), that is required for the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonic acid. Since biosynthesis of both cholesterol and coenzyme Q (CoQ) requires mevalonic acid as a precursor, it was considered that lovastatin therapy would also result in a lowering of cellular CoQ levels. This study was conducted to determine whether lovastatin treatment does decrease CoQ levels and whether such decreases can be prevented by CoQ supplementation. Forty-five adult male Holtzman rats were randomly assigned to one of three treatment groups. Controls were fed ground laboratory rat chow ad libitum. The other two groups were fed ground laboratory rat chow containing 400 mg of lovastatin per kg of diet ad libitum. One of the lovastatin-fed groups received CoQ10 (15 mg per kg of body weight) daily via stomach intubation. After 4 weeks, samples of heart, liver, and blood were analyzed for CoQ concentrations. Results indicated that CoQ concentrations in all tissues analyzed were decreased in lovastatin-treated rats. Lovastatin-treated animals that were supplemented with CoQ10 had blood, heart, and liver CoQ10 concentrations that approximated or exceeded those of control animals. It is concluded that lovastatin does indeed lower tissue concentrations of CoQ and that a return to normal can be achieved by supplementation with CoQ.


Difference equation for tracking perturbations in systems of Boolean nested canalyzing functions.
This paper studies the spread of perturbations through networks composed of Boolean functions with special canalyzing properties. Canalyzing functions have the property that at least for one value of one of the inputs the output is fixed, irrespective of the values of the other inputs. In this paper the focus is on partially nested canalyzing functions, in which multiple, but not all inputs have this property in a cascading fashion. They naturally describe many relationships in real networks. For example, in a gene regulatory network, the statement "if gene A is expressed, then gene B is not expressed regardless of the states of other genes" implies that A is canalyzing. On the other hand, the additional statement "if gene A is not expressed, and gene C is expressed, then gene B is automatically expressed; otherwise gene B's state is determined by some other type of rule" implies that gene B is expressed by a partially nested canalyzing function with more than two variables, but with two canalyzing variables. In this paper a difference equation model of the probability that a network node's value is affected by an initial perturbation over time is developed, analyzed, and validated numerically. It is shown that the effect of a perturbation decreases towards zero over time if the Boolean functions are canalyzing in sufficiently many variables. The maximum dynamical impact of a perturbation is shown to be comparable to the average impact for a wide range of values of the average sensitivity of the network. Percolation limits are also explored; these are parameter values which generate a transition of the expected perturbation effect to zero as other parameters are varied, so that the initial perturbation does not scale up with the parameters once the percolation limits are reached.


Addressing the vaccine confidence gap.
Vaccines--often lauded as one of the greatest public health interventions--are losing public confidence. Some vaccine experts have referred to this decline in confidence as a crisis. We discuss some of the characteristics of the changing global environment that are contributing to increased public questioning of vaccines, and outline some of the specific determinants of public trust. Public decision making related to vaccine acceptance is neither driven by scientific nor economic evidence alone, but is also driven by a mix of psychological, sociocultural, and political factors, all of which need to be understood and taken into account by policy and other decision makers. Public trust in vaccines is highly variable and building trust depends on understanding perceptions of vaccines and vaccine risks, historical experiences, religious or political affiliations, and socioeconomic status. Although provision of accurate, scientifically based evidence on the risk-benefit ratios of vaccines is crucial, it is not enough to redress the gap between current levels of public confidence in vaccines and levels of trust needed to ensure adequate and sustained vaccine coverage. We call for more research not just on individual determinants of public trust, but on what mix of factors are most likely to sustain public trust. The vaccine community demands rigorous evidence on vaccine efficacy and safety and technical and operational feasibility when introducing a new vaccine, but has been negligent in demanding equally rigorous research to understand the psychological, social, and political factors that affect public trust in vaccines.


PKC-θ function at the immunological synapse: prospects for therapeutic targeting.
Protein kinase C (PKC)-θ regulates conventional effector T (Teff) cell function. Since this initial finding, it has become clear that the role of PKC-θ in T cells is complex. PKC-θ plays a central role in Teff cell activation and survival, and negatively regulates stability of the immunological synapse (IS). Recent studies demonstrated that PKC-θ is required for the development of natural CD4(+)Foxp3(+) regulatory T (Treg) cells, and mediates negative regulation of Treg cell function. Here, we examine the role of PKC-θ in the IS, evidence for its distinct localization in Treg cells and the therapeutic implications of inhibiting PKC-θ in Teff cells, to reduce effector function, and in Treg cells, to increase suppressor function, for the prevention and treatment of autoimmune and alloimmune disease states.