Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded?
The connection between gut microbiota and energy homeostasis and inflammation and its role in the pathogenesis of obesity-related disorders are increasingly recognized. Animals models of obesity connect an altered microbiota composition to the development of obesity, insulin resistance, and diabetes in the host through several mechanisms: increased energy harvest from the diet, altered fatty acid metabolism and composition in adipose tissue and liver, modulation of gut peptide YY and glucagon-like peptide (GLP)-1 secretion, activation of the lipopolysaccharide toll-like receptor-4 axis, and modulation of intestinal barrier integrity by GLP-2. Instrumental for gut microbiota manipulation is the understanding of mechanisms regulating gut microbiota composition. Several factors shape the gut microflora during infancy: mode of delivery, type of infant feeding, hospitalization, and prematurity. Furthermore, the key importance of antibiotic use and dietary nutrient composition are increasingly recognized. The role of the Western diet in promoting an obesogenic gut microbiota is being confirmation in subjects. Following encouraging results in animals, several short-term randomized controlled trials showed the benefit of prebiotics and probiotics on insulin sensitivity, inflammatory markers, postprandial incretins, and glucose tolerance. Future research is needed to unravel the hormonal, immunomodulatory, and metabolic mechanisms underlying microbe-microbe and microbiota-host interactions and the specific genes that determine the health benefit derived from probiotics. While awaiting further randomized trials assessing long-term safety and benefits on clinical end points, a healthy lifestyle--including breast lactation, appropriate antibiotic use, and the avoidance of excessive dietary fat intake--may ensure a friendly gut microbiota and positively affect prevention and treatment of metabolic disorders.


Applicability of a single 5 color cytoplasmic markers tube as primary panel for immunophenotyping of acute leukemia: A Gujarat Cancer and Research Institute experience.
Flow cytometry is highly sensitive for detection and quantitative analysis of surface and intracellular antigens in malignant hemopoietic cells. Immunophenotyping is a routine practice for classification and lineage assignment of acute leukemia. In the present study, our aim is to identify the role of a single 5 color, CD45, myeloperoxidase (MPO), cCD79a, cCD3, and Tdt, cytoplasmic markers combination as a primary tube. We compared with final diagnosis on the basis of morphology, cytochemistry, and primary and secondary panels of immunophenotyping and also with other study. We have included 455 new cases of acute leukemias with applied primary and secondary panels of markers for immunophenotyping. We analyzed sensitivity and specificity of different subsets with combination of positive and negative markers. MPO was positive in 61.4% of acute myeloid leukemia (AML) cases. All 184 (100%) cases of the AML were negative for cCD3 and cCD79a co-expression. cCD79a expression was highly sensitive as 98.5% B-acute lymphoblastic leukemia (B-ALL) expressed it. cCD3 expression was detected in 100% cases of T-ALL, and its co-expression was not seen in B-ALL and AML. Our study indicates that there was very good correlation of 5-color cytoplasmic tube-based diagnosis versus final diagnosis based on morphology, cytochemistry, and flow cytometry. We can use this 5-color cytoplasmic tube method to make immunophenotyping cost-effective.


Recovery in Borderline Personality Disorder (BPD): a qualitative study of service users' perspectives.
Symptom improvement in Borderline Personality Disorder (BPD) is more common than previously hypothesised. However, it remains unclear whether it reflects service users' personal goals of recovery. The present study aimed to explore what service users with BPD view as recovery. 48 service users were recruited from secondary mental health services and their views on their personal goals and the meaning of recovery were explored in in-depth semi-structured interviews. The study drew on grounded theory and thematic analysis. Service users believed that recovery involved developing self-acceptance and self-confidence, gaining control over emotions, improving relationships, employment, and making progress in symptoms like suicidality and self-harming. They felt that psychotherapies for BPD often had an extreme focus on specific areas, like self-harming or relationships, and that some of their goals were neglected. Although full recovery was seen as a distant goal, interviewees felt that they could learn how to deal with their problems in more effective ways and make meaningful progress in their lives. Specialist therapies for BPD explicitly address some of the recovery goals that are important to service users, whereas other goals are only indirectly or poorly addressed. Professionals might need to work with service users towards devising comprehensive individualised case formulations, including all treatment targets that are important to service users, their priorities, and long-term plans on how their targets might be met and which services might be involved.


Advances in the causes and management of community acquired pneumonia in adults.
Community acquired pneumonia remains a common cause of morbidity and mortality. Usually, the causal organism is not identified and treatment remains empiric. Recent computed tomography and magnetic resonance imaging studies have challenged the accuracy of the clinical diagnosis of pneumonia, and epidemiologic studies are changing our perspective of what causes community acquired pneumonia, especially the role of viral pathogens and the frequent finding of multiple pathogens. The past decade has seen increasing overuse of empiric coverage of meticillin resistant Staphylococcus aureus and antibiotic resistant Gram negative pathogens owing to inappropriate application of guidelines for healthcare associated pneumonia. Optimal treatment remains a matter for debate, especially in very sick patients, including the role of combination antibiotic therapy and corticosteroids. Pneumonia care bundles are being defined to improve outcomes. Increased recognition of both acute and long term cardiac complications is shifting our concept of pneumonia from an acute lung disease to a multisystem problem with adverse chronic health consequences.


NAC selectively inhibit cancer telomerase activity: A higher redox homeostasis threshold exists in cancer cells.
Telomerase activity controls telomere length, and this plays an important role in stem cells, aging and tumors. Antioxidant was shown to protect telomerase activity in normal cells but inhibit that in cancer cells, but the underlying mechanism is elusive. Here we found that 7721 hepatoma cells held a higher redox homeostasis threshold than L02 normal liver cells which caused 7721 cells to have a higher demand for ROS; MnSOD over-expression in 7721 decreased endogenous reactive oxygen species (ROS) and inhibited telomerase activity; Akt phosphorylation inhibitor and NAC both inhibited 7721 telomerase activity. The over-elimination of ROS by NAC resulted in the inhibition of Akt pathway. Our results suggest that ROS is involved in the regulation of cancer telomerase activity through Akt pathway. The different intracellular redox homeostasis and antioxidant system in normal cells and tumor cells may be the cause of the opposite effect on telomerase activity in response to NAC treatment. Our results provide a theoretical base of using antioxidants selectively inhibit cancer telomerase activity. Findings of the present study may provide insights into novel approaches for cancer treatment.


Benefits of a Food Supplement Containing Boswellia serrata and Bromelain for Improving the Quality of Life in Patients with Osteoarthritis: A Pilot Study.
Background: Osteoarthritis (OA) is a joint disease involving articular cartilage degeneration causing patients pain, joint stiffness, physical disability, and significantly reducing their quality of life (QoL). Purpose: The aim of this study was to assess whether the daily consumption of a gastroresistant food supplement formulation containing a combination of Boswellia serrata and bromelain could improve the QoL of patients suffering from various forms of OA. Materials and Methods: Forty-nine patients were enrolled in this pilot study conducted from June 2015 to October 2016. Patients took a Boswellia- and bromelain-based supplement for a period between 1 and 6 months. At baseline and at the end of the study, patients completed a self-assessment QoL questionnaire regarding their independence in performing daily activities. QoL scores were compared between baseline and follow-up by means of the Wilcoxon signed-rank test in all patients and in the subgroups of patients with knee, hip, or generalized OA. Results: Forty-nine patients, 6 men and 43 women, aged between 23 and 92 years, (mean age 63.24) participated in the study. At follow-up (3.0 ± 0.7 months), a significant improvement was observed for 7 of 10 QoL questions and, overall, for the total QoL score. The most significant improvements were observed in the joints that were more strongly affected at baseline. A similar trend was observed when separately considering patients with knee, hip, or generalized OA. No patients experienced adverse events and no drug interactions were reported. Conclusions: From this pilot study, it emerges that the use of the gastroresistant formulation containing the combination of Boswellia and bromelain supplements can represent a valuable nonpharmacological tool for improving the QoL of patients suffering from different forms of OA. Further studies should be conducted to confirm this first evidence.


Challenges in measuring complications and death due to invasive Salmonella infections.
Despite the highest burden of Typhoid fever in children globally, exact estimates of morbidity and mortality are lacking due to scarcity of published data. Despite a high prevalence and a socioeconomic burden in developing countries, published data with morbidity and mortality figures are limited especially Africa and South American regions. Data from the community is insufficient and most case fatality estimates are extrapolations from hospital based studies that do not cover all geographical regions, and include cases which may or not be culture confirmed, MDR resistant or sensitive cases, or from mixed populations of age (adults and children). Complications of typhoid such as intestinal perforation, bone marrow suppression, and encephalopathy are dependent on MDR/Fluoroquinolone resistant Salmonella infection, comorbidities such as malnutrition, and health-care access. Data is again insufficient to estimate the true burden of Typhoid Fever in different regions and groups of populations. Although there has been a rapid decline in cases in developed countries with the advent of improved sanitization, timely and easy access to health care and laboratories, this is still not the case in the developing countries where Typhoid deaths are still occurring. The way forward is to develop rapid and cost effective point of care diagnostic tests, put in place validated clinical algorithms for suspected clinical cases, and design prospective, and community based studies in different groups, implement maintenance of electronic health records in large public sector hospitals and regions to identify populations that will benefit most from the implementation of vaccine. Policies on public health education and typhoid vaccine may help to reduce morbidity and mortality due to the disease.


Neural decoding of visual imagery during sleep.
Visual imagery during sleep has long been a topic of persistent speculation, but its private nature has hampered objective analysis. Here we present a neural decoding approach in which machine-learning models predict the contents of visual imagery during the sleep-onset period, given measured brain activity, by discovering links between human functional magnetic resonance imaging patterns and verbal reports with the assistance of lexical and image databases. Decoding models trained on stimulus-induced brain activity in visual cortical areas showed accurate classification, detection, and identification of contents. Our findings demonstrate that specific visual experience during sleep is represented by brain activity patterns shared by stimulus perception, providing a means to uncover subjective contents of dreaming using objective neural measurement.


Occupationally embedded exercise versus rote exercise: a choice between occupational forms by elderly nursing home residents.
The provision of options in the occupational form that encourages meaningful choices and subsequent purposeful occupational performances is a basic premise of occupational therapy. This study examines the preferences of elderly nursing home residents when presented with an occupationally embedded exercise versus a rote exercise and addresses the methodological problems identified in similar past research. Fifty-two elderly nursing home residents were presented with a choice between an occupationally embedded exercise that involved unilateral dunking of a small, spongy ball into a basketball hoop and a rote exercise that involved moving the arm above the head in a simulation of the dunking exercise. Both exercises required flexion of the shoulder joint. Random assignment of the 52 subjects into one of four groups controlled for the order of the presentation of the exercises and the order of the choice statements. Sixty-nine percent of the subjects chose the occupationally embedded exercise. Analysis with the significance of a proportion statistic revealed a statistically significant difference (z = 2.77; p (one-tailed) = .003). Results were consistent with the hypothesis that elderly nursing home residents would tend to choose the occupationally embedded exercise. To further confirm this basic premise of occupational therapy, future studies that investigate therapeutic patterns of movement embedded in common occupations are recommended.


Inhibitory effect of Ferula asafoetida L. (Umbelliferae) on Blastocystis sp. subtype 3 growth in vitro.
Asafoetida is an oleo-gum-resin obtained from many Ferula species and frequently used in traditional medicine. The current study aimed to evaluate the activity of asafoetida against the in vitro growth of Blastocystis sp. Asafoetida as powder-form (Ap) and oil-form (Ao) extracts at concentrations of 2, 4, 8, 16, and 20 mg/ml and 5, 10, 25, 40, and 50 mg/ml, respectively were incubated with isolates of Blastocystis sp. subtype 3 for 24, 72, and 144 h and compared to the reference antiprotozoan drug metronidazole at concentrations of 10, 100, and 500 μg/ml. Asafoetida either as Ap or Ao decreased counts and viability of all tested isolates of Blastocystis sp. subtype 3 which was confirmed by microscopy. The degree of the inhibitory effect was dependent on the concentration, form, as well as the time of incubation with asafoetida extracts. The lowest concentrations of Ap and Ao that caused complete (100 %) inhibition of Blastocystis growth and highest (100 %) percentage inhibition of multiplication was 16 and 40 mg/ml, respectively; mean counts at these concentrations either did not differ or decreased significantly when compared to metronidazole control (p < 0.05). Also, the parasites did not resume growth after re-cultivation in asafoetida-free medium when examined further after 48, 72, and 144 h of cultivation. These findings demonstrate the potential of phytomedicine asafoetida as a potent natural alternative for treatment of Blastocystis sp.infection.


Oligosaccharides in several Philippine indigenous food legumes: determination, localization and removal.
The oligosaccharide profile of raw mature seeds of seven different legumes indigenous to the Philippines was measured in 70% ethanol extracts of the seeds by thin layer chromatography using HPTLC plates and quantified by a densitometer. Based on the results, the legumes could be ranked according to decreasing oligosaccharide content or flatulence potential as follows: Sam-samping (Clitoria ternatea) greater than hyacinth bean (Dolichos lablab) greater than sabawel (Mucuna pruriens) greater than lima bean (Phaseolus lunatus) greater than swordbean (Canavalia gladiata) greater than rice bean (Vigna umbellata) greater than jack bean (Canavalia ensiformis). Sam-samping had 4.79% total oligosaccharides and hyacinth bean or batao, 3.66%. A jack bean accession had 1.79% oligosaccharides. Simple processing methods were tested to detoxify the oligosaccharides. Soaking the batao seeds had no effect while boiling even resulted in a net 23-31% increase in the levels of raffinose, stachyose and verbascose. On the other hand, two min of dry roasting resulted in complete removal of oligosaccharides whereas germination resulted in about 30-40% decrease after 1 and 2 days, respectively.


Gallic acid protects RINm5F beta-cells from glucolipotoxicity by its antiapoptotic and insulin-secretagogue actions.
Gallic acid is claimed to possess antioxidant, antiinflammatory and cytoprotective effects. Since pancreatic islets from Type 2 diabetic patients have functional defects, it was hypothesized that glucolipotoxicity might induce apoptosis in beta-cells and gallic acid could offer protection. To test this, RINm5F beta-cells were exposed to high glucose (25 microM) or palmitate (500 microM) or a combination of both for 24 h in the presence and absence of gallic acid. Cells subjected to glucolipotoxicity in the absence and presence of gallic acid were assessed for DNA damage by comet assay. Apoptosis was inferred by caspase-3 protein expression and caspase-3 activity and changes in Bcl-2 mRNA. RT-PCR was used to analyse PDX-1, insulin and UCP-2 mRNA expression in RINm5F beta-cells and insulin levels were quantified from the cell culture supernatant. NFkappaB signal was studied by EMSA, immunofluorescence and Western blot analysis. While RINm5F beta-cells subjected to glucolipotoxicity exhibited increased DNA damage, apoptotic markers and NFkappaB signals, all these apoptotic perturbations were resisted by gallic acid. Gallic acid dose-dependently increased insulin secretion in RINm5F beta-cells and upregulated mRNA of PDX-1 and insulin. It is suggested that the insulin-secretagogue and transcriptional regulatory action of gallic acid is a newly identified mechanism in our study.


Role of blood vessels in the neuronal migration.
The proper development and functioning of the vertebrate brain depends on the correct positioning of neuronal precursors which is achieved by the widespread and far-ranging migration of cells from their birthplaces. The vast majority of neuronal precursors use cellular substrates for their migration. Until very recently, it was assumed that these cellular substrates were either glial (glia-mediated or gliophilic migration) or neuronal (neuron-mediated or neurophilic migration) in nature. The widely studied examples of gliophilic and neurophilic migrations in the developing brain are displacement of neuronal precursors along the processes of radial glia in the developing cortex and migration of neurons expressing gonadotropin-releasing hormone (GnRH) along the vomeronasal axons, respectively. Recent data indicate, however, that neuronal precursors might also use blood vessels as a physical substrate for their migration. The vasculature-guided (vasophilic) migration of neuronal precursors has been observed not only under normal conditions, in the healthy brain, but also following strokes. The purpose of this review is to highlight emerging principles and delineate putative mechanisms of vasculature-guided neuronal migration under both normal and pathological conditions.


Self-assembled nanostructures from peptide-synthetic hybrid block copolymers: complex, stimuli-responsive rod-coil architectures.
The synthesis, solution and solid state self-assembly properties of a series of polyisoprene-b-poly(epsilon-benzyloxycarbonyl-L-lysine) PI-b-PZLys and polyisoprene-b-poly(L-lysine) PI-b-PLys block copolymers have been examined. The formation of stimuli-responsive micelles in water has been studied as a function of pH and ionic strength using static and dynamic light scattering, UV-circular dichroism and transmission electron microscopy. The observed change in the micelles dimensions has been directly attributed to the conformational transition in the secondary structure of polypeptide chains. In bulk, these rod-coil copolymers form self-assembled structures that have been characterized using DSC, DMA, WAXS and SAXS techniques. Hexagonal in lamellar (HL) and more interestingly hexagonal in hexagonal (HH) morphologies have been evidenced as a function of the chemical composition.


Relative contribution of shoot and ear photosynthesis to grain filling in wheat under good agronomical conditions assessed by differential organ δ13C.
During grain filling in C3 cereals, the shoot (particularly the flag leaf) and the ear are believed to play major roles as sources of assimilates. However, both the cost and the intrusive nature of most of the methodologies available to investigate this have prevented conclusive results being obtained. This study compared the carbon isotope composition (δ(13)C) in its natural abundance in mature kernels with the δ(13)C of the water-soluble fraction of the peduncle, glumes, and awns to assess the relative contribution of the shoot (understood as the whole set of photosynthetic organs below the peduncle) and ear to grain filling in a set of highly productive wheat lines from the International Maize and Wheat Improvement Center, Mexico, under good agronomic conditions. In overall terms, the contribution of the ear was greater in comparison with that of the shoot. The specific contribution of the flag leaf blade to grain filling was also assessed by comparing the δ(13)C of grains with the δ(13)C of the water-soluble fraction of the flag leaf and the awns. The contribution of the flag leaf was minor, ranging between 3 and 18%. Complementary analyses performed such as gas-exchange rates and the accumulated water-soluble carbohydrates in both organs and light intercepted by the canopy at different strata suggested that the ear has a photosynthetic capacity at least comparable to that of the flag leaf. In this sense, selection for a higher contribution of ear photosynthesis to grain yield in breeding programmes could be addressed with the use of stable isotopes.


Physiological performance of warm-adapted marine ectotherms: Thermal limits of mitochondrial energy transduction efficiency.
Thermal regimes in aquatic systems have profound implications for the physiology of ectotherms. In particular, the effect of elevated temperatures on mitochondrial energy transduction in tropical and subtropical teleosts may have profound consequences on organismal performance and population viability. Upper and lower whole-organism critical temperatures for teleosts suggest that subtropical and tropical species are not susceptible to the warming trends associated with climate change, but sub-lethal effects on energy transduction efficiency and population dynamics remain unclear. The goal of the present study was to compare the thermal sensitivity of processes associated with mitochondrial energy transduction in liver mitochondria from the striped mojarra (Eugerres plumieri), the whitemouth croaker (Micropogonias furnieri) and the palometa (Trachinotus goodei), to those of the subtropical pinfish (Lagodon rhomboides) and the blue runner (Caranx crysos). Mitochondrial function was assayed at temperatures ranging from 10 to 40°C and results obtained for both tropical and subtropical species showed a reduction in the energy transduction efficiency of the oxidative phosphorylation (OXPHOS) system in most species studied at temperatures below whole-organism critical temperature thresholds. Our results show a loss of coupling between O2 consumption and ATP production before the onset of the critical thermal maxima, indicating that elevated temperature may severely impact the yield of ATP production per carbon unit oxidized. As warming trends are projected for tropical regions, increasing water temperatures in tropical estuaries and coral reefs could impact long-term growth and reproductive performance in tropical organisms, which are already close to their upper thermal limit.


Longitudinal measurement of serum neurofilament light in presymptomatic familial Alzheimer's disease.
To investigate how serum neurofilament light (NfL) concentration changes through the course of disease in familial Alzheimer's disease (FAD) and to assess when NfL concentration first increases. NfL was measured using an ultrasensitive immunoassay in 117 serum samples from 61 individuals from families with PSEN1 or APP mutations in a longitudinal study (mean ± SD = 1.9 ± 1.1 visits/patient; inter-visit interval = 1.8 ± 1.1 years). The relationship between NfL concentration and estimated years to/from symptom onset (EYO) was modelled using linear regression, including all time points and robust standard errors to allow for repeated measurements, adjusting for age at visit and sex. Also, for the 27 participants who became symptomatic (during or before the study), NfL concentration was also modelled against known actual years to/from onset (AYO). There were 15 non-carriers and 46 mutation carriers (21 symptomatic; 25 presymptomatic). NfL concentration was increased (p = 0.045) in mutation carriers compared with non-carriers 15 years prior to expected symptom onset, increasing progressively thereafter. There was a significant inter- and intra-individual variability in the longitudinal pattern of change. Modelling NfL for the 27 mutation carriers with known AYO also showed a progressive increase over time. There is evidence that serum NfL is increased more than a decade before the onset of clinical symptoms in FAD and rises thereafter. While there is variability in change over time, both within and between individuals, and more work is needed to understand the sources of this variability, serum NfL remains a promising, accessible biomarker of early neurodegeneration in presymptomatic Alzheimer's disease.


The Evaluation of Carotid Atherosclerosis in Patients with the HIV-1 Infection: The Role of the Antiretroviral Therapy.
The recognition and the assessment of the carotid intimal thickness helps in predicting the risk of the cardiovascular events in Human Immunodeficiency Virus (HIV) infected patients who are on Antiretroviral Therapy (ART). The objective of this study was to assess and compare the carotid intimal thickness in HIV positive individuals who were on antiretroviral therapy with HIV positive individuals who were not on anti-retroviral therapy. All the HIV positive individuals who were 20 years old and above, who had been diagnosed by the National AIDS Control Organization (NACO) guidelines were included in the study. The HIV positive individuals who were diagnosed with diabetes mellitus and hypertension were excluded from the study. The study subjects were divided into 2 groups i.e. HIV patients who were on anti-retroviral therapy and HIV patients who were not on anti-retroviral therapy. The patients had to be on anti-retroviral therapy for a minimum of 6 months for them to be included in the first group. The data was collected by using a semi structured, pre-tested proforma, which included the demographic details, the duration of the HIV infection, details of the antiretroviral treatment, a history of smoking/ alcohol consumption and details on the assessments of the metabolic syndrome. A total of 42 patients were included in the study. Among them, 28 were males (66.7%) and 14 were females (33.3%). Twenty six patients were on ART and the remaining patients were treatment naive. There were significant differences with regards to their age and the duration of the HIV infection, which was longer in the patients who were on ART (p= 0.049, p=0.003 respectively). The Body Mass Index (BMI), the waist: hip ratio, the mid-arm circumference, the waist circumference, the skin fold thickness and the carotid intimal-media thickness were higher in the HIV patients who were on ART as compared to those in the treatment naive patients, though the difference was statistically insignificant. The carotid intimal thickness was higher in the HIV patients who were on ART as compared to those in the treatment naïve HIV infected patients.


Characterization and factors associated with sleep quality in adolescents with bipolar I disorder.
Sleep disturbance is an early marker for bipolar disorder (BD) onset in youth. We characterized sleep quality in adolescents experiencing mania within the last 6-12 months. We examined the association between mood and sleep in 27 adolescents with BD and 24 matched healthy controls (HC). Subjects were assessed by parent and teen report of sleep, a semi-structured clinical interview, the Young Mania Rating Scale (YMRS), and the Childhood Depression Rating Scale (CDRS-R). Average BD youth YMRS (mean 20.3 ± 7.3) and CDRS-R (mean 42.4 ± 14.1) scores indicated they were still ill at time of assessment. Compared to HCs, adolescents with BD have distinct patterns of prolonged sleep onset latency, frequent nighttime awakenings, and increased total time awake. Mood symptoms, specifically excessive guilt, self-injurious behavior, and worsening evening mood, interfered with sleep. Further studies are needed to determine whether early regulation of sleep would improve long-term outcome in BD youth.


Establishing a core outcome set for treatment of uncomplicated appendicitis in children: study protocol for an international Delphi survey.
Appendicitis is a global disease affecting roughly 1 in every 12 people in the world, with the highest incidence between ages 10 and 19 years. To date, a wide variety of health outcomes have been reported in randomised controlled trials and meta-analyses evaluating treatments for appendicitis. This is especially the case in studies comparing non-operative treatment with operative treatment. A set of standard outcomes, to be reported in all future trials, is needed to allow for adequate comparison and interpretation of clinical trial results and to make data pooling possible. This protocol describes the development of such a global core outcome set (COS) to allow unified reporting of treatment interventions in children with acute uncomplicated appendicitis. We use current international standard methodology for the development and reporting of this COS. Its development consists of three phases: (1) an update of the most recent systematic review on outcomes reported in uncomplicated paediatric appendicitis research to identify additional outcomes, (2) a three-step global Delphi study to identify a set of core outcomes for which there is consensus between parents and (paediatric) surgeons and (3) an expert meeting to finalise the COS and its definitions. Children and young people will be involved through their parents during phase 2 and will be engaged directly using a customised face-to-face approach. The medical research ethics committee of the Academic Medical Center Amsterdam has approved the study. Each participating country/research group will ascertain ethics board approval. Electronic informed consent will be obtained from all participants. Results will be presented in peer-reviewed academic journals and at (international) conferences. COMET registration: 1119.


Estimating the obstetric costs of female genital mutilation in six African countries.
To estimate the cost to the health system of obstetric complications due to female genital mutilation (FGM) in six African countries. A multistate model depicted six cohorts of 100,000 15-year-old girls who survived until the age of 45 years. Cohort members were modelled to have various degrees of FGM, to undergo childbirth according to each country's mortality and fertility statistics, and to have medically attended deliveries at the frequency observed in the relevant country. The risk of obstetric complications was estimated based on a 2006 study of 28,393 women. The costs of each complication were estimated in purchasing power parity dollars (I$) for 2008 and discounted at 3%. The model also tracked life years lost owing to fatal obstetric haemorrhage. Multivariate sensitivity analysis was used to estimate the uncertainty around the findings. The annual costs of FGM-related obstetric complications in the six African countries studied amounted to I$ 3.7 million and ranged from 0.1 to 1% of government spending on health for women aged 15-45 years. In the current population of 2.8 million 15-year-old women in the six African countries, a loss of 130,000 life years is expected owing to FGM's association with obstetric haemorrhage. This is equivalent to losing half a month from each lifespan. Beyond the immense psychological trauma it entails, FGM imposes large financial costs and loss of life. The cost of government efforts to prevent FGM will be offset by savings from preventing obstetric complications.


Cortisol as a marker for improvement in mindfulness-based stress reduction.
While much attention has been devoted to examining the beneficial effects of Mindfulness-Based Stress Reduction programs on patients' ability to cope with various chronic medical conditions, most studies have relied on self-report measures of improvement. Given that these measures may not accurately reflect physiological conditions, there is a need for an objective marker of improvement in research evaluating the beneficial effects of stress management programs. Cortisol is the major stress hormone in the human organism and as such is a promising candidate measure in the study of the effects of Mindfulness-Based Stress Reduction programs. In conjunction with other biological measures, the use of cortisol levels as a physiological marker of stress may be useful to validate self-reported benefits attributed to this program. In the current manuscript, we review the available literature on the role of cortisol as a physiological marker for improvement with regards to mindfulness practice, and make recommendations for future study designs.


Tight Junction Proteins and Signaling Pathways in Cancer and Inflammation: A Functional Crosstalk.
The ability of epithelial cells to organize through cell-cell adhesion into a functioning epithelium serves the purpose of a tight epithelial protective barrier. Contacts between adjacent cells are made up of tight junctions (TJ), adherens junctions (AJ), and desmosomes with unique cellular functions and a complex molecular composition. These proteins mediate firm mechanical stability, serves as a gatekeeper for the paracellular pathway, and helps in preserving tissue homeostasis. TJ proteins are involved in maintaining cell polarity, in establishing organ-specific apical domains and also in recruiting signaling proteins involved in the regulation of various important cellular functions including proliferation, differentiation, and migration. As a vital component of the epithelial barrier, TJs are under a constant threat from proinflammatory mediators, pathogenic viruses and bacteria, aiding inflammation and the development of disease. Inflammatory bowel disease (IBD) patients reveal loss of TJ barrier function, increased levels of proinflammatory cytokines, and immune dysregulation; yet, the relationship between these events is partly understood. Although TJ barrier defects are inadequate to cause experimental IBD, mucosal immune activation is changed in response to augmented epithelial permeability. Thus, the current studies suggest that altered barrier function may predispose or increase disease progression and therapies targeted to specifically restore the barrier function may provide a substitute or supplement to immunologic-based therapies. This review provides a brief introduction about the TJs, AJs, structure and function of TJ proteins. The link between TJ proteins and key signaling pathways in cell proliferation, transformation, and metastasis is discussed thoroughly. We also discuss the compromised intestinal TJ integrity under inflammatory conditions, and the signaling mechanisms involved that bridge inflammation and cancer.


Biology of stress revisited: intracellular mechanisms and the conceptualization of stress.
Application of allostatic theory to stress during the 1990s refocused attention on internal responses to a perceived hazard, and the last 20 years has seen considerable developments in the biological contexts of stress. Evidence from neuroscience now suggests that secretion of the hormone cortisol is not only stimulated by the outcomes of cognitive transaction but it also feeds back and contributes positively to the cognitive adaptation that is a feature of stress resilience. More recently, the operative intracellular mechanisms are beginning to be understood and provide an insight into the regulation and maintenance of intracellular homeostasis that underpins adaptive change and vulnerability. The maintenance or appropriate modulation of intracellular homeostasis usually provides a buffering of potential adverse interactions. However, the capacity to do so is diminished during chronic stress leading to intracellular and subsequently systemic, homeostatic failure and hence maladaptation. This area of research seems far removed from cognitive theory, but placing intracellular homeostasis at the core of cognitive and biological responses supports the concept of stress as a genuinely psycho-biological phenomenon.


Plasma skin regeneration technology.
Plasma skin regeneration is a novel type of skin rejuvenation technology developed over the last 3 years. Plasma is the fourth state of matter in which electrons are stripped from atoms to form an ionized gas. Although high temperature plasmas have been used in surgery for over a decade, plasma had previously been used as a conduction medium for electric current. Unlike lasers which rely on the principle of selective photothermolysis to deliver heat to specific targets in the skin, plasma technology delivers heat energy directly to tissue upon contact without reliance on skin chromophores. The plasma itself produces controlled thermal damage to the skin surface to elicit changes such as new collagen formation and improvement in photodamaged skin. The technology can be used at varying energies for different depths of effect, from superficial epidermal effects to deeper dermal heating.


Will HPV vaccination prevent cervical cancer?
We conducted a critical appraisal of published Phase 2 and 3 efficacy trials in relation to the prevention of cervical cancer in women. Our analysis shows the trials themselves generated significant uncertainties undermining claims of efficacy in these data. There were 12 randomised control trials (RCTs) of Cervarix and Gardasil. The trial populations did not reflect vaccination target groups due to differences in age and restrictive trial inclusion criteria. The use of composite and distant surrogate outcomes makes it impossible to determine effects on clinically significant outcomes. It is still uncertain whether human papillomavirus (HPV) vaccination prevents cervical cancer as trials were not designed to detect this outcome, which takes decades to develop. Although there is evidence that vaccination prevents cervical intraepithelial neoplasia grade 1 (CIN1) this is not a clinically important outcome (no treatment is given). Trials used composite surrogate outcomes which included CIN1. High efficacy against CIN1+ (CIN1, 2, 3 and adenocarcinoma in situ (AIS)) does not necessarily mean high efficacy against CIN3+ (CIN3 and AIS), which occurs much less frequently. There are too few data to clearly conclude that HPV vaccine prevents CIN3+. CIN in general is likely to have been overdiagnosed in the trials because cervical cytology was conducted at intervals of 6-12 months rather than at the normal screening interval of 36 months. This means that the trials may have overestimated the efficacy of the vaccine as some of the lesions would have regressed spontaneously. Many trials diagnosed persistent infection on the basis of frequent testing at short intervals, i.e. less than six months. There is uncertainty as to whether detected infections would clear or persist and lead to cervical changes.


Processing halftone color images by vector space methods.
The reproduction of color images by color halftoning can be characterized by the Neugebauer model/equation. However, the Neugebauer equation is not easy to solve because of the highly nonlinear relationship between the underlying Neugebauer primaries and the colorants. We attempt to solve the Neugebauer equation by vector space methods. The proposed method of solution is applicable to any number of colorants, although our experimental results are confined to the CMY and CMYK cases. Among the constraints we consider are those related to a bound on the permissible amount of total ink and a bound on the total cost of applying colorants to achieve a satisfactory level of color reproduction. Our results demonstrate that the vector space method is a feasible approach for solving for the required amounts of colorants in the constrained color halftoning problem.


Functional and cellular responses in a novel rodent model of anterior ischemic optic neuropathy.
Anterior ischemic optic neuropathy (AION) is caused by sudden loss of vascular supply to retinal ganglion cell (RGC) axons in the anterior portion of the optic nerve and is a major cause of optic nerve dysfunction. There has been no easily obtainable animal model of this disorder. The current study was conducted to design a novel model of rodent AION (rAION), to enable more detailed study of this disease. A novel rodent photoembolic stroke model was developed that is directly analogous to human AION. Using histologic, electrophysiological, molecular- and cell biological methods, the early changes associated with isolated RGC axonal ischemia were characterized. Functional (electrophysiological) changes occurred in RGCs within 1 day after rAION, with a loss of visual evoked potential (VEP) amplitude that persisted in the long term. The retinal gene expression pattern rapidly changed after rAION induction, with an early (<1 day) initial induction of c-Fos mRNA, and loss of RGC-specific gene expression. RGC-specific protein expression declined 2 days after detectable mRNA level changes, and immunostaining suggested that multiple retinal layers react to isolated RGC axonal ischemia. rAION rapidly results in electrophysiological and histologic changes similar to clinical AION, with reactive responses in primary and supporting neuronal cell layers. The rAION model can enable a detailed analysis of the individual retinal and optic nerve changes that occur after optic nerve stroke, which may be useful in determining possible therapeutic interventions for this disorder.


Retroviral expression of Wnt-1 and Wnt-7b produces different effects in mouse mammary epithelium.
Several Wnt genes are expressed in the postnatal mouse mammary gland and are thought to be involved in mammary gland development. Ectopic expression of Wnt-1, which is not normally expressed in the mammary gland, drives the formation of a pre-neoplastic hyperplasia. Cell culture-based assays have shown that Wnt-1 and some mammary-expressed Wnts transform C57MG cells. This has led to the suggestion that Wnt-1 functions as an oncogene through the inappropriate activation of developmental events that are normally controlled by the 'transforming' class of Wnts. In this study, Wnt-7b was expressed in vivo using recombinant retroviruses. Wnt-7b did not alter normal mammary gland development despite having similar effects to Wnt-1 in cell culture. We conclude that the in vitro classification of Wnts as 'transforming' does not correlate with the transformation in vivo. To facilitate the analysis of Wnt-expression, a lacZ-containing, bicistronic recombinant retrovirus was developed. Immunohistochemistry and electron microscopy identified retrovirally transduced myoepithelial and luminal epithelial cells in normal and hyperplastic tissues. The distribution of transduced cells in mammary outgrowths was consistent with current models of mammary stem cell identity.


Screening outcomes following implementation of digital breast tomosynthesis in a general-population screening program.
Early data on breast cancer screening utilizing digital breast tomosynthesis (DBT) combined with digital mammography (DM) have shown improvements in false-positive and false-negative screening rates compared with DM alone. However, these trials were performed at sites where conventional mammographic screening was concurrently performed, possibly leading to selection biases or with complex, multireader algorithms not reflecting general clinical practice. Our study reports the impact on screening outcomes for DBT screening implemented in an entire clinic population. Recall rates, cancer detection, and positive predictive values of screening were compared for 15571 women screened with DBT and 10728 screened with DM alone prior to DBT implementation at a single breast imaging center. Generalized linear mixed-effects models were used to estimate the odds ratio (OR) for recall rate adjusted for age, race, presence of prior mammograms, breast density and reader. All statistical tests were two-sided. DBT screening showed a statistically significant reduction in recalls compared to DM alone. For the entire population, there were 16 fewer recalls (8.8% vs 10.4%, P <.001, adjusted OR = 0.80, 95% confidence interval [CI] = 0.74 to 0.88, P < .001) and 0.9 additional cancers detected per 1000 screened with DBT compared to DM alone. There was a statistically significant increase in PPV1 (6.2% vs 4.4%, P = .047). In women younger than age 50 years screened with DBT, there were 17 fewer recalls (12.3% vs 14.0%, P = .02) and 3.6 additional cancer detected per 1000 screened (5.7 vs 2.2 per 1000, P = .02). Our data support the clinical implementation of DBT in breast cancer screening; however, larger prospective trials are needed to validate our findings in specific patient subgroups.


Molecular basis for a new bovine model of Niemann-Pick type C disease.
Niemann-Pick type C disease is a lysosomal storage disease affecting primarily the nervous system that results in premature death. Here we present the first report and investigation of Niemann-Pick type C disease in Australian Angus/Angus-cross calves. After a preliminary diagnosis of Niemann-Pick type C, samples from two affected calves and two obligate carriers were analysed using single nucleotide polymorphism genotyping and homozygosity mapping, and NPC1 was considered as a positional candidate gene. A likely causal missense variant on chromosome 24 in the NPC1 gene (NM_174758.2:c.2969C>G) was identified by Sanger sequencing of cDNA. SIFT analysis, protein alignment and protein modelling predicted the variant to be deleterious to protein function. Segregation of the variant with disease was confirmed in two additional affected calves and two obligate carrier dams. Genotyping of 403 animals from the original herd identified an estimated allele frequency of 3.5%. The Niemann-Pick type C phenotype was additionally confirmed via biochemical analysis of Lysotracker Green, cholesterol, sphingosine and glycosphingolipids in fibroblast cell cultures originating from two affected calves. The identification of a novel missense variant for Niemann-Pick type C disease in Angus/Angus-cross cattle will enable improved breeding and management of this disease in at-risk populations. The results from this study offer a unique opportunity to further the knowledge of human Niemann-Pick type C disease through the potential availability of a bovine model of disease.


Observation of phase-sensitive temporal correlations in the resonance fluorescence from two-level atoms.
We have made what we believe is the first observation of phase-dependent temporal correlations in the fluorescent field emitted by coherently driven two-level atoms in free space. We measured the temporal fluctuations of the fluorescent field when the resonant driving field was in phase and out of phase with the local-oscillator field.


Multivalent interaction-based carbohydrate biosensors for signal amplification.
Multivalent interaction between boronic acids immobilized on quartz crystal microbalance (QCM) sensor surface and the carbohydrates modified Au-nanoparticle (AuNP) has been demonstrated for the development of a sensitive carbohydrate biosensor. Briefly, a boronic acid-containing polymer (boropolymer) as multivalent carbohydrate receptor was oriented immobilized on the cysteamine coated electrode through isourea bond formation. Carbohydrates were conjugated to AuNPs to generate a multivalent carbohydrates moiety to amplify the response signal. Thus, the binding of the carbohydrate conjugated AuNPs to the boropolymer surface are multivalent which could simultaneously increase the binding affinity and specificity. We systematically studied the binding between five carbohydrates conjugated AuNPs and the boropolymer. Our studies show that the associate constant (K(a)) was in the order of fucose<glucose<mannose<galactose<maltose. A linear response in the range from 23 μM to 3.83 mM was observed for mannose conjugated AuNPs and the boropolymer recognition elements, with the lower detection limit of 1.5 μM for the carbohydrate analytes. Furthermore, the multivalent binding between carbohydrates and boronic acids are reversible and allow the regeneration of boropolymer surface by using 1M acetic acid so as to sequentially capture and release the carbohydrate analytes.


Trading up: the fitness consequences of divorce in monogamous birds.
Social and genetic mating systems play an important role in natural and sexual selection, as well as in the dynamics of populations. In socially monogamous species different genetic mating patterns appear when individuals mate outside the breeding pair within a breeding season (extra-pair mating) or when they change partners between two breeding seasons (widowing or divorce). Divorce can be defined as having occurred when two previously paired individuals are alive during the next breeding season and at least one of them has re-mated with a new partner. In socially monogamous birds divorce is widespread, but it is not clear whether it is a behavioural adaptation to improve the quality of a mating decision or whether, alternatively, it results as a non-selected consequence of other processes: existing studies suggest a heterogeneous set of results with respect to this central question. This heterogeneity could result from a number of factors, ranging from the methodological approaches used, to population- or species-specific characters. In this review we use phylogenetic meta-analyses to assess the evidence that divorce is adaptive (in terms of breeding success) across 64 species of socially monogamous birds. Second, we explore biological and methodological reasons for the heterogeneity in the results of previous studies. Results of our analyses supported the hypothesis that divorce is, in general, an adaptive behavioural strategy as: (1) divorce is triggered by relatively low breeding success; (2) there is a positive change in breeding success as a result of divorce. More specifically, while controlling for methodological moderators, we show that: (i) earlier stages of breeding are better predictors of divorce than later stages (r = 0.231; 95% CI: 0.061-0.391 for clutch size; similar for laying date); (ii) females benefited from divorce more than males in terms of increasing breeding success between successive breeding attempts, with different stages of the breeding cycle improving at different rates (e.g. r = 0.637; 95% CI: 0.328-0.817 for brood-level measures). We show that the effect size was dependent on the methodological approach used across studies and argue that research on the adaptive nature of divorce should be cautious when designing the study and interpreting the results. Altogether, by providing strong evidence that divorce is an adaptive strategy across monogamous birds, the results of our analysis provide a firm ground for further exploration of external covariates of divorce (e.g. demographic factors) and the mechanisms underlying the differences in the effect sizes of the proximal fitness causes and consequences of divorce.


Chorionic villus sampling: a 15-year experience.
The authors describe experiences gained over the period of 1984-1999 at two medical centers with chorionic villus sampling (CVS). Altogether 1,149 CVSs had been performed between the 10th and 32nd gestational weeks. Prior to 1993 the transcervical approach (TC-CVS), after 1994 the transabdominal method (TA-CVS) was used. Analysis of data collected within the framework of this study was based on the following factors: indications for sampling, complications and incidence of pregnancy loss. 91.6% of the CVSs were carried out for the purposes of cytogenetic examination of the fetus. Over the past few years an increasing number of procedures had been carried out for molecular-genetic tests (7.6% of the total number of cases). Though the primary indication for cytogenetic tests was the advanced age of the mother, a remarkable increase in the number of samplings had taken place for the purpose of examining "suspicious ultrasound findings", minor anomalies detected by ultrasound. In this group the proportion of pathological cases was significantly higher (14%) than in all the other samplings, carried out for other indications. This data in itself underlines the importance of ultrasound screening performed in the 18-20th weeks of gestation. Over the first half of the period being reviewed (1984-1993, TC-CVS), a fetal loss of 4.8% occurring within 3 weeks from the date of sampling, dropped to 1.7% in the period subsequent to year 1994 (TA-CVS). In cases of TA-CSV, both the complications and spontaneous abortions were fewer. In 74.1% of the cases studied, birth had taken place after the 37th week of gestation. Premature births (6.4%) and stillbirth rate (1.1%) did not exceed normal rates observed in the general population. On the basis of our results, it is safe to say that in prenatal diagnosis, TA-CVS is a real alternative method of mid-trimester amniocentesis and it is recommended for use at any stage of the pregnancy.


Anti-inflammatory effect of Moringa oleifera Lam. seeds on acetic acid-induced acute colitis in rats.
Anti-inflammatory, immuno-modulatory, and antioxidant properties of Moringa oleifera Lam. suggest that it might have beneficial effects on colitis. The present study was performed to investigate the anticolitis effect of Moringa oleifera seeds hydro-alcoholic extract (MSHE) and its chloroform fraction (MCF) on acetic acid-induced colitis in rats. Both MSHE and MCF with three increasing doses (50, 100, and 200 mg/kg) were administered orally to separate groups of male Wistar rats, 2 h before ulcer induction (using acetic acid 4%) and continued for 5 days. Prednisolone (4 mg/kg) and normal saline (1 ml/kg) were used in reference and control groups, respectively. All rats were sacrificed 24 h after the last dose (at day 6) and tissue injuries were assessed macroscopically and pathologically. Extracts with three doses mentioned before were effective to reduce weight of distal colon (8 cm) as a marker for inflammation and tissue edema. Three doses of MSHE and two greater doses of MCF (100 and 200 mg/kg) were effective to reduce ulcer severity, area, and index as well as mucosal inflammation severity and extent, crypt damage, invasion involvement, total colitis index, and MPO activity compared with controls. MCF (50 mg/kg) was not significantly effective in reducing evaluated parameters of colitis compared with controls. It is concluded that MSHE and MCF were both effective to treat experimental colitis and this might be attributed to their similar major components, biophenols and flavonoids. Since the efficacy was evident even in low doses of MSHE, presence of active constituents with high potency in seeds is persuasive.


A national survey of screening for congenital dislocation of the hip.
To identify current screening and management practices for congenital dislocation of the hip (CDH), and determine the extent to which ultrasound imaging of the hips is practised throughout the United Kingdom and the Irish Republic. Postal questionnaire to paediatricians responsible for the routine neonatal care of infants in all maternity units in the UK and the Irish Republic. Questionnaires were returned for 254 maternity units (92% response rate). By 1994, 69% of maternity units had access to ultrasound imaging of the hips, compared to 14% in 1984. Ultrasound imaging of the hip was not used for universal primary screening, but in 93% of units was undertaken for further assessment of infants with clinically detected hip instability or those identified as being at high risk of CDH, or both. Clinical screening of newborn infants was performed by junior paediatricians, but training with a 'Baby Hippy' hip simulator model was provided in only 37% of units. Treatment of clinically detected hip instability, initiated by an orthopaedic surgeon in 93% of units, varied widely in type and duration. Ultrasound imaging of the hip is increasingly used in the UK for secondary, rather than primary, screening. Current recommendations are implemented to a variable extent nationally, and the existing wide variation in screening and management for CDH reflects a lack of research evidence to support current screening practices. The effectiveness of screening for CDH needs to be established.


Human P450 CYP17A1: Control of Substrate Preference by Asparagine 202.
CYP17A1 is a key steroidogenic enzyme known to conduct several distinct chemical transformations on multiple substrates. In its hydroxylase activity, this enzyme adds a hydroxyl group at the 17α position of both pregnenolone and progesterone at approximately equal rates. However, the subsequent 17,20 carbon-carbon scission reaction displays variable substrate specificity in the numerous CYP17A1 isozymes operating in vertebrates, manifesting as different Kd and kcat values when presented with 17α-hydroxypregnenlone (OHPREG) versus 17α-hydroxyprogesterone (OHPROG). Here we show that the identity of the residue at position 202 in human CYP17A1, thought to form a hydrogen bond with the A-ring alcohol substituent on the pregnene- nucleus, is a key driver of this enzyme's native preference for OHPREG. Replacement of asparagine 202 with serine completely reverses the preference of CYP17A1, more than doubling the rate of turnover of the OHPROG to androstenedione reaction and substantially decreasing the rate of formation of dehydroepiandrosterone from OHPREG. In a series of resonance Raman experiments, it was observed that, in contrast with the case for the wild-type protein, in the mutant the 17α alcohol of OHPROG tends to form a H-bond with the proximal rather than terminal oxygen of the oxy-ferrous complex. When OHPREG was a substrate, the mutant enzyme was found to have a H-bonding interaction with the proximal oxygen that is substantially weaker than that of the wild type. These results demonstrate that a single-point mutation in the active site pocket of CYP17A1, even when far from the heme, has profound effects on steroidogenic selectivity in androgen biosynthesis.


A continuous stimuli-responsive system for NIR-II fluorescence/photoacoustic imaging guided photothermal/gas synergistic therapy.
Nanosystems responsive to a tumor microenvironment (TME) have recently attracted great attention due to their potential in precision cancer theranostics. However, theranostic nanosystems with a TME-activated consecutive cascade for the accurate diagnosis and treatment of cancer have rarely been exploited. Herein, an activatable theranostic nanosystem (Bi2S3-Ag2S-DATS@BSA-N3 NYs) is designed and constructed on the basis of a one-pot biomineralization method and surface functional modification to improve second near-infrared (NIR-II) fluorescence/photoacoustic (PA) imaging-guided photothermal therapy (PTT)/gas therapy (GT). Based on enhanced penetration and retention (EPR) effect-mediated tumor accumulation, the tumor-overexpressed glutathione (GSH) can accelerate hydrogen sulfide (H2S) generation from the nanoparticles by reacting with the encapsulated diallyl trisulfide (DATS). Meanwhile, the in situ released H2S can be used not only for gas therapy, but also to start the reduction of -N3(-) to -NH2(+), thereby enhancing the tumor-specific aggregation of NYs. As a result, the activatable nanosystems with excellent tumor accumulation and biodistribution could achieve an accurate NIR-II/PA dual-modality imaging for guiding the synergistic anticancer efficacy (PTT/GT). Thus, this work provides a promising TME-mediated continuously responsive strategy for efficient anticancer therapy.


Reducing Invasive Care for Low-risk Febrile Infants Through Implementation of a Clinical Pathway.
Significant variation in management of febrile infants exists both nationally and within our institution. Risk stratification can be used to identify low-risk infants who can be managed as outpatients without lumbar puncture (LP) or antibiotics. Our objective was to reduce invasive interventions for febrile infants aged 29 to 60 days at low risk for serious bacterial infection (SBI) through implementation of a clinical pathway supported by quality improvement (QI). The evidence-based clinical pathway was developed and implemented by a multidisciplinary team with continuous-process QI to sustain use. Low-risk infants who underwent LP, received antibiotics, and were admitted to the hospital were compared pre- and postpathway implementation with SBI in low-risk infants and appropriate care for high-risk infants as balancing measures. Of 350 included patients, 220 were pre- and 130 were postpathway implementation. With pathway implementation in July 2016, invasive interventions decreased significantly in low-risk infants, with LPs decreasing from 32% to 0%, antibiotic administration from 30% to 1%, and hospital admission from 17% to 2%. Postimplementation, there were 0 SBIs in low-risk infants versus 29.2% in high-risk infants. The percentage of high-risk patients receiving care per pathway remained unchanged. Improvement was sustained for 12 months through QI interventions, including order-set development and e-mail reminders. Implementation of a clinical pathway by using QI methods resulted in sustained reduction in invasive interventions for low-risk febrile infants without missed SBIs. Clinical pathways and QI can be key strategies in the delivery of evidence-based care for febrile infants.


Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide.
The androgen receptor (AR) is widely expressed in breast cancers and has been proposed as a therapeutic target in estrogen receptor alpha (ER) negative breast cancers that retain AR. However, controversy exists regarding the role of AR, particularly in ER + tumors. Enzalutamide, an AR inhibitor that impairs nuclear localization of AR, was used to elucidate the role of AR in preclinical models of ER positive and negative breast cancer. We examined nuclear AR to ER protein ratios in primary breast cancers in relation to response to endocrine therapy. The effects of AR inhibition with enzalutamide were examined in vitro and in preclinical models of ER positive and negative breast cancer that express AR. In a cohort of 192 women with ER + breast cancers, a high ratio of AR:ER (≥2.0) indicated an over four fold increased risk for failure while on tamoxifen (HR = 4.43). The AR:ER ratio had an independent effect on risk for failure above ER % staining alone. AR:ER ratio is also an independent predictor of disease-free survival (HR = 4.04, 95% CI: 1.68, 9.69; p = 0.002) and disease specific survival (HR = 2.75, 95% CI: 1.11, 6.86; p = 0.03). Both enzalutamide and bicalutamide inhibited 5-alpha-dihydrotestosterone (DHT)-mediated proliferation of breast cancer lines in vitro; however, enzalutamide uniquely inhibited estradiol (E2)-mediated proliferation of ER+/AR + breast cancer cells. In MCF7 xenografts (ER+/AR+) enzalutamide inhibited E2-driven tumor growth as effectively as tamoxifen by decreasing proliferation. Enzalutamide also inhibited DHT- driven tumor growth in both ER positive (MCF7) and negative (MDA-MB-453) xenografts, but did so by increasing apoptosis. AR to ER ratio may influence breast cancer response to traditional endocrine therapy. Enzalutamide elicits different effects on E2-mediated breast cancer cell proliferation than bicalutamide. This preclinical study supports the initiation of clinical studies evaluating enzalutamide for treatment of AR+ tumors regardless of ER status, since it blocks both androgen- and estrogen- mediated tumor growth.


Continuous tank reactor synthesis of highly substituted sulphobutylether β-cyclodextrins.
Batch synthesis of sulphobutyl ether β-cyclodextrin (also known as SBE-β-CD or SBECD) is a process effectively divided into three main stages, i.e. initial reagent dissolution, a sulphoalkylation reaction and final reaction quenching. This reaction is followed by downstream processing and purification, and ultimate isolation of the solid SBECD material. However, a feature associated with using this synthetic method is that a high proportion of lower substituted SBECD is observed. There is therefore a need to provide an improved synthetic method for producing higher substituted cyclodextrins. The authors here present a Continuous Tank Reactor (CTR) method for preparing sulphobutyl ether-cyclodextrins. The method comprises first contacting cyclodextrin with a base to form activated cyclodextrin. The method then involves separately contacting the activated cyclodextrin with an 1,4-butane sultone to form sulphoalkyl ether-cyclodextrin. The activation reaction is carried out in batch synthesis mode and the sulphoalkylation reaction is carried out under continuous flow conditions resulting in a novel method for the synthesis of highly derivatised cyclodextrins. The work is particularly concerned with producing controlled substitution in sulphobutyl ether β-cyclodextrins and novel compositions of highly substituted sulphoalkyl ether β-cyclodextrins are described.


[Hepatitis B and C in HIV coinfection].
Hepatitis B and C virus infections are a leading cause of death in HIV-positive patients. Furthermore, the management of these infections is complicated. Psychosocial problems and comorbidities are frequent barriers to the optimal management of these patients. Furthermore, the rapid changes in treatment strategies particularly in Hepatitis C make it difficult to treat patients outside specialized centers. An improvement in treatment uptake and efficacy can only be achieved through coordinated efforts between private care physicians and specialized centers.


Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner.
Infection with Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the stomach. Tumorigenic transformation of gastric epithelium induced by H. pylori is a highly complex process driven by an active interplay between bacterial virulence and host factors, many aspects of which remain obscure. In this work, we investigated the degradation of p53 tumour suppressor induced by H. pylori. Expression of p53 protein in gastric biopsies was assessed by immunohistochemistry. Gastric cells were co-cultured with H. pylori strains isolated from high-gastric risk and low-gastric risk areas and assessed for expression of p53, p14ARF and cytotoxin-associated gene A (CagA) by immunoblotting. siRNA was used to inhibit activities of ARF-BP1 and Human Double Minute 2 (HDM2) proteins. Our analysis demonstrated that H. pylori strains expressing high levels of CagA virulence factor and associated with a higher gastric cancer risk more strongly suppress p53 compared with low-risk strains in vivo and in vitro. We found that degradation of p53 induced by bacterial CagA protein is mediated by host HDM2 and ARF-BP1 E3 ubiquitin ligases, while the p14ARF protein counteracts H. pylori-induced signalling. Our results provide novel evidence that tumorigenicity associated with H. pylori infection is linked to inhibition of p53 protein by CagA. We propose a model in which CagA-induced degradation of p53 protein is determined by a relative level of p14ARF. In cells in which p14ARF levels were decreased due to hypermethylation or deletion of the p14ARF gene, H. pylori efficiently degraded p53, whereas p53 is protected in cells expressing high levels of p14ARF.


Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT).
Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT > 1-4×MIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment. This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (ƒT > MICECOFF and ƒT > 4×MICECOFF) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes. A total of 147 patients were included, of whom 63.3% achieved PDT of 100%ƒT > MICECOFF and 36.7% achieved 100%ƒT > 4×MICECOFF. Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2, and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100%ƒT > MICECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival. Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients. Netherlands Trial Registry (EXPAT trial), NTR 5632 . Registered on 7 December 2015.


Ubiquitin-mediated fluctuations in MHC class II facilitate efficient germinal center B cell responses.
Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation and selection. Selection involves B cells competing for T cell help based on the amount of antigen they capture and present on their MHC class II (MHCII) proteins. How GC B cells are able to rapidly and repeatedly transition between mutating their B cell receptor genes and then being selected shortly after is not known. We report that MHCII surface levels and degradation are dynamically regulated in GC B cells. Through ectopic expression of a photoconvertible MHCII-mKikGR chimeric gene, we found that individual GC B cells differed in the rates of MHCII protein turnover. Fluctuations in surface MHCII levels were dependent on ubiquitination and the E3 ligase March1. Increases in March1 expression in centroblasts correlated with decreases in surface MHCII levels, whereas CD83 expression in centrocytes helped to stabilize MHCII at that stage. Defects in MHCII ubiquitination caused GC B cells to accumulate greater amounts of a specific peptide-MHCII (pMHCII), suggesting that MHCII turnover facilitates the replacement of old complexes. We propose that pMHCII complexes are periodically targeted for degradation in centroblasts to favor the presentation of recently acquired antigens, thereby promoting the fidelity and efficiency of selection.


DBD--taxonomically broad transcription factor predictions: new content and functionality.
DNA-binding domain (DBD) is a database of predicted sequence-specific DNA-binding transcription factors (TFs) for all publicly available proteomes. The proteomes have increased from 150 in the initial version of DBD to over 700 in the current version. All predicted TFs must contain a significant match to a hidden Markov model representing a sequence-specific DNA-binding domain family. Access to TF predictions is provided through http://transcriptionfactor.org, where new search options are now provided such as searching by gene names in model organisms, searching for all proteins in a particular DBD family and specific organism. We illustrate the application of this type of search facility by contrasting trends of DBD family occurrence throughout the tree of life, highlighting the clear partition between eukaryotic and prokaryotic DBD expansions. The website content has been expanded to include dedicated pages for each TF containing domain assignment details, gene names, links to external databases and links to TFs with similar domain arrangements. We compare the increase in number of predicted TFs with proteome size in eukaryotes and prokaryotes. Eukaryotes follow a slower rate of increase in TFs than prokaryotes, which could be due to the presence of splice variants or an increase in combinatorial control.


Masculinity causes speeding in young men.
The goal of this study was to examine if masculinity is causally responsible for speeding in young men. Participants (83 males) were randomly assigned to a masculine, feminine, or neutral priming condition. Priming consisted in active listening to either masculine, feminine, or neutral words coming from the car radio while driving in a high-end driving simulator. Results showed that when the concept of masculinity was activated by priming, participants' driving speed increased significantly from the beginning to the end of the driving simulation as compared to the neutral and the feminine condition. Results are discussed with respect to real life health implications.


Assessment of driving capability through the use of clinical and psychomotor tests in relation to blood cannabinoids levels following oral administration of 20 mg dronabinol or of a cannabis decoction made with 20 or 60 mg Delta9-THC.
Delta(9)-Tetrahydrocannabinol (THC) is frequently found in the blood of drivers suspected of driving under the influence of cannabis or involved in traffic crashes. The present study used a double-blind crossover design to compare the effects of medium (16.5 mg THC) and high doses (45.7 mg THC) of hemp milk decoctions or of a medium dose of dronabinol (20 mg synthetic THC, Marinol on several skills required for safe driving. Forensic interpretation of cannabinoids blood concentrations were attempted using the models proposed by Daldrup (cannabis influencing factor or CIF) and Huestis and coworkers. First, the time concentration-profiles of THC, 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) (active metabolite of THC), and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THCCOOH) in whole blood were determined by gas chromatography-mass spectrometry-negative ion chemical ionization. Compared to smoking studies, relatively low concentrations were measured in blood. The highest mean THC concentration (8.4 ng/mL) was achieved 1 h after ingestion of the strongest decoction. Mean maximum 11-OH-THC level (12.3 ng/mL) slightly exceeded that of THC. THCCOOH reached its highest mean concentration (66.2 ng/mL) 2.5-5.5 h after intake. Individual blood levels showed considerable intersubject variability. The willingness to drive was influenced by the importance of the requested task. Under significant cannabinoids influence, the participants refused to drive when they were asked whether they would agree to accomplish several unimportant tasks, (e.g., driving a friend to a party). Most of the participants reported a significant feeling of intoxication and did not appreciate the effects, notably those felt after drinking the strongest decoction. Road sign and tracking testing revealed obvious and statistically significant differences between placebo and treatments. A marked impairment was detected after ingestion of the strongest decoction. A CIF value, which relies on the molar ratio of main active to inactive cannabinoids, greater than 10 was found to correlate with a strong feeling of intoxication. It also matched with a significant decrease in the willingness to drive, and it matched also with a significant impairment in tracking performances. The mathematic model II proposed by Huestis et al. (1992) provided at best a rough estimate of the time of oral administration with 27% of actual values being out of range of the 95% confidence interval. The sum of THC and 11-OH-THC blood concentrations provided a better estimate of impairment than THC alone. This controlled clinical study points out the negative influence on fitness to drive after medium or high dose oral THC or dronabinol.


Height and skeletal morphology in relation to modern life style.
Height and skeletal morphology strongly relate to life style. Parallel to the decrease in physical activity and locomotion, modern people are slimmer in skeletal proportions. In German children and adolescents, elbow breadth and particularly relative pelvic breadth (50th centile of bicristal distance divided by body height) have significantly decreased in recent years. Even more evident than the changes in pelvic morphology are the rapid changes in body height in most modern countries since the end-19th and particularly since the mid-20th century. Modern Japanese mature earlier; the age at take-off (ATO, the age at which the adolescent growth spurt starts) decreases, and they are taller at all ages. Preece-Baines modelling of six national samples of Japanese children and adolescents, surveyed between 1955 and 2000, shows that this gain in height is largely an adolescent trend, whereas height at take-off (HTO) increased by less than 3 cm since 1955; adolescent growth (height gain between ATO and adult age) increased by 6 cm. The effect of globalization on the modern post-war Japanese society ("community effect in height") on adolescent growth is discussed.


Convergent and Divergent Validity Between the KTK and MOT 4-6 Motor Tests in Early Childhood.
The aim of this study was to investigate the convergent and divergent validity between the Body Coordination Test for Children (KTK) and the Motor Proficiency Test for 4- to 6-Year-Old Children (MOT 4-6). A total of 638 children (5-6 yr old) took part in the study. The results showed a moderately positive association between the total scores of both tests (r(s) = .63). Moreover, the KTK total score correlated more highly with the MOT 4-6 gross motor score than with the MOT 4-6 fine motor score (r(s) = .62 vs. .32). Levels of agreement were moderate when identifying children with moderate or severe motor problems and low at best when detecting children with higher motor-competence levels. This study provides evidence of convergent and divergent validity between the KTK and MOT 4-6. However, given the moderate to low levels of agreement, either measurement may lead to possible categorization errors. Children's motor competence should therefore not be judged based on the result of a single test.


Perspective on control options for Echinococcus multilocularis with particular reference to Japan.
Following a brief introduction of recent advances in molecular and immunological technology for detection of persons and animals infected with Echinococcus multilocularis and an overview of the current situation of alveolar echinococcosis (AE) in Japan, perspectives on control options are discussed with reference to different epidemiological situations. AE is considered the most serious parasitic zoonosis in temperate and arctic regions of the northern hemisphere. The number of human cases differs drastically among regions. While high numbers of patients are apparently associated with high E. multilocularis prevalence in domestic dogs, e.g. in parts of Alaska and western China, the number of cases is moderate or low in areas where the parasite is mainly transmitted by wild canid species (e.g. in central Europe or temperate North America). However, the severity of the disease, the absence of curative treatment for most cases, the high cost of long-term chemotherapy and the anxiety caused for the population in highly endemic areas call for the development of preventive strategies even in regions where human AE is rare. Furthermore, in view of (1) drastically increasing numbers and infection rates of foxes involved in transmission of E. multilocularis, and (2) increasingly close contact between humans and foxes e.g. in Europe and Japan, there is considerable concern that AE incidences may in future increase in these regions. Control options depend on a variety of factors including the species of canid principally responsible for transmission and the socio-economic situation in the region. Where domestic dogs (stray or owned) are the principal hosts for E. multilocularis, control options can include those applicable to E. granulosus, i.e. reduction of the number of stray dogs, registration and regular preventive chemotherapy of owned dogs, and information campaigns for the population promoting low-risk behaviour for man and dogs. Where E. multilocularis is mainly transmitted by wild canids, the situation is far more difficult with preventive strategies still being in trial stage. Integrated control measures could include prevention information campaigns, restricting access of pet animals (dogs and cats) to rodents, chemotherapy of foxes on local or regional scales, and strategies to minimize contacts between people and foxes.


Costs of measures to control tuberculosis/HIV in public primary care facilities in Cape Town, South Africa.
To measure the costs and estimate the cost-effectiveness of the ProTEST package of tuberculosis/human immunodeficiency virus (TB/HIV) interventions in primary health care facilities in Cape Town, South Africa. We collected annual cost data retrospectively using ingredients-based costing in three primary care facilities and estimated the cost per HIV infection averted and the cost per TB case prevented. The range of costs per person for the ProTEST interventions in the three facilities were: US$ 7-11 for voluntary counselling and testing (VCT), US$ 81-166 for detecting a TB case, US$ 92-183 for completing isoniazid preventive therapy (IPT) and US$ 20-44 for completing six months of cotrimoxazole preventive therapy. The estimated cost per HIV infection averted by VCT was US$ 67-112. The cost per TB case prevented by VCT (through preventing HIV) was US$ 129-215, by intensified case finding was US$ 323-664 and by IPT was US$ 486-962. Sensitivity analysis showed that the use of chest X-rays for IPT screening decreases the cost-effectiveness of IPT in preventing TB cases by 36%. IPT screening with or without tuberculin purified protein derivative screening was almost equally cost-effective. We conclude that the ProTEST package is cost saving. Despite moderate adherence, linking prevention and care interventions for TB and HIV resulted in the estimated costs of preventing TB being less than previous estimates of costs of treating it. VCT was less expensive than previously reported in Africa.


A new twist in the feedback loop: stress-activated MDM2 destabilization is required for p53 activation.
The p53 tumor suppressor is a transcription factor that is activated by diverse genotoxic and cytotoxic stresses. Upon activation, p53 prevents the proliferation of genetically unstable cells by regulating the expression of genes that initiate cell cycle arrest, apoptosis, and DNA repair. Consequently, p53 must be kept inactive in unstressed cells as its inappropriate activation can cause premature senescence and death. p53 inhibition occurs primarily through the E3 ubiquitin ligase, MDM2. Because MDM2 is also a p53 target gene, stresses paradoxically activate p53 while simultaneously increasing MDM2 expression. Therefore, a challenge has been to explain how the abundant MDM2 is prevented from inhibiting p53, thus ensuring that p53 can execute an appropriate stress response. Here we discuss a new mechanism for p53 activation involving DNA damage-induced auto-degradation of MDM2. Our data reveal that DNA damage leads to the destabilization of MDM2, which correlates with p53 stabilization and target gene induction. Conversely, p53 levels and activity decrease when MDM2 returns to a more stable state later in the stress response. The destabilization of MDM2 is required for p53 activation, as blocking MDM2 degradation via proteasome inhibition prevents p53 transactivation in DNA-damaged cells by enabling MDM2 to bind and inhibit p53. MDM2 destabilization is controlled by DNA damage-activated post-translational modifications and by its own RING domain, implying a possible role for the RING domain-interacting protein, MDMX, in regulating MDM2 stability. We propose that accelerated degradation of MDM2 limits its binding to p53 during a stress response and enables p53 to accumulate and remain active, even as p53 transcriptionally activates more MDM2. Thus, the induction of MDM2 RNA by activated p53 may create a reserve of MDM2 that can inactivate p53 once the DNA damage stimulus has abated and MDM2 is restabilized. As many tumors inactivate wild type p53 through MDM2 overexpression, exploiting the pathways that trigger MDM2 auto-degradation may be an important new strategy for chemotherapeutic intervention.


Perovskite oxides: materials science in catalysis.
In a time of growing need for catalysts, perovskites have been rediscovered as a family of catalysts of such great diversity that a broad spectrum of scientific disciplines have been brought to bear in their study and application. Because of the wide range of ions and valences which this simple structure can accommodate, the perovskites lend themselves to chemical tailoring. It is relatively simple to synthesize perovskites because of the flexibility of the structure to diverse chemistry. Many of the techniques of ceramic powder preparation are applicable to perovskite catalysts. In their own right, they are therefore of interest as a model system for the correlation of solid-state parameters and catalytic mechanisms. Such correlations [See figure in the PDF file] have recently been found between the rate and selectivity of oxidation-reduction reactions and the thermodynamic and electronic parameters of the solid. For commercial processes such as those mentioned in the introduction, perovskite catalysts have not yet proven to be practical. Much of the initial interest in these catalysts related to their use in automobile exhaust control. Current interest in this field centers on noble metalsubstituted perovskites resistant to S poisoning for single-bed, dual-bed, and three-way catalyst configurations. The formulations commercially tested to date have shown considerable promise, but long-term stability has not yet been achieved. A very large fraction of the elements that make up presently used commercial catalysts can be incorporated in the structure of perovskite oxides. Conversely, it is anticipated that perovskite oxides, appropriately formulated, will show catalytic activity for a large variety of chemical conversions. Even though this expectation is by no means a prediction of commercial success in the face of competition by existing catalyst systems, it makes these oxides attractive models in the study of catalytic chemical conversion. By appropriate formulation many desirable properties can be tailored, including the valence state of transition metal ions, the binding energy and diffusion of O in the lattice, the distance between active sites, and the magnetic and conductive properties of the solid. Only a very small fraction of possible perovskite formulations have been explored as catalysts. It is expected that further investigation will greatly expand the scope of perovskite catalysis, extend the understanding of solid-state parameters in catalysis, and contribute to the development of practical catalytic processes.


Reduction in invasive pneumococcal disease following implementation of the conjugate vaccine in the Oxfordshire region, England.
Pneumococcal conjugate vaccine to seven capsular types has been highly effective in the US since its introduction in 2000. The same vaccine was adopted by the UK in 2006. Ongoing surveillance since 1995 of invasive pneumococcal disease (IPD) in Oxfordshire, UK, allowed assessment of the impact of vaccine intervention. The vaccine significantly reduced IPD among the target group, children under 2 years of age; incidence rate ratio (IRR)=0.62 (95 % CI 0.43-0.90) (P=0.008) comparing the 3 years pre- and post-implementation with a residual incidence of 22.4/100 000 children. The reduction was even greater when comparing 11 years pre- with the 3 years post-implementation of vaccine; IRR=0.53 (0.39-0.70) (P<0.0001). There was a marked direct effect of the vaccine evidenced by substantial reductions in the seven serotypes contained in the vaccine. There was also a clear reduction in IPD for those serotypes contained in the vaccine among those older than 2 years when comparing both the 3 and 11 year pre-PCV7 time periods, with IRR=0.57 (0.47-0.69) (P<0.0001) and IRR=0.50 (0.43-0.58) (P<0.0001), respectively, indicating a strong herd effect. There was a significant, though moderate, rise in the serotypes not contained in the vaccine, with clear evidence for replacement in some serotypes.


Low saturation fluence antiresonant quantum dot SESAMs for MIXSEL integration.
Quantum dot (QD) semiconductor saturable absorber mirrors (SESAMs) offer a larger design freedom than standard quantum well (QW) SESAMs. QD density, QD growth conditions, number of QD-layers, and post-growth annealing were optimized to independently reduce the saturation fluence and adjust the modulation depth for an antiresonant SESAM that supported for the first time passive modelocking of a vertical external-cavity surface emitting laser (VECSEL) with the same spot size on gain and absorber. The same spot size is a requirement for the modelocked integrated external-cavity surface emitting laser (MIXSEL) concept which enables wafer-scale fabrication of the ultrafast semiconductor laser. The antiresonant SESAM design has low dispersion, is less susceptible to growth errors, and is therefore very promising for short pulse generation and MIXSEL integration.


Massive genome erosion and functional adaptations provide insights into the symbiotic lifestyle of Sodalis glossinidius in the tsetse host.
Sodalis glossinidius is a maternally transmitted endosymbiont of tsetse flies (Glossina spp.), an insect of medical and veterinary significance. Analysis of the complete sequence of Sodalis' chromosome (4,171,146 bp, encoding 2,432 protein coding sequences) indicates a reduced coding capacity of 51%. Furthermore, the chromosome contains 972 pseudogenes, an inordinately high number compared with that of other bacterial species. A high proportion of these pseudogenes are homologs of known proteins that function either in defense or in the transport and metabolism of carbohydrates and inorganic ions, suggesting Sodalis' degenerative adaptations to the immunity and restricted nutritional status of the host. Sodalis possesses three chromosomal symbiosis regions (SSR): SSR-1, SSR-2, and SSR-3, with gene inventories similar to the Type-III secretion system (TTSS) ysa from Yersinia enterolitica and SPI-1 and SPI-2 from Salmonella, respectively. While core components of the needle structure have been conserved, some of the effectors and regulators typically associated with these systems in pathogenic microbes are modified or eliminated in Sodalis. Analysis of SSR-specific invA transcript abundance in Sodalis during host development indicates that the individual symbiosis regions may exhibit different temporal expression profiles. In addition, the Sodalis chromosome encodes a complete flagella structure, key components of which are expressed in immature host developmental stages. These features may be important for the transmission and establishment of symbiont infections in the intra-uterine progeny. The data suggest that Sodalis represents an evolutionary intermediate transitioning from a free-living to a mutualistic lifestyle.


Gene stacking in 1-year-cycling APETALA1 citrus plants for a rapid evaluation of transgenic traits in reproductive tissues.
Rapid flowering is crucial to perform functional genomic studies to investigate reproductive biology characteristics and fruit quality-related traits in fruit trees. However, long generation cycles of woody plants considerably delay this evaluation. Through genetic transformation, juvenile periods can be significantly shortened by overexpression of flower meristem-identity genes. Transgenic APETALA1 (AP1) citrus plants behave as rapid-cycling trees, since 1-year-old seedlings promptly show precocious flowering and fruiting. By transgene stacking into these short-generation AP1 and nptII/GUS-positive plants, expression of novel transgenes could theoretically be examined as quickly as 1 year after retransformation. Establishment of the selection and regeneration conditions for the production of retransformed individuals with marker genes is detailed in this communication. Hpt and bar genes were used as the second selectable marker genes. PCR and Southern blot analyses confirmed the recovery of retransformed shoots. AP1 transcript accumulation and GUS and GFP expression were assessed in leaves, and flowers and fruit organs of rapid-cycling retransformed lines, respectively, as early as 1 year after plant generation and during three consecutive years, demonstrating that the principle of stable transgene stacking on early-fruiting transgenic trees is feasible.


Human mating strategies: from past causes to present consequences.
In both humans and nonhuman animals, mating strategies represent a set of evolutionary adaptations aimed at promoting individual fitness by means of reproduction with the best possible partners. Given this critical role, mating strategies influence numerous aspects of human life. In particular, between-sex divergence in the intensity of intrasexual competition could account for robust cross-cultural sex differences in psychology and behavior (e.g., personality, psychiatric disorders, social behavior, violence). Several other factors (including individual differences, relationship type and environment) affect-in an evolutionarily consistent manner-variation in mating strategy that individuals pursue (as one example, awareness of one's own attractiveness impinges on mating standards). Here we provide an overview of relevant theoretical frameworks and empirical evidence on variation in mating strategies. Given its multifaceted nature and intense research interest over several decades, this is a challenging task, and we highlight areas where further investigation is warranted in order to achieve a clearer picture and resolve apparent inconsistencies. However, we suggest that addressing outstanding questions using a variety of different methodological approaches, a deeper understanding of the cognitive representations involved in mating strategies is within reach. WIREs Cogn Sci 2018, 9:e1456. doi: 10.1002/wcs.1456 This article is categorized under: Cognitive Biology > Evolutionary Roots of Cognition Neuroscience > Behavior Neuroscience > Cognition.


Lifestyle factors and 5-year abdominal fat accumulation in a minority cohort: the IRAS Family Study.
The objective of this study was to examine whether lifestyle factors were associated with 5-year change in abdominal fat measured by computed tomography (CT) in the Insulin Resistance and Atherosclerosis (IRAS) Family Study. We obtained abdominal CT scans at baseline and at 5 years, from African Americans (AA) (N = 339) and Hispanic Americans (N = 775), aged 18-81 years. Visceral (VAT) and subcutaneous (SAT) adipose tissue was measured at the L4/L5 vertebral level. Physical activity was documented by self-report of vigorous activity and a 1-year recall instrument. Dietary intake was assessed at follow-up using a semi-quantitative food frequency questionnaire referencing the previous year. Generalized linear models, accounting for family structure, were used to assess the associations between percent change in fat accumulation and smoking, physical activity, total calories, polyunsaturated, monounsaturated, protein, and saturated fat intake, percent of calories from sweets, and soluble and insoluble fiber. Soluble fiber intake and participation in vigorous activity were inversely related to change in VAT, independent of change in BMI. For each 10 g increase in soluble fiber, rate of VAT accumulation decreased by 3.7% (P = 0.01). Soluble fiber was not associated with change in SAT (0.2%, P = 0.82). Moderately active participants had a 7.4% decrease in rate of VAT accumulation and a 3.6% decrease in rate of SAT accumulation versus less active participants (P = 0.003 and P = 0.01, respectively). Total energy expenditure was also inversely associated with accumulation of VAT. Soluble fiber intake and increased physical activity were related to decreased VAT accumulation over 5 years.