Capillary ion chromatography of inorganic anions on octadecyl silica monolith modified with an amphoteric surfactant.
A reversed-phase monolithic silica based capillary column (Onyx C(18), 150 mm x 0.1 mm) was modified with the amphoteric surfactant, N-dodecyl-N,N-(dimethylammonio)undecanoate (DDMAU) and evaluated for the separation and determination of inorganic anions using on-column capacitively coupled contactless conductivity detection (C(4)D). The chromatographic performance of the column was evaluated and under optimal conditions separation efficiencies of 56,200 plates per meter or 7025 plates per column (at detection point) were observed (for iodide). Direct plumbing of the capillary column to the micro-injector and on-column detection eliminated extra-column band broadening, thus allowing accurate analysis of van Deemter curves obtained for the monolithic capillary column. The calculated value for the C-term in the obtained van Deemter curve was between 3 and 4 ms for inorganic anions, allowing for the utilisation of relatively high flow rates without significant losses in efficiency. The performance of the C(4)D detector was investigated and compared for detection on an open tubular capillary column and on the modified monolithic silica capillary column. The on-column detection approach did not result in any significant decrease in peak sensitivity for the monolith compared to responses recorded for open tubular capillary columns, and in addition meant the system could be applied to rapid separations by simple variation in apparent column length. The proposed chromatographic system allowed for detection of common anions at sub-ppm level with a 10 nL injection volume. Additionally, on-column detection allowed visualisation of the development of the separation at any point in time and evaluation of the longitudinal uniformity of the ion-exchange coating.


Human APOBEC1 cytidine deaminase edits HBV DNA.
Retroviruses, hepadnaviruses, and some other retroelements are vulnerable to editing by single stranded DNA cytidine deaminases. Of the eleven human genes encoding such enzymes, eight have demonstrable enzymatic activity. Six of seven human APOBEC3 are able to hyperedit HBV DNA, frequently on both strands. Although human APOBEC1 (hA1) is not generally expressed in normal liver, hA1 can edit single stranded DNA in a variety of experimental assays. The possibility of ectopic expression of hA1 in vivo cannot be ruled out and interestingly, transgenic mice with A1 expressed under a liver specific promoter develop hepatocellular carcinoma. The impact of hA1 on HBV in tissue culture is varied with reports noting either reduced DNA synthesis or not, with cytidine deamination taking a low profile. We sought to examine the hA1 editing activity on replicating HBV. Using highly sensitive 3DPCR it was possible to show that hA1 edits the HBV minus DNA strand as efficiently as hA3G, considered the reference deaminase for HIV and HBV. The dinucleotide specificity of editing was unique among human cytidine deaminases providing a hallmark of use in a posteriori analyses of in vivo edited genomes. Analysis of sequences derived from the serum of two chronic carriers, indicated that hA1 explained only a small fraction of edited HBV genomes. By contrast, several human APOBEC3 deaminases were active including hA3G.


Retinal topography and spectral sensitivity of the Port Jackson shark (Heterodontus portusjacksoni).
In this study, we investigated the visual system of the Port Jackson shark Heterodontus portusjacksoni, a shallow-dwelling benthic species and generalist predator endemic to the temperate coastal waters around southern Australia. Measurements of retinal spectral sensitivity in juvenile sharks, made using single flash and heterochromatic flicker photometry under conditions of dark- or light-adaptation, indicated a peak sensitivity at around 500 nm, with no evidence of a spectral shift with increasing levels of light adaptation. Histological sections of the retina revealed a heavily rod dominated retina containing only a few small cell profiles in the photoreceptor layer that might represent a sparse cone population or may be immature rods. Assessment of retinal topography in juvenile sharks indicated the presence of a distinct specialisation for increased visual spatial acuity in the form of a horizontal streak of higher rod photoreceptor (~80,000 rods mm-2 ) and ganglion cell (~1,800 cells mm-2 ) densities across the horizontal meridian of the eye. This specialization would be adaptive for panoramic sampling of the part of the visual field corresponding to the substrate-water interface and remove the need for H. portusjacksoni to move its eyes extensively when resting on the sea floor. The estimated upper limit of spatial resolving power in juvenile H. portusjacksoni was 3.14 cycles deg-1 , which is at the lower end of values measured in elasmobranchs. Taken together, these results suggest that the retina of H. portusjacksoni is well adapted for nocturnal vision.


Menstrual cycle phase and carbohydrate ingestion alter immune response following endurance exercise and high intensity time trial performance test under hot conditions.
Sex hormones are known to regulate some responses during exercise. Evaluation of the differences in exercise response with regard to menstrual cycle will help understand the menstrual cycle phase specific adaptations to exercise and athletic performance. We investigated the effects of menstrual cycle phase and carbohydrate (CHO) ingestion on immune response during endurance exercise at 30°C. Six healthy women completed 4 trials comprising 90 min of cycling at 50% peak aerobic power [Formula: see text] and a high intensity time trial performance test (POST). They ingested a placebo- or CHO-containing beverage during the trials, which were performed during both the follicular and luteal phases of the menstrual cycle. In all trials, thermoregulatory, cardiorespiratory, and immune responses were measured during exercise and after POST. Although the thermoregulatory responses differed between the menstrual cycle phases, the cardiorespiratory responses were not different. After placebo ingestion, leukocyte concentration (cells/μL) at POST (15.9 × 10(3)) in the luteal phase was significantly higher than that in the follicular phase (12.9 × 10(3)). The rise in leukocyte concentration was attenuated upon CHO ingestion, and the difference between menstrual cycle phases disappeared. A significant positive correlation was found between leukocyte concentration and serum free fatty acid concentrations. Interleukin-6, calprotectin, and myeloperoxidase concentrations significantly increased at POST in all trials, but no significant differences were observed between menstrual cycle phase or beverage type. Concentrations of other cytokines did not change during exercise in any of the 4 trials. Menstrual cycle phase and beverage type had no significant effect on the POST outcome. Thus, differences in leukocyte mobilization between menstrual cycle phases could result from the effect of sex hormones on substrate utilization. The menstrual cycle affected circulating leukocyte concentrations during endurance exercise with POST when a placebo was ingested. Therefore, we recommend ingesting CHO beverages to attenuate immune disturbances, especially in the luteal phase, even though they are unlikely to enhance test performance.


Will We Ever Agree on Protein Requirements in the Intensive Care Unit?
The precise value of the normal adult protein requirement has long been debated. For many reasons-one of them being the difficulty of carrying out long-term nutrition experiments in free-living people-uncertainty is likely to persist indefinitely. By contrast, the controlled environment of the intensive care unit and relatively short trajectory of many critical illnesses make it feasible to use hard clinical outcome trials to determine protein requirements for critically ill patients in well-defined clinical situations. This article suggests how the physiological principles that underlie our understanding of normal protein requirements can be incorporated into the design of such clinical trials. The main focus is on 3 principles: (1) the rate of body nitrogen loss roughly predicts an individual's minimum protein requirement and is thus essential to measure to identify individual patients and clinical situations in which the minimum protein requirement is importantly increased, (2) existing muscle mass sets an upper limit on the rate at which amino acids can be mobilized from muscle for transfer to central proteins and sites of injury and is thus important to monitor to identify patients who are at greatest risk of protein deficiency-related adverse outcomes, and (3) negative energy balance increases the dietary protein requirement, so calorie-deprived patients-whether obese or not-should be enrolled in hard clinical outcome trials that compare the current practice of "permissive underfeeding" (underprovision of all nutrients, including protein) with hypocaloric nutrition supplemented by a suitably generous amount of protein.


Reproduction of mucosal disease with cytopathogenic bovine viral diarrhoea virus selected in vitro.
Isolates of non-cytopathogenic bovine viral diarrhoea (BVD) virus from 18 persistently infected calves from one herd were compared by using monoclonal antibodies directed against the major viral glycoprotein gp53. All the isolates displayed an almost identical reaction pattern. Based on this antigenic analysis three cytopathogenic BVD and three non-cytopathogenic BVD viruses closely related to the non-cytopathogenic BVD herd isolate were selected. Six of the persistently infected calves were inoculated with a pool of the three closely related cytopathogenic BVD viruses and two with a pool of the three non-cytopathogenic BVD viruses. In addition three animals were infected with one closely related cytopathogenic BVD strain (Indiana) and two animals with the antigenetically different cytopathogenic BVD viral strain A1138/69. Regardless of the inoculation route all the animals superinfected with closely related cytopathogenic BVD viruses developed the characteristic lesions of mucosal disease within 14 days of infection. Animals which were inoculated with non-cytopathogenic BVD viruses which closely resembled the herd isolate, or with cytopathogenic BVD viruses which did not resemble the herd isolate did not develop any signs of disease. However, the latter group produced antibodies to the superinfecting virus.


Average biometry of the cornea in a large population of Iranian school children.
This work establishes the average Scheimpflug corneal tomography for a population of 4953 healthy Iranian primary school children. These data were transformed to determine the corneal position and orientation in three-dimensional space, followed by a model fit that combines a biconic with a Zernike expansion. Girls were found to have slightly steeper corneas than boys. Both corneal surfaces show negative conic constants and significant higher-order aspheric Zernike terms. The corneal surfaces are decentered and misaligned with respect to each other and to the line of sight. Consequently, the average corneal surfaces may be considered as decentered and misaligned higher-order aspheres.


Generalized DNA barcode design based on Hamming codes.
The diversity and scope of multiplex parallel sequencing applications is steadily increasing. Critically, multiplex parallel sequencing applications methods rely on the use of barcoded primers for sample identification, and the quality of the barcodes directly impacts the quality of the resulting sequence data. Inspection of the recent publications reveals a surprisingly variable quality of the barcodes employed. Some barcodes are made in a semi empirical fashion, without quantitative consideration of error correction or minimal distance properties. After systematic comparison of published barcode sets, including commercially distributed barcoded primers from Illumina and Epicentre, methods for improved, Hamming code-based sequences are suggested and illustrated. Hamming barcodes can be employed for DNA tag designs in many different ways while preserving minimal distance and error-correcting properties. In addition, Hamming barcodes remain flexible with regard to essential biological parameters such as sequence redundancy and GC content. Wider adoption of improved Hamming barcodes is encouraged in multiplex parallel sequencing applications.


A survey of georgia adult protective service staff: implications for older adult injury prevention and policy.
The aging population is a rapidly growing demographic. Isolation and limited autonomy render many of the elderly vulnerable to abuse, neglect and exploitation. As the population grows, so does the need for Adult Protective Services (APS). This study was conducted to examine current knowledge of older adult protection laws in Georgia among APS staff and to identify training opportunities to better prepare the APS workforce in case detection and intervention. The Georgia State University Institute of Public Health faculty developed a primary survey in partnership with the Georgia Division of Aging Services' leadership to identify key training priority issues for APS caseworkers and investigators. A 47-item electronic questionnaire was delivered to all APS employees via work-issued email accounts. We conducted descriptive analyses, t-tests and chi-square analyses to determine APS employees' baseline knowledge of Georgia's elder abuse policies, laws and practices, as well as examine associations of age, ethnicity, and educational attainment with knowledge. We used a p-value of 0.05 and 95% confidence intervals to determine statistical significance of analyses performed. Ninety-two out of 175 APS staff responded to the survey (53% response rate). The majority of respondents were Caucasian (56%) women (92%). For over half the survey items, paired sample t-tests revealed significant differences between what APS staff reported as known and what APS staff members indicated they needed to know more about in terms of elder abuse and current policies. Chi-square tests revealed that non-Caucasians significantly preferred video conferencing as a training format (44% compared to 18%), [χ(2)(1) = 7.102, p < .008], whereas Caucasians preferred asynchronous online learning formats (55% compared to 28%) [χ(2)(1) =5.951, p < .015]. Results from this study provide the Georgia Division of Aging with insight into specific policy areas that are not well understood by APS staff. Soliciting input from intended trainees allows public health educators to tailor and improve training sessions. Trainee input may result in optimization of policy implementation, which may result in greater injury prevention and protection of older adults vulnerable to abuse, neglect and exploitation.


The effects of the number of consecutive night shifts on sleep duration and quality.
Objectives The organization of night shift work affects sleep duration and quality. The aim of this study was to investigate the effects of the number of consecutive night shifts on sleep duration and quality among police officers with night shift work as part of their normal schedule. Methods This quasi-experimental, within-subject crossover study included 73 police officers. All participants performed three work schedules: two, four and seven consecutive night shifts followed by the same number of recovery days, ie, day work or days off (2+2, 4+4, and 7+7). Sleep assessed through sleep diaries and actigraphy after all night shifts and recovery days (totaling 26 days) was compared by use of repeated measures analysis. Results Participants experienced shorter sleep duration (with and without naps), more premature awakening, less difficulty falling asleep, and more non-refreshing sleep after night shifts compared with recovery days. Sleep duration and quality did not change with increasing number of consecutive night shifts. Sleep was shorter and of poorer quality after the last night shift in the 2+2 and 4+4 work schedule compared with the second and fourth night shift, respectively, in the 7+7 schedule. Conclusion Sleep duration was reduced after night shift work and did not increase with more consecutive night shifts, which leads to accumulated sleep debt. Sleep duration was shortest and sleep quality was poorest after the last night shift in a series of night shifts.


Inherited Risk for Autism Through Maternal and Paternal Lineage.
Autism spectrum disorder (ASD) is highly familial, with a positively skewed male-to-female ratio that is purported to arise from the so-called female protective effect. A serious implication of a female protective effect is that familial ASD liability would be expected to aggregate asymptomatically in sisters of affected probands, who would incur elevated rates of ASD among their offspring. Currently, there exist no data on second-generation recurrence rates among families affected by ASD. We analyzed data from the Swedish National Patient Register and the Multi-Generation Register for a cohort of children born between 2003 and 2012. ASD was ascertained in both the child and parental generations. Among 847,732 children, 13,103 (1.55%) children in the cohort were diagnosed with ASD. Among their maternal/paternal aunts and uncles, 1744 (0.24%) and 1374 (0.18%) were diagnosed with ASD, respectively. Offspring of mothers with a sibling(s) diagnosed with ASD had higher rates of ASD than the general population (relative risk, 3.05; 95% confidence interval, 2.52-3.64), but not more than would be predicted for second-degree relatives within a generation, and only slightly more than was observed for fathers with siblings with ASD (relative risk, 2.08; 95% confidence interval, 1.53-2.67). Models adjusting for temporal trends and for psychiatric history in the parental generation did not alter the results. These findings establish a robust general estimate of ASD transmission risk for siblings of individuals affected by ASD, the first ever reported. Our findings do not suggest female protective factors as the principal mechanism underlying the male sex bias in ASD.


Omega-3 fatty acids for postoperative atrial fibrillation: alone or in combination with antioxidant vitamins?
The effects of omega-3 polyunsaturated fatty acids (PUFA) on the prevention of postoperative atrial fibrillation (POAF) are inconclusive in current studies. Moreover, the most appropriate composition of PUFA to play the protective role is unclear. The aim of this meta-analysis was to ascertain the protective role of PUFA on POAF and the most appropriate composition. Studies were identified through PubMed, CENTRAL, EMBASE, reviews and reference lists of relevant papers. The odds ratio (OR) was calculated for POAF. Statistical analyses were performed with Review Manager 5.0. Eleven randomised controlled trials with 3137 patients were included in the analysis. The use of PUFA alone did not reduce the incidence of POAF compared with the control (OR: 0.76; 95% confidence interval [CI]: 0.57-1.03; P=0.08; I(2)=52%). However, combination therapy with PUFA and vitamins C and E reduced the incidence of POAF by 68% (OR: 0.32; 95%CI: 0.17-0.60; P=0.0005; I(2)=38%). Subgroup analysis indicated that the ratio of EPA/DHA 1:2 was effective in preventing POAF (OR: 0.35; 95%CI: 0.24-0.50; P<0.00001; I(2)=0%), while the ratio not 1:2 failed. Combination therapy with PUFA and vitamins C and E is effective in the prevention of POAF while PUFA alone is not. The ratio of EPA/DHA may influence the incidence of POAF, and 1:2 may be most appropriate. Studies about PUFA on the prevention of POAF are still worthwhile to be conducted in the future.


Objective assessment of alcohol consumption in early pregnancy using phosphatidylethanol: a cross-sectional study.
Alcohol consumption during pregnancy is associated with major birth defects and developmental disabilities. Questionnaires concerning alcohol consumption during pregnancy underestimate alcohol use while the use of a reliable and objective biomarker for alcohol consumption enables more accurate screening. Phosphatidylethanol can detect low levels of alcohol consumption in the previous two weeks. In this study we aimed to biochemically assess the prevalence of alcohol consumption during early pregnancy using phosphatidylethanol in blood and compare this with self-reported alcohol consumption. To evaluate biochemically assessed prevalence of alcohol consumption during early pregnancy using phosphatidylethanol levels, we conducted a prospective, cross-sectional, single center study in the largest tertiary hospital of the Netherlands. All adult pregnant women who were under the care of the obstetric department of the Erasmus MC and who underwent routine blood testing at a gestational age of less than 15 weeks were eligible. No specified informed consent was needed. The study was conducted between September 2016 and October 2017. In total, we received 1,002 residual samples of 992 women. After applying in- and exclusion criteria we analyzed 684 samples. Mean gestational age of all included women was 10.3 weeks (SD 1.9). Of these women, 36 (5.3 %) tested positive for phosphatidylethanol, indicating alcohol consumption in the previous two weeks. Of women with a positive phosphatidylethanol test, 89 % (n = 32) did not express alcohol consumption to their obstetric care provider. One in nineteen women consumed alcohol during early pregnancy with a high percentage not reporting this use to their obstetric care provider. Questioning alcohol consumption by an obstetric care provider did not successfully identify (hazardous) alcohol consumption. Routine screening with phosphatidylethanol in maternal blood can be of added value to identify women who consume alcohol during pregnancy.


STUDIES ON THE TREATMENT OF HUMAN TRYPANOSOMIASIS WITH TRYPARSAMIDE (THE SODIUM SALT OF N-PHENYLGLYCINEAMIDE-p-ARSONIC ACID).
The present study of the action of tryparsamide in human trypanosomiasis concludes a series of chemical and biological investigations in a particular problem of chemotherapy and thus represents the final step in a logical method of approach to such a problem. It has been shown that tryparsamide, the sodium salt of N-phenylglycineamide-p-arsonic acid, possesses a marked trypanocidal activity in human trypanosomiasis caused by Tr. gambiense. Single doses of from 0.5 to 5.0 gm. produced a peripheral sterilization of lymph glands and blood in an average of 6 to 12 hours. The duration of the peripheral sterilization following single doses of 17 to 83 mg. per kilo ranged from 17 to 58 days in patients who ultimately showed a return of trypanosomes to the peripheral blood. In a number of patients, however, treated with single doses of 9 to 68 mg. per kilo, no such relapse was detected during an observation period of from 40 to 111 days. The drug is extremely soluble in water and may be administered intramuscularly as well as intravenously. The immediate trypanocidal action after intramuscular administration was as rapid as that following the intravenous route while the duration of peripheral sterilization was appreciably longer. Relatively few repeated doses produced in advanced cases a marked and rapid diminution of the cells of the spinal fluid and were associated with definite improvement of mental and nervous symptoms. The occurrence of visual disturbances in certain advanced cases was the only untoward effect detected during the course of the work, and was apparently related to a too frequent administration of the drug. The condition was transitory in the majority of instances and resumption of treatment was not followed by a recurrence of this symptom. The general beneficial effect of the drug was a noticeable feature of its action in both early and advanced cases as shown by the disappearance of subjective symptoms, by the return of the pulse and temperature to normal limits, by the pronounced improvement of the blood picture, and by well marked gains in weight.


Physical comorbidities increase the risk of psychiatric comorbidity in multiple sclerosis.
Risk factors for psychiatric comorbidity in multiple sclerosis (MS) are poorly understood. We evaluated the association between physical comorbidity and incident depression, anxiety disorder, and bipolar disorder in a MS population relative to a matched general population cohort. Using population-based administrative data from Alberta, Canada we identified 9624 persons with MS, and 41,194 matches. Using validated case definitions, we estimated the incidence of depression, anxiety disorder, and bipolar disorder, and their association with physical comorbidities using Cox regression, adjusting for age, sex, socioeconomic status, and index year. In both populations, men had a lower risk of depression and anxiety disorders than women, as did individuals who were ≥45 years versus <45 years at the index date. The risk of bipolar disorder declined with increasing age. The risks of incident depression (HR 1.92; 1.82-2.04), anxiety disorders (HR 1.52; 1.42-1.63), and bipolar disorder (HR 2.67; 2.29-3.11) were higher in the MS population than the matched population. These associations persisted essentially unchanged after adjustment for covariates including physical comorbidities. Multiple physical comorbidities were associated with psychiatric disorders in both populations. Persons with MS are at increased risk of psychiatric comorbidity generally, and some physical comorbidities are associated with additional risk.


Aod1, the immunoregulatory locus controlling abrogation of tolerance in neonatal thymectomy-induced autoimmune ovarian dysgenesis, maps to mouse chromosome 16.
Mice thymectomized at three days of age (D3Tx) develop during adulthood a variety of organ-specific autoimmune diseases, including autoimmune ovarian dysgenesis (AOD). The phenotypic spectrum of AOD is characterized by the development of anti-ovarian autoantibodies, oophoritis, and atrophy. The D3Tx model of AOD is unique in that disease induction depends exclusively on perturbation of the normal developing immune system, is T-cell-mediated, and is strain specific. For example, D3Tx A/J mice are highly susceptible to AOD, whereas C57BL/6J mice are resistant. After D3Tx, self ovarian antigens, expressed at physiological levels, trigger an autoimmune response capable of eliciting disease. The D3Tx model provides, therefore, the opportunity to focus on the mechanisms of self-tolerance that are relevant to disease pathogenesis. Previous studies indicate that the principal mechanisms involved in AOD susceptibility are genetically controlled and govern developmental processes associated with the induction and maintenance of peripheral tolerance. We report here the mapping of the Aod1 locus to mouse chromosome 16 within a region encoding several loci of immunologic relevance, including scid, Igl1, VpreB, Igll, Igl1r, Mtv6 (Mls-3), Ly-7, Ifnar, and Ifgt.


Diagnosis and medical management of patients with intermittent claudication.
Intermittent claudication is a symptom complex associated with atherosclerosis of the aorta and lower extremities. It is a clinical marker of systemic atherosclerosis, and therefore, management cannot be considered isolated from treatment of underlying risk factors of atherosclerosis. The focus of the management is twofold. The first is to reduce morbidity and mortality from cardiovascular events, including myocardial infarction and stroke. The second focus is to improve the functional status of patients who have impairment of daily activities secondary to symptoms of claudication through pharmacologic and rehabilitative means, that is, exercise. Exercise is the cornerstone of therapy. A conservative approach is favored in patients who have mild and moderate symptoms of claudication. Intervention with percutaneous techniques or surgery is generally reserved for patients who have severe impairment of lifestyle or threatened tissue.


Health coaching to promote healthier lifestyle among older people at moderate risk for cardiovascular diseases, diabetes and depression: a study protocol for a randomized controlled trial in Sweden.
The challenge of an aging population in the society makes it important to find strategies to promote health for all. The aim of this study is to evaluate if repeated health coaching in terms of motivational interviewing, and an offer of wide range of activities, will contribute to positive lifestyle modifications and health among persons aged 60-75 years, with moderately elevated risk for cardiovascular disease (CVD), diabetes, or mild depression. Men and women between 60 and 75 are recruited in four regions in Sweden if they fulfill one or more of the four inclusion criteria. • Current reading of blood pressure (140-159/90-99) without medication. • Current reading of blood sugar (Hba1c 42-52 mmol/mol) without medication. • A current waist-circumference of ≥94 cm for men and ≥80 for women. • A minor/mild depression (12-20 points) according to Montgomery-Åsberg Depression Rating Scale without medication.Individuals with a worse result than inclusion criteria are treated according to regular guidelines at the PHCs and therefore not included. Exclusion criteria for the study are dementia, mental illness or other condition deemed unsuitable for participation. All participants fill out a questionnaire at baseline, and at the 6-, 12- and 18-month follow-ups containing questions on demographic characteristics, social life, HRQoL, lifestyle habits, general health/medication, self-rated mental health, and sense of coherence. At the 12-month follow-up, the health coach will give each participant a second questionnaire to capture attitudes and perceptions related to health coaching and venues/activities offered. Qualitative data will be collected twice to obtain a deeper understanding of perceptions and attitudes related to health and lifestyle/lifestyle modifications. A health economic assessment will be performed. Individual costs for health care utilisation will be collected and QALY-scores will be estimated. Several drawbacks can be identified when conducting research in real life. However, many of the identified problems can diminish the positive results of the intervention and if the intervention shows positive effects they might be underestimated. Current Controlled Trials ISRCTN01396033.


Juveniles exposed to embryonic corticosterone have enhanced flight performance.
Exposure to maternally derived glucocorticoids during embryonic development impacts offspring phenotype. Although many of these effects appear to be transiently 'negative', embryonic exposure to maternally derived stress hormones is hypothesized to induce preparative responses that increase survival prospects for offspring in low-quality environments; however, little is known about how maternal stress influences longer-term survival-related performance traits in free-living individuals. Using an experimental elevation of yolk corticosterone (embryonic signal of low maternal quality), we examined potential impacts of embryonic exposure to maternally derived stress on flight performance, wing loading, muscle morphology and muscle physiology in juvenile European starlings (Sturnus vulgaris). Here we report that fledglings exposed to experimentally increased corticosterone in ovo performed better during flight performance trials than control fledglings. Consistent with differences in performance, individuals exposed to elevated embryonic corticosterone fledged with lower wing loading and had heavier and more functionally mature flight muscles compared with control fledglings. Our results indicate that the positive effects on a survival-related trait in response to embryonic exposure to maternally derived stress hormones may balance some of the associated negative developmental costs that have recently been reported. Moreover, if embryonic experience is a good predictor of the quality or risk of future environments, a preparative phenotype associated with exposure to apparently negative stimuli during development may be adaptive.


Metabolic Acidemia in Live Births at 35 Weeks of Gestation or Greater.
To estimate the incidence of metabolic acidemia and assess its association with a variety of obstetric complications in a large cohort of singleton live births at 35 weeks of gestation or greater. We analyzed obstetric complications and neonatal outcomes associated with metabolic acidemia in singleton newborns delivered at 35 weeks of gestation or greater. Metabolic acidemia was identified as an umbilical artery pH of less than 7.0 and a base deficit of 12 mmol/L or greater from umbilical cord blood gas analyses performed immediately after delivery. The primary outcome of interest was seizures in the immediate newborn period. Between January 1, 1988, and December 31, 2013, a total of 1,265 (3.9/1,000, 95% confidence interval [CI] 3.7-4.1) neonates were identified with metabolic acidemia among 323,027 live births with cord gas analysis. Virtually every recorded obstetric complication was significantly associated with metabolic acidemia. All measures of neonatal morbidity except necrotizing enterocolitis were also significantly increased in the presence of metabolic acidemia. Seizures occurred in 367 of 323,027 (1.1/1,000, 95% CI 1.0-1.3) neonates. Only 19.1% (95% CI 15.2-23.5%) occurred in those with metabolic acidemia. Among the 1,265 with metabolic acidemia, 70 were diagnosed with neonatal seizures, for a prevalence of 5.5% (95% CI 4.3-6.9) in the acidotic group. Neonatal acidemia at birth is rare in deliveries occurring at or after 35 weeks of gestation. Seizures occur in less than one in 10 newborns with metabolic acidemia. Approximately 80% of seizures in neonates at this gestational age occur in nonacidemic neonates. III.


Seeing fearful body language overcomes attentional deficits in patients with neglect.
Survival depends to some extent on the ability to detect salient signals and prepare an appropriate response even when attention is engaged elsewhere. Fearful body language is a salient signal of imminent danger, easily observable from a distance and indicating to the observer which adaptive action to prepare for. Here we investigated for the first time whether fearful body language modulates the spatial distribution of attention and enhances visual awareness in neurological patients with severe attentional disorders. Patients with visual extinction and hemispatial neglect following right parietal injury have a rightward attentional bias accompanied by loss of awareness for contralesional left stimuli, especially when competing stimuli appear to the right. Three such patients were tested with pictures of fearful, happy, and neutral bodily expressions briefly presented either unilaterally in the left or right visual field, or to both fields simultaneously. On bilateral trials, unattended and task-irrelevant fearful bodily expressions modulated attentional selection and visual awareness. Fearful bodily expressions presented in the contralesional unattended visual field simultaneously with neutral bodies in the ipsilesional field were detected more often than left-side neutral or happy bodies. This demonstrates that despite pathological inattention and parietal damage, emotion and action-related information in fearful body language may be extracted automatically, biasing attentional selection and visual awareness. Our findings open new perspectives on the role of bodily expressions in attentional selection and suggest that a neural network in intact fronto-limbic and visual areas may still mediate reorienting of attention and preparation for action upon perceiving fear in others.


Prediction of fluid responsiveness in ventilated patients.
Fluid administration is the first-line therapy in patients with acute circulatory failure. The main goal of fluid administration is to increase the cardiac output and ultimately the oxygen delivery. Nevertheless, the decision to administer fluids or not should be carefully considered, since half of critically ill patients are fluid unresponsive, and the deleterious effects of fluid overload clearly documented. Thus, except at the initial phase of hypovolemic or septic shock, where hypovolemia is constant and most of the patients responsive to the initial fluid resuscitation, it is of importance to test fluid responsiveness before administering fluids in critically ill patients. The static markers of cardiac preload cannot reliably predict fluid responsiveness, although they have been used for decades. To address this issue, some dynamic tests have been developed over the past years. All these tests consist in measuring the changes in cardiac output in response to the transient changes in cardiac preload that they induced. Most of these tests are based on the heart-lung interactions. The pulse pressure or stroke volume respiratory variations were first described, following by the respiratory variations of the vena cava diameter or of the internal jugular vein diameter. Nevertheless, all these tests are reliable only under strict conditions limiting their use in many clinical situations. Other tests such as passive leg raising or end-expiratory occlusion act as an internal volume challenge. To reliably predict fluid responsiveness, physicians must choose among these different dynamic tests, depending on their respective limitations and on the cardiac output monitoring technique which is used. In this review, we will summarize the most recent findings regarding the prediction of fluid responsiveness in ventilated patients.


The National Programme to Eliminate Lymphatic Filariasis from Ethiopia.
Lymphatic filariasis (LF) is one of the most debilitating and disfiguring diseases common in Ethiopia and is caused by Wuchereria bancrofti. Mapping for LF has shown that 70 woredas (districts) are endemic and 5.9 million people are estimated to be at risk. The national government's LF elimination programme commenced in 2009 in 5 districts integrated with the onchocerciasis programme. The programme developed gradually and has shown significant progress over the past 6 years, reaching 100% geographical coverage for mass drug administration (MDA) by 2016. To comply with the global LF elimination goals an integrated morbidity management and disability prevention (MMDP) guideline and a burden assessment programme has also been developed; MMDP protocols and a hydrocoele surgical handbook produced for country-wide use. In Ethiopia, almost all LF endemic districts are co-endemic with malaria and vector control aspects of the activities are conducted in the context of malaria programme as the vectors for both diseases are mosquitoes. In order to monitor the elimination, 11 sentinel and spot-check sites have been established and baseline information has been collected. Although significant achievements have been achieved in the scale up of the LF elimination programme, there is still a need to strengthen operational research to generate programme-relevant evidence, to increase access to morbidity management services, and to improve monitoring and evaluation of the LF programme. However, the current status of implementation of the LF national programme indicates that Ethiopia is poised to achieve the 2020 goal of elimination of LF. Nevertheless, to achieve this goal, high and sustained treatment coverage and strong monitoring and evaluation of the programme are essential.


MRSA decolonization failure-are biofilms the missing link?
Device-associated infections due to biofilm-producing methicillin-resistant Staphylococcus aureus (MRSA) have been recently associated with the failure of antibiotic treatment and decolonization measures. The goal of our study was to evaluate the extent to which the formation of biofilms influenced the efficacy of topical decolonization agents or disinfectants such as mupirocin (MUP), octenidine (OCT), chlorhexidine (CHG), polyhexanide (POL), and chloroxylenol (CLO). Bacterial killing in biofilms by the disinfectants and MUP was determined as the reduction [%] in metabolic activity determined by a biofilm viability assay that uses kinetic analysis of metabolic activity. The test substances were diluted in water with standardized hardness (WSH) at 25 °C at the standard concentration as well as half the standard concentration to demonstrate the dilution effects in a practical setting. The tested concentrations were: CHG 1%, 2%; OCT 0.1%, 0.05%; PH 0.04%, 0.02%; and CLO 0.12%, 0.24%. A test organism suspension, 1 mL containing ~1 × 109 bacterial cells/mL, and 1 mL of sterile WSH were mixed and incubated for six different exposure times (15 s, 1, 3, 5, 10 and 20 min) after the test substance was added. Additionally, the bactericidal effects of all substances were tested on planktonic bacteria and measured as the log10 reduction. The disinfectants OCT and CHG showed good efficacy in inhibiting MRSA in biofilms with reduction rates of 94 ± 1% and 91 ± 1%, respectively. POL, on the other hand, had a maximum efficacy of only 81 ± 7%. Compared to the tested disinfectants, MUP showed a significantly lower efficacy with <20% inhibition (p < .05). Bactericidal effects were the greatest for CHG (log10 reduction of 9.0), followed by OCT (7.7), POL (5.1), and CLO (6.8). MUP, however, showed a very low bactericidal effect of only 2.1. Even when the exposure time was increased to 24 h, 2% MUP did not show sufficient bactericidal effect. Our data provide evidence that OCT and CHG are effective components for disinfection of MRSA-biofilms. On the other hand, exposure to MUP at the standard concentrations in topical preparations did not effectively inhibit MRSA-biofilms and also did not show adequate bactericidal effects. Combining an MUP-based decolonization regimen with a disinfectant such as OCT or CHG could decrease decolonization failure.


Causes and consequences of repeatability, flexibility and individual fine-tuning of migratory timing in pike.
Many organisms undertake migrations between foraging and breeding habitats and while it is assumed that reproductive timing affects fitness, little is known about the degree of individual consistency, and about the causes and consequences of individual variation in migratory timing in organisms other than birds. Here, we report on a 6-year mark-recapture study, including 2048 individuals, of breeding migration in anadromous pike (Esox lucius), an iteroparous top-predatory fish that displays homing behaviour. By repeated sampling across years at a breeding site, we first quantify individual variation both within and between breeding events and then investigate phenotypic correlates and fitness consequences of arrival timing to the breeding site. Our data demonstrate that males arrive before females, that large males arrive later than small males, that the timing of breeding migration varies among years and that individuals are consistent in their timing across years relative to other individuals in the population. Furthermore, data on return rates indicate that arrival time is under stabilizing viability selection, and that individuals who are more flexible in their timing of arrival during the first reproductive years survive longer compared with less flexible individuals. Finally, longitudinal data demonstrate that individuals consistently fine-tune their arrival timing across years, showing that the timing of arrival to breeding sites is influenced by experience. These findings represent rare evidence of how between- and within-individual variations in migratory timing across breeding events are correlated with phenotypic and fitness traits in an ecologically important keystone species. Our results emphasize the importance of considering variation in migratory timing both between and within individuals in studies investigating the fitness consequences of migratory behaviour and have implications for future management.


Dynamic Functional Connectivity between order and randomness and its evolution across the human adult lifespan.
Functional Connectivity (FC) during resting-state or task conditions is not static but inherently dynamic. Yet, there is no consensus on whether fluctuations in FC may resemble isolated transitions between discrete FC states rather than continuous changes. This quarrel hampers advancing the study of dynamic FC. This is unfortunate as the structure of fluctuations in FC can certainly provide more information about developmental changes, aging, and progression of pathologies. We merge the two perspectives and consider dynamic FC as an ongoing network reconfiguration, including a stochastic exploration of the space of possible steady FC states. The statistical properties of this random walk deviate both from a purely "order-driven" dynamics, in which the mean FC is preserved, and from a purely "randomness-driven" scenario, in which fluctuations of FC remain uncorrelated over time. Instead, dynamic FC has a complex structure endowed with long-range sequential correlations that give rise to transient slowing and acceleration epochs in the continuous flow of reconfiguration. Our analysis for fMRI data in healthy elderly revealed that dynamic FC tends to slow down and becomes less complex as well as more random with increasing age. These effects appear to be strongly associated with age-related changes in behavioural and cognitive performance.


Clinical utility of vitamin d testing: an evidence-based analysis.
This report from the Medical Advisory Secretariat (MAS) was intended to evaluate the clinical utility of vitamin D testing in average risk Canadians and in those with kidney disease. As a separate analysis, this report also includes a systematic literature review of the prevalence of vitamin D deficiency in these two subgroups.This evaluation did not set out to determine the serum vitamin D thresholds that might apply to non-bone health outcomes. For bone health outcomes, no high or moderate quality evidence could be found to support a target serum level above 50 nmol/L. Similarly, no high or moderate quality evidence could be found to support vitamin D's effects in non-bone health outcomes, other than falls. VITAMIN D: Vitamin D is a lipid soluble vitamin that acts as a hormone. It stimulates intestinal calcium absorption and is important in maintaining adequate phosphate levels for bone mineralization, bone growth, and remodelling. It's also believed to be involved in the regulation of cell growth proliferation and apoptosis (programmed cell death), as well as modulation of the immune system and other functions. Alone or in combination with calcium, Vitamin D has also been shown to reduce the risk of fractures in elderly men (≥ 65 years), postmenopausal women, and the risk of falls in community-dwelling seniors. However, in a comprehensive systematic review, inconsistent results were found concerning the effects of vitamin D in conditions such as cancer, all-cause mortality, and cardiovascular disease. In fact, no high or moderate quality evidence could be found concerning the effects of vitamin D in such non-bone health outcomes. Given the uncertainties surrounding the effects of vitamin D in non-bone health related outcomes, it was decided that this evaluation should focus on falls and the effects of vitamin D in bone health and exclusively within average-risk individuals and patients with kidney disease. Synthesis of vitamin D occurs naturally in the skin through exposure to ultraviolet B (UVB) radiation from sunlight, but it can also be obtained from dietary sources including fortified foods, and supplements. Foods rich in vitamin D include fatty fish, egg yolks, fish liver oil, and some types of mushrooms. Since it is usually difficult to obtain sufficient vitamin D from non-fortified foods, either due to low content or infrequent use, most vitamin D is obtained from fortified foods, exposure to sunlight, and supplements. CONDITION AND TARGET POPULATION Vitamin D deficiency may lead to rickets in infants and osteomalacia in adults. Factors believed to be associated with vitamin D deficiency include: darker skin pigmentation,winter season,living at higher latitudes,skin coverage,kidney disease,malabsorption syndromes such as Crohn's disease, cystic fibrosis, andgenetic factors.Patients with chronic kidney disease (CKD) are at a higher risk of vitamin D deficiency due to either renal losses or decreased synthesis of 1,25-dihydroxyvitamin D. Health Canada currently recommends that, until the daily recommended intakes (DRI) for vitamin D are updated, Canada's Food Guide (Eating Well with Canada's Food Guide) should be followed with respect to vitamin D intake. Issued in 2007, the Guide recommends that Canadians consume two cups (500 ml) of fortified milk or fortified soy beverages daily in order to obtain a daily intake of 200 IU. In addition, men and women over the age of 50 should take 400 IU of vitamin D supplements daily. Additional recommendations were made for breastfed infants. A Canadian survey evaluated the median vitamin D intake derived from diet alone (excluding supplements) among 35,000 Canadians, 10,900 of which were from Ontario. Among Ontarian males ages 9 and up, the median daily dietary vitamin D intake ranged between 196 IU and 272 IU per day. Among females, it varied from 152 IU to 196 IU per day. In boys and girls ages 1 to 3, the median daily dietary vitamin D intake was 248 IU, while among those 4 to 8 years it was 224 IU. VITAMIN D TESTING: Two laboratory tests for vitamin D are available, 25-hydroxy vitamin D, referred to as 25(OH)D, and 1,25-dihydroxyvitamin D. Vitamin D status is assessed by measuring the serum 25(OH)D levels, which can be assayed using radioimmunoassays, competitive protein-binding assays (CPBA), high pressure liquid chromatography (HPLC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). These may yield different results with inter-assay variation reaching up to 25% (at lower serum levels) and intra-assay variation reaching 10%. The optimal serum concentration of vitamin D has not been established and it may change across different stages of life. Similarly, there is currently no consensus on target serum vitamin D levels. There does, however, appear to be a consensus on the definition of vitamin D deficiency at 25(OH)D < 25 nmol/l, which is based on the risk of diseases such as rickets and osteomalacia. Higher target serum levels have also been proposed based on subclinical endpoints such as parathyroid hormone (PTH). Therefore, in this report, two conservative target serum levels have been adopted, 25 nmol/L (based on the risk of rickets and osteomalacia), and 40 to 50 nmol/L (based on vitamin D's interaction with PTH). ONTARIO CONTEXT: VOLUME #ENTITYSTARTX00026; COST: The volume of vitamin D tests done in Ontario has been increasing over the past 5 years with a steep increase of 169,000 tests in 2007 to more than 393,400 tests in 2008. The number of tests continues to rise with the projected number of tests for 2009 exceeding 731,000. According to the Ontario Schedule of Benefits, the billing cost of each test is $51.7 for 25(OH)D (L606, 100 LMS units, $0.517/unit) and $77.6 for 1,25-dihydroxyvitamin D (L605, 150 LMS units, $0.517/unit). Province wide, the total annual cost of vitamin D testing has increased from approximately $1.7M in 2004 to over $21.0M in 2008. The projected annual cost for 2009 is approximately $38.8M. EVIDENCE-BASED ANALYSIS: The objective of this report is to evaluate the clinical utility of vitamin D testing in the average risk population and in those with kidney disease. As a separate analysis, the report also sought to evaluate the prevalence of vitamin D deficiency in Canada. The specific research questions addressed were thus: What is the clinical utility of vitamin D testing in the average risk population and in subjects with kidney disease?What is the prevalence of vitamin D deficiency in the average risk population in Canada?What is the prevalence of vitamin D deficiency in patients with kidney disease in Canada?Clinical utility was defined as the ability to improve bone health outcomes with the focus on the average risk population (excluding those with osteoporosis) and patients with kidney disease. A literature search was performed on July 17th, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1998 until July 17th, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology. Observational studies that evaluated the prevalence of vitamin D deficiency in Canada in the population of interest were included based on the inclusion and exclusion criteria listed below. The baseline values were used in this report in the case of interventional studies that evaluated the effect of vitamin D intake on serum levels. Studies published in grey literature were included if no studies published in the peer-reviewed literature were identified for specific outcomes or subgroups. Considering that vitamin D status may be affected by factors such as latitude, sun exposure, food fortification, among others, the search focused on prevalence studies published in Canada. In cases where no Canadian prevalence studies were identified, the decision was made to include studies from the United States, given the similar policies in vitamin D food fortification and recommended daily intake. Studies published in EnglishPublications that reported the prevalence of vitamin D deficiency in CanadaStudies that included subjects from the general population or with kidney diseaseStudies in children or adultsStudies published between January 1998 and July 17(th) 2009 EXCLUSION CRITERIA: Studies that included subjects defined according to a specific disease other than kidney diseaseLetters, comments, and editorialsStudies that measured the serum vitamin D levels but did not report the percentage of subjects with serum levels below a given threshold Prevalence of serum vitamin D less than 25 nmol/LPrevalence of serum vitamin D less than 40 to 50 nmol/LSerum 25-hydroxyvitamin D was the metabolite used to assess vitamin D status. Results from adult and children studies were reported separately. Subgroup analyses according to factors that affect serum vitamin D levels (e.g., seasonal effects, skin pigmentation, and vitamin D intake) were reported if enough information was provided in the studies The quality of the prevalence studies was based on the method of subject recruitment and sampling, possibility of selection bias, and generalizability to the source population. The overall quality of the trials was examined according to the GRADE Working Group criteria. (ABSTRACT TRUNCATED)


Uracils at nucleotide position 9-11 are required for the rapid turnover of miR-29 family.
MicroRNAs are endogenous small RNA molecules that regulate gene expression. Although the biogenesis of microRNAs and their regulation have been thoroughly elucidated, the degradation of microRNAs has not been fully understood. Here by using the pulse-chase approach, we performed the direct measurement of microRNA lifespan. Five representative microRNAs demonstrated a general feature of relatively long lifespan. However, the decay dynamic varies considerably between these individual microRNAs. Mutation analysis of miR-29b sequence revealed that uracils at nucleotide position 9-11 are required for its rapid decay, in that both specific nucleotides and their position are critical. The effect of uracil-rich element on miR-29b decay dynamic occurs in duplex but not in single strand RNA. Moreover, analysis of published data on microRNA expression profile during development reveals that a substantial subset of microRNAs with the uracil-rich sequence tends to be down-regulated compared to those without the sequence. Among them, Northern blotting shows that miR-29c and fruit fly bantam possess a relatively rapid turnover rate. The effect of uracil-rich sequence on microRNA turnover depends on the sequence context. The present work indicates that microRNAs contain sequence information in the middle region besides the sequence element at both ends.


Sensitive Detection of Plasmodium vivax Using a High-Throughput, Colourimetric Loop Mediated Isothermal Amplification (HtLAMP) Platform: A Potential Novel Tool for Malaria Elimination.
Plasmodium vivax malaria has a wide geographic distribution and poses challenges to malaria elimination that are likely to be greater than those of P. falciparum. Diagnostic tools for P. vivax infection in non-reference laboratory settings are limited to microscopy and rapid diagnostic tests but these are unreliable at low parasitemia. The development and validation of a high-throughput and sensitive assay for P. vivax is a priority. A high-throughput LAMP assay targeting a P. vivax mitochondrial gene and deploying colorimetric detection in a 96-well plate format was developed and evaluated in the laboratory. Diagnostic accuracy was compared against microscopy, antigen detection tests and PCR and validated in samples from malaria patients and community controls in a district hospital setting in Sabah, Malaysia. The high throughput LAMP-P. vivax assay (HtLAMP-Pv) performed with an estimated limit of detection of 1.4 parasites/ μL. Assay primers demonstrated cross-reactivity with P. knowlesi but not with other Plasmodium spp. Field testing of HtLAMP-Pv was conducted using 149 samples from symptomatic malaria patients (64 P. vivax, 17 P. falciparum, 56 P. knowlesi, 7 P. malariae, 1 mixed P. knowlesi/P. vivax, with 4 excluded). When compared against multiplex PCR, HtLAMP-Pv demonstrated a sensitivity for P. vivax of 95% (95% CI 87-99%); 61/64), and specificity of 100% (95% CI 86-100%); 25/25) when P. knowlesi samples were excluded. HtLAMP-Pv testing of 112 samples from asymptomatic community controls, 7 of which had submicroscopic P. vivax infections by PCR, showed a sensitivity of 71% (95% CI 29-96%; 5/7) and specificity of 93% (95% CI87-97%; 98/105). This novel HtLAMP-P. vivax assay has the potential to be a useful field applicable molecular diagnostic test for P. vivax infection in elimination settings.


Lynch Syndrome Screening in the Gynecologic Tract: Current State of the Art.
Lynch syndrome underlies approximately 5% of endometrial cancers and ∼1% of ovarian cancers. Gynecologic malignancies are often the presenting cancer in these patients. Therefore, there is considerable benefit to identifying these patients and enrolling them and affected family members in surveillance programs for secondary malignancies. The molecular basis for Lynch syndrome is a defect in the DNA mismatch repair (MMR) system. Tumors can be screened for these defects using immunohistochemistry to identify loss of MMR proteins or by enlisting polymerase chain reaction to identify the microsatellite instability that attends dysfunctional MMR. However, diagnostic confirmation of Lynch syndrome requires germline mutational testing. The algorithm for screening endometrial carcinomas for Lynch syndrome remains a subject of debate, with some studies supporting universal screening and others proposing a hybrid approach informed by clinicopathologic features. This review discusses the rationales and relative merits of current Lynch syndrome-screening approaches for endometrial and ovarian cancers and provides pathologists with an informed approach to Lynch syndrome testing in gynecologic cancers. It also addresses the clinical difficulties presented by cases with discordant screening and germline results (Lynch-like cancers) and emphasizes the critical role of strong communication with clinician and genetic counseling colleagues to ensure that the significance of a positive screening test is appropriately conveyed to patients. Finally, it discusses the need for more nuanced cost-effective analyses and the potential role for next-generation sequencing panels in future screening efforts.


Sexual selection unhandicapped by the Fisher process.
A population genetic model of sexual selection is constructed in which, at equilibrium, males signal their quality by developing costly ornaments, and females pay costs to use the ornaments in mate choice. It is shown that the form of the equilibrium is uninfluenced by the Fisher process, that is, by self-reinforcement of female preferences. This is a working model of the handicap principle applied to sexual selection, and places Zahavi's handicap principle on the same logical footing as the Fisher process, in that each can support sexual selection without the presence of the other. A way of measuring the relative importance of the two processes is suggested that can be applied to both theories and facts. A style of modelling that allows simple genetics and complicated biology to be combined is recommended.


Nonreplicable publications are cited more than replicable ones.
We use publicly available data to show that published papers in top psychology, economics, and general interest journals that fail to replicate are cited more than those that replicate. This difference in citation does not change after the publication of the failure to replicate. Only 12% of postreplication citations of nonreplicable findings acknowledge the replication failure. Existing evidence also shows that experts predict well which papers will be replicated. Given this prediction, why are nonreplicable papers accepted for publication in the first place? A possible answer is that the review team faces a trade-off. When the results are more "interesting," they apply lower standards regarding their reproducibility.


Modelling the role of microbial p-cresol in colorectal genotoxicity.
Background: A greater understanding of mechanisms explaining the interactions between diet and the gut microbiota in colorectal cancer is desirable. Genotoxic microbial metabolites present in the colon may be implicated in carcinogenesis and potentially influenced by diet. Aims: We hypothesised that microbial p-cresol is a colonic genotoxin and set out to model potential exposures in the colon and the effects of these exposures on colonic cells. Methods: Batch culture fermentations with human faecal inoculate were used to determine the synthesis of p-cresol and other metabolites in response to various substrates. The fermentation supernatants were evaluated for genotoxicity and the independent effects of p-cresol on colonic cells were studied in vitro. Results: In batch culture fermentation, supplementary protein increased the synthesis of phenols, indoles and p-cresol, whereas supplementary fructoligosaccharide (FOS) increased the synthesis of short chain fatty acids. The p-cresol was the greatest predictor of genotoxicity against colonocytes in the fermentation supernatants. Spiking fermentation supernatants with exogenous p-cresol further increased DNA damage, and independently p-cresol induced DNA damage in a dose-dependent manner against HT29 and Caco-2 cells and influenced cell cycle kinetics. Conclusions: In the colon p-cresol may reach physiologically significant concentrations which contribute to genotoxic exposures in the intestinal lumen, p-cresol production may be attenuated by substrate, and therefore diet, making it a potential modifiable biomarker of genotoxicity in the colon.


Antiproliferative effects of the somatostatin analogue octreotide (SMS 201-995) on ZR-75-1 human breast cancer cells in vivo and in vitro.
The somatostatin analogue octreotide (SMS 201-995) inhibits secretion and growth of certain tumor cells, and current efforts are directed toward the elucidation of its mode of antiproliferative action. In this study, the effect of octreotide on the growth of ZR-75-1 human breast cancer cells has been characterized in immunodeficient nude mice and in cell culture. These results have been related to the expression of somatostatin receptors in vivo and in vitro. Continuous infusion of 10 micrograms/kg/h of octreotide yielded plasma levels of 5.7 ng/ml and elicited highly significant growth inhibitory effects on solid ZR-75-1 breast tumors in nude mice. After 2 and 4 weeks of treatment, tumor volumes in the octreotide group were 39.1 and 36.7% of those of control animals treated with vehicle, respectively. Autoradiographic studies demonstrated that 8 of 12 ZR-75-1 tumors studied were somatostatin receptor positive. When ZR-75-1 tumor cells were exposed in vitro to nanomolar concentrations of octreotide, a dose-dependent inhibition of cell growth was observed in the presence of 5% fetal calf serum or under serum-free conditions using epidermal growth factor, insulin-like growth factor type I, or insulin as growth stimulus. In parallel receptor-binding experiments, ZR-75-1 cells were shown to express specific high-affinity somatostatin receptors (Kd value = 0.9 nM, Bmax = 6000 sites/cell). From these experiments, we conclude that octreotide is a powerful inhibitor of ZR-75-1 tumor cell growth in nude mice and in culture. This inhibitory action of octreotide and the presence of somatostatin receptors on ZR-75-1 tumor cells in vitro and in vivo suggest a direct, somatostatin receptor-mediated effect of octreotide.


Ecology, biology and distribution of spotted-fever tick vectors in Brazil.
Spotted-fever-caused Rickettsia rickettsii infection is in Brazil the major tick-borne zoonotic disease. Recently, a second and milder human rickettsiosis caused by an agent genetically related to R. parkeri was discovered in the country (Atlantic rainforest strain). Both diseases clearly have an ecological background linked to a few tick species and their environment. Capybaras (Hydrochoerus hydrochaeris) and Amblyomma cajennense ticks in urban and rural areas close to water sources are the main and long-known epidemiological feature behind R. rickettsii-caused spotted-fever. Unfortunately, this ecological background seems to be increasing in the country and disease spreading may be foreseen. Metropolitan area of São Paulo, the most populous of the country, is embedded in Atlantic rainforest that harbors another important R. rickettsii vector, the tick Amblyomma aureolatum. Thus, at the city-forest interface, dogs carry infected ticks to human dwellings and human infection occurs. A role for R. rickettsii vectoring to humans of a third tick species, Rhipicephalus sanguineus in Brazil, has not been proven; however, there is circumstantial evidence for that. A R. parkeri-like strain was found in A. ovale ticks from Atlantic rainforest and was shown to be responsible for a milder febrile human disease. Rickettsia-infected A. ovale ticks are known to be spread over large areas along the Atlantic coast of the country, and diagnosis of human infection is increasing with awareness and proper diagnostic tools. In this review, ecological features of the tick species mentioned, and that are important for Rickettsia transmission to humans, are updated and discussed. Specific knowledge gaps in the epidemiology of such diseases are highlighted to guide forthcoming research.


PARP Inhibition Combined With Thoracic Irradiation Exacerbates Esophageal and Skin Toxicity in C57BL6 Mice.
Poly (ADP-ribose) polymerase (PARP) inhibitors have been shown to enhance the radiosensitivity of cancer cells in vitro in a replication-dependent manner. Their in vivo radiosensitizing effects have also been demonstrated in preclinical tumor models. However, whether PARP inhibition can enhance the response to radiation therapy in normal tissues has been largely neglected. We hypothesized that PARP inhibition might also potentiate the response of replicating normal tissues to radiation therapy. In this study, we examined the normal tissue response in mice treated with PARP inhibitors (BMN673 or AZD2281) in combination with thoracic irradiation. The antitumor effects of fractionated irradiation (5 Gy × 4) in combination with BMN673 were evaluated in nude mice bearing established Calu-6 human lung cancer xenografts. The normal tissue response was evaluated in C57BL6 mice that were treated with BMN673 or AZD2281 combined with fractionated irradiation, 5 Gy × 4, delivered to the whole thorax. Body weight and histology of the esophagus and skin in the field of irradiation were examined. The DNA damage response in the esophagus and skin was assessed by γH2AX immunohistochemistry. While PARP inhibition enhanced irradiation-induced tumor growth inhibition in nude mice, it was also associated with significant body weight loss and increased damage to the esophagus and skin within the field of irradiation in C57BL6 mice. PARP inhibition compromised the repair of irradiation-induced DNA damage in the esophagus and skin. Although PARP inhibition enhanced the antitumor response to fractionated irradiation, it also enhanced the irradiation response in replicating normal tissues. Therefore, our study suggests that additional caution may be warranted in the clinical development of combination therapies using PARP inhibitors and radiation therapy, in particular where the field of irradiation includes the esophagus.


DNA repair in the trinucleotide repeat disorders.
Inherited diseases caused by unstable repeated DNA sequences are rare, but together represent a substantial cause of morbidity. Trinucleotide repeat disorders are severe, usually life-shortening, neurological disorders caused by nucleotide expansions, and most have no disease-modifying treatments. Longer repeat expansions are associated with genetic anticipation (ie, earlier disease onset in successive generations), although the differences in age at onset are not entirely accounted for by repeat length. Such phenotypic variation within disorders implies the existence of additional modifying factors in pathways that can potentially be modulated to treat disease. A genome-wide association study detected genetic modifiers of age at onset in Huntington's disease. Similar findings were seen in the spinocerebellar ataxias, indicating an association between DNA damage-response and repair pathways and the age at onset of disease. These studies also suggest that a common genetic mechanism modulates age at onset across polyglutamine diseases and could extend to other repeat expansion disorders. Genetic defects in DNA repair underlie other neurodegenerative disorders (eg, ataxia-telangiectasia), and DNA double-strand breaks are crucial to the modulation of early gene expression, which provides a mechanistic link between DNA repair and neurodegeneration. Mismatch and base-excision repair are important in the somatic expansion of repeated sequences in mouse models of trinucleotide repeat disorders, and somatic expansion of the expanded CAG tract in HTT correlates with age at onset of Huntington's disease and other trinucleotide repeat disorders. WHERE NEXT?: To understand the common genetic architecture of trinucleotide repeat disorders and any further genetic susceptibilities in individual disorders, genetic analysis with increased numbers of variants and sample sizes is needed, followed by sequencing approaches to define the phenotype-modifying variants. The findings must then be translated into cell biology analyses to elucidate the mechanisms through which the genetic variants operate. Genes that have roles in the DNA damage response could underpin a common DNA repeat-based mechanism and provide new therapeutic targets (and hence therapeutics) in multiple trinucleotide repeat disorders.


A useful tool for retained washer retrieval when removing iliosacral screws.
Iliosacral screw removal is occasionally necessary during index or revision pelvic ring surgery. This procedure can necessitate a two-step process: screw removal followed by retained washer removal. On attempted removal of the screw-washer complex, the washer will not uncommonly dissociate itself from the screw. Its retrieval can be challenging, add unnecessary operative time, and result in larger incisions and increased soft tissue disruptions. This article introduces a simple technique for retained washer retrieval when removing or exchanging iliosacral screws. This technique involves an "interference fit" between the retained washer and a screw or tap of larger diameter, allowing for reliable and simple washer extraction. Advantages of this technique include removal through the same soft tissue tract as initial screw insertion and subsequent screw removal. It also obviates the need for introduction of various clamps to extract the washer, which can result in soft tissue injury and increased reliance on fluoroscopy.


Photoperiodism in Lemna: Reversal of NightInterruption Depends on Color of the Main Photoperiod.
With main photoperiods of red or white light, the inhibition of flowering in Lemna perpusilla 6746 caused by interruptions of the night with red light cannot be reversed by far-red light, since far-red light itself is highly inhibitory. However, with a main photoperiod of blue light, far-red light is much less inhibitory and partially reverses the effect of red night-interruptions. If the main blue photoperiod is terminated by a brief red exposure, reversibility is abolished, as the far-red light is again fully inhibitory. This latter effect can be reversed by far-red light. These results add light quality to the already known characteristics of the main light period which affect reversibility in the dark period, and are consistent with the idea that the effects of blue light on photoperiodism in L. perpusilla are mediated exclusively by phytochrome.


Effect of slow-release fluoride devices and casein phosphopeptide/amorphous calcium phosphate nanocomplexes on enamel remineralization in vitro.
To investigate the remineralization effect of slow-release fluoride glass devices (SFGD), casein phosphopeptide/amorphous calcium phosphate nanocomplexes (CPP-ACP) and SFGD and CPP-ACP together on enamel pH cycling in vitro. Eighty bovine enamel slabs were allocated to each of 4 groups (20/group): SFGD; CPP-ACP; SFGD + CPP-ACP; control. Baseline surface microhardness (SMH; Knoop number) was measured for all slabs which were then subjected to a pH cycling regime for 10 days, and SMH was then remeasured. The pH cycling regime involved immersion 5 times daily (each for 5 min) in demineralization solution with the slabs immersed in artificial saliva between dipping. The treatment for the enamel slabs in the SFGD group involved exposure all the time to 2 SFGD devices per group during the cycling regime. In contrast, slabs in the CPP-ACP group were exposed to CPP-ACP slurry once daily for 30 min after the last demineralization challenge of the day. The slabs in the SFGD + CPP-ACP group received both treatments as the SFGD and CPP-ACP groups. The control group received no treatment during the cycling. There was a statistically significant difference in enamel SMH change among the groups (one-way ANOVA; p < 0.0001). Enamel SMH values in the SFGD, CPP-ACP and SFGD + CPP-ACP groups were all significantly higher than in the control group (Bonferroni; p < 0.0001). There was no significant difference in enamel SMH between the SFGD and CPP-ACP groups (p > 0.05). The use of both SFGD + CPP-ACP showed a non-significant trend for improvement in enamel SMH in comparison to SFGD or CPP-ACP alone.


Mechanical ventilation for a child with quadriplegia.
Parents generally have the right to make medical decisions for their children. This right can be challenged when the parents' decision seems to go against the child's interests. The toughest such decisions are for a child who will survive with physical and neurocognitive impairments. We discuss a case of a 5-year-old boy who suffered a spinal injury as a result of a motor vehicle accident and whose father requests discontinuation of life support. Many experts recommend a "trial of therapy" to clarify both prognosis and quality of life. The key ethical question, then, is not whether to postpone a decision to forego mechanical ventilation. Instead, the key question is how long to wait. Parents should be allowed time to see what life will be like for themselves and for their child. Most of the time, life turns out better than they might have imagined. Comments are provided by 2 pediatric intensivists, Drs William Novotny and Ronald Perkin of East Carolina University, and by a specialist in rehabilitation, Dr Debjani Mukherjee of the Rehabilitation Institute of Chicago.


Structural basis of the Ca(2+)-dependent association between S100C (S100A11) and its target, the N-terminal part of annexin I.
S100C (S100A11) is a member of the S100 calcium-binding protein family, the function of which is not yet entirely clear, but may include cytoskeleton assembly and dynamics. S100 proteins consist of two EF-hand calcium-binding motifs, connected by a flexible loop. Like several other members of the family, S100C forms a homodimer. A number of S100 proteins form complexes with annexins, another family of calcium-binding proteins that also bind to phospholipids. Structural studies have been undertaken to understand the basis of these interactions. We have solved the crystal structure of a complex of calcium-loaded S100C with a synthetic peptide that corresponds to the first 14 residues of the annexin I N terminus at 2.3 A resolution. We find a stoichiometry of one peptide per S100C monomer, the entire complex structure consisting of two peptides per S100C dimer. Each peptide, however, interacts with both monomers of the S100C dimer. The two S100C molecules of the dimer are linked by a disulphide bridge. The structure is surprisingly close to that of the p11-annexin II N-terminal peptide complex solved previously. We have performed competition experiments to try to understand the specificity of the S100-annexin interaction. By solving the structure of a second annexin N terminus-S100 protein complex, we confirmed a novel mode of interaction of S100 proteins with their target peptides; there is a one-to-one stoichiometry, where the dimeric structure of the S100 protein is, nevertheless, essential for complex formation. Our structure can provide a model for a Ca(2+)-regulated annexin I-S100C heterotetramer, possibly involved in crosslinking membrane surfaces or organising membranes during certain fusion events.


MichelaNglo: sculpting protein views on web pages without coding.
The sharing of macromolecular structural information online by scientists is predominantly performed via 2D static images, since the embedding of interactive 3D structures in webpages is non-trivial. Whilst the technologies to do so exist, they are often only implementable with significant web coding experience. Michelaɴɢʟo is an accessible and open-source web-based application that supports the generation, customization and sharing of interactive 3D macromolecular visualizations for digital media without requiring programming skills. A PyMOL file, PDB file, PDB identifier code or protein/gene name can be provided to form the basis of visualizations using the NGL JavaScript library. Hyperlinks that control the view can be added to text within the page. Protein-coding variants can be highlighted to support interpretation of their potential functional consequences. The resulting visualizations and text can be customized and shared, as well as embedded within existing websites by following instructions and using a self-contained download. Michelaɴɢʟo allows researchers to move away from static images and instead engage, describe and explain their protein to a wider audience in a more interactive fashion. Michelaɴɢʟo is hosted at michelanglo.sgc.ox.ac.uk. The Python code is freely available at https://github.com/thesgc/MichelaNGLo, along with documentations about its implementation.


A longitudinal study of blood folate levels and depressive symptoms among young women in the Southampton Women's Survey.
Lower blood folate levels have been associated with depression in cross-sectional surveys, but no studies have examined the relationship prospectively to determine whether the relationship is causal. A follow-up study was designed to examine whether lower blood folate levels predict incident depressive symptoms. Women aged 20-34 years registered in general practices in Southampton, UK, were asked to participate. Baseline assessment included the general health questionnaire (GHQ-12) measure of anxiety and depression, and socioeconomic factors, diet, smoking and alcohol intake. Two years later, participants' general practice (GP) records were examined for evidence of incident symptoms of depression. At baseline, 5051 women completed the GHQ-12 and had red cell folate levels measured, of whom 1588 (31.4%) scored above the threshold for case level symptoms of anxiety and depression on the GHQ-12. Two years later, GP records for 3996 (79.1%) were examined, but 1264 with baseline evidence of depression were excluded from follow-up analysis. Incident depressive symptoms were recorded for 307 (11.2%) of the remaining 2732. Lower red cell folate levels were associated with caseness on the GHQ-12 (adjusted prevalence ratio 0.99 per 100 nmol/l red cell folate, 95% CI 0.98 to 1.00). No relationship was found between red cell folate levels and incident depressive symptoms over 2 years (adjusted hazard ratio 1.00, 95% CI 0.97 to 1.03). Low folate levels were not associated with subsequent depressive symptoms. This suggests that lower blood folate levels may be a consequence rather than a cause of depressive symptoms.


Evaluation of a Brief Sleep Intervention Designed to Improve the Sleep, Mood, and Cognitive Performance of Esports Athletes.
This study evaluated a brief sleep intervention designed to improve the sleep, mood, and cognitive performance of professional electronic sports (esports) athletes from three major esports regions (i.e., Asia, North America, and Oceania). Fifty-six esports athletes from South Korea (N = 34), the United States (N = 7), and Australia (N = 15) completed the study. Participants completed an initial 2-week pre-intervention phase to establish a baseline, followed by a 2-week intervention phase that involved a group sleep education class, 1:1 session with a trained clinical psychologist, and daily biofeedback. A wrist activity monitor and daily sleep diary were used to monitor sleep during both phases, while at pre- and post-intervention, participants completed a battery of sleep and mood questionnaires and underwent cognitive performance testing. Sleep knowledge increased from pre- to post-intervention (d = 0.83 [95% CI −1.21, −0.43], p =< 0.001), while there were modest improvements in sleep diary estimates (i.e., sleep onset latency (Mdiff = −2.9 min, p = 0.02), sleep onset time (Mdiff = −12 min, p = 0.03), and sleep efficiency (Mdiff = 1.1%, p = 0.004)) and wrist activity monitor estimates (i.e., sleep onset time (Mdiff = −18 min, p = 0.01)). Insomnia severity scores decreased significantly (d = 0.47 [95% CI 0.08, 0.84], p = 0.001), while sleepiness scores increased but not meaningfully (d = 0.23 [95% CI −0.61, 0.14], p = 0.025). However, there was no significant change in mood (i.e., depression and anxiety) or cognitive performance scores (i.e., mean reaction time or lapses). Sleep interventions for esports athletes require further investigation. Future research should examine whether a stepped-care model, whereby increasing therapeutic input is provided as needed, can optimize sleep, mood, and cognitive performance outcomes.


Self-learning based Fourier ptychographic microscopy.
Fourier Ptychographic Microscopy (FPM) is a newly proposed computational imaging method aimed at reconstructing a high-resolution wide-field image from a sequence of low-resolution images. These low-resolution images are captured under varied illumination angles and the FPM recovery routine then stitches them together in the Fourier domain iteratively. Although FPM has achieved success with static sample reconstructions, the long acquisition time inhibits real-time application. To address this problem, we propose here a self-learning based FPM which accelerates the acquisition and reconstruction procedure. We first capture a single image under normally incident illumination, and then use it to simulate the corresponding low-resolution images under other illumination angles. The simulation is based on the relationship between the illumination angles and the shift of the sample's spectrum. We analyze the importance of the simulated low-resolution images in order to devise a selection scheme which only collects the ones with higher importance. The measurements are then captured with the selection scheme and employed to perform the FPM reconstruction. Since only measurements of high importance are captured, the time requirements of data collection as well as image reconstruction can be greatly reduced. We validate the effectiveness of the proposed method with simulation and experimental results showing that the reduction ratio of data size requirements can reach over 70%, without sacrificing image reconstruction quality.


Relation of risk of systemic lupus erythematosus to west African admixture in a Caribbean population.
Risk of systemic lupus erythematosus (SLE) is higher in people of west African descent than in Europeans. The objective of this study was to distinguish between genetic and environmental explanations for this ethnic difference by examining the relationship of disease risk to individual admixture (defined as the proportion of the genome that is of west African ancestry); 124 cases of SLE and 219 matched controls resident in Trinidad were studied. Analysis of admixture was restricted to 52 cases and 107 controls who reported no Indian or Chinese ancestry. These individuals were typed with a panel of 26 single-nucleotide polymorphisms and five insertion/deletion polymorphisms chosen to have large allele frequency differentials between west African, European and Native American populations. A Bayesian model for population admixture, individual admixture and locus ancestry was fitted by Markov chain simulation. Mean west African admixture (M) was 0.81 in cases and 0.74 in controls (P=0.01). The risk ratio for SLE associated with unit change in M was estimated as 32.5 with a 95% confidence interval (CI) of 2.0-518. Adjustment for measures of socioeconomic status (household amenities in childhood and years of education) altered this risk ratio only slightly (adjusted risk ratio: 28.4, 95% CI 1.7-485). These results support an additive genetic model for the ethnic difference in risk of SLE between west Africans and Europeans, rather than an environmental explanation or an "overdominant" model in which risk is higher in heterozygous than in homozygous individuals. This conclusion lays a basis for localizing the genes underlying this ethnic difference in risk of SLE by admixture mapping.


Neurobiological and behavioural studies of affective instability in clinical populations: a systematic review.
To evaluate the neurobiological, psychophysical and behavioural measures of affective instability in clinical populations. A range of medical and psychological science electronic databases were searched (including MEDLINE, EMBASE, and PsycINFO). Hand searching and reference checking are also included. Reviews, systematic reviews, experimental and cross-sectional studies, providing affective instability in neurobiological and behavioural measurements in clinical populations. Studies were selected, data were extracted and quality was appraised. Twenty-nine studies were included, 6 of which were review studies (one a meta-analysis) and 23 of which were primary studies, across a wide variety of disorders including ADHD, bipolar affective disorder, schizophrenia, severe mood dysregulation, major depression, and borderline personality disorder. The bulk of the studies converge on the role of the amygdala, particularly in borderline personality disorders, and how it connects with other areas of the brain. Future research needs to extend these findings across diagnoses and development.


SIRT1 promotes DNA repair activity and deacetylation of Ku70.
Human SIRT1 controls various physiological responses including cell fate, stress, and aging, through deacetylation of its specific substrate protein. In processing DNA damage signaling, SIRT1 attenuates a cellular apoptotic response by deacetylation of p53 tumor suppressor. The present study shows that, upon exposure to radiation, SIRT1 could enhance DNA repair capacity and deacetylation of repair protein Ku70. Ectopically over-expressed SIRT1 resulted in the increase of repair of DNA strand breakages produced by radiation. On the other hand, repression of endogenous SIRT1 expression by SIRT1 siRNA led to the decrease of this repair activity, indicating that SIRT1 can regulate DNA repair capacity of cells with DNA strand breaks. In addition, we found that SIRT1 physically complexed with repair protein Ku70, leading to subsequent deacetylation. The dominant-negative SIRT1, a catalytically inactive form, did not induce deacetylation of Ku70 protein as well as increase of DNA repair capacity. These observations suggest that SIRT1 modulates DNA repair activity, which could be regulated by the acetylation status of repair protein Ku70 following DNA damage.


Forward and backward helicity scattering coefficients for systems with discrete rotational symmetry.
The forward and backward scattering off linear systems with discrete rotational symmetries R(z)(2π/n) with n ≥ 3 are shown to be restricted by symmetry reasons. Along the symmetry axis, forward scattering can only be helicity preserving and backward scattering can only be helicity flipping. These restrictions do not exist for n < 3. If, in addition to the n ≥ 3 discrete rotational symmetry, the system has duality symmetry (obeys the helicity conservation law), it will exhibit zero backscattering. The results pinpoint the underlying symmetry reasons for some notable scattering properties of R(z)(2π/4) symmetric systems that have been reported in the metamaterials and radar literature. Applications to planar metamaterials and solar cells are briefly discussed.


Cytokines and Pancreatic β-Cell Apoptosis.
The discovery 30 years ago that inflammatory cytokines cause a concentration, activity, and time-dependent bimodal response in pancreatic β-cell function and viability has been a game-changer in the fields of research directed at understanding inflammatory regulation of β-cell function and survival and the causes of β-cell failure and destruction in diabetes. Having until then been confined to the use of pathophysiologically irrelevant β-cell toxic chemicals as a model of β-cell death, researchers could now mimic endocrine and paracrine effects of the cytokine response in vitro by titrating concentrations in the low to the high picomolar-femtomolar range and vary exposure time for up to 14-16h to reproduce the acute regulatory effects of systemic inflammation on β-cell secretory responses, with a shift to inhibition at high picomolar concentrations or more than 16h of exposure to illustrate adverse effects of local, chronic islet inflammation. Since then, numerous studies have clarified how these bimodal responses depend on discrete signaling pathways. Most interest has been devoted to the proapoptotic response dependent upon mainly nuclear factor κ B and mitogen-activated protein kinase activation, leading to gene expressional changes, endoplasmic reticulum stress, and triggering of mitochondrial dysfunction. Preclinical studies have shown preventive effects of cytokine antagonism in animal models of diabetes, and clinical trials demonstrating proof of concept are emerging. The full clinical potential of anticytokine therapies has yet to be shown by testing the incremental effects of appropriate dosing, timing, and combinations of treatments. Due to the considerable translational importance of enhancing the precision, specificity, and safety of antiinflammatory treatments of diabetes, we review here the cellular, preclinical, and clinical evidence of which of the death pathways recently proposed in the Nomenclature Committee on Cell Death 2012 Recommendations are activated by inflammatory cytokines in the pancreatic β-cell to guide the identification of antidiabetic targets. Although there are still scarce human data, the cellular and preclinical studies point to the caspase-dependent intrinsic apoptosis pathway as the prime effector of inflammatory β-cell apoptosis.


An angiographic atlas of intracranial arterial diameters associated with cerebral aneurysms.
The successful treatment of intracranial aneurysms is dependent on a full understanding of the anatomic relationship of a given aneurysm to its parent artery(s) and nearby branches. Furthermore, new endovascular technologies are often limited by size constraints. Currently, there is no complete atlas describing diameters for each major intracranial arterial segment. We sought to obtain these data by performing a systematic analysis of selected cerebral angiography images from the International Study of Unruptured Intracranial Aneurysms (ISUIA). Four hundred and forty-five patients with unruptured intracranial aneurysms from the ISUIA database were reviewed. Using previously described techniques, artery diameters were measured for all arteries involved in the aneurysm neck for each patient. Measurements were obtained from 695 different aneurysm-associated arterial segments among 445 patient angiograms (mean 1.6 measurements per aneurysm). Artery diameters, mean, median, SEM and IQRs based upon the different arterial segments are presented. This angiographic almanac of aneurysm-associated intracranial arterial diameters may be of benefit in establishing standard norms through which devices, protocols and research aims may be developed.


Feasibility and Acceptability of Smart Augmented Reality Assisting Patients with Medication Pillbox Self-Management.
Complex prescribed medicine regimens require extensive self-management. Handling multiple pills can be confusing; using a pillbox organiser is a common strategy. A smart Medication Coach Intelligent Agent (MCIA) can support patients in handling medicine. The aim of this research was to evaluate the feasibility and acceptability of the MCIA. A prototype was tested with 15 participants, age 17-76, filled a pillbox according to prescription assisted by the MCIA implemented in a Microsoft HoloLens. A quantitative method using questionnaires was applied. Results showed that using the MCIA implemented in an AR-headset, to assist people with prescribed polypharmacy regimen in filling a pillbox, was feasible and acceptable. There was a difference related to age regarding people's willingness to use an AR-headset for medication self-management. People older than 65 felt less comfortable using the technology and were also more hesitant to use the technology than those under 65.


[Laparoscopic treatment of UPJ obstruction in ectopic pelvic kidneys in children].
To assess the feasibility and safety of a laparoscopic approach to UPJ obstruction (UPJO) in ectopic pelvic kidneys. In a retrospective analysis we selected 14 children, aged 6 months to 17 years, 12 males, 2 females, who had been treated in our Department between January 2004 and June 2011. 9 patients presented ureteropelvic junction obstruction (in 3 cases pelvic stones coexisted) with normal/moderately reduced (> or = 25%) relative function at radionuclide scan (MAG3), 3 nonfunctioning kidneys associated or not to hypertension, 2 congenital hypo-dysplastic kidneys. The evaluation of each patient involved the medical history, ultrasound examination, VCUG, MAG3 diuresis renogram and MRI in some cases. Of the patients presenting UPJO, 5 underwent dismembered pyeloplasty with pyelolithotomy, if required, and 4 pelvic derotation with straightening of the uretero-pelvic junction. A previous cystoscopic placement of a Double J stent was utilized. This facilitated the identification and dissection around the pelvis. With the patient in Trendelenburg position we utilized an umbilical trocar and two trocar in the right and left iliac fossae; an additional trocar, when required, was inserted more cephalad on the midclavear line contralaterally to the lesion. The derotation of ureteropelvic junction was obtained by freeing the kidney's lower pole and by placing intraperitoneally the junction protected with a Double J stent. This was obtained by suturing the peritoneum behind the ureteropelvic junction resulting in a forward rotation of the major axis of the kidney and a straightening of the junction. The 5 patients presenting nonfunctioning ectopic kidneys underwent laparoscopic nephrectomy. While the removal of congenital hypoplasic kidneys resulted easy, the removal of nonfunctioning kidneys was more difficult due to their complex vascular situation and for the embryonic disposition. The operating time varied between 40 to 200 minutes. No patient required conversion to open surgery. The hypertension resolved after nephrectomy in all cases. 2 cases of dismembered pyeloplasty required a placement of Double J stent due the recurrence of symptoms and ! patient is waiting for redo operation. The pelvic derotation showed an improvement of diuretic MAG3 renogram and the function remained stable and patiens are symptoms-free. The UPJO in ectopic pelvic kidneys presents a large spectrum of presentation. The laparoscopic approach provides good surgical exposure, and operative times are acceptable compared to those of laparoscopic procedure in anatomically normal kidneys. It has also proved a very useful tool in the non-functioning kidney nephrectomy thank to the help of magnification in the identification of numerous aberrant vessels that are quite often found in the pelvic kidneys. The derotation of the pelvis seems a useful procedure in moderate obstruction even if a longer followup is needed.


Following multi-component reactions in liquid medium using spectral band-fitting techniques.
The kinetics of the hydrolysis reaction of p-nitrophenyl butyrate catalyzed by a single-site mutant of Fusarium solani pisi cutinase, supported on zeolite NaY by adsorption, was followed using ultraviolet-visible (UV/Vis) in situ diode array spectrophotometry. Spectral band-fitting techniques allowed the use of in situ diode array spectrophotometry to obtain quantitative data on the concentrations of the various species present in an aqueous reaction medium even in the presence of the solid catalyst particles, which interfere with the absorption measurements. This technique overcame the problems arising from the variable light scattering produced by these highly dispersible catalyst particles. Kinetic modeling of the reaction system was used to compute estimates of the reaction rate constants involved.