The Frequency and Effective Factors of Exclusive Breastfeeding for the First Six Months in Babies Born in Erzincan Province in 2016.
The World Health Organization emphasizes that it is essential that infants be fed only breast milk for the first six months. This study is designed to investigate the frequency of exclusive breastfeeding and the related factors during the first six months in infants born in 2016 in Erzincan province. Our study is a cross-sectional study, and the study population consisted of 2166 babies born in 2016, and registered with the family physicians. The sample size was calculated as 635 with a 95% confidence interval and 3% error margin, assuming that the frequency of exclusive breastfeeding in first six months is 30%. The family physicians were randomly selected. Mothers included in the study were determined by random sampling method. The data were collected by interviewing the mothers individually, and then analyzed in the SPSS (IBM, SPSS Corp.; Armonk, NY, USA) 21.0 package program. In this study, the rate of infants who received only breast milk for the first six months was calculated as 45.7%. The average period of exclusive breastfeeding was 4.4±2.03 months. It was observed that the children of mothers with prenatal and postnatal education received only breast milk for longer time. Also, mothers who do not work, those who do not use tobacco after birth, and those without depression also fed their children with only breast milk for longer time. In pacifiers or bottle users, infants receiving other nutrients after birth had a lower rate of exclusive breastfeeding for the first six months. In our study, it has been observed that to increase the rate of exclusive breastfeeding, it is necessary to increase the education before and after the birth; to not use any other nutrients, pacifier, or bottle after delivery; and to spend adequate time with the baby.


Roles for Golgi Glycans in Oogenesis and Spermatogenesis.
Glycosylation of proteins by N- and O-glycans or glycosaminoglycans (GAGs) mostly begins in the endoplasmic reticulum and is further orchestrated in the Golgi compartment via the action of >100 glycosyltransferases that reside in this complex organelle. The synthesis of glycolipids occurs in the Golgi, also by resident glycosyltransferases. A defect in the glycosylation machinery may impair the functions of glycoproteins and other glycosylated molecules, and lead to a congenital disorder of glycosylation (CDG). Spermatogenesis in the male and oogenesis in the female are tightly regulated differentiation events leading to the production of functional gametes. Insights into roles for glycans in gamete production have been obtained from mutant mice following deletion or inactivation of genes that encode a glycosylation activity. In this review, we will summarize the effects of altering the synthesis of N-glycans, O-glycans, proteoglycans, glycophosphatidylinositol (GPI) anchored proteins, and glycolipids during gametogenesis in the mouse. Glycosylation genes whose deletion causes embryonic lethality have been investigated following conditional deletion using various Cre recombinase transgenes with a cell-type specific promoter. The potential effects of mutations in corresponding glycosylation genes of humans will be discussed in relation to consequences to fertility and potential for use in contraception.


Legal abortion levels and trends by woman's age at termination.
Assessments of abortion levels and trends by women's age at termination can be used to monitor trends in unintended pregnancy by age and can inform relevant programs and policies. Legal abortion incidence data were compiled from national statistical offices and nationally representative surveys of more than 40 countries where legal abortion is generally available. Age-specific abortion rates and percentage distributions of abortions by age were computed, and trends since 1996 and 2003 were examined. Subregional and regional estimates were developed for geographic areas where the majority of the population was represented by the data. The median year for the most recent estimates of abortions by woman's age was 2009. Adolescents accounted for a smaller share of abortions than their share of the population in the majority of eligible countries with data. In most countries, the highest age-specific abortion rates and proportions of abortions were among women aged 20-29. Since 1996, adolescent abortion rates have increased the most in Belgium, the Netherlands and Scotland (22-42%), and have decreased the most in Estonia, Hungary, Iceland, Slovakia and Slovenia (40-55%). The proportion of abortions obtained by adolescents was higher in North America (18%) than in Europe overall (11%), although the proportion in Northern Europe (18%) was the same as that in North America. Higher abortion rates in particular age-groups probably reflect higher-than-average levels of unmet need for contraception or difficulty using methods consistently and effectively, and a stronger desire to avoid childbearing. Each of the patterns observed has implications for service and information needs within countries.


Dynamic interaction of TTDA with TFIIH is stabilized by nucleotide excision repair in living cells.
Transcription/repair factor IIH (TFIIH) is essential for RNA polymerase II transcription and nucleotide excision repair (NER). This multi-subunit complex consists of ten polypeptides, including the recently identified small 8-kDa trichothiodystrophy group A (TTDA)/ hTFB5 protein. Patients belonging to the rare neurodevelopmental repair syndrome TTD-A carry inactivating mutations in the TTDA/hTFB5 gene. One of these mutations completely inactivates the protein, whereas other TFIIH genes only tolerate point mutations that do not compromise the essential role in transcription. Nevertheless, the severe NER-deficiency in TTD-A suggests that the TTDA protein is critical for repair. Using a fluorescently tagged and biologically active version of TTDA, we have investigated the involvement of TTDA in repair and transcription in living cells. Under non-challenging conditions, TTDA is present in two distinct kinetic pools: one bound to TFIIH, and a free fraction that shuttles between the cytoplasm and nucleus. After induction of NER-specific DNA lesions, the equilibrium between these two pools dramatically shifts towards a more stable association of TTDA to TFIIH. Modulating transcriptional activity in cells did not induce a similar shift in this equilibrium. Surprisingly, DNA conformations that only provoke an abortive-type of NER reaction do not result into a more stable incorporation of TTDA into TFIIH. These findings identify TTDA as the first TFIIH subunit with a primarily NER-dedicated role in vivo and indicate that its interaction with TFIIH reflects productive NER.


Measuring early language development in preschool children with autism spectrum disorder using the MacArthur Communicative Development Inventory (Infant Form).
Parent report data on early language development measured using the MacArthur Communicative Development Inventory (CDI-Infant Form) was collected on 134 preschool children with autism spectrum disorder. The pattern of development of understanding of phrases, word comprehension and expression, and production of gestures, was compared to the typical pattern. In common with typical development there was considerable variability in language acquisition, although for the group as a whole this was significantly delayed compared to the normal course. In addition, atypical patterns were identified in the emergence of language skills in the sample. Comprehension of words was delayed in comparison to word production, and production of early gestures (involving sharing reference) was delayed relative to production of later gestures (involving use of objects). However, other aspects of language development were similar to that found in typically developing infants, including word comprehension being in advance of word production in absolute terms, gesture production acting as a 'bridge' between word comprehension and word production and the broad pattern of acquisition across word categories and word forms. The implications for assessment and intervention with preschool children with autism spectrum disorder are discussed.


Genetic counseling communication with an African American BRCA1 kindred.
We studied communication in genetic counseling sessions conducted with an African American, Breast Cancer 1, Early Onset (BRCA1) kindred in the USA. The Roter Interaction Analysis System (RIAS) was used to code and compare two sessions of 46 participants (26 females and 20 males) before and after they underwent genetic testing. Three certified genetic counselors and one medical geneticist conducted the sessions. When compared to pre-test communication, most of the providers' post-test communication was devoted to the provision of biomedical information (including screening recommendations) with fewer questions and psychosocial statements. Clients contributed a similar proportion to the total session dialogue in pre- and post-test sessions (40%). A larger proportion of their post-test session was devoted to indicating receptiveness to provider information than in the pre-test session. We found when providers were informing clients that they were BRCA1 mutation carriers, they provided more biomedical and psychosocial information and asked more psychosocial questions than when talking with non-carriers. This study provides the first description of genetic counseling communication for pre- and post-test BRCA1 sessions with African American individuals.


Improving nonalcoholic fatty liver disease classification performance with latent diffusion models.
Integrating deep learning with clinical expertise holds great potential for addressing healthcare challenges and empowering medical professionals with improved diagnostic tools. However, the need for annotated medical images is often an obstacle to leveraging the full power of machine learning models. Our research demonstrates that by combining synthetic images, generated using diffusion models, with real images, we can enhance nonalcoholic fatty liver disease (NAFLD) classification performance even in low-data regime settings. We evaluate the quality of the synthetic images by comparing two metrics: Inception Score (IS) and Fréchet Inception Distance (FID), computed on diffusion- and generative adversarial network (GAN)-generated images. Our results show superior performance for the diffusion-generated images, with a maximum IS score of 1.90 compared to 1.67 for GANs, and a minimum FID score of 69.45 compared to 100.05 for GANs. Utilizing a partially frozen CNN backbone (EfficientNet v1), our synthetic augmentation method achieves a maximum image-level ROC AUC of 0.904 on a NAFLD prediction task.


Classic bladder exstrophy: Frequent 22q11.21 duplications and definition of a 414 kb phenocritical region.
Classic bladder exstrophy (CBE) is the most common form of the bladder exstrophy and epispadias complex. Previously, we and others have identified four patients with a duplication of 22q11.21 among a total of 96 unrelated CBE patients. Here, we investigated whether this chromosomal aberration was commonly associated with CBE/bladder exstrophy and epispadias complex in an extended case-control sample. Multiplex ligation-dependent probe amplification and microarray-based analysis were used to identify 22q11.21 duplications in 244 unrelated bladder exstrophy and epispadias complex patients (including 217 CBE patients) and 665 healthy controls. New duplications of variable size were identified in four CBE patients and one control. Pooling of our previous and present data (eight duplications in 313 CBE patients) yielded a combined odds ratio of 31.86 (95% confidence interval, 4.24-1407.97). Array-based sequence capture and high-throughput targeted re-sequencing established that all breakpoints resided within the low-copy repeats 22A to 22D. Comparison of the eight duplications revealed a 414 kb phenocritical region harboring 12 validated RefSeq genes. Characterization of these 12 candidate genes through whole-mount in situ hybridization of mouse embryos at embryonic day 9.5 suggested that CRKL, THAP7, and LZTR1 are CBE candidate genes. Our data suggest that duplication of 22q11.21 increases CBE risk and implicate a phenocritical region in disease formation.


Thyroid Cancer after Childhood Exposure to External Radiation: An Updated Pooled Analysis of 12 Studies.
Studies have causally linked external thyroid radiation exposure in childhood with thyroid cancer. In 1995, investigators conducted relative risk analyses of pooled data from seven epidemiologic studies. Doses were mostly <10 Gy, although childhood cancer therapies can result in thyroid doses >50 Gy. We pooled data from 12 studies of thyroid cancer patients who were exposed to radiation in childhood (ages <20 years), more than doubling the data, including 1,070 (927 exposed) thyroid cancers and 5.3 million (3.4 million exposed) person-years. Relative risks increased supralinearly through 2-4 Gy, leveled off between 10-30 Gy and declined thereafter, remaining significantly elevated above 50 Gy. There was a significant relative risk trend for doses <0.10 Gy (P < 0.01), with no departure from linearity (P = 0.36). We observed radiogenic effects for both papillary and nonpapillary tumors. Estimates of excess relative risk per Gy (ERR/Gy) were homogeneous by sex (P = 0.35) and number of radiation treatments (P = 0.84) and increased with decreasing age at the time of exposure. The ERR/Gy estimate was significant within ten years of radiation exposure, 2.76 (95% CI, 0.94-4.98), based on 42 exposed cases, and remained elevated 50 years and more after exposure. Finally, exposure to chemotherapy was significantly associated with thyroid cancer, with results supporting a nonsynergistic (additive) association with radiation.


Endogenous serotonin contributes to a developmental decrease in long-term potentiation in the rat visual cortex.
The primary visual cortex shows synaptic plasticity during a postnatal "critical period," and its plasticity declines with development. Indeed, we found a developmental decrease in the induction of long-term potentiation (LTP) in the rat visual cortex. In visual cortex slices obtained from 2- to 3-week-old rats, tetanic stimulation (100 Hz for 1 sec, twice at an interval of 30 sec) of the white matter reproducibly induced LTP of field potentials in layer II/III. However, in slices from 5-week-old rats, the same tetanic stimulation failed to induce LTP. We hypothesized that endogenous serotonin (5-HT) is responsible for the developmental decrease in visual cortex LTP, because the induction of visual cortex LTP was suppressed by the addition of exogenous 5-HT (10 microm) and because the amount of 5-HT in the visual cortex increased during development. To test this hypothesis, we investigated the effect of methysergide, a 5-HT receptor antagonist, on the induction of visual cortex LTP. When visual cortex slices from 5-week-old rats were perfused with 50 microm methysergide, tetanic stimulation of the white matter induced robust LTP in layer II/III. Furthermore, serotonergic neurons were lesioned by intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT). LTP was induced in visual cortex slices from 5,7-DHT-treated, 5-week-old rats. These results suggest that the induction of visual cortex LTP in 5-week-old rats is suppressed by endogenous 5-HT. 5-HT may be a factor that determines a critical period for synaptic plasticity in the rat visual cortex.


Altered Brain Dynamics in Patients With Type 1 Diabetes During Working Memory Processing.
It is now generally accepted that diabetes increases the risk for cognitive impairment, but the precise mechanisms are poorly understood. A critical problem in linking diabetes to cognitive impairment is that patients often have multiple comorbidities (e.g., obesity, hypertension) that have been independently linked to cognitive deficits. In the study reported here we focused on young adults with and without type 1 diabetes who were virtually free of such comorbidities. The two groups were matched on major health and demographic factors, and all participants completed a verbal working memory task during magnetoencephalographic brain imaging. We hypothesized that patients would have altered neural dynamics in verbal working memory processing and that these differences would directly relate to clinical disease measures. Accordingly, we found that patients had significantly stronger neural responses in the superior parietal cortices during memory encoding and significantly weaker activity in parietal-occipital regions during maintenance compared with control subjects. Moreover, disease duration and glycemic control were both significantly correlated with neural responses in various brain regions. In conclusion, young healthy adults with type 1 diabetes already have aberrant neural processing relative to their peers without diabetes, using compensatory responses to perform the task, and glucose management and duration may play a central role.


Wave acceleration of electrons in the Van Allen radiation belts.
The Van Allen radiation belts are two regions encircling the Earth in which energetic charged particles are trapped inside the Earth's magnetic field. Their properties vary according to solar activity and they represent a hazard to satellites and humans in space. An important challenge has been to explain how the charged particles within these belts are accelerated to very high energies of several million electron volts. Here we show, on the basis of the analysis of a rare event where the outer radiation belt was depleted and then re-formed closer to the Earth, that the long established theory of acceleration by radial diffusion is inadequate; the electrons are accelerated more effectively by electromagnetic waves at frequencies of a few kilohertz. Wave acceleration can increase the electron flux by more than three orders of magnitude over the observed timescale of one to two days, more than sufficient to explain the new radiation belt. Wave acceleration could also be important for Jupiter, Saturn and other astrophysical objects with magnetic fields.


Does non-invasive brain stimulation applied over the dorsolateral prefrontal cortex non-specifically influence mood and emotional processing in healthy individuals?
The dorsolateral prefrontal cortex (DLPFC) is often targeted with non-invasive brain stimulation (NIBS) to modulate in vivo human behaviors. This brain region plays a key role in mood, emotional processing, and attentional processing of emotional information. In this article, we ask the question: when we target the DLPFC with NIBS, do we modulate these processes altogether, non-specifically, or can we modulate them selectively? We thus review articles investigating the effects of NIBS applied over the DLPFC on mood, emotional processing, and attentional processing of emotional stimuli in healthy subjects. We discuss that NIBS over the DLPFC can modulate emotional processing and attentional processing of emotional stimuli, without specifically influencing mood. Indeed, there seems to be a lack of evidence that NIBS over the DLPFC influences mood in healthy individuals. Finally, there appears to be a hemispheric lateralization: when applied over the left DLPFC, NIBS improved processing of positive stimuli and reduced selective attention for stimuli expressing anger, whereas when applied over the right DLPFC, it increased selective attention for stimuli expressing anger.


Prediction of functional capacity during six-minute walk among patients with chronic heart failure.
Formulae for predicting functional capacity during 6-minute walk are lacking and the accuracy of the existing formulae has been challenged in deferent populations. The purpose of this study was to develop an equation that would be useful in predicting functional capacity in form of maximum oxygen consumption) (V0 2 ) in Chronic Heart Failure Patients (CHF) during exercise. Sixty-five subjects were recruited for the study. The procedure required the subjects to walk on a self paced speed on a 20 meter marked level ground for 6 minutes. The distance covered in 6 minutes was measured and the speed calculated. The result showed that the distance covered was highly correlated with the VO2 (0.65, p< 0.01). The regression analysis revealed that a linear equation model developed was a good predictor of V0 2 for the group. The study concluded that in situation where sophisticated equipments are lacking, this equation might be useful during exercise supervision for patients with CHF. [VO2 (mlkg-1 min-1) = 0.0105 x distance (m) + 0.0238 age (yr) - 0.03085 weight (kg) + 5.598].


WITHDRAWN: Non-aspirin, non-steroidal anti-inflammatory drugs for treating osteoarthritis of the knee.
Osteoarthritis(OA) is the most common rheumatic disease. Simple analgesics are now accepted as the appropriate first line pharmacological treatment of uncomplicated OA. Non-aspirin NSAIDs are licensed for the relief of pain and inflammation arising from rheumatic disease. To determine whether there is a difference in the relative efficacy of individual non-steroidal anti-inflammatory drugs (NSAIDs) when used in the management of osteoarthritis (OA) of the knee. We searched Medline (1966-1995) and Bids Embase (Jan-Dec, 1980-1995). The searches were limited to publications in the English language, and were last performed in November 1996. We used modified Cochrane Collaboration search strategy to identify all randomised controlled trials. The MeSH heading "osteoarthritis" was combined with the generic names of the 17 non-aspirin NSAIDs licensed in the UK for the management of OA in general practice. The search of Embase used the term "osteoarthritis" if present in the abstract, title or keywords, and was combined with the generic names of the 17 non-aspirin NSAIDs, only if they were mentioned in the title, abstract or keywords. All double blind, randomised controlled trials, in the English language, comparing the efficacy of two non-aspirin NSAIDs in the management of osteoarthritis of the knee, were selected. Only trials with subjects aged 16 years and over, with clinical and/or radiological confirmation of the diagnosis of OA knee were included. Studies which compared one "trial" NSAID with one "reference" NSAID were included provided they were non-aspirin NSAIDs available in the UK and were licensed for the treatment of OA by general practitioners. Trials which were placebo-controlled and which also involved the comparison of two NSAIDs were also included. The methodological design of each study was scored according to a pre-determined system. The three main outcome measures of pain, physical function and patient global assessment were chosen based on the core set agreed upon by OMERACT (Outcome Measures in Rheumatology Clinical Trials). These were used to determine the power of each trial. The equivalency of NSAID doses was calculated using the percentage of the recommended maximum daily dose. Sample size estimates for the detection of clinically relevant changes in outcome measures used in the assessment of OA knee were used for power calculations. These calculations were performed to determine whether the trials were of a sufficient size to detect clinically relevant differences which were statistically significant. The calculations incorporate estimates of standard deviation, and minimum, median and maximum differences (delta) between drugs which are deemed to be clinically important. The number of "withdrawals due to lack of efficacy" was also selected as an outcome measure for this review. The Peto odds ratio and 95% confidence intervals were calculated where possible. The results of studies which compared the same trial and reference NSAIDs were combined where possible. Of the 1151 trials identified by the search strategy, 22 involved knee osteoarthritis only. Sixteen of these trials fulfilled the inclusion criteria and were entered in the review. Eight NSAIDs were represented in these trials. Etodolac was represented in 11 trials. The reference NSAID in these trials was piroxicam (n=3), naproxen(n=3), diclofenac (n=3), indomethacin (n=1), and, nabumetone (n=1). The reported methodological design of the trials was poor, with a median score of 3 (out of a maximum of 8). The results of the trials comparing the same trial and reference NSAIDs were pooled for the outcome "withdrawal due to lack of efficacy". For the comparison, etodolac versus piroxicam, the odds ratio favoured etodolac i.e. patients receiving etodolac were less likely to withdraw due to lack of efficacy. The dose of etodolac used in each of these three studies, however, was greater than the corresponding dose of piroxicam (based on percentage maximum daily dose). The significance of these results is therefore questionable. For the comparisons etodolac versus diclofenac, and etodolac versus naproxen, there were no clear differences between treatments. In one study [Bellamy 1993], a statistically significant difference was detected between treatments with regard to withdrawals due to lack of efficacy. In this trial, which compared equivalent NSAID doses, diclofenac was the favoured NSAID compared to tenoxicam(p=0.04). Two studies showed a statistical difference in patient global assessment of condition, which favoured the trial NSAID. In both cases the trial NSAID was etodolac, used in doses approximately 25-44% greater than the reference NSAID. Two studies showed a statistically significant difference in pain relief between NSAIDs. The trial NSAID in both cases was again etodolac but the doses exceeded those of the reference NSAIDs. In spite of the large number of publications in this area, there are few randomized controlled trials. Furthermore, most trials comparing two or more NSAIDs suffer from substantial design errors. From the results of this review it is concluded that no substantial evidence is available related to efficacy, to distinguish between equivalent recommended doses of NSAIDs. Had studies employed appropriate doses of comparator drug, most would have been sufficiently powerful to detect clinically important differences in efficacy. As differences in efficacy between NSAIDs have not been recorded, the selection of an NSAID for prescription for OA knee should be based upon relative safety, patient acceptability and cost.


Google matrix analysis of DNA sequences.
For DNA sequences of various species we construct the Google matrix [Formula: see text] of Markov transitions between nearby words composed of several letters. The statistical distribution of matrix elements of this matrix is shown to be described by a power law with the exponent being close to those of outgoing links in such scale-free networks as the World Wide Web (WWW). At the same time the sum of ingoing matrix elements is characterized by the exponent being significantly larger than those typical for WWW networks. This results in a slow algebraic decay of the PageRank probability determined by the distribution of ingoing elements. The spectrum of [Formula: see text] is characterized by a large gap leading to a rapid relaxation process on the DNA sequence networks. We introduce the PageRank proximity correlator between different species which determines their statistical similarity from the view point of Markov chains. The properties of other eigenstates of the Google matrix are also discussed. Our results establish scale-free features of DNA sequence networks showing their similarities and distinctions with the WWW and linguistic networks.


Pastoralists' indigenous selection criteria and other breeding practices of the long-horned Ankole cattle in Uganda.
The criteria for identification, selection and kinship assignment of Ankole cattle and their roles to pastoralists were studied on 248 farms in Kiboga, Mbarara, Mpigi and Sembabule districts of Uganda using a questionnaire, administered during one-to-one interviews. Farms were randomly sampled along transects originating from the headquarters of each of the 19 sub-counties studied. We found that male Ankole cattle are reared for income from sales, meat for home use and ceremonies, aesthetic value and to maintain cultural heritage. Female cattle are mainly kept for milk production, income from sales, heritage and aesthetics, and in few cases, for home use as meat. Other functions included savings, manure and butter production. All cattle are named at birth with coat colour or pattern being the main identification criterion; hence, it is also useful in assigning kinship. Selection criteria for males are more stringent than for females. On most farms, all females are kept for further breeding and are only culled in cases of poor reproductive health. Primary emphasis in selecting males is on the performance of ancestors in milk and reproductive traits, and then on the qualities of the bull itself. Bulls are selected mainly focusing on a big body frame and size, horns that are white, large and curved upward and a plain dark red "ruhogo" coat colour. The results of this study show that pastoralists have a rich body of indigenous knowledge on this breed, and this should effectively be incorporated into planned selective improvement schemes of the Ankole cattle breed.


Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology.
Progesterone, a female sex hormone, is known to induce secretory changes in the lining of the uterus essential for successful implantation of a fertilized egg. It has been suggested that a causative factor in many cases of miscarriage may be inadequate secretion of progesterone. Therefore, clinicians use progestogens (drugs that interact with the progesterone receptors), beginning in the first trimester of pregnancy, in an attempt to prevent spontaneous miscarriage. This is an update of a review, last published in 2013. To assess the efficacy and safety of progestogens as a preventative therapy against recurrent miscarriage. For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (6 July 2017) and reference lists from relevant articles, attempting to contact trial authors where necessary, and contacted experts in the field for unpublished works. Randomized or quasi-randomized controlled trials comparing progestogens with placebo or no treatment given in an effort to prevent miscarriage. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two reviewers assessed the quality of the evidence using the GRADE approach. Thirteen trials (2556 women) met the inclusion criteria. Nine of the included trials compared treatment with placebo and the remaining four trials compared progestogen administration with no treatment. The trials were a mix of multicenter and single-center trials, conducted in Egypt, India, Jordan, UK and USA. In six trials women had had three or more consecutive miscarriages and in seven trials women had suffered two or more consecutive miscarriages. Routes, dosage and duration of progestogen treatment varied across the trials. The majority of trials were at low risk of bias for most domains. Eleven trials (2359 women) contributed data to the analyses.The meta-analysis of all women, suggests that there is probably a reduction in the number of miscarriages for women given progestogen supplementation compared to placebo/controls (average risk ratio (RR) 0.69, 95% confidence interval (CI) 0.51 to 0.92, 11 trials, 2359 women, moderate-quality evidence). A subgroup analysis comparing placebo-controlled versus non-placebo-controlled trials and different routes of administration showed no differences between subgroups for miscarriage. However, there appears to be a subgroup difference for miscarriage between women with three or more prior miscarriages compared to women with two or more miscarriages, with a more pronounced effect in women with three or more prior miscarriages. However, it should be noted that there was high heterogeneity in the subgroup of women with three or more prior miscarriages.None of the trials reported on any secondary maternal outcomes, including severity of morning sickness, thromboembolic events, depression, admission to a special care unit, or subsequent fertility.There was probably a slight benefit for women receiving progestogen seen in the outcome of live birth rate (RR 1.11, 95% CI 1.00 to 1.24, 7 trials, 2086 women, moderate-quality evidence). While the rate of preterm birth is probably reduced for women receiving progestogen, this outcome was mainly driven by one trial and thus should be interpreted with great caution (RR 0.59, 95% CI 0.39 to 0.89, 5 trials, 811 women, moderate-quality evidence). No clear differences were seen for women receiving progestogen for the other secondary outcomes of neonatal death or fetal genital abnormalities. A possible reduction in stillbirth was seen, but again this outcome was driven mainly by one trial and should be interpreted with caution (RR 0.38, 95% CI 0.24 to 0.58, 3 trials, 1199 women). There may be little or no difference in the rate of low birthweight and trials did not report on the secondary child outcomes of teratogenic effects or admission to a special care unit. For women with unexplained recurrent miscarriages, supplementation with progestogen therapy probably reduces the rate of miscarriage in subsequent pregnancies.


Targeting the Plasmodium vivax equilibrative nucleoside transporter 1 (PvENT1) for antimalarial drug development.
Infection with Plasmodium falciparum and vivax cause most cases of malaria. Emerging resistance to current antimalarial medications makes new drug development imperative. Ideally a new antimalarial drug should treat both falciparum and vivax malaria. Because malaria parasites are purine auxotrophic, they rely on purines imported from the host erythrocyte via Equilibrative Nucleoside Transporters (ENTs). Thus, the purine import transporters represent a potential target for antimalarial drug development. For falciparum parasites the primary purine transporter is the P. falciparum Equilibrative Nucleoside Transporter Type 1 (PfENT1). Recently we identified potent PfENT1 inhibitors with nanomolar IC50 values using a robust, yeast-based high throughput screening assay. In the current work we characterized the Plasmodium vivax ENT1 (PvENT1) homologue and its sensitivity to the PfENT1 inhibitors. We expressed a yeast codon-optimized PvENT1 gene in Saccharomyces cerevisiae. PvENT1-expressing yeast imported both purines ([(3)H]adenosine) and pyrimidines ([(3)H]uridine), whereas wild type (fui1Δ) yeast did not. Based on radiolabel substrate uptake inhibition experiments, inosine had the lowest IC50 (3.8 μM), compared to guanosine (14.9 μM) and adenosine (142 μM). For pyrimidines, thymidine had an IC50 of 183 μM (vs. cytidine and uridine; mM range). IC50 values were higher for nucleobases compared to the corresponding nucleosides; hypoxanthine had a 25-fold higher IC50 than inosine. The archetypal human ENT1 inhibitor 4-nitrobenzylthioinosine (NBMPR) had no effect on PvENT1, whereas dipyridamole inhibited PvENT1, albeit with a 40 μM IC50, a 1000-fold less sensitive than human ENT1 (hENT1). The PfENT1 inhibitors blocked transport activity of PvENT1 and the five known naturally occurring non-synonymous single nucleotide polymorphisms (SNPs) with similar IC50 values. Thus, the PfENT1 inhibitors also target PvENT1. This implies that development of novel antimalarial drugs that target both falciparum and vivax ENT1 may be feasible.


Clonorchis sinensis infection and increasing risk of cholangiocarcinoma in the Republic of Korea.
To evaluate the prevalence and risk factors of Clonorchis sinensis infection, an epidemiologic survey was performed (3,169 residents; age range: 30-87 years; mean age = 59; 1,973 women) in three areas with different mortality rates of cholangiocarcinoma. C. sinensis prevalence was 2.1% in Chuncheon, 7.8% in Chungju, and 31.3% in Haman, where cholangiocarcinoma incidence rate was 0.3, 1.8, and 5.5 per 100,000 persons, respectively. Of the four major risk factors for C. sinensis (male sex, alcohol consumption, raw freshwater fish intake, and area of residence), area was the strongest. Efforts to discourage raw freshwater fish intake, treat egg carriers, and protect water sources from C. sinensis contamination should be strengthened in the Republic of Korea.


Antihyperglycemic effects of short term resveratrol supplementation in type 2 diabetic patients.
The objective of this study was to examine the effectiveness of resveratrol in lowering blood glucose in the presence of standard antidiabetic treatment in patients with type 2 diabetes, in a randomized placebo-controlled double-blinded parallel clinical trial. A total of 66 subjects with type 2 diabetes were enrolled in this study and randomly assigned to intervention group which was supplemented with resveratrol at a dose 1 g/day for 45 days and control group which received placebo tablets. Body weight, blood pressure, fasting blood glucose, haemoglobin A1c, insulin, homeostatic assessments for insulin resistance, triglycerides, total cholesterol, low density lipoprotein, high density lipoprotein, and markers of liver and kidney damage were measured at baseline and after 45 days of resveratrol or placebo supplementation. Resveratrol treatment significantly decreased systolic blood pressure, fasting blood glucose, haemoglobin A1c, insulin, and insulin resistance, while HDL was significantly increased, when compared to their baseline levels. On the other hand, the placebo group had slightly increased fasting glucose and LDL when compared to their baseline levels. Liver and kidney function markers were unchanged in the intervention group. Overall, this study showed that resveratrol supplementation exerted strong antidiabetic effects in patients with type 2 diabetes.


Calcium Channel Activity during Pollen Tube Growth and Reorientation.
We have shown previously that the inhibition of pollen tube growth and its subsequent reorientation in Agapanthus umbellatus are preceded by an increase in cytosolic free calcium ([Ca2+]c), suggesting a role for Ca2+ in signaling these processes. In this study, a novel procedure was used to measure Ca2+ channel activity in living pollen tubes subjected to various growth reorienting treatments (electrical fields and ionophoretic microinjection). The method involves adding extracellular Mn2+ to quench the fluorescence of intracellular Indo-1 at its ca2+-insensitive wavelength (isosbestic point). The spatial and temporal kinetics of Ca2+ channel activity correlated well with measurements of [Ca2+]c dynamics obtained by fluorescence ratio imaging of Indo-1. Tip-focused gradients in Ca2+ channel activity and [Ca2+]c were observed and quantified in growing pollen tubes and in swollen pollen tubes before reoriented growth. In nongrowing pollen tubes, Ca2+ channel activity was very low and [Ca2+]c gradients were absent. Measurements of membrane potential indicated that the growth reorienting treatments induced a depolarization of the plasma membrane, suggesting that voltage-gated Ca2+ channels might be activated.


Molecular mapping of an adult plant stem rust resistance gene Sr56 in winter wheat cultivar Arina.
This article covers detailed characterization and naming of QSr.sun - 5BL as Sr56 . Molecular markers linked with adult plant stem rust resistance gene Sr56 were identified and validated for marker-assisted selection. The identification of new sources of adult plant resistance (APR) and effective combinations of major and minor genes is well appreciated in breeding for durable rust resistance in wheat. A QTL, QSr.sun-5BL, contributed by winter wheat cultivar Arina providing 12-15 % reduction in stem rust severity, was reported in an Arina/Forno recombinant inbred line (RIL) population. Following the demonstration of monogenic segregation for APR in the Arina/Yitpi RIL population, the resistance locus was formally named Sr56. Saturation mapping of the Sr56 region using STS (from EST and DArT clones), SNP (9 K) and SSR markers from wheat chromosome survey sequences that were ordered based on synteny with Brachypodium distachyon genes in chromosome 1 resulted in the flanking of Sr56 by sun209 (SSR) and sun320 (STS) at 2.6 and 1.2 cM on the proximal and distal ends, respectively. Investigation of conservation of gene order between the Sr56 region in wheat and B. distachyon showed that the syntenic region defined by SSR marker interval sun209-sun215 corresponded to approximately 192 kb in B. distachyon, which contains five predicted genes. Conservation of gene order for the Sr56 region between wheat and Brachypodium, except for two inversions, provides a starting point for future map-based cloning of Sr56. The Arina/Forno RILs carrying both Sr56 and Sr57 exhibited low disease severity compared to those RILs carrying these genes singly. Markers linked with Sr56 would be useful for marker-assisted pyramiding of this gene with other major and APR genes for which closely linked markers are available.


High-resolution reconstruction of fluorescent inclusions in mouse thorax using anatomically guided sampling and parallel Monte Carlo computing.
We present a method for high-resolution reconstruction of fluorescent images of the mouse thorax. It features an anatomically guided sampling method to retrospectively eliminate problematic data and a parallel Monte Carlo software package to compute the Jacobian matrix for the inverse problem. The proposed method was capable of resolving microliter-sized femtomole amount of quantum dot inclusions closely located in the middle of the mouse thorax. The reconstruction was verified against co-registered micro-CT data. Using the proposed method, the new system achieved significantly higher resolution and sensitivity compared to our previous system consisting of the same hardware. This method can be applied to any system utilizing similar imaging principles to improve imaging performance.


Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402.
The rituximab extended schedule or retreatment trial (RESORT; E4402) was a phase 3 randomized prospective trial comparing maintenance rituximab (MR) versus a retreatment (RR) dosing strategy in asymptomatic, low tumour burden indolent lymphoma. A planned exploratory sub-study compared the two strategies for small lymphocytic (SLL) and marginal zone lymphomas (MZL). Patients responding to rituximab weekly × 4 were randomized to MR (single dose rituximab every 3 months until treatment failure) or RR (rituximab weekly × 4) at the time of each progression until treatment failure. The primary endpoint was time to treatment failure (TTTF). Patients with SLL (n = 57), MZL (n = 71) and unclassifiable small B-cell lymphoma (n = 3) received induction rituximab. The overall response rate (ORR) was 40% [95% confidence interval (CI) 31-49%; SLL ORR 22·8%; MZL ORR 52·1%]; all 52 responders were randomized. At a median of 4·3 years from randomization, treatment failure occurred in 18/23 RR and 15/29 MR. The median TTTF was 1·4 years for RR and 4·8 years for MR (P = 0·012); median time to first cytotoxic therapy was 6·3 years for RR and not reached for MR (P = 0·0002). Survival did not differ (P = 0·72). In low tumour burden SLL and MZL patients responding to rituximab induction, MR significantly improved TTTF as compared with RR.


Effects of hypothalamic lesions on the body temperature rhythm of the golden hamster.
The effects of electrolytic and neurotoxic lesions of the suprachiasmatic nucleus (SCN) and preoptic area (POA) of the anterior hypothalamus were studied by temperature telemetry in the golden hamster (Mesocricetus auratus) examined under two ambient temperature conditions: 24 degrees C and 6 degrees C. Although attempted lesions with microinjections of ibotenic acid proved unsuccessful, electrolytic lesions of the SCN eliminated the circadian rhythm of body temperature (CRT), indicating an active role of this nucleus in the establishment of the CRT. Electrolytic lesions of the POA, but not of the SCN, resulted in an increased amplitude of the CRT at both 24 degrees C and 6 degrees C, with the lower ambient temperature enhancing this amplitude change to a greater extent. These results suggest that the POA and the SCN are independently responsible for the homeostatic and circadian regulation of body temperature, respectively. The increased amplitude of the CRT after POA lesions raises the possibility that the thermoregulatory system may oppose rather than defend the circadian control of body temperature in normal animals, which is consistent with several recent behavioral findings.


Comparison of Rotation Force to Maintain Acetabular Ventroversion after Double Pelvic Osteotomy and 2.5 Pelvic Osteotomy in a Canine Cadaveric Model.
The aim of this article was to compare the force required to maintain the acetabular ventroversion after double pelvic osteotomy (DPO) and modified triple pelvic osteotomy (2.5PO). Unilateral DPO (group A) and unilateral modified DPO (group B = 2.5PO) were performed on cadaveric canine pelves (n = 10/group). The twisting moment required to maintain fragment position for DPO and 2.5DPO was compared. Mean twisting moment for the DPO group [5.92 N/m ± 2.59 (range, 2.61-12.17 N/m)] and the 2.5PO group [2.11 N/m ± 0.93 (range, 0.63 -3.85 N/m)] was significantly different (p < 0.01). Dorsal cortex osteotomy of the ischium decreases the acetabular segment rotation force. Decreased force may facilitate acetabular rotation during DPO procedure.


ADAR2 induces reproducible changes in sequence and abundance of mature microRNAs in the mouse brain.
Adenosine deaminases that act on RNA (ADARs) deaminate adenosines to inosines in double-stranded RNAs including miRNA precursors. A to I editing is widespread and required for normal life. By comparing deep sequencing data of brain miRNAs from wild-type and ADAR2 deficient mouse strains, we detect editing sites and altered miRNA processing at high sensitivity. We detect 48 novel editing events in miRNAs. Some editing events reach frequencies of up to 80%. About half of all editing events depend on ADAR2 while some miRNAs are preferentially edited by ADAR1. Sixty-four percent of all editing events are located within the seed region of mature miRNAs. For the highly edited miR-3099, we experimentally prove retargeting of the edited miRNA to novel 3' UTRs. We show further that an abundant editing event in miR-497 promotes processing by Drosha of the corresponding pri-miRNA. We also detect reproducible changes in the abundance of specific miRNAs in ADAR2-deficient mice that occur independent of adjacent A to I editing events. This indicates that ADAR2 binding but not editing of miRNA precursors may influence their processing. Correlating with changes in miRNA abundance we find misregulation of putative targets of these miRNAs in the presence or absence of ADAR2.


Doppler-based fetal heart rate analysis markers for the detection of early intrauterine growth restriction.
One indicator for fetal risk of mortality is intrauterine growth restriction (IUGR). Whether markers reflecting the impact of growth restriction on the cardiovascular system, computed from a Doppler-derived heart rate signal, would be suitable for its detection antenatally was studied. We used a cardiotocography archive of 1163 IUGR cases and 1163 healthy controls, matched for gestation and gender. We assessed the discriminative power of short-term variability and long-term variability of the fetal heart rate, computed over episodes of high and low variation aiming to separate growth-restricted fetuses from controls. Metrics characterizing the sleep state distribution within a trace were also considered for inclusion into an IUGR detection model. Significant differences in the risk markers comparing growth-restricted with healthy fetuses were found. When used in a logistic regression classifier, their performance for identifying IUGR was considerably superior before 34 weeks of gestation. Long-term variability in active sleep was superior to short-term variability [area under the receiver operator curve (AUC) of 72% compared with 71%]. Most predictive was the number of minutes in high variation per hour (AUC of 75%). A multivariate IUGR prediction model improved the AUC to 76%. We suggest that heart rate variability markers together with surrogate information on sleep states can contribute to the detection of early-onset IUGR.


Wingless effects mesoderm patterning and ectoderm segmentation events via induction of its downstream target sloppy paired.
Inactivation of either the secreted protein Wingless (Wg) or the forkhead domain transcription factor Sloppy Paired (Slp) has been shown to produce similar effects in the developing Drosophila embryo. In the ectoderm, both gene products are required for the formation of the segmental portions marked by naked cuticle. In the mesoderm, Wg and Slp activities are crucial for the suppression of bagpipe (bap), and hence visceral mesoderm formation, and the promotion of somatic muscle and heart formation within the anterior portion of each parasegment. In this report, we show that, during these developmental processes, wg and slp act in a common pathway in which slp serves as a direct target of Wg signals that mediates Wg effects in both germ layers. We present evidence that the induction of slp by Wg involves binding of the Wg effector Pangolin (Drosophila Lef-1/TCF) to multiple binding sites within a Wg-responsive enhancer that is located in 5' flanking regions of the slp1 gene. Based upon our genetic and molecular analysis, we conclude that Wg signaling induces striped expression of Slp in the mesoderm. Mesodermal Slp is then sufficient to abrogate the induction of bagpipe by Dpp/Tinman, which explains the periodic arrangement of trunk visceral mesoderm primordia in wild type embryos. Conversely, mesodermal Slp is positively required, although not sufficient, for the specification of somatic muscle and heart progenitors. We propose that Wg-induced slp provides striped mesodermal domains with the competence to respond to subsequent slp-independent Wg signals that induce somatic muscle and heart progenitors. We also propose that in wg-expressing ectodermal cells, slp is an integral component in an autocrine feedback loop of Wg signaling.


Reticular chemistry: occurrence and taxonomy of nets and grammar for the design of frameworks.
The structures of all 1127 three-periodic extended metal-organic frameworks (MOFs) reported in the Cambridge Structure Database have been analyzed, and their underlying topology has been determined. It is remarkable that among the almost infinite number of net topologies that are available for MOFs to adopt, only a handful of nets are actually observed. The discovery of this inversion between expected and observed nets led us to deduce a system of classification "taxonomy" for interpreting and rationalizing known MOF structures, as well as those that will be made in future. The origin of this inversion is attributed to the different modes with which MOF synthesis has been approached. Specifically, three levels of complexity are defined that embody rules "grammar" for the design of MOFs and other extended structures. This system accounts for the present proliferation of MOF structures of high symmetry nets, but more importantly, it provides the basis for designing a building block that "codes" for a specific structure and, indeed, only that structure.


Progress In Interoperability: Measuring US Hospitals' Engagement In Sharing Patient Data.
Achieving an interoperable health care system remains a top US policy priority. Despite substantial efforts to encourage interoperability, the first set of national data in 2014 suggested that hospitals' engagement levels were low. With 2015 data now available, we examined the first national trends in engagement in four domains of interoperability: finding, sending, receiving, and integrating electronic patient information from outside providers. We found small gains, with 29.7 percent of hospitals engaging in all four domains in 2015 compared to 24.5 percent in 2014. The two domains with the most progress were sending (with an increase of 8.1 percentage points) and receiving (an increase of 8.4 percentage points) information, while there was no change in integrating systems. Hospitals' use for patient care of data from outside providers was low, with only 18.7 percent of hospitals reporting that they "often" used these data. Our results reveal that hospitals' progress toward interoperability is slow and that progress is focused on moving information between hospitals, not on ensuring usability of information in clinical decisions.


Tissue-engineered lung: an in vivo and in vitro comparison of polyglycolic acid and pluronic F-127 hydrogel/somatic lung progenitor cell constructs to support tissue growth.
In this study, we describe the isolation and characterization of a population of adult-derived or somatic lung progenitor cells (SLPC) from adult mammalian lung tissue and the promotion of alveolar tissue growth by these cells (both in vitro and in vivo) after seeding onto synthetic polymer scaffolds. After extended in vitro culture, differentiating cells expressed Clara cell 10kDa protein, surfactant protein-C, and cytokeratin but did not form organized structures. When cells were combined with synthetic scaffolds, polyglycolic acid (PGA) or Pluronic F-127 (PF-127), and maintained in vitro or implanted in vivo, they expressed lung-specific markers for Clara cells, pneumocytes, and respiratory epithelium and organized into identifiable pulmonary structures (including those similar to alveoli and terminal bronchi), with evidence of smooth muscle development. Although PGA has been shown to be an excellent polymer for culture of specific cell types in vitro, in vivo culture in an immunocompetent host induced a foreign body response that altered the integrity of the developing lung tissue. Use of PF-127/cell constructs resulted in the development of tissue with less inflammatory reaction. These data suggest that the therapeutic use of engineered tissues requires both the use of specific cell phenotypes, as well as the careful selection of synthetic polymers, to facilitate the assembly of functional tissue.


Reducing hospital admissions in remote Australia through the establishment of a palliative and chronic disease respite facility.
There are limited respite services for palliative care patients and their families in the Northern Territory (NT). The high prevalence of complex chronic diseases, limited access to primary care services, and the poor living situations of many Aboriginal and Torres Strait Islander Australians result in high hospitalisation rates and pressure on tertiary health services. Palliative Care NT identified a need for a flexible, community based, culturally appropriate respite service in Alice Springs. It was of particular interest to assess the impact of the respite service on the extent to which hospital resources were accessed by this population of patients. Respite service use and hospital use data were collected over two time periods: the 12 months prior to the establishment of the service; and the first 10 months of the operation of the service. The financial implications of the facility were assessed in terms of the National Weighted Activity Unit (NWAU). Of primary interest in this study was the impact of the respite service on admissions to the Emergency Department (ED), to the Wards, and to the Intensive Care Unit (ICU). The amount of ventilator hours consumed was also of interest. Overall, there was a mean cost saving of $1882.50 per episode for hospital admissions with a reduction in: hospital admissions; mean length of stay; Intensive Care Unit (ICU) hours; and ventilator hours. The establishment of the respite service has met an important and unmet need in Alice Springs: provision of respite where none has existed before. The service did assist with savings to the health department which could contribute to the cost of the facility over time. Two features of the respite facility that may have contributed to the savings generated were the enhanced coordination of care for patients with complex chronic diseases, as well as improved medication compliance and symptom management.


Chronic blockade of CB(1) receptors reverses startle gating deficits and associated neurochemical alterations in rats reared in isolation.
Pharmacological interventions aimed at restoring the endocannabinoid system functionality have been proposed as potential tools in the treatment of schizophrenia. Based on our previous results suggesting a potential antipsychotic-like profile of the CB(1) receptor inverse agonist/antagonist, AM251, here we further investigated the effect of chronic AM251 administration on the alteration of the sensorimotor gating functions and endocannabinoid levels induced by isolation rearing in rats. Using the post-weaning social isolation rearing model, we studied its influence on sensorimotor gating functions through the PPI paradigm. The presence of alterations in the endocannabinoid levels as well as in dopamine and glutamate receptor densities was explored in specific brain regions following isolation rearing. The effect of chronic AM251 administration on PPI response and the associated biochemical alterations was assessed. The disrupted PPI response in isolation-reared rats was paralleled by significant alterations in 2-AG content and dopamine and glutamate receptor densities in specific brain regions. Chronic AM251 completely restored normal PPI response in isolated rats. This behavioural recovery was paralleled by the normalization of 2-AG levels in all the brain areas analysed. Furthermore, AM251 partially antagonized isolation-induced changes in dopamine and glutamate receptors. These results demonstrate the efficacy of chronic AM251 treatment in the recovery of isolation-induced disruption of PPI. Moreover, AM251 counteracted the imbalances in the endocannabinoid content, specifically 2-AG levels, and partially reversed the alterations in dopamine and glutamate systems associated with the disrupted behaviour. Together, these findings support the potential antipsychotic-like activity of CB(1) receptor blockade. This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.


Enhancing coparenting, parenting, and child self-regulation: effects of family foundations 1 year after birth.
This study investigated whether a psycho-educational program with modest dosage (eight sessions), delivered in a universal framework through childbirth education programs and targeting the coparenting relationship would have a positive impact on observed family interaction and child behavior at 6-month follow-up (child age 1 year). One hundred sixty-nine couples, randomized to intervention and control conditions, participated in videotaped family observation tasks at pretest (during pregnancy) and at child age 1 year (2003-2007). Coparenting, parenting, couple relationship, and child self-regulatory behaviors were coded by teams of raters. Intent-to-treat analyses of program effects controlled for age, education, and social desirability. Evidence of significant (p < 0.05) program effects at follow-up emerged in all four domains. Effect sizes ranged from 0.28 to 1.01. Targeting the coparenting relationship at the transition to parenthood represents an effective, non-stigmatizing means of promoting parenting quality and child adjustment.


Analysis of a marine picoplankton community by 16S rRNA gene cloning and sequencing.
The phylogenetic diversity of an oligotrophic marine picoplankton community was examined by analyzing the sequences of cloned ribosomal genes. This strategy does not rely on cultivation of the resident microorganisms. Bulk genomic DNA was isolated from picoplankton collected in the north central Pacific Ocean by tangential flow filtration. The mixed-population DNA was fragmented, size fractionated, and cloned into bacteriophage lambda. Thirty-eight clones containing 16S rRNA genes were identified in a screen of 3.2 x 10(4) recombinant phage, and portions of the rRNA gene were amplified by polymerase chain reaction and sequenced. The resulting sequences were used to establish the identities of the picoplankton by comparison with an established data base of rRNA sequences. Fifteen unique eubacterial sequences were obtained, including four from cyanobacteria and eleven from proteobacteria. A single eucaryote related to dinoflagellates was identified; no archaebacterial sequences were detected. The cyanobacterial sequences are all closely related to sequences from cultivated marine Synechococcus strains and with cyanobacterial sequences obtained from the Atlantic Ocean (Sargasso Sea). Several sequences were related to common marine isolates of the gamma subdivision of proteobacteria. In addition to sequences closely related to those of described bacteria, sequences were obtained from two phylogenetic groups of organisms that are not closely related to any known rRNA sequences from cultivated organisms. Both of these novel phylogenetic clusters are proteobacteria, one group within the alpha subdivision and the other distinct from known proteobacterial subdivisions. The rRNA sequences of the alpha-related group are nearly identical to those of some Sargasso Sea picoplankton, suggesting a global distribution of these organisms.


Effectiveness of hypnosis in reducing mild essential hypertension: a one-year follow-up.
The present study investigates the effectiveness of hypnosis in reducing mild essential hypertension. Thirty participants were randomly assigned to hypnosis (standardized, individual 8-session hypnosis treatment) or to a control group (no treatment). Results show that hypnosis is effective in reducing blood pressure in the short term but also in the middle and long terms. We did not find any relationship between the practice of self-hypnosis and the evolution of blood pressure or between anxiety, personality factors, and therapeutic results. The implications of the results of the psychological treatment of hypertension are discussed.


Factors associated with treatment response to etanercept in juvenile idiopathic arthritis.
Since the introduction of biologic therapies, the pharmacological treatment approach for juvenile idiopathic arthritis (JIA) has changed substantially, with achievement of inactive disease as a realistic goal. To determine the response to therapy after initiation of etanercept therapy among patients with JIA and to examine the association between baseline factors and response to etanercept treatment. The Arthritis and Biologicals in Children Register, an ongoing prospective observational study since 1999, includes all Dutch JIA patients who used biologic agents. All biologically naive patients who started etanercept before October 2009 were included, with follow-up data to January 2011. Among the 262 patients, 185 (71%) were female, 46 (18%) had systemic-onset, and the median age at initiation of etanercept treatment was 12.4 years. Excellent response (inactive disease or discontinuation earlier due to disease remission), intermediate response (more than 50% improvement from baseline, but no inactive disease), and poor response (less than 50% improvement from baseline or discontinuation earlier due to ineffectiveness or intolerance) evaluated 15 months after initiation of etanercept. At 15 months after treatment initiation, 85 patients (32%) were considered excellent responders; 92 (36%), intermediate responders; and 85 (32%), poor responders. Compared with an intermediate or poor response, an excellent response was associated with lower baseline disability score (range, 0-3 points, with 0 being the best score; adjusted odds ratio [OR] per point increase, 0.49; 95% CI, 0.33-0.74); fewer disease-modifying antirheumatic drugs (DMARD) (including methotrexate) used before initiating etanercept (adjusted OR per DMARD used, 0.64; 95% CI, 0.43-0.95), and younger age at onset (adjusted OR per year increase, 0.92; 95% CI, 0.84-0.99). Compared with an intermediate or excellent response, a poor response was associated with systemic JIA (adjusted OR systemic vs nonsystemic categories, 2.92; 95% CI, 1.26-6.80), and female sex (adjusted OR female vs male, 2.16; 95% CI, 1.12-4.18). Within the first 15 months of etanercept treatment, 119 patients experienced 1 or more infectious, noninfectious, or serious adverse events, including 37 among those with an excellent response, 36 with an intermediate response, and 46 with a poor response. Within the first 15 months of treatment, 61 patients discontinued etanercept treatment, including 4 with an excellent response, 0 with an intermediate response, and 57 with a poor response. In a secondary analysis of 262 patients with a median follow-up of 35.6 months after initiation of etanercept, a range of 37% to 49% of patients reached inactive disease. The mean adherence to etanercept was 49.2 months (95% CI, 46.4-52.0) for patients with an excellent response after 15 months, 47.5 months (95% CI, 44.9-50.1) for patients with an intermediate response, and 17.4 months (95% CI, 13.6-21.2) for patients with a poor response. Among patients with JIA who initiated treatment with etanercept, one-third achieved an excellent response, one-third an intermediate response, and one-third a poor response to therapy. Achievement of an excellent response was associated with low baseline disability scores, DMARDs used before initiating etanercept, and younger age at onset of JIA. Achievement of a poor treatment response was associated with systemic JIA and female sex.


Get your team to do what it says it's going to do.
It's one thing to set goals-and entirely another to get the people in your organization to actually accomplish them. To make the leap from vision to execution, you can't just define what needs doing; you also need to spell out the details of getting it done. One motivational tool that enables this is "if-then planning," which helps people express and carry out their intentions. If-then plans work because contingencies are built into our neurological wiring, says social psychologist Halvorson. Humans are very good at encoding information in "If x, then y" terms and using such connections to guide their behavior, often unconsciously. When people decide exactly when, where, and how they'll fulfill a goal, they create a link in their brains between the situation or cue (If or when x happens) and the behavior that should follow (then I will do y). This creates powerful triggers for action. To date, most of the research on if-then plans has focused on individuals, but new studies show that they're very effective with groups, improving performance by sharpening focus and prompting members to execute key activities in a timely manner. If-then planning helps organizations avoid poorly expressed goals, groupthink, the tendency to cling to lost causes, and other problems. It pinpoints conditions for success, increases everyone's sense of responsibility, and helps close the troublesome gap between knowing and doing.


Computational roles of plastic probabilistic synapses.
The probabilistic nature of synaptic transmission has remained enigmatic. However, recent developments have started to shed light on why the brain may rely on probabilistic synapses. Here, we start out by reviewing experimental evidence on the specificity and plasticity of synaptic response statistics. Next, we overview different computational perspectives on the function of plastic probabilistic synapses for constrained, statistical and deep learning. We highlight that all of these views require some form of optimisation of probabilistic synapses, which has recently gained support from theoretical analysis of long-term synaptic plasticity experiments. Finally, we contrast these different computational views and propose avenues for future research. Overall, we argue that the time is ripe for a better understanding of the computational functions of probabilistic synapses.


Prostate tumor-induced angiogenesis is blocked by exosomes derived from menstrual stem cells through the inhibition of reactive oxygen species.
Mesenchymal stem cells (MSCs) secrete exosomes that are capable of modifying the tumor environment through different mechanisms including changes in the cancer-cell secretome. This activity depends on their cargo content that is largely defined by their cellular origin. Endometrial cells are fine regulators of the angiogenic process during the menstrual cycle that includes an angiostatic condition that is associated with the end of the cycle. Hence, we studied the angiogenic activity of menstrual stem cells (MenSCs)-secreted exosomes on prostate PC3 tumor cells. Our results showed that exosomes induce a reduction in VEGF secretion and NF-κB activity. Lower reactive oxygen species (ROS) production in exosomes-treated cells was detected by the DCF method, suggesting that the inhibition of the intracellular ROS impacts both NF-κB and VEGF pathways. We confirmed using tubule formation and plug transplantation assays that MenSCs-exosomes suppress the secretion of pro-angiogenic factors by the PC3 cells in a ROS-dependent manner. The inhibition of the tumor angiogenesis and, consequently, the tumor growth was also confirmed using a xenograft mouse model. Additionally, the anti-tumoral effect was associated with a reduction of tumor hemoglobin content, vascular density and inhibition of VEGF and HIF-1α expression. Importantly, we demonstrate that the exosomes anti-angiogenic effect is specific to the menstrual cell source, as bone marrow MSCs-derived exosomes showed an opposite effect on the VEGF and bFGF expression in tumor cells. Altogether, our results indicate that MenSCs-derived exosomes acts as blockers of the tumor-induced angiogenesis and therefore could be suitable for anti-cancer therapies.


Resveratrol induces differentiation markers expression in anaplastic thyroid carcinoma via activation of Notch1 signaling and suppresses cell growth.
Anaplastic thyroid carcinoma (ATC) is an extremely aggressive malignancy with undifferentiated features, for which conventional treatments, including radioactive iodine ablation, are usually not effective. Recent evidence suggests that the Notch1 pathway is important in the regulation of thyroid cancer cell growth and expression of thyrocyte differentiation markers. However, drug development targeting Notch1 signaling in ATC remains largely underexplored. Previously, we have identified resveratrol out of over 7,000 compounds as the most potent Notch pathway activator using a high-throughput screening method. In this study, we showed that resveratrol treatment (10-50 μmol/L) suppressed ATC cell growth in a dose-dependent manner for both HTh7 and 8505C cell lines via S-phase cell-cycle arrest and apoptosis. Resveratrol induced functional Notch1 protein expression and activated the pathway by transcriptional regulation. In addition, the expression of thyroid-specific genes including TTF1, TTF2, Pax8, and sodium iodide symporter (NIS) was upregulated in both ATC cell lines with resveratrol treatment. Notch1 siRNA interference totally abrogated the induction of TTF1 and Pax8 but not of TTF2. Moreover, Notch1 silencing by siRNA decreased resveratrol-induced NIS expression. In summary, our data indicate that resveratrol inhibits cell growth and enhances redifferentiation in ATC cells dependent upon the activation of Notch1 signaling. These findings provide the first documentation for the role of resveratrol in ATC redifferentiation, suggesting that activation of Notch1 signaling could be a potential therapeutic strategy for patients with ATC and thus warrants further clinical investigation.


Surface characterization of poly(L-lactic acid)-methoxy poly(ethylene glycol) diblock copolymers by static and dynamic contact angle measurements, FTIR, and ATR-FTIR.
The surface composition and surface free energy properties of two types of amphiphilic and semicrystalline diblock copolymers consisting of poly(L-lactic acid) coupled to (methoxy poly(ethylene glycol) (PLLA-MePEG) having differing block lengths of PEG were investigated by using static and dynamic contact angle measurements, transmission Fourier infrared spectroscopy (FTIR), and attenuated total reflection spectroscopy (ATR-FTIR) and compared with results obtained from PLLA and MePEG homopolymers. The contact angle results were evaluated by using the van Oss-Good method (acid-base method), and it was determined that the Lewis base surface tension coefficient (gamma-) of the copolymers increased with an increase of the PEG molar content at the copolymer surface. This result is in good agreement with the transmission FTIR and ATR-FTIR results but not proportional to them, indicating that the surfaces of the copolymers are highly mobile and that the molecular rearrangement takes place upon contact with a polar liquid drop. The dynamic contact angle measurements showed that the strong acid-base interaction between the oxygen atoms in the copolymer backbone of the relatively more hydrophilic PEG segments with the Lewis acidic groups of the polar and hydrogen-bonding water molecules enabled the surface molecules to restructure (conformational change) at the contact area, so that the PEG segments moved upward, whereas the apolar methyl pendant groups of PLLA segments buried downward.


Fullerenol nanoparticles suppress RANKL-induced osteoclastogenesis by inhibiting differentiation and maturation.
Bone health requires regulation of homeostatic equilibrium between osteoblasts and osteoclasts. The over-activation of osteoclasts can disrupt bone metabolism, resulting in osteoporosis and other bone-loss diseases. Fullerenol, a polyhydroxy derivative of fullerene, exhibits excellent biocompatibility. Here we show that fullerenol nanoparticles exert two functions: inhibition of osteoclastic differentiation and blockage of pre-osteoclast fusion to restructure osteoclast maturation and function. Experimentally, the nanoparticles reduced pre-osteoclast migration and inhibited ruffled border formation to block their maturation. In addition, fullerenol dose-dependently restricted the differentiation of bone marrow macrophage cells (BMMs) to form osteoclasts following treatment with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor (NF)-κB (RANKL) to activate NF-κB and mitogen activating protein kinase (MAPK) signaling pathways. It is possible that the very small size of fullerenol allows it to directly cross the cellular membrane to access the cytoplasm and regulate osteoclastogenesis from BMMs. Our results suggest that fullerenol could be used to treat bone-loss diseases such as osteoporosis.


An updated evaluation of potential health hazards associated with exposures to asbestos-containing drywall accessory products.
Following a previously published (2012) evaluation of the potential health hazards related to the use of asbestos-containing drywall accessory products, additional information regarding asbestos exposures during the use of accessory products, as well as studies of chrysotile asbestos risk as a function of exposure, have been published in the peer-reviewed literature. The purpose of this analysis is to update the original evaluation with this new information. It was previously estimated that a professional drywaller performing joint compound-associated tasks could have a lifetime cumulative chrysotile exposure of 12-26 f/cc-year. Using conservative assumptions regarding airborne asbestos levels during different drywalling tasks, task duration, and job tenure, we found that a range of 4.3-36.3 f/cc-year is a plausible estimate of a career drywaller's cumulative asbestos exposure from historical joint compound use. The estimated range for bystander exposures would be below (sometimes significantly below) this range depending on the frequency and duration of work near drywallers. Further, the estimated drywaller and bystander total fiber exposures were well below a recently published "no-observed adverse effect level, best estimate" for predominately chrysotile exposures of 89-168 f/cc-year for lung cancer and 208-415 f/cc-year for mesothelioma. We also determined that, even if the chrysotile or possibly talc ingredients in the drywall products had contained asbestiform tremolite, the cumulative tremolite exposures would have been well below a recently published tremolite no-effect level of 0.5-2.6 f/cc-year. Based on our calculations, typical drywall work using asbestos-containing drywall accessory products is not expected to increase the risk of asbestos-related lung cancer or mesothelioma. These conclusions are consistent with the lack of epidemiological evidence that drywall work resulted in an increased incidence of asbestos-related disease in the drywall trades.


New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases.
The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.


Ideas and Spirit of the Balkan Cities Association of Nephrology, Dialysis, Transplantation and Artificial Organs (Bantao) Connect Nephrologists from the Balkan Cities - From the Foundation to the 15th Bantao Congress.
The Balkan Cities Association of Nephrology, Dialysis, Transplantation and Artificial Organs (BANTAO) was established in Ohrid, Republic of Macedonia on October 9, 1993 during the First Congress of the Macedonian Society of Nephrology, Dialysis, Transplantation and Artificial Organs (MSNDTAO). The idea of the founders was that such Society would have a clear impact on several aspects of practice and research in nephrology and artificial organs in the Balkans, firstly, by increasing its international visibility and potential collaborative work, and recognition by international organizations. Secondly, such a society would facilitate the exchange of experience and knowledge between experts in our area. In addition, it would be a very positive symbolic act showing that collaborative work for the betterment of life is possible and desirable in our area and that coming together will bear better fruits at the human and cultural levels. It will also send a very clear signal to the outside world that the Balkans can be a place of collaboration and mutual understanding. Several international bodies such as the International Society of Artificial Organs and the International Faculty of Artificial Organs have signaled their interest in and support for the creation of such a society. Despite the turbulent times in the Balkan Peninsula, the First BANTAO Congress was held in Varna from September 22 to 24, 1995, which was an impressive event. F. Valderrabano, Chairman of the EDTA-ERA registry reported on that event with a lot of sympathy in the paper entitled "Nephrologists of the Balkan countries meet across political frontiers and war fronts - an example to politicians. The foundation of and the Second Congress of BANTAO were also well accepted by the colleagues nephrologists from Russia. The Second Congress was held on September 6-10, 1997 in Struga, the Third BANTAO Congress was held on September 18-20, 1998 in Belgrade, the Fourth Congress of BANTAO was held in Izmir on November 14-16, 1999, the Fifth Congress of BANTAO was held in Thessaloniki on September 30 - October 3, 2001, the 6th BANTAO Congress was held in Varna, on October 6-9, 2003, the 7th BANTAO Congress was held in Ohrid, on September 8-11, 2005, the 8th BANTAO Congress was held in Belgrade, on September 16-19, 2007, the 9th BANTAO Congress was held in Antalya, November 18-22, 2009, the 10th BANTAO Congress was held in Chalkidiki, October 13-15, 2011, the 11th BANTAO Congress was held from 26 to 29 September 2013 in Timisoara on the 20th Anniversary of the foundation of BANTAO, the 12th BANTAO Congress was held on October 15-18, 2015 in Opatija, the 13th BANTAO Congress was held on 4-8 October, 2017 in Sarajevo, the 14th BANTAO Congress was held on September 20-23, 2018, in Budva and the 15th BANTAO Congress was held in Skopje, 26-29 September 2019. Another milestone in the life of BANTAO was the appearance of the BANTAO journal in 2003, which has been published biannually since then. In the past 17 years there have been 33 editions of the journal and seven supplements reporting BANTAO congresses. The editors of the journal past and present are: 2003-2005 (Dimitar Nenov); 2005-2009 (Ali Basci); 2009-(Goce Spasovski). Up to date, more than 400 papers have been published. The BANTAO journal is registered on EBSCO, DOAJ, SCOPUS, and has become a strong 'glue' among nephrologists from the Balkan cities. The BANTAO congresses and the BANTAO journal have succeeded in elevating nephrology knowledge and thus increased the standards of nephrology patient care throughout the Balkans. Standing above the divisive forces of politics, language and war, BANTAO gives a living example that collaboration and humility are feasible in times of maddening destruction, and are transformative.


Varenicline efficacy and safety among methadone maintained smokers: a randomized placebo-controlled trial.
To test the efficacy and safety of varenicline as an aid to smoking cessation in methadone-maintained smokers. Multicenter, randomized, double-blind, placebo-controlled trial with random assignment to 12 weeks of varenicline 1 mg twice daily (n = 57) or matched placebo (n = 55), with in-person and telephone counseling. Urban methadone programs in the Bronx, New York City, New York, USA. Methadone maintenance patients, smoking ≥5 cigarettes/day, interested in quitting, stable in methadone treatment, without current Axis I psychiatric disorders, suicidal ideation or recent suicide attempts. Seven-day point prevalence abstinence verified by expired carbon monoxide (CO) < 8 parts per million at week 12 (primary outcome); carbon monoxide (CO)-verified abstinence, cigarettes/day, incident Axis I psychiatric illness, suicidal ideation or serious adverse events (SAEs) at weeks 2, 4, 8, 12 or 24 (secondary outcomes). Baseline demographic, smoking and clinical factors were similar between groups. Retention at 24 weeks was 90%. Subjects receiving varenicline were more likely than those receiving placebo to achieve abstinence (10.5 versus 0%, P = 0.03; effect size 10.5%, 95% confidence interval (CI) = 4.4-19.3%) and to reduce smoking (median five versus two cigarettes/day, P < 0.001) at 12 weeks. These effects were not maintained after drug treatment ceased. Incident psychiatric illness (OR= 0.84, 95% CI = 0.16, 4.4) and suicidality [odds ratio (OR) = 0.88, 95% CI 0.2, 3.9] were not different between groups. There were no psychiatric or cardiac SAEs. Varenicline can aid short-term smoking abstinence in methadone-maintained smokers.


Caenorhabditis elegans glp-4 Encodes a Valyl Aminoacyl tRNA Synthetase.
Germline stem cell proliferation is necessary to populate the germline with sufficient numbers of cells for gametogenesis and for signaling the soma to control organismal properties such as aging. The Caenorhabditis elegans gene glp-4 was identified by the temperature-sensitive allele bn2 where mutants raised at the restrictive temperature produce adults that are essentially germ cell deficient, containing only a small number of stem cells arrested in the mitotic cycle but otherwise have a morphologically normal soma. We determined that glp-4 encodes a valyl aminoacyl transfer RNA synthetase (VARS-2) and that the probable null phenotype is early larval lethality. Phenotypic analysis indicates glp-4(bn2ts) is partial loss of function in the soma. Structural modeling suggests that bn2 Gly296Asp results in partial loss of function by a novel mechanism: aspartate 296 in the editing pocket induces inappropriate deacylation of correctly charged Val-tRNA(val). Intragenic suppressor mutations are predicted to displace aspartate 296 so that it is less able to catalyze inappropriate deacylation. Thus glp-4(bn2ts) likely causes reduced protein translation due to decreased levels of Val-tRNA(val). The germline, as a reproductive preservation mechanism during unfavorable conditions, signals the soma for organismal aging, stress and pathogen resistance. glp-4(bn2ts) mutants are widely used to generate germline deficient mutants for organismal studies, under the assumption that the soma is unaffected. As reduced translation has also been demonstrated to alter organismal properties, it is unclear whether changes in aging, stress resistance, etc. observed in glp-4(bn2ts) mutants are the result of germline deficiency or reduced translation.


Lack of gene amplification as a mechanism of CDK4 activation in human neuroblastoma.
Neuroblastoma is the most frequent solid tumor in childhood. We have analysed 48 neuroblastomas of different stages and degrees of cellular differentiation for CDK4 amplification by a fluorescent differential PCR assay. We explored the relative densitometric measure of a 119 bp fragment of the CDK4 gene versus an 82 bp fragment of the IFNG gene. We were not able to detect any case of CDK4 gene amplification in the neuroblastomas. In conclusion, CDK4 activation does not seem to be relevant to the development of neuroblastomas, at least through gene amplification.


Animals in the Zika Virus Life Cycle: What to Expect from Megadiverse Latin American Countries.
Zika virus (ZIKV) was first isolated in 1947 in primates in Uganda, West Africa. The virus remained confined to the equatorial regions of Africa and Asia, cycling between infecting monkeys, arboreal mosquitoes, and occasionally humans. The ZIKV Asiatic strain was probably introduced into Brazil in or around late 2013. Presently, ZIKV is in contact with the rich biodiversity in all Brazilian biomes, bordering on other Latin American countries. Infections in Brazilian primates have been reported recently, but the overall impact of this virus on wildlife in the Americas is still unknown. The current epidemic in the Americas requires knowledge on the role of mammals, especially nonhuman primates (NHPs), in ZIKV transmission to humans. The article discusses the available data on ZIKV in host animals and issues of biodiversity, rapid environmental change, and impact on human health in megadiverse Latin American countries. The authors reviewed scientific articles and recent news stories on ZIKV in animals, showing that 47 animal species from three orders (mammals, reptiles, and birds) have been investigated for the potential to establish a sylvatic cycle. The review aims to contribute to epidemiological studies and the knowledge on the natural history of ZIKV. The article concludes with questions that require urgent attention in epidemiological studies involving wildlife in order to understand their role as ZIKV hosts and to effectively control the epidemic.


A longitudinal twin study of the association between childhood autistic traits and psychotic experiences in adolescence.
This twin study investigated whether autistic traits during childhood were associated with adolescent psychotic experiences. Data were collected from a community sample of approximately 5000 twin pairs, which included 32 individuals with diagnosed autism spectrum conditions (ASC). Parents rated autistic traits in the twins at four points between ages 8-16 years. Positive, negative, and cognitive psychotic experiences were assessed at age 16 years using self- and parent-report scales. Longitudinal twin analyses tested the associations between these measures. Autistic traits correlated weakly or nonsignificantly with positive psychotic experiences (paranoia, hallucinations, and grandiosity), and modestly with cognitive psychotic experiences (cognitive disorganisation). Higher correlations were observed for parent-rated negative symptoms and self-reported anhedonia, although the proportion of variance in both accounted for by autistic traits was low (10 and 31 %, respectively). The majority of the genetic influences on negative symptoms and anhedonia were independent of autistic traits. Additionally, individuals with ASC displayed significantly more negative symptoms, anhedonia, and cognitive disorganisation than controls. Autistic traits do not appear to be strongly associated with psychotic experiences in adolescence; associations were also largely restricted to negative symptoms. Of note, the degree to which the genetic and environmental causes of autistic traits influenced psychotic experiences was limited. These findings thus support a phenotypic and etiological distinction between autistic traits and psychotic experiences.


Copy-number variation of cancer-gene orthologs is sufficient to induce cancer-like symptoms in Saccharomyces cerevisiae.
Copy-number variation (CNV), rather than complete loss of gene function, is increasingly implicated in human disease. Moreover, gene dosage is recognised as important in tumourigenesis, and there is an increasing realisation that CNVs may not be just symptomatic of the cancerous state but may, in fact, be causative. However, the identification of CNV-related phenotypes for mammalian genes is a slow process, due to the technical difficulty of constructing deletion mutants. Using the genome-wide deletion library for the model eukaryote, Saccharomyces cerevisiae, we have identified genes (termed haploproficient, HP) which, when one copy is deleted from a diploid cell, result in an increased rate of proliferation. Since haploproficiency under nutrient-sufficient conditions is a novel phenotype, we sought here to characterise a subset of the yeast haploproficient genes which seem particularly relevant to human cancers. We show that, for a subset of HP genes, heterozygous deletion is sufficient to cause aberrant cell cycling and altered rates of apoptosis, phenotypes associated with cancer in mammalian cells. A majority of these yeast genes are the orthologs of mammalian cancer genes, and hence our studies suggest that CNV of these oncogenic orthologs may be sufficient to lead to tumourigenesis in human cells. Moreover, where not already implicated, this cluster of cancer-like phenotypes in this model eukaryote may be predictive of the involvement in cancer of the mammalian orthologs of these yeast HP genes. Using the yeast set as a model, we show that the response to a range of anti-cancer drugs is strongly dependent on gene dosage, such that intermediate concentrations of the drugs can actually increase a mutant's growth rate. The exploitation of data on the phenotypic impact of heterozygosis in Saccharomyces cerevisiae has permitted the prediction of CNVs affecting tumourigenesis in humans. Our yeast data also suggest that the identification of CNVs in tumour cells may assist both the selection of anti-cancer drugs and the dosages at which they should be administered if they are to be a beneficial, rather than a deleterious, therapy.


G6PD gene variants and its association with malaria in a Sri Lankan population.
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that plays an important role in many cellular functions. Deficiency of this enzyme results from point mutations in the coding region of the G6PD gene. G6PD-deficiency is important in malaria, as certain anti-malarial drugs could induce haemolysis in such patients and mutations in this gene may influence the susceptibility or resistance to the disease. Detailed information on genetic variations in the G6PD gene for Sri Lankan populations is yet to be revealed. This study describes a set of G6PD mutations present in a Sri Lankan population and their association with uncomplicated malaria. DNA was extracted from 1,051 individuals. Sixty-eight SNPs in the region of the G6PD gene were genotyped. A database created during the 1992-1993 malaria epidemic for the same individuals was used to assess the associations between the G6PD SNPs and parasite density or disease severity of uncomplicated malaria infections. Linkage disequilibrium for SNPs and haplotype structures were identified. Seventeen genetic variants were polymorphic in this population. The mutant allele was the major allele in 9 SNPs. Common G6PD variants already described in Asians or South-Asians seemed to be absent or rare in this population. Both the severity of disease in uncomplicated malaria infections and parasitaemia were significantly lower in males infected with Plasmodium falciparum carrying the ancestral allele of rs915942 compared to those carrying the mutant allele. The parasite density of males infected with P. falciparum was significantly lower also in those who possessed the mutant alleles of rs5986877, rs7879049 and rs7053878. Two haplotype blocks were identified, where the recombination rates were higher in males with no history of malaria when compared to those who have experienced the disease in the past. This is the most detailed survey of G6PD SNPs in a Sri Lankan population undertaken so far that enabled novel description of single nucleotide polymorphisms within the G6PD gene. A few of these genetic variations identified, demonstrated a tendency to be associated with either disease severity or parasite density in uncomplicated disease in males. Known G6PD gene polymorphisms already described from elsewhere were either absent or rare in the local study population.


EpiFloripa Aging cohort study: methods, operational aspects, and follow-up strategies.
To describe the sample plan, operational aspects, and strategies used in the 2009/2010 and 2013/2014 EpiFloripa Aging Study. The EpiFloripa Aging is a population-based longitudinal study with 1,705 older adults (60 years or more) living in the municipality of Florianópolis, State of Santa Catarina, Brazil, in 2009/2010 (baseline). The research was conducted with a face-to-face interviews, organized into blocks of identification, socioeconomic, mental health, health and life habits, global functionality, falls, physical activity, morbidities, use of health services, use of medications, food, oral health, and violence, evaluated in the first (2009/2010) and in the second wave (2013/2014). Additionally, in the second wave, we investigated the issue of discrimination and quality of life. The response rate of the first wave was 89.2% (n = 1,705). The baseline sample, with predominance of women (63.9%), was similar to the 2010 Census regarding age for women and slightly different for younger men. In the second wave, 1,197 participants were interviewed (response rate of 70.3%). Follow-up losses were only observed for the variable age group (p = 0.003), and predominantly for those aged 80 years or more. Mortality data linkage and active search for participants were used as a follow-up strategies. This study used strategies that were able to help locate the participants and maintain adherence, which ensured a good response rate during investigations.


A Comprehensive Analysis of the Small GTPases Ypt7 Involved in the Regulation of Fungal Development and Secondary Metabolism in Monascus ruber M7.
Ypts (yeast protein transports),also called as ras-associated binding GTPases (Rab), are the largest group of the small GTPases family, which have been extensively studied in model eukaryotic cells and play a pivotal role in membane trafficking, while this study showed potential regulation role of Ypts in fungi. One of Ypts, Ypt7 may be involved in fungal development and secondary metabolism, but the exact mechanism still exists a controversy. In current study, the functions of a Monascus ypt7 homologous gene (mrypt7) from Monascus ruber M7 was investigated by combination of gene-deletion (Δmrypt7), overexpression (M7::PtrpC-mrypt7) and transcriptome analysis. Results showed that the radial growth rate of Δmrypt7 was significantly slower than M. ruber M7, little conidia and ascospores can be observed in Δmrypt7, but the yield of intracellular secondary metabolites was dramatically increased. Simultaneously, the mrypt7 overexpression strain possessed similar capacity for sporulation and secondary metabolism observed in M. ruber M7. Transcriptome results further illustrated that mrypt7 could coordinate with numerous genes involved in the vegetative growth, conidiogenesis, secondary metabolism biosynthesis and transportation of M. ruber M7. Combined with the similar effect of Ypt7 homologs on other fungi, we propose that Ypt7 works more like a global regulatory factor in fungi. To our knowledge, it is the first time to investigate Ypt7 functions in Monascus. It could also improve the understanding of Ypt7 functions in fungi.