Description of Campylobacter curvus and C. curvus-like strains associated with sporadic episodes of bloody gastroenteritis and Brainerd's diarrhea.
Campylobacter curvus is a rarely encountered Campylobacter species in human, animal, and environmental samples. During the course of two investigations, one involving a search for possible bacterial agents causing bloody gastroenteritis and a second concerning a small outbreak of Brainerd's diarrhea in northern California, 20 strains of C. curvus or C. curvus-like organisms were isolated by a microfiltration technique and prolonged incubation. The results suggest that C. curvus may be an underappreciated Campylobacter that may be involved in sporadic and outbreak cases of bloody or chronic diarrhea in humans.


Coronary dominance and prognosis in patients undergoing coronary computed tomographic angiography: results from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry.
Coronary computed tomographic angiography (CCTA) has become an important tool for non-invasive diagnosis of coronary artery disease (CAD). Coronary dominance can be assessed by CCTA; however, the predictive value of coronary dominance is controversially discussed. The aim of this study was to evaluate the prevalence and prognosis of coronary dominance in a large prospective, international multicentre cohort of patients undergoing CCTA. The study population consisted of 6382 patients with or without CAD (47% females, 53% males, mean age 56.9 ± 12.3 years) who underwent CCTA and were followed over a period of 60 months. Right or left coronary dominance was determined. Right dominance was present in 91% (n = 5817) and left in 9% (n = 565) of the study population. At the end of follow-up, outcome in patients with obstructive CAD (>50% luminal stenosis) and right dominance was similar compared with patients with left dominance [hazard ratio (HR) 0.46, 95% CI 0.16-1.32, P = 0.15]. Furthermore, no differences were observed for the type of coronary dominance in patients with non-obstructive CAD (HR 0.95, 95% CI 0.41-2.21, P = 0.8962) or normal coronary arteries (HR 1.04, 95% CI 0.68-1.59, P = 0.9). Subgroup analysis in patients with left main disease revealed an elevated hazard of the combined endpoint for left dominance (HR 6.45, 95% CI 1.66-25.0, P = 0.007), but not for right dominance. In our study population, survival after 5 years of follow-up did not differ significantly between patients with left or right coronary dominance. Thus, assessment of coronary vessel dominance by CCTA may not enhance risk stratification in patients with normal coronary arteries or obstructive CAD, but may add prognostic information for specific subpopulations.


A qualitative systematic review of patients' experience of osteoporosis using meta-ethnography.
We aimed to systematically review qualitative studies exploring the experience of living with osteoporosis to develop new conceptual understanding. We identified themes about the invisibility/visibility of osteoporosis, the experience of uncertainty of living with osteoporosis (OP) and living with an ageing body and the place of gender. The aim of this review was to systematically review the body of qualitative studies exploring the experience of living with either osteoporosis or osteopenia and to use meta-ethnography to develop new conceptual understanding. We systematically reviewed and integrated the findings of qualitative research from four bibliographic databases (Medline, Embase, Cinahl, Psychinfo) to September 2015 in order to increase our conceptual understanding of the lived experience of osteoporosis and osteopenia. Articles were appraised for quality; each was independently read by two researchers to identify concepts which were compared and developed into a conceptual model. Our findings demonstrate that coming to terms with a diagnosis of osteoporosis is linked to its relative visibility or invisibility. For some, OP has not become manifest and self-identity is intact (biographical integrity). For others, OP is profoundly manifest and self-identity is no long intact (biographical fracture). We also demonstrate that overwhelming uncertainty pervades the experience of OP. Our final theme demonstrates how the experience of OP is set within a cultural context with certain views about ageing and gender. Our synthesis has highlighted the wealth of qualitative data about osteoporosis and osteopenia. Despite the increasing body of literature on the subject, there remains a need to adjust our interactions with patients. This will allow clinicians to understand how patients can be helped to receive and understand their diagnosis and move forward in partnership with healthcare providers to promote optimal management of the disease.


Automated planar electrode electrophysiology in drug discovery: examples of the use of QPatch in basic characterization and high content screening on Na(v), K(Ca)2.3, and K(v)11.1 channels.
Planar chip technology has strongly facilitated the progress towards fully automated electrophysiological systems that, in contrast to the traditional patch clamp technology, have the capability of parallel compound testing. The throughput has been increased from testing below 10 compounds per day to a realized capacity approaching high throughput levels. Many pharmaceutical companies have implemented automated planar chip electrophysiology in their drug discovery process, particularly at the levels of lead optimization, secondary screening and safety testing, whereas primary screening is generally not performed. In this review, we briefly discuss the technology and give examples from selected NeuroSearch ion channel programs, where one of the systems, the QPatch, has been evaluated for use in lead optimization and primary screening campaigns, where high information content was a requirement.


Videoconferencing to reduce stress among hospitalized children.
Family-Link is a videoconferencing program that allows hospitalized children and their parents to virtually visit family members and friends using laptops, webcams, and a secure Wi-Fi connection. We evaluated the association of Family-Link use on the reduction in stress experienced by children during hospitalization. We offered Family-Link to pediatric patients who had an expected length of hospitalization equal to or greater than 4 days. We measured the stress levels of hospitalized children at admission and discharge using the previously published Parental Stress Survey. We used propensity score matching and multivariable linear regression methods to evaluate the relationship between the use of Family-Link and stress experienced by children during hospitalization. We included a total of 367 children in the study: 232 Family-Link users and 135 non-Family-Link users. Using the propensity score matching method, we found that the use of Family-Link was significantly associated with a greater reduction in overall mean stress compared with non-Family-Link users among the cohort of patients who lived closer to the hospital and had shorter lengths of hospitalization (β = 0.23; 95% confidence interval, 0.03 to 0.43; P < .05). In this cohort, the reduction in overall mean stress was 37% greater among Family-Link users than non-Family-Link users. The use of videoconferencing by some hospitalized children and families to conduct virtual visits with family and friends outside of the hospital was associated with a greater reduction in stress during hospitalization than those who did not use videoconferencing.


Optical sensor nanoparticles in artificial sediments--a new tool to visualize O2 dynamics around the rhizome and roots of seagrasses.
Seagrass communities provide important ecosystems services in coastal environments but are threatened by anthropogenic impacts. Especially the ability of seagrasses to aerate their below-ground tissue and immediate rhizosphere to prevent sulfide intrusion from the surrounding sediment is critical for their resilience to environmental disturbance. There is a need for chemical techniques that can map the O2 distribution and dynamics in the seagrass rhizosphere upon environmental changes and thereby identify critical stress thresholds of e.g. water flow, turbidity, and O2 conditions in the water phase. In a novel experimental approach, we incorporated optical O2 sensor nanoparticles into a transparent artificial sediment matrix consisting of pH-buffered deoxygenated sulfidic agar. Seagrass growth and photosynthesis was not inhibited in the experimental setup when the below-ground biomass was immobilized in the artificial sulfidic sediment with nanoparticles and showed root growth rates (∼ 5 mm day(-1)) and photosynthetic quantum yields (∼ 0.7) comparable to healthy seagrasses in their natural habitat. We mapped the real-time below ground O2 distribution and dynamics in the whole seagrass rhizosphere during experimental manipulation of light exposure and O2 content in the overlaying water. Those manipulations showed that oxygen release from the belowground tissue is much higher in light as compared to darkness and that water column hypoxia leads to diminished oxygen levels around the rhizome/roots. Oxygen release was visualized and analyzed on a whole rhizosphere level, which is a substantial improvement to existing methods relying on point measurements with O2 microsensors or partial mapping of the rhizosphere in close contact with a planar O2 optode. The combined use of optical nanoparticle-based sensors with artificial sediments enables imaging of chemical microenvironments in the rhizosphere of aquatic plants at high spatiotemporal resolution with a relatively simple experimental setup and thus represents a significant methodological advancement for studies of environmental impacts on aquatic plant ecophysiology.


Identification of drug targets by chemogenomic and metabolomic profiling in yeast.
To advance our understanding of disease biology, the characterization of the molecular target for clinically proven or new drugs is very important. Because of its simplicity and the availability of strains with individual deletions in all of its genes, chemogenomic profiling in yeast has been used to identify drug targets. As measurement of drug-induced changes in cellular metabolites can yield considerable information about the effects of a drug, we investigated whether combining chemogenomic and metabolomic profiling in yeast could improve the characterization of drug targets. We used chemogenomic and metabolomic profiling in yeast to characterize the target for five drugs acting on two biologically important pathways. A novel computational method that uses a curated metabolic network was also developed, and it was used to identify the genes that are likely to be responsible for the metabolomic differences found. The combination of metabolomic and chemogenomic profiling, along with data analyses carried out using a novel computational method, could robustly identify the enzymes targeted by five drugs. Moreover, this novel computational method has the potential to identify genes that are causative of metabolomic differences or drug targets.


ERRγ is not required for skeletal development but is a RUNX2-dependent negative regulator of postnatal bone formation in male mice.
To assess the effects of the orphan nuclear Estrogen receptor-related receptor gamma (ERRγ) deficiency on skeletal development and bone turnover, we utilized an ERRγ global knockout mouse line. While we observed no gross morphological anomalies or difference in skeletal length in newborn mice, by 8 weeks of age ERRγ +/- males but not females exhibited increased trabecular bone, which was further increased by 14 weeks. The increase in trabecular bone was due to an increase in active osteoblasts on the bone surface, without detectable alterations in osteoclast number or activity. Consistent with the histomorphometric results, we observed an increase in gene expression of the bone formation markers alkaline phosphatase (Alp) and bone sialoprotein (Bsp) in bone and increase in serum ALP, but no change in the osteoclast regulators receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) or the resorption marker carboxy-terminal collagen crosslinks (CTX). More colony forming units-alkaline phosphatase and -osteoblast (CFU-ALP, CFU-O respectively) but not CFU-fibroblast (CFU-F) formed in ERRγ +/- versus ERRγ +/+ stromal cell cultures, suggesting that ERRγ negatively regulates osteoblast differentiation and matrix mineralization but not mesenchymal precursor number. By co-immunoprecipitation experiments, we found that ERRγ and RUNX2 interact in an ERRγ DNA binding domain (DBD)-dependent manner. Treatment of post-confluent differentiating bone marrow stromal cell cultures with Runx2 antisense oligonucleotides resulted in a reduction of CFU-ALP/CFU-O in ERRγ +/- but not ERRγ +/+ mice compared to their corresponding sense controls. Our data indicate that ERRγ is not required for skeletal development but is a sex-dependent negative regulator of postnatal bone formation, acting in a RUNX2- and apparently differentiation stage-dependent manner.


Inherited p53 gene mutations in breast cancer.
Recent evidence has implicated germ-line mutations of the p53 gene as the cause of cancer susceptibility in the Li-Fraumeni syndrome, associated with the development of breast cancer and other neoplasms. Furthermore, somatic mutations of the p53 gene have been detected in a high percentage of non-familial breast cancers. We therefore sought to identify potential carriers of p53 gene mutations in a cohort of patients with early onset breast cancer. We examined 126 consecutive patients who developed breast cancer at or before the age of 40 for mutations of p53 within conserved regions of the gene. One patient with an inherited germ-line mutation of the p53 gene was identified but the functional significance of this mutation was not clear. It thus appears that only a small percentage of patients with breast cancer under the age of 40 carry germ-line mutations of the p53 gene, an observation which has implications for potential screening and risk assessment in such patients.


Single photon emission computed tomography (SPECT) of anxiety disorders before and after treatment with citalopram.
Several studies have now examined the effects of selective serotonin reuptake inhibitor (SSRI) treatment on brain function in a variety of anxiety disorders including obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and social anxiety disorder (social phobia) (SAD). Regional changes in cerebral perfusion following SSRI treatment have been shown for all three disorders. The orbitofrontal cortex (OFC) (OCD), caudate (OCD), medial pre-frontal/cingulate (OCD, SAD, PTSD), temporal (OCD, SAD, PTSD) and, thalamic regions (OCD, SAD) are some of those implicated. Some data also suggests that higher perfusion pre-treatment in the anterior cingulate (PTSD), OFC, caudate (OCD) and antero-lateral temporal region (SAD) predicts subsequent treatment response. This paper further examines the notion of overlap in the neurocircuitry of treatment and indeed treatment response across anxiety disorders with SSRI treatment. Single photon emission computed tomography (SPECT) using Tc-99 m HMPAO to assess brain perfusion was performed on subjects with OCD, PTSD, and SAD before and after 8 weeks (SAD) and 12 weeks (OCD and PTSD) treatment with the SSRI citalopram. Statistical parametric mapping (SPM) was used to compare scans (pre- vs post-medication, and responders vs non-responders) in the combined group of subjects. Citalopram treatment resulted in significant deactivation (p = 0.001) for the entire group in the superior (t = 4.78) and anterior (t = 4.04) cingulate, right thalamus (t = 4.66) and left hippocampus (t = 3.96). Deactivation (p = 0.001) within the left precentral (t = 4.26), right mid-frontal (t = 4.03), right inferior frontal (t = 3.99), left prefrontal (3.81) and right precuneus (t= 3.85) was more marked in treatment responders. No pattern of baseline activation distinguished responders from non-responders to subsequent pharmacotherapy. Although each of the anxiety disorders may be mediated by different neurocircuits, there is some overlap in the functional neuro-anatomy of their response to SSRI treatment. The current data are consistent with previous work demonstrating the importance of limbic circuits in this spectrum of disorders. These play a crucial role in cognitive-affective processing, are innervated by serotonergic neurons, and changes in their activity during serotonergic pharmacotherapy seem crucial.


Systematic review of statistics on causes of deaths in hospitals: strengthening the evidence for policy-makers.
To systematically review the reliability of hospital data on cause of death and encourage periodic reviews of these data using a standard method. We searched Google Scholar, Pubmed and Biblioteca Virtual de la Salud for articles in English, Spanish and Portuguese that reported validation studies of data on cause of death. We analysed the results of 199 studies that had used medical record reviews to validate the cause of death reported on death certificates or by the vital registration system. The screened studies had been published between 1983 and 2013 and their results had been reported in English (n = 124), Portuguese (n = 25) or Spanish (n = 50). Only 29 of the studies met our inclusion criteria. Of these, 13 had examined cause of death patterns at the population level - with a view to correcting cause-specific mortality fractions - while the other 16 had been undertaken to identify discrepancies in the diagnosis for specific diseases before and after medical record review. Most of the selected studies reported substantial misdiagnosis of causes of death in hospitals. There was wide variation in study methodologies. Many studies did not describe the methods used in sufficient detail to be able to assess the reproducibility or comparability of their results. The assumption that causes of death are being accurately reported in hospitals is unfounded. To improve the reliability and usefulness of reported causes of death, national governments should do periodic medical record reviews to validate the quality of their hospital cause of death data, using a standard.


Bioresorbable silicon electronics for transient spatiotemporal mapping of electrical activity from the cerebral cortex.
Bioresorbable silicon electronics technology offers unprecedented opportunities to deploy advanced implantable monitoring systems that eliminate risks, cost and discomfort associated with surgical extraction. Applications include postoperative monitoring and transient physiologic recording after percutaneous or minimally invasive placement of vascular, cardiac, orthopaedic, neural or other devices. We present an embodiment of these materials in both passive and actively addressed arrays of bioresorbable silicon electrodes with multiplexing capabilities, which record in vivo electrophysiological signals from the cortical surface and the subgaleal space. The devices detect normal physiologic and epileptiform activity, both in acute and chronic recordings. Comparative studies show sensor performance comparable to standard clinical systems and reduced tissue reactivity relative to conventional clinical electrocorticography (ECoG) electrodes. This technology offers general applicability in neural interfaces, with additional potential utility in treatment of disorders where transient monitoring and modulation of physiologic function, implant integrity and tissue recovery or regeneration are required.


Misidentification of mental health symptoms in presence of organic diseases and delirium during psychiatric liaison consulting.
To identify predictors of misidentification of organic mental disorders and delirium in patients undergoing psychiatric liaison consultation. Data were collected at Santa Casa de São Paulo between July of 2009 and March of 2013. We included in our analysis all inpatients for whom the requesting service judged that a psychiatric consultation was required for a possible mental health condition. Outcomes of interest were the instances of misidentification where a condition was initially deemed to be of a psychiatric nature, whereas the final diagnosis by the liaison psychiatric team was of an organic disease or delirium. Our predictors were the clinical specialty of the requesting service, requester and patient characteristics. A series of generalised linear models were used to evaluate misidentification risks. A total of 947 subjects met our inclusion criteria, 14.6% having a final liaison diagnosis of organic mental disorder and 8.1% of delirium. Older patients were significantly associated with increased risk of misidentification for both organic conditions (OR 3.01 - 95% CI 2.01, 4.5) and delirium (OR 3.92 - 2.4, 6.39). Educational interventions in general hospitals focused on preventing psychiatric misdiagnosis should target in-hospital services where patients tend to be older.


PPARgamma in human and mouse physiology.
The peroxisome proliferator activated receptor gamma (PPARgamma) is a member in the nuclear receptor superfamily which mediates part of the regulatory effects of dietary fatty acids on gene expression. As PPARgamma also coordinates adipocyte differentiation, it is an important component in storing the excess nutritional energy as fat. Our genes have evolved into maximizing energy storage, and PPARgamma has a central role in the mismatch between our genes and our affluent western society which results in a broad range of metabolic disturbances, collectively known as the metabolic syndrome. A flurry of human and mouse studies has shed new light on the mechanisms how the commonly used insulin sensitizer drugs and PPARgamma activators, thiazolidinediones, act, and which of their physiological effects are dependent of PPARgamma. It is now evident that the full activation of PPARgamma is less advantageous than targeted modulation of its activity. Furthermore, new roles for PPARgamma signaling have been discovered in inflammation, bone morphogenesis, endothelial function, cancer, longevity, and atherosclerosis, to mention a few. Here we draw together and discuss these recent advances in the research into PPARgamma biology.


Cigarette Smoking, Coffee Consumption, Alcohol Intake, and Risk of Crohn's Disease and Ulcerative Colitis: A Mendelian Randomization Study.
Crohn's disease (CD) and ulcerative colitis (UC) are widely associated with smoking in epidemiological studies, whereas there are conflicting results for the association between CD and UC for both coffee and alcohol consumption. Herein, we aimed to investigate whether cigarette smoking and alcohol and coffee consumption are causally associated with either CD or UC. We utilized 540 genome-wide significant single-nucleotide polymorphisms for 3 potentially addictive substances-nicotine, alcohol, and caffeine-to assess the association of smoking, coffee, and alcohol consumption with CD and UC (12,194 CD cases, 12,366 UC cases, and 25,042 controls of European ancestry), using Mendelian randomization analysis. Mendelian randomization estimates were used to evaluate the effect of the exposure factors on CD and UC risk. Sensitivity analysis was employed to test for any directional pleiotropy. We found evidence for a positive causal association between the age of smoking initiation and UC risk and between alcohol consumption and CD risk, which disappeared after sensitivity analysis for both associations (P > 0.05). No evidence for a causal association between cigarettes per day, smoking initiation, smoking cessation, and coffee consumption variables and UC or CD was found. We found no clear evidence that either genetically predicted smoking, coffee consumption, or alcohol consumption are causally associated with the risk for CD or UC, although our findings indicate a potential positive association between the age of smoking and UC and between alcohol consumption and CD.


Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.
Alzheimer's disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.


The Effect of Systemic Steroid on Hearing Preservation After Cochlear Implantation via Round Window Approach: A Guinea Pig Model.
When administered perioperatively, systemic dexamethasone will reduce the hearing loss associated with cochlear implantation (CI) performed via the round window approach. The benefits of electroacoustic stimulation have led to interest in pharmacological interventions to preserve hearing after CI. Thirty guinea pigs were randomly divided into three experimental groups: a control group; a 3-day infusion group; and a 7-day infusion group. Dexamethasone was delivered via a mini-osmotic pump for either 3 or 7 days after CI via the round window. Pure tone-evoked auditory brainstem response (ABR) thresholds were monitored for a period of 12 weeks after CI. The cochleae were then collected for histology. At 4 and 12 weeks after CI, ABR threshold shifts were significantly reduced in both 7-day and 3-day infusion groups compared with the control group. Furthermore, the 7-day infusion group has significantly reduced ABR threshold shifts compared with the 3-day infusion group. The total tissue response, including fibrosis and ossification, was significantly reduced in the 7-day infusion group compared with the control group. On multiple regression the extent of fibrosis predicted hearing loss across most frequencies, while hair cell counts predicted ABR thresholds at 32 kHz. Hearing protection after systemic administration of steroids is more effective when continued for at least a week after CI. Similarly, this treatment approach was more effective in reducing the fibrosis that encapsulates the CI electrode. Reduced fibrosis seemed to be the most likely explanation for the hearing protection.


Simple and Procedural Reaction Time for Mild Traumatic Brain Injury in a Hyperbaric Oxygen Clinical Trial.
Simple reaction time (SRT) and procedural reaction time (PRT) are speed-of-processing tasks in the Automated Neuropsychological Assessment Metrics (ANAM) that may be sensitive to mild traumatic brain injury (mTBI). The investigators measured SRT and PRT throughput (correct responses per minute) at baseline, 6 weeks, and 13 weeks in military personnel with mTBI randomized to local care or 40 chamber sessions (sham-1.2 atmospheres absolute [ATA] air, hyperbaric oxygen-1.5 ATA O2). Scores were assessed at baseline using univariate analysis of variance and across time with repeated measures methods. Data reported as throughput standard scores (mean = 100, SD = 15). Seventy-two participants with ongoing symptoms after mTBI enrolled in the study (three female, median age 31 years, mean three lifetime concussion events, most recent mTBI 23 months prior). Sixty-four had Automated Neuropsychological Assessment Metrics data at 13 weeks. SRT and PRT throughput standard scores were comparable across groups at baseline. Over time, SRT scores did not change in the hyperbaric oxygen or sham groups and decreased in the local care group. PRT throughput standard scores increased from baseline to mid-intervention and decreased from mid-intervention to postintervention in all groups. Repeated measures change over time in SRT (p = 0.23), and PRT (p = 0.17) scores were not different among groups. This study may be underpowered to detect statistically significant change.


Maternal and fetal genetic contribution to gestational weight gain.
Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG. A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight). Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG. We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.


Impact of Propionic Acid on Liver Damage in Rats.
Propionic acid (PA) is a short chain fatty acid, a common food preservative and metabolic end product of enteric bacteria in the gut. The present study was undertaken to investigate the effect of PA on liver injury in male rats. Male western albino rats were divided into two groups. The first group served as normal control, the second was treated with PA. The activities of serum hepatospecific markers such as aspartate transaminase, alanine transaminase, and alkaline phosphatase were estimated. Antioxidant status in liver tissues was estimated by determining the level of lipid peroxidation and activities of enzymatic and non-enzymatic antioxidants. Sodium and potassium levels were also measured in liver tissue. PA treatment caused significant changes in all hepatospecific markers. Biochemical analysis of liver homogenates from PA-treated rats showed an increase in oxidative stress markers like lipid peroxidation and lactate dehydrogenase, coupled with a decrease in glutathione, vitamin C and glutathione S- transferase. However, PA exposure caused no change in sodium and potassium levels in liver tissue. Our study demonstrated that PA persuade hepatic damage in rats.


Participation rates in cervical cancer screening: experience in rural Northern Greece.
Cervical cancer is one of the most common causes of cancer mortality among women worldwide but it is one of the most preventable cancers due to the Pap smear test. The aim of this study was to estimate the participation rate of females in screening of cervical cancer with Pap smear test. The study took place in a hospital in Rural Northern Greece during April and May 2007. Convenience sampling was performed and questionnaires were completed by 214 eligible females aged 20-64 years. One hundred and twenty four (57.9%) of the participants had had a Pap-test at some point in their lifetime. 72 of them (33.65%) had the test performed for the first time according to current guidelines. 13.6% were unaware about the recommended onset age of the test, 16.4% did not know the proper intervals, while 22.4% did not know the recommended upper age limit. 32.6% were informed by mass media, family members and friends. The take-up rates, the source of information and the setting where the examination was performed were related to age, origin, income, educational status, type of occupation and place of residence. Disparities in participation rates were detected. Special efforts should be made by National Health Services towards enhancing secondary prevention of cervical cancer by increasing participation rates of older women, those with lower educational background, females with low income, Roma, retired or unemployed and residents of rural areas.


Do Rural Second Homes Shape Commensal Microbiota of Urban Dwellers? A Pilot Study among Urban Elderly in Finland.
According to the hygiene and biodiversity hypotheses, increased hygiene levels and reduced contact with biodiversity can partially explain the high prevalence of immune-mediated diseases in developed countries. A disturbed commensal microbiota, especially in the gut, has been linked to multiple immune-mediated diseases. Previous studies imply that gut microbiota composition is associated with the everyday living environment and can be modified by increasing direct physical exposure to biodiverse materials. In this pilot study, the effects of rural-second-home tourism were investigated on the gut microbiota for the first time. Rural-second-home tourism, a popular form of outdoor recreation in Northern Europe, North America, and Russia, has the potential to alter the human microbiota by increasing exposure to nature and environmental microbes. The hypotheses were that the use of rural second homes is associated with differences in the gut microbiota and that the microbiota related to health benefits are more diverse or common among the rural-second-home users. Based on 16S rRNA Illumina MiSeq sequencing of stool samples from 10 urban elderly having access and 15 lacking access to a rural second home, the first hypothesis was supported: the use of rural second homes was found to be associated with lower gut microbiota diversity and RIG-I-like receptor signaling pathway levels. The second hypothesis was not supported: health-related microbiota were not more diverse or common among the second-home users. The current study encourages further research on the possible health outcomes or causes of the observed microbiological differences. Activities and diet during second-home visits, standard of equipment, surrounding environment, and length of the visits are all postulated to play a role in determining the effects of rural-second-home tourism on the gut microbiota.


Age and sex differences, and changing trends, in the use of evidence-based therapies in acute coronary syndromes: perspectives from a multinational registry.
A limited number of studies have examined the age and sex differences, and potentially changing trends, in cardiac medication and procedure use in patients hospitalized with an acute coronary syndrome (ACS). Using data from a large multinational study, we examined the age and sex differences, and changing trends (1999-2007) therein, in the hospital use of evidence-based therapies in patients hospitalized with an ACS using data from the Global Registry of Acute Coronary Events (n=50 096). After adjustment for several variables, in comparison with men below 65 years, patients in other age-sex strata had a significantly lower odds of receiving aspirin [odds ratios (ORs) for men 65-74, 75-84, and >or=85 years, women <65, 65-74, 75-84, and >or=85 years were 0.86, 0.84, 0.72, 0.80, 0.86, 0.68 and 0.46, respectively], angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ORs, 1.08, 1.01, 0,71, 0.83, 0.90, 0.89, and 0.63), beta blockers (ORs, 0.66, 0.52, 0.53, 0.67, 0.54, 0.53, and 0.52), statins (ORs, 0.72, 0.49, 0.29, 0.82, 0.68, 0.44, and 0.22), and undergoing coronary artery bypass graft surgery or a percutaneous coronary intervention (ORs, 0.79, 0.53, 0.21, 0.64, 0.57, 0.38, and 0.13) during their acute hospitalization. Age and sex differences in the receipt of these therapies remained relatively unchanged during the period under study. Although there were increasing trends in the use of evidence-based medications and cardiac procedures over time, important gaps in the utilization of effective cardiac treatment modalities persist in elderly patients and younger women.


Spontaneous posterior iliac crest regeneration enabling second bone graft harvest; a case report.
We present a case of a revision spinal fusion in which successful bone graft reharvesting was performed from the posterior iliac crest 4 years after initial intracortical harvesting. To date, only anterior iliac crest regeneration has been reported in orthopedic trauma patients. A 70-year-old man with a history of two prior instrumented lumbar fusion operations developed thoracolumbar kyphosis junctional to the lumbosacral fusion mass. His first operation was an instrumented posterolateral lumbar fusion L1 to L5, where bone graft was harvested from the right iliac crest using the intracortical harvesting technique. The second procedure was performed 18 months later and consisted of an extension of the fusion to the sacrum due to L5-S1 level derived symptoms. The bone graft for this procedure was taken with the same technique from the left iliac crest. The development of thoracolumbar junctional kyphosis necessitated the third operation, which consisted of a same-day anterior-posterior extension of the fusion to T10. Prior to this third procedure, a spinal computer tomography was performed that documented regeneration of the cancellous bone in the right iliac crest. This permitted reharvesting of almost 40 ml of cancellous bone using the intracortical bone harvesting technique from the right iliac crest. Histological analysis showed mature bone. Cancellous bone regeneration and restoration of the local anatomy of the ilium are possible after intracortical bone harvesting. This regeneration can provide autologous bone graft to assist fusion in subsequent operations.


Insulin antibodies retard and insulin accelerates growth and differentiation in early embryos.
The physiologic function of insulin in early embryonic life is unknown. We have shown that insulin is present in unfertilized eggs and in chick embryos at 2-3 days of development, even before the emergence of the endocrine pancreas. To define insulin's role, we exposed 2-day-old chick embryos to anti-insulin antibodies and followed their development up to day 5. Antibody-treated embryos had a higher rate of growth retardation and death by days 3-5 of embryogenesis, compared with controls. Among the survivors, biochemical maturation was delayed at days 4 and 5; weight, protein, total creatine kinase activity, and creatine kinase-MB were decreased in antibody-treated embryos. By contrast, insulin (50 ng/embryo) administered to 2-day-old embryos yielded nearly symmetrical stimulatory results. These findings suggest that endogenous insulin plays a probable physiologic role regulating growth and differentiation in early embryos. In addition, the findings provide some clues to a possible function for insulin produced outside the organism's own beta cells.


Consistency of state statutes with the Centers for Disease Control and Prevention HIV testing recommendations for health care settings.
In September 2006, the Centers for Disease Control and Prevention (CDC) released the "Revised Recommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-care Settings" to improve screening and diagnosis. The CDC now recommends that all patients in all health care settings be offered opt-out HIV screening without separate written consent and prevention counseling. State law on HIV testing is widely assumed to be a barrier to implementing the recommendations. To help policymakers and providers better understand their own legal context and to correct possible misunderstandings about statutory compatibility, a state-by-state review (including Washington, DC) of all statutes pertaining to HIV testing was performed and the consistency of these laws with the new recommendations was systematically assessed. Criteria were developed for classifying state statutory frameworks as consistent, neutral, or inconsistent with the new recommendations, and the implications for implementation of the CDC recommendations in these various legal contexts were examined. The statutory frameworks of 34 states and Washington, DC, were found to be either consistent with or neutral to the new CDC recommendations, which would enable full implementation. Statutory frameworks of 16 states were inconsistent with the new CDC recommendations, which would preclude implementation of 1 or more of the novel provisions without legislative change. In the 2 years since release of the recommendations, 9 states have passed new legislation to move from being inconsistent to consistent with the guidelines. State statutory laws are evolving toward greater compliance with the CDC recommendations. Policymakers, provider groups, consumer advocates, and other stakeholders should ensure that HIV screening practices comply with existing state law and work to amend inconsistent laws if they are interested in implementing the CDC recommendations.


Prenatal cocaine exposure selectively reduces mesocortical dopamine release.
The effect of prenatal exposure to cocaine on the release of [3H]dopamine and on presynaptic dopamine autoreceptor regulation of [3H]dopamine release in prelabeled frontal cortical, cingulate cortical and striatal slices was investigated. The release of [3H]dopamine that is evoked by high K+ was reduced by 20 to 28% in the cortical regions but not in striatum. This effect was observed at 10 days of age and persisted up to postnatal day 120 in rabbits that were exposed to cocaine during gestational days 8 to 29. Spontaneous [3H]dopamine release was increased by 18 to 22% in frontal and cingulate cortices but not in striatum of the 10- but not the 50- or 120-day-old rabbit that was exposed to cocaine during gestational days 8 to 29. Total [3H]dopamine accumulated in brain slices examined on postnatal days 10, 50 or 120 was not affected by prenatal cocaine exposure. Incubation of slices with dopamine dose-dependently inhibited K(+)-evoked [3H]dopamine release in both cortical and striatal slices. Prenatal cocaine exposure enhanced the responsiveness to in vitro dopamine in the two cortical regions but not in striatum. Fetal cocaine exposure did not affect the levels of dopamine or its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in frontal cortex or striatum. Similarly, no apparent differences in dopamine metabolism, as indicated by the ratio of 3,4-dihydroxyphenylacetic acid + homovanillic acid/dopamine, were observed in these brain areas. These findings demonstrate that prenatal cocaine exposure selectively affects depolarization-evoked [3H]dopamine release and its regulation by presynaptic dopamine autoreceptor in cortical areas.(ABSTRACT TRUNCATED AT 250 WORDS)


Risk Criteria in Hospital Site Selection: A Systematic Review.
Hospitals should be safe and remain functional in emergencies and disasters as it is mentioned in the Sendai Framework. Proper selection of a hospital location has a direct effect on survival of affected population in disasters as well as cost and benefit of the hospital in non-emergency situation. Different studies applied different criteria for Hospital Site Selection (HSS). The present study through a systematic review aimed to find out a categorized criteria list that have been used for (HSS) in the literature. In accordance with the PRISMA statement, "PubMed", "ScienceDirect", "Google Scholar", and "Scopus" were searched up to end of 2015. All English Articles that were published in peer-reviewed journals and had discussed site selection criteria for hospitals were included. Out of 41 articles, 15 met the inclusion criteria in which 39 general criteria for HSS were applied. These criteria were categorized in six main groups including cost, demand, environmental, administrative, disaster risk, and "other" concerns through a focus group discussion. Accordingly, the application percentage of cost, demand, environmental, administrative, disaster risk, and "other" concerns in the articles was 100, 93.3, 53.3, 33.3, 20.0, and 13.3 respectively. The least devoted attention was to disaster risk issues. Few researchers applied risk related criteria for HSS. Further consideration of "risk of hazards" and "burden of diseases" in comprehensive studies, is recommended for HSS to guide the decision makers for building more resilient hospitals. Keywords Hospital, Site selection, Systematic review, Disaster risk.


Measurement of subfoveal choroidal thickness after cataract surgery in enhanced depth imaging optical coherence tomography.
To compare subfoveal choroidal thickness (SFCT) before and after uneventful cataract surgery using enhanced depth imaging optical coherence tomography (EDI-OCT). A prospective study was conducted on 115 eyes of 95 patients who had phacoemulsification. Measurements of SFCT were performed preoperatively, 1 day (D1), 7 days (D7), 1 month (M1), and 3 months (M3) after surgery using the EDI-OCT technique. Central retinal thickness (CRT) was measured before surgery and at M1 and M3. The 95 patients had a mean age of 76 ± 8.3 years. The mean SFCT at baseline was 224 ± 75 μm. It showed a negative correlation with age and axial length (P = 0.03). The SFCT significantly increased after surgery with a mean value of 232 ± 76 μm at D1 (P < 0.001), 237 ± 78 μm at M1 (P < 0.001), and 232 ± 76 μm at M3 (P < 0.001). The mean CRT increased from 234 ± 48 μm at baseline to 248 ± 48 μm at M1 (P = 0.005), and 252 ± 81 μm at M3 (P = 0.001). Three (2.6%) patients developed a pseudophakic cystoid macular edema (PCME). The greatest progression of SFCT after phacoemulsification was observed for these patients. It preceded the occurrence of pseudophakic cystoid macular edema (PCME) by 1 month. Mean SFCT increased after cataract surgery. The changes in baseline SFCT were greater in PCME patients and preceded the increase in CRT.


Maternal-child adrenocortical attunement in early childhood: continuity and change.
This study evaluated continuity and change in maternal-child hypothalamic-pituitary-adrenal axis attunement in early childhood. Participants were drawn from a prospective study of 1,292 mother-child dyads, which were racially diverse, predominantly low-income, and non-urban. Child focused stress tasks designed to elicit anger, fear, and frustration were administered during early infancy, later infancy, and toddlerhood. Mothers' and children's saliva samples (later assayed for cortisol) were collected before and after the tasks. The strength of mother-child adrenocortical attunement was conserved across infancy and toddlerhood. The magnitude of maternal-child adrenocortical attunement decreased in response to the child-focused stress tasks. Maternal sensitivity and the child's task-related emotional reactivity moderated adrenocortical attunement across the task, with greater maternal sensitivity during a free-play, and lower levels of child emotional reactivity during the stress tasks, stabilizing attunement from pre- to post-task levels. The findings advance our understanding of individual differences in the social regulation of adrenocortical activity in early childhood.


Fecal carriage of extended-spectrum beta-lactamase and ampc beta-lactamase-producing enterobacteriaceae in a turkish community.
Community-acquired infection caused by extended-spectrum beta-lactamase (ESBL)-producing microorganisms has an increasing frequency. The aim of this study was to determine the fecal carriage of ESBL and AmpC beta-lactamase-producing Enterobacteriaceae in community and to investigate cefotaxime-M (CTX-M) genes among ESBL isolates. A total of 1402 fecal specimens which were collected from outpatients included in the study. ESBL screening, ESBL production, and AmpC beta-lactamase detection were performed. Matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) was used for identification of species. Antibiotic susceptibilities of the isolates were detected by disk diffusion method. CTX-M beta-lactamase genes were investigated by polymerase chain reaction. During the study period, a total of 1402 fecal samples were analysed with ESBL screening test and 490 Enterobacteriaceae strains isolated from these samples (Escherichia coli [n = 461, 94.1%], Klebsiella pneumoniae [n = 25, 5.1%], and Enterobacter cloacae [n = 4, 0.8%]). Fecal carriage of ESBL-producing Enterobacteriaceae in the community was 34.3%. AmpC beta-lactamases were detected in 26 (5.3%), and the frequency of CTX-M was found as 96.9%. The resistance rates of the E. coli strains to fluoroquinolones, trimethoprim-sulfamethoxazole, and carbapenems were 31.2%, 33.3%, and 0%, respectively. The relative high prevalence of fecal carriage of ESBL-producing bacteria in community warrants further study in this field including developing policies about antimicrobial use and close monitoring of resistance patterns.


Genome-wide analysis for identification of salt-responsive genes in common wheat.
To identify salt-responsive genes in wheat, global expression analysis of transcripts was carried out using oligo-DNA microarrays. Microarrays have been designed from approximately 32,000 unique wheat genes classified from a large number of expressed sequence tags (ESTs). Two-week-old seedlings of wheat were treated with 150 mM NaCl for 1, 6, and 24 h, and their roots and shoots were separately subjected to analyses. Consequently, 5,996 genes showed changes in expression of more than twofold and were classified into 12 groups according to correlations in expression patterns. These salt-responsive genes were assigned functions using the Gene Ontology (GO). Genes assigned to transcription factor, transcription-regulator activity, and DNA-binding functions were preferentially classified into early response groups. On the other hand, those assigned transferase and transporter activity were classified into late response groups. These data suggest that multiple signal transduction pathways in response to salinity exist in wheat. Transcription factors (TFs) which have been reported as participants in salt-tolerant pathway changed their expression levels in response to salt treatment. Among them, only a few TFs show high sequence homologies to genes in rice. These investigations suggest that salt-responsive genes identified by this study are candidates for salt-stress tolerance uniquely in wheat.


Purified cytochrome b from human granulocyte plasma membrane is comprised of two polypeptides with relative molecular weights of 91,000 and 22,000.
A new method has been developed for purification of cytochrome b from stimulated human granulocytes offering the advantage of high yields from practical quantities of whole blood. Polymorphonuclear leukocytes were treated with diisopropylfluorophosphate, degranulated and disrupted by nitrogen cavitation. Membranes enriched in cytochrome b were prepared by differential centrifugation. Complete solubilization of the cytochrome from the membranes was achieved in octylglucoside after a 1-M salt wash. Wheat germ agglutinin-conjugated Sepharose 4B specifically bound the solubilized cytochrome b and afforded a threefold purification. Eluate from the immobilized wheat germ agglutinin was further enriched by chromatography on immobilized heparin. The final 260-fold purification of the b-type cytochrome with a 20-30% yield was achieved by velocity sedimentation in sucrose density gradients. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of the purified preparation revealed two polypeptides of Mr 91,000 and Mr 22,000. Treatment of the 125I-labeled, purified preparation with peptide:N-glycosidase F, which removes N-linked sugars, decreased relative molecular weight of the larger species to approximately 50,000, whereas beta-elimination, which removes O-linked sugars, had little or no effect on the mobility of the Mr-91,000 polypeptide. Neither of the deglycosylation conditions had any effect on electrophoretic mobility of the Mr-22,000 polypeptide. Disuccinimidyl suberate cross-linked the two polypeptides to a new Mr of 120,000-135,000 by SDS-PAGE. Antibody raised to the purified preparation immunoprecipitated spectral activity and, on Western blots, bound to the Mr-22,000 polypeptide but not the Mr-91,000 polypeptide. Western blot analysis of granulocytes from patients with X-linked chronic granulomatous disease revealed a complete absence of the Mr-22,000 polypeptide. These results (a) suggest that the two polypeptides are in close association and are part of the cytochrome b, (b) provide explanation for the molecular weight discrepancies previously reported for the protein, and (c) further support the involvement of the cytochrome in superoxide production in human neutrophils.


Anti-inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up-regulation of dual specificity phosphatase 1.
It is thought that the anti-inflammatory effects of glucocorticoids (GCs) are largely due to GC receptor (GR)-mediated transrepression of NF-κB and other transcription factors, whereas side effects are caused by activation of gene expression (transactivation). Selective GR modulators (SGRMs) that preferentially promote transrepression should retain anti-inflammatory properties whilst causing fewer side effects. Contradicting this model, we found that anti-inflammatory effects of the classical GC dexamethasone were partly dependent on transactivation of the dual specificity phosphatase 1 (DUSP1) gene. We wished to determine whether anti-inflammatory effects of SGRMs are also mediated by DUSP1. Dissociated properties of two SGRMs were confirmed using GR- and NF-κB-dependent reporters, and capacity to activate GC-responsive elements of the DUSP1 gene was tested. Effects of SGRMs on the expression of DUSP1 and pro-inflammatory gene products were assessed in various cell lines and in primary murine Dusp1(+/+) and Dusp1(-/-) macrophages. The SGRMs were able to up-regulate DUSP1 in several cell types, and this response correlated with the ability of the compounds to suppress COX-2 expression. Several anti-inflammatory effects of SGRMs were ablated or significantly impaired in Dusp1(-/-) macrophages. Like dexamethasone, SGRMs appear to exert anti-inflammatory effects partly via the up-regulation of DUSP1. This finding has implications for how potentially therapeutic novel GR ligands are identified and assessed.


The perceived efficacy of various "future-ologies" and complementary medicine.
To examine the relationship between beliefs in ways of telling the future (astrology, graphology, palmistry etc) and beliefs in complementary and alternative medicine (CAM). Participants completed a short questionnaire that requested that they rate the efficacy of 8 CAM therapies along with 12 other ways of predicting the future ranging from the well known and established (astrology) to the less well known (tasseography, oneiromancy). Short descriptions of each were provided. They also answered four attitude statements on science as applied to medicine. Two hundred three (130 female, 73 male) adult Britains obtained from a university subject panel served as unpaid volunteer subjects. CAM therapies were judged as modestly effective and most of the other "-ologies" ineffective. Further analysis confirmed two clear factors with the different methods loading on two different factors. Regressions showed females who were less concerned with scientific evaluations but more concerned with treatment believed more in the efficacy of the "future-ologies." Also females, who had heard of fewer "future-ologies" but more CAM practices were more likely to believe in the efficacy of CAM therapies. Belief in CAM is unrelated to belief in "future-ologies." Interest in the scientific evaluations of treatment is the best predictor of beliefs about efficacy.


NOSH-sulindac (AVT-18A) is a novel nitric oxide- and hydrogen sulfide-releasing hybrid that is gastrointestinal safe and has potent anti-inflammatory, analgesic, antipyretic, anti-platelet, and anti-cancer properties.
Sulindac is chemopreventive and has utility in patients with familial adenomatous polyposis; however, side effects preclude its long-term use. NOSH-sulindac (AVT-18A) releases nitric oxide and hydrogen sulfide, was designed to be a safer alternative. Here we compare the gastrointestinal safety, anti-inflammatory, analgesic, anti-pyretic, anti-platelet, and anti-cancer properties of sulindac and NOSH-sulindac administered orally to rats at equimolar doses. Gastrointestinal safety: 6h post-administration, number/size of hemorrhagic lesions in stomachs were counted. Tissue samples were frozen for PGE2, SOD, and MDA determination. Anti-inflammatory: 1h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 5h. Anti-pyretic: fever was induced by LPS (ip) an hour before administration of the test drugs, core body temperature was measured hourly for 5h. Analgesic: time-dependent analgesic effects were evaluated by carrageenan-induced hyperalgesia. Antiplatelet: anti-aggregatory effects were studied on collagen-induced platelet aggregation of human platelet-rich plasma. Anti-cancer: We examined the effects of NOSH-sulindac on the growth properties of 12 human cancer cell lines of six different tissue origins. Both agents reduced PGE2 levels in stomach tissue; however, NOSH-sulindac did not cause any stomach ulcers, whereas sulindac caused significant bleeding. Lipid peroxidation induced by sulindac was higher than that from NOSH-sulindac. SOD activity was significantly lowered by sulindac but increased by NOSH-sulindac. Both agents showed similar anti-inflammatory, analgesic, anti-pyretic, and anti-platelet activities. Sulindac increased plasma TNFα whereas this rise was lower in the NOSH-sulindac-treated animals. NOSH-sulindac inhibited the growth of all cancer cell lines studied, with potencies of 1000- to 9000-fold greater than that of sulindac. NOSH-sulindac inhibited cell proliferation, induced apoptosis, and caused G2/M cell cycle block. These results demonstrate that NOSH-sulindac is gastrointestinal safe, and maintains the anti-inflammatory, analgesic, antipyretic, and antiplatelet properties of its parent compound sulinsac, with anti-growth activity against a wide variety of human cancer cells.


Evidence and possible mechanisms of rare maternal-fetal transmission of SARS-CoV-2.
While SARS-CoV-2 infection has spread rapidly worldwide, data remains scarce about the natural history of infection in pregnant women and the risk of mother-to-fetal transmission. Current data indicates that viral RNA levels in maternal blood are low and there is no evidence of placental infection with SARS-CoV-2. Published reports to date suggest that perinatal transmission of SARSCoV- 2 can occur but is rare. Among 179 newborns tested for SARS-CoV2 at birth from mothers with COVID-19, transmission was suspected in 8 cases, 5 with positive nasopharyngeal SARS-CoV-2 RT-PCR and 3 with SARS-CoV-2 IgM. However, these cases arise from maternal infection close to childbirth and there are no information about exposition during first or second trimester of pregnancy. Welldesigned prospective cohort studies with rigorous judgement criteria are needed to determine the incidence and risk factors for perinatal transmission of SARS-CoV-2.


A role for cadherins in tissue formation.
We have produced null mutant mouse embryonic stem cells for the cell adhesion molecule E-cadherin. Such E-cadherin-/- ES cells are defective in cell aggregation; this defect can be corrected by transfection with cDNA for either E-cadherin or N-cadherin driven by a constitutive promoter. The presence (or absence) of E-cadherin regulates the expression of the transcription factor T-brachyury, indicating that cadherins play a role in linking cell surface receptors and gene expression. Comparative analysis of the parental and the genetically altered ES cell lines was performed to examine cell differentiation and the capability to form organized tissues. While differentiating E-cadherin-/- ES cells are still able to express various early and late differentiation markers, they show a clear-cut deficiency in forming organized structures. This phenotype can be rescued by constitutive expression of E-cadherin, which results exclusively in formation of epithelia. In contrast, rescue transfectants expressing N-cadherin show no epithelial structures, instead forming neuroepithelium and cartilage. These results provide the first evidence that specific cadherins directly stimulate differentiation into certain types of tissues.


Domain specificity of MAP3K family members, MLK and Tak1, for JNK signaling in Drosophila.
A highly diverse set of protein kinases functions as early responders in the mitogen- and stress-activated protein kinase (MAPK/SAPK) signaling pathways. For instance, humans possess 14 MAPK kinase kinases (MAP3Ks) that activate Jun kinase (JNK) signaling downstream. A major challenge is to decipher the selective and redundant functions of these upstream MAP3Ks. Taking advantage of the relative simplicity of Drosophila melanogaster as a model system, we assessed MAP3K signaling specificity in several JNK-dependent processes during development and stress response. Our approach was to generate molecular chimeras between two MAP3K family members, the mixed lineage kinase, Slpr, and the TGF-β activated kinase, Tak1, which share 32% amino acid identity across the kinase domain but otherwise differ in sequence and domain structure, and then test the contributions of various domains for protein localization, complementation of mutants, and activation of signaling. We found that overexpression of the wild-type kinases stimulated JNK signaling in alternate contexts, so cells were capable of responding to both MAP3Ks, but with distinct outcomes. Relative to wild-type, the catalytic domain swaps compensated weakly or not at all, despite having a shared substrate, the JNK kinase Hep. Tak1 C-terminal domain-containing constructs were inhibitory in Tak1 signaling contexts, including tumor necrosis factor-dependent cell death and innate immune signaling; however, depressing antimicrobial gene expression did not necessarily cause phenotypic susceptibility to infection. These same constructs were neutral in the context of Slpr-dependent developmental signaling, reflecting differential subcellular protein localization and by inference, point of activation. Altogether, our findings suggest that the selective deployment of a particular MAP3K can be attributed in part to its inherent sequence differences, cellular localization, and binding partner availability.


Human cancer cell lines: Experimental models for cancer cells in situ? For cancer stem cells?
Established human cancer cell lines are routinely used as experimental models for human cancers. Their validity for such use is analyzed and discussed, with particular focus on thyroid tumors. Although cell lines retain some properties of the cells of origin, from the points of view of their genetics, epigenetics and gene expression, they show clear differences in these properties compared to in vivo tumors. This can be explained by a prior selection of initiating cells and a Darwinian evolution in vitro. The properties of the cell lines are compared to those of the postulated cancer stem cells and their use as models in this regard are discussed. Furthermore, other proper and possible uses of the cell lines are discussed.


Respecification of vertebral identities by retinoic acid.
In higher vertebrates, the formation of the body axis proceeds in a craniocaudal direction during gastrulation. Cell biological evidence suggests that mesoderm formation and specification of axial positions occur simultaneously. Exposure of gastrulating embryos to retinoic acid induces changes in axial patterns, e.g. anterior and posterior homeotic transformations of vertebrae. These morphological changes are accompanied by changes in the nonidentical, overlapping expression domains of Hox genes. In this report the influence of retinoic acid, administered at the end of and after gastrulation, on vertebral patterns is described. Anterior transformations and truncations affecting the caudal part of the vertebral column characterize animals exposed on day 8 and 9. 4 hours after retinoic acid administration on day 8 + 5 hours, Hox-1.8, Hox-1.9, and Hox-4.5 transcripts were not detected in their usual posterior expression domains, whereas transcripts of the anterior Hox-1.5 gene remained unaffected. 4 days after RA exposure on day 8 + 5 hours, Hox-1.8 expression was shifted posteriorly by an effectively low dose of RA, which induced the formation of supernumerary ribs. Hox-1.8 expression was limited to posterior, disorganized mesenchyme, bulging out neural tube, some intestinal loops and the hindlimb in truncated embryos exposed to a high dose of RA. A causal relation between the delayed activation of posterior Hox genes and anterior transformations or agenesis of vertebrae is discussed. On day 10.5 posterior transformations begin to occur in the cervical region, while later exposures again affect more caudal structures. The distribution of the transformations along the vertebral column indicates an influence of RA on migrating sclerotome cells before they are finally fixed in the cartilagenous vertebrae. The findings show that the mesodermal segments originally specified during gastrulation can be respecified in their second migratory phase, with effects spreading for a second time in a craniocaudal direction. The transformations are discussed with regard to a molecular specification of axial levels by Hox codes, defined as combinations of expressed Hox genes.


Impact of chronic statin therapy on clinical presentation and underlying lesion morphology in patients undergoing percutaneous intervention: an ADAPT-DES IVUS substudy.
Previous intravascular ultrasound (IVUS) studies have not established a relationship between chronic statin use and plaque morphology and composition in patients undergoing percutaneous coronary intervention (PCI). We sought to use pre-PCI grayscale and virtual histology (VH)-IVUS to assess plaque morphology and composition in patients treated with chronic statin therapy compared with patients who were not taking statins before admission and PCI. In a prespecified substudy of the Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents study, pre-PCI grayscale and VH-IVUS were performed in 780 patients with 916 culprit and 765 nonculprit lesions. Overall, 338 patients were treated with chronic statin therapy before admission. Statin-treated patients were older and had a higher prevalence of coronary risk factors. Statin-treated patients were more likely to present with stable angina, whereas non-statin-treated patients more frequently presented with acute myocardial infarction. Grayscale and VH-IVUS findings showed that lesions in statin-treated patients had a smaller plaque burden, but more dense calcium. Statin-treated patients had more calcified thick-cap fibroatheromas (9.2 vs. 3.7%, P=0.0007), but fewer VH-defined thin-cap fibroatheromas (45.2 vs. 56.1%, P=0.001) or plaque ruptures (26.6 vs. 38.4%, P=0.0001). In a propensity-matched population (n=249 in each group), similar results were obtained as regards clinical presentation and grayscale and VH-IVUS findings. Chronic statin use in patients with coronary artery disease was associated with more stable clinical presentation and IVUS findings consistent with greater lesion stability (fewer VH-thin-cap fibroatheromas and plaque ruptures and more calcified thick-cap fibroatheromas).


Visual search strategies of soccer players executing a power vs. placement penalty kick.
When taking a soccer penalty kick, there are two distinct kicking techniques that can be adopted; a 'power' penalty or a 'placement' penalty. The current study investigated how the type of penalty kick being taken affected the kicker's visual search strategy and where the ball hit the goal (end ball location). Wearing a portable eye tracker, 12 university footballers executed 2 power and placement penalty kicks, indoors, both with and without the presence of a goalkeeper. Video cameras were used to determine initial ball velocity and end ball location. When taking the power penalty, the football was kicked significantly harder and more centrally in the goal compared to the placement penalty. During the power penalty, players fixated on the football for longer and more often at the goalkeeper (and by implication the middle of the goal), whereas in the placement penalty, fixated longer at the goal, specifically the edges. Findings remained consistent irrespective of goalkeeper presence. Findings indicate differences in visual search strategy and end ball location as a function of type of penalty kick. When taking the placement penalty, players fixated and kicked the football to the edges of the goal in an attempt to direct the ball to an area that the goalkeeper would have difficulty reaching and saving. Fixating significantly longer on the football when taking the power compared to placement penalty indicates a greater importance of obtaining visual information from the football. This can be attributed to ensuring accurate foot-to-ball contact and subsequent generation of ball velocity. Aligning gaze and kicking the football centrally in the goal when executing the power compared to placement penalty may have been a strategy to reduce the risk of kicking wide of the goal altogether.


Long-term mortality risk in patients with an implantable cardioverter-defibrillator: Influence of heart rate and QRS duration.
A paucity of studies has investigated the role of autonomic cardiac regulation as well as cardiac conduction in relation to prognosis in implantable cardioverter-defibrillator (ICD) patients. Therefore, we examined the association of heart rate and QRS duration with long-term mortality risk in first-time ICD patients, adjusting also for measures of emotional distress. Resting heart rate and QRS duration were assessed prior to ICD implantation in 448 patients. Primary study endpoint was all-cause mortality (up to 6.0 year follow-up, median follow-up of 5.6 years (IQR: 1.9)). The impact of heart rate and QRS duration on time to all-cause mortality was separately assessed with Cox proportional hazard regression analysis, adjusting for clinical factors and symptoms of depression and anxiety. Mean (SD) heart rate was 68.0 ± 13.3 bpm and mean QRS duration was 130.9 ± 36.9 ms. Heart rate of ≥80 bpm was associated with increased risk of mortality (HR=1.86; 95% CI=1.15-3.00; p=.011) in unadjusted analysis. In adjusted analyses, this relationship remained significant both with depression (HR=1.86, 95% CI=1.12-3.09; p=.017) and anxiety (HR=1.82, 95% CI=1.10-3.03; p=.021) and clinical measures as covariates. QRS duration of ≥120 ms was associated with impaired prognosis in unadjusted analysis (HR=2.00, 95% CI=1.27-3.14; p=.003), but was reduced to non-significance in adjusted analysis when medical comorbidities were included (HR=1.15, 95% CI=0.70-1.89; p=.60). This study shows that increased heart rate is associated with impaired prognosis. Since heart rate is a relatively easy measurable parameter of autonomic functioning, heart rate should be included as a measure for risk stratification in daily clinical practice.


Relation of Bone Mineral Density with Homocysteine and Cathepsin K levels in Postmenopausal Women.
Homocysteine (HCY) interferes with collagen cross-linking in bones and stimulates osteoclast activity. The activated osteoclasts secrete cathepsin K (CathK), a cysteine protease, in eminent quantity during bone resorption. Hyperhomocysteinemia may effect bone mineral density (BMD) through CathK. We, therefore, examined the relation between HCY and BMD along with CathK, 25-hydroxyvit-D (25[OH]D), intact parathyroid hormone (iPTH), and Vitamin B12. We recruited a total of 93 postmenopausal women between the age group of 45-60 years, attending the Endocrinology outpatient department at King George's Medical University, Lucknow. BMD was done by DXA scan using Hologic QDR1000 system. Based on the WHO criteria, patients were segregated into three groups as follows; normal bone mass, osteopenia, and osteoporosis. All women underwent routine biochemical laboratory parameters, HCY, Vitamin B12, and CathK levels. Among 93 postmenopausal women, 56% (52) had osteoporosis. Nineteen percent (18) had normal BMD (mean age, 53.22 ± 8.5 years) and 23 (25%) had osteopenia (mean age 52.86 ± 6.67 years). The mean age in the osteoporetic group was 56.2 ± 6.9 years. The median (interquartile range) levels of HCY in the three groups were 14.5 μmol/L (12.2-24.7), 15.05 μmol/L (12.1-19.9) and 13.2 μmol/L (10.3-17.0), respectively. CathK levels were similar in three groups 7.6 ng/ml (7.0-80.5), 8.3 ng/ml (7.3-8.5), and 8.6 ng/ml (7.2-8.9). Both HCY and CathK were found positively associated with serum phosphorus (r = 0.584, P < 2.01 and r = 0.249, P < 0.05, respectively). Levels of HCY positively correlate with PTH (r = 0.303, P < 0.01) and inversely with Vitamin B12 (r = -0.248, P < 0.05). No significant association was seen between CathK level and 25(OH) D, iPTH, serum calcium. Low bone mass by DXA is a significant problem in postmenopausal females. HCY and CathK do not reliably correlate with bone loss in postmenopausal women although phosphorus metabolism may play a role.


Bias-free true random-number generator.
We propose what we believe to be a new approach to nondeterministic random-number generation. The randomness originated from the uncorrelated nature of consecutive laser pulses with Poissonian photon statistics and that of photon number detections is used to generate random bit, and the von Neumann correction method is used to extract the final random bit. This method is proved to be bias free in randomness generation, provided that the single photon detections are mutually independent. Further, it has the advantage in fast random bit generation, since no postprocessing is needed. A true random-number generator based on this method is realized, and its randomness is tested and guaranteed using three statistical test batteries.


Subspace projection approaches to classification and visualization of neural network-level encoding patterns.
Recent advances in large-scale ensemble recordings allow monitoring of activity patterns of several hundreds of neurons in freely behaving animals. The emergence of such high-dimensional datasets poses challenges for the identification and analysis of dynamical network patterns. While several types of multivariate statistical methods have been used for integrating responses from multiple neurons, their effectiveness in pattern classification and predictive power has not been compared in a direct and systematic manner. Here we systematically employed a series of projection methods, such as Multiple Discriminant Analysis (MDA), Principal Components Analysis (PCA) and Artificial Neural Networks (ANN), and compared them with non-projection multivariate statistical methods such as Multivariate Gaussian Distributions (MGD). Our analyses of hippocampal data recorded during episodic memory events and cortical data simulated during face perception or arm movements illustrate how low-dimensional encoding subspaces can reveal the existence of network-level ensemble representations. We show how the use of regularization methods can prevent these statistical methods from over-fitting of training data sets when the trial numbers are much smaller than the number of recorded units. Moreover, we investigated the extent to which the computations implemented by the projection methods reflect the underlying hierarchical properties of the neural populations. Based on their ability to extract the essential features for pattern classification, we conclude that the typical performance ranking of these methods on under-sampled neural data of large dimension is MDA>PCA>ANN>MGD.


Molecular genetic and biochemical analyses of FGF23 mutations in familial tumoral calcinosis.
Fibroblast growth factor 23 (FGF23) is a hormone required for normal renal phosphate reabsorption. FGF23 gain-of-function mutations result in autosomal dominant hypophosphatemic rickets (ADHR), and FGF23 loss-of-function mutations cause familial hyperphosphatemic tumoral calcinosis (TC). In this study, we identified a novel recessive FGF23 TC mutation, a lysine (K) substitution for glutamine (Q) (160 C>A) at residue 54 (Q54K). To understand the molecular consequences of all known FGF23-TC mutants (H41Q, S71G, M96T, S129F, and Q54K), these proteins were stably expressed in vitro. Western analyses revealed minimal amounts of secreted intact protein for all mutants, and ELISA analyses demonstrated high levels of secreted COOH-terminal FGF23 fragments but low amounts of intact protein, consistent with TC patients' FGF23 serum profiles. Mutant protein function was tested and showed residual, yet decreased, bioactivity compared with wild-type protein. In examining the role of the FGF23 COOH-terminal tail (residues 180-251) in protein processing and activity, truncated mutants revealed that the majority of the residues downstream from the known FGF23 SPC protease site ((176)RXXR(179)/S(180)) were not required for protein secretion. However, residues adjacent to the RXXR site (between residues 188 and 202) were required for full bioactivity. In summary, we report a novel TC mutation and demonstrate a common defect of reduced FGF23 stability for all known FGF23-TC mutants. Finally, the majority of the COOH-terminal tail of FGF23 is not required for protein secretion but is required for full bioactivity.


Extracellular matrix glycoprotein biglycan enhances vascular smooth muscle cell proliferation and migration.
Proteoglycans are produced and secreted by vascular smooth muscle cells, but the pathophysiological role of these glycoproteins in the vasculature is an enigma. Because the small leucine-rich proteoglycan (SLRP) biglycan is overexpressed in arteriosclerotic lesions, we produced mice constitutively overexpressing biglycan in the vascular smooth muscle, in order to examine the effects on vascular pathology. In the aorta and renal vasculature, increased vascular proliferation was seen both in the basal state and after infusion of angiotensin II (Ang II) in the transgenic mice compared with wild-type controls. In addition, the combination of biglycan overexpression and Ang II infusion resulted in marked increases in vascular smooth muscle cell proliferation and migration in the coronary arteries, as well as increases in fibrosis surrounding the vessels. In vitro, biglycan caused an increase in thymidine incorporation and migration of vascular smooth muscle cells, whereas these parameters were unchanged or reduced in endothelial cells. Moreover, addition of biglycan resulted in an increase in cdk2 expression and decrease in p27 levels in the vascular smooth muscle cells. These results suggest that this extracellular matrix SLRP may be involved in the regulation of vascular smooth muscle growth and migration through cdk2- and p27-dependent pathways. Furthermore, changes in biglycan expression could be a factor influencing the susceptibility of arteries to vascular injury, and may play a direct role in the pathogenesis of vascular lesions.


Maternal supplementation with docosahexaenoic acid during pregnancy does not affect early visual development in the infant: a randomized controlled trial.
The docosahexaenoic acid (DHA) intake of pregnant women is lower than estimates of the DHA accretion by the fetus, and recommendations were made to increase the DHA intake of pregnant women. The objective of this study was to determine whether the supplementation of pregnant women with DHA improved the visual acuity of infants at 4 mo. We conducted a blinded assessment of a subset of healthy, full-term infants born to women enrolled in a double-blind, randomized controlled trial called the DHA for Maternal and Infant Outcomes (DOMInO) trial. Women were randomly assigned to consume DHA-rich fish-oil capsules (≈800 mg DHA/d in the treatment group) or vegetable oil capsules (control group) from midpregnancy to delivery. The primary outcome was the sweep visual evoked potential (VEP) acuity at 4 mo. The VEP latency at 4 mo was a secondary outcome. Mean (±SD) VEP acuity did not differ between treatment and control groups [treatment group: 8.37 ± 2.11 cycles per degree (cpd), n = 89; control group: 8.55 ± 1.86 cpd, n = 93; P = 0.55]. VEP latencies also did not differ between groups. Irrespective of the group, maternal smoking in pregnancy was independently associated with poorer VEP acuity in the infant. DHA supplementation in women with singleton pregnancies does not enhance infant visual acuity in infants at 4 mo of age. Visual acuity in infancy is adversely associated with maternal smoking in pregnancy. This trial was registered at www.anzctr.org.au as ACTRN12606000327583. The DOMInO trial was registered at www.anzctr.org.au as ACTRN12605000569606.


Sedentary time and blood pressure in Australian toddlers: The get-up study longitudinal results.
Epidemiological data suggests that the genesis of cardiovascular disease occurs during childhood. Sedentary time (ST) is a main driver of high blood pressure (BP) in adolescents and adults. However, associations between ST and cardiovascular health in young children are uncertain. Prospective associations between ST and BP were assessed among 172 toddlers (88 boys), aged 19.5 ± 3.9 months at baseline, recruited from the GET-UP! Study, Australia and followed over a 12-month period. BP was measured with a digital monitor and z-scores were computed by age and sex for systolic and diastolic BP. Total ST was measured over 7 days using Actigraph accelerometers and expressed over a 24-h period. Multilevel linear regression models were used to assess regression coefficients and standard errors, predicting BP at follow-up from ST at baseline. Analyses controlled for socio-economic status, height, age, gender, group (intervention or control) and zWC at baseline. Adjusted analyses showed that total ST did not predict systolic or diastolic BP (β = 0.0009, p = 0.368 and β = 0.002, p = 0.05, respectively). Most likely, longer follow-up periods might be needed to confirm or rule out our results, as the effects of cumulative ST over time on BP values are prone to manifest later in life and track into adolescence and adulthood.


Proton Transport Chains in Glucose Metabolism: Mind the Proton.
The Embden-Meyerhof-Parnas (EMP) pathway comprises eleven cytosolic enzymes interacting to metabolize glucose to lactic acid [CH3CH(OH)COOH]. Glycolysis is largely considered as the conversion of glucose to pyruvate (CH3COCOO-). We consider glycolysis to be a cellular process and as such, transporters mediating glucose uptake and lactic acid release and enable the flow of metabolites through the cell, must be considered as part of the EMP pathway. In this review, we consider the flow of metabolites to be coupled to a flow of energy that is irreversible and sufficient to form ordered structures. This latter principle is highlighted by discussing that lactate dehydrogenase (LDH) complexes irreversibly reduce pyruvate/H+ to lactate [CH3CH(OH)COO-], or irreversibly catalyze the opposite reaction, oxidation of lactate to pyruvate/H+. However, both LDH complexes are considered to be driven by postulated proton transport chains. Metabolism of glucose to two lactic acids is introduced as a unidirectional, continuously flowing pathway. In an organism, cell membrane-located proton-linked monocarboxylate transporters catalyze the final step of glycolysis, the release of lactic acid. Consequently, both pyruvate and lactate are discussed as intermediate products of glycolysis and substrates of regulated crosscuts of the glycolytic flow.


The crystal structure of palmitoyl protein thioesterase-2 (PPT2) reveals the basis for divergent substrate specificities of the two lysosomal thioesterases, PPT1 and PPT2.
Mutations in palmitoyl protein thioesterase-1 (PPT1) have been found to cause the infantile form of neuronal ceroid lipofuscinosis, which is a lysosomal storage disorder characterized by impaired degradation of fatty acid-modified proteins with accumulation of amorphous granular deposits in cortical neurons, leading to mental retardation and death. Palmitoyl protein thioesterase-2 (PPT2) is a second lysosomal hydrolase that shares a 26% identity with PPT1. A previous study had suggested that palmitoyl-CoA was the preferred substrate of PPT2. Furthermore, PPT2 did not hydrolyze palmitate from the several S-palmitoylated protein substrates. Interestingly, PPT2 deficiency in a recent transgenic mouse model is associated with a form of neuronal ceroid lipofuscinosis, suggesting that PPT1 and -2 perform non-redundant roles in lysosomal thioester catabolism. In the current paper, we present the crystal structure of PPT2 at a resolution of 2.7 A. Comparisons of the structures of PPT1 and -2 show very similar architectural features; however, conformational differences in helix alpha4 lead to a solvent-exposed lipid-binding groove in PPT1. The limited space between two parallel loops (beta3-alphaA and beta8-alphaF) located immediately above the lipid-binding groove in PPT2 restricts the binding of fatty acids with bulky head groups, and this binding groove is significantly larger in PPT1. This structural difference accounts for the ability of PPT2 to hydrolyze an unbranched structure such as palmitoyl-CoA but not palmitoylcysteine or palmitoylated proteins. Furthermore, differences in fatty acid chain length specificity of PPT1 and -2, also reported here, are explained by the structure and may provide a biochemical basis for their non-redundant roles.


Mapping of QTLs underlying flowering time in sorghum [Sorghum bicolor (L.) Moench].
Due to its critical importance in crop yield, the photoperiodic regulation of flowering time is considered an important trait in sorghum breeding programs. In this study, quantitative trait loci for flowering time were detected using an F(2) population derived from a cross between Kikuchi Zairai, a late-flowering cultivar originating from Japan and SC112, an early-flowering cultivar originating from Ethiopia. F(2) plants were grown with their parents under a natural day length and a 12 h day length. Two linkage maps were constructed using 213 simple sequence repeats markers. Nine quantitative trait loci controlling flowering time were identified in F(2) plants grown under a natural day length, whereas 7 QTLs were identified under a 12 h day length. Five QTLs controlling flowering time were shared under both of the day length conditions.


Congenital prosopagnosia in a child: Neuropsychological assessment, eye movement recordings and training.
Here we report the assessment and treatment of a 6-year-old boy (L.G.) who was referred to us for congenital prosopagnosia (CP). We investigated his performance using a test battery and eye movement recordings pre- and post-training. L.G. showed deficits in recognising relatives and learning new faces, and misrecognition of unfamiliar people. Eye movement recordings showed that L.G. focused on the lower part of stimuli in naming tasks based on familiar or unfamiliar incomplete or complete faces. The training focused on improving his ability to explore internal features of faces, to discriminate specific facial features of familiar and unfamiliar faces, and to provide his family with strategies to use in the future. At the end of the training programme L.G. no longer failed to recognise close and distant relatives and classmates and did not falsely recognise unknown people.


Dual Strategies for Argonaute2-Mediated Biogenesis of Erythroid miRNAs Underlie Conserved Requirements for Slicing in Mammals.
While Slicer activity of Argonaute is central to RNAi, conserved roles of slicing in endogenous regulatory biology are less clear, especially in mammals. Biogenesis of erythroid Dicer-independent mir-451 involves Ago2 catalysis, but mir-451-KO mice do not phenocopy Ago2 catalytic-dead (Ago2-CD) mice, suggesting other needs for slicing. Here, we reveal mir-486 as another dominant erythroid miRNA with atypical biogenesis. While it is Dicer dependent, it requires slicing to eliminate its star strand. Thus, in Ago2-CD conditions, miR-486-5p is functionally inactive due to duplex arrest. Genome-wide analyses reveal miR-486 and miR-451 as the major slicing-dependent miRNAs in the hematopoietic system. Moreover, mir-486-KO mice exhibit erythroid defects, and double knockout of mir-486/451 phenocopies the cell-autonomous effects of Ago2-CD in the hematopoietic system. Finally, we observe that Ago2 is the dominant-expressed Argonaute in maturing erythroblasts, reflecting a specialized environment for processing slicing-dependent miRNAs. Overall, the mammalian hematopoietic system has evolved multiple conserved requirements for Slicer-dependent miRNA biogenesis.


Going back to the roots: the microbial ecology of the rhizosphere.
The rhizosphere is the interface between plant roots and soil where interactions among a myriad of microorganisms and invertebrates affect biogeochemical cycling, plant growth and tolerance to biotic and abiotic stress. The rhizosphere is intriguingly complex and dynamic, and understanding its ecology and evolution is key to enhancing plant productivity and ecosystem functioning. Novel insights into key factors and evolutionary processes shaping the rhizosphere microbiome will greatly benefit from integrating reductionist and systems-based approaches in both agricultural and natural ecosystems. Here, we discuss recent developments in rhizosphere research in relation to assessing the contribution of the micro- and macroflora to sustainable agriculture, nature conservation, the development of bio-energy crops and the mitigation of climate change.


Evolutionary Local Search of Fuzzy Rules through a novel Neuro-Fuzzy encoding method.
This paper proposes a new approach for constructing fuzzy knowledge bases using evolutionary methods. We have designed a genetic algorithm that automatically builds neuro-fuzzy architectures based on a new indirect encoding method. The neuro-fuzzy architecture represents the fuzzy knowledge base that solves a given problem; the search for this architecture takes advantage of a local search procedure that improves the chromosomes at each generation. Experiments conducted both on artificially generated and real world problems confirm the effectiveness of the proposed approach.


[Workers in primary health care and partner violence against women].
Morbidity associated to partner violence against women (PVAW) justify these patients repeated visits to Health Services. Primary Care is the ideal place for detectión and first aid, due to its easy accesibility and continuated assistance. Nevertheless, numbers show important difficulties to achieve this goal. Our aim is to find out the level of knowledge, opinions, awareness about organizacional barriers and improvement proposals suggested by the workers of primary care. Cross-sectional descriptive study using an anonymous and voluntary survey during the months of August and September 2010, targeted to all professionals who perform their work in a Primary Care Area of Madrid. We made a descriptive analysis of variables and used chi(2) to compare the answers. Answer rate is 170 (21.4%). There are stereotypes regarding battered woman and perpetrador. 118 (70.7%) professionals believe that this is a major problem and 154 (91.7%) that usually goes unnoticed. 91 (55.2%) know their legal commitments. 73 (51.8%) think that there are organizational barriers, among them: the burden of care 50(29%), lack of specific training 40(23.5), lack of knowledge about the procedure to be followed 20(11.8%) and about the professional responsabilities 12 (7%). All profesional categoríes showed an average level of knowledge, except for social workers that was high. Primary Care workers think that PVAW is an important issue that usually goes unnoticed. Half of them know the legal commitments o detección. There are organizacional barriers and stereotypes.


Development of Anti-Insect Microencapsulated Polypropylene Films Using a Large Scale Film Coating System.
Films containing microencapsulated cinnamon oil (CO) were developed using a large-scale production system to protect against the Indian meal moth (Plodia interpunctella). CO at concentrations of 0%, 0.8%, or 1.7% (w/w ink mixture) was microencapsulated with polyvinyl alcohol. The microencapsulated CO emulsion was mixed with ink (47% or 59%, w/w) and thinner (20% or 25%, w/w) and coated on polypropylene (PP) films. The PP film was then laminated with a low-density polyethylene (LDPE) film on the coated side. The film with microencapsulated CO at 1.7% repelled P. interpunctella most effectively. Microencapsulation did not negatively affect insect repelling activity. The release rate of cinnamaldehyde, an active repellent, was lower when CO was microencapsulated than that in the absence of microencapsulation. Thermogravimetric analysis exhibited that microencapsulation prevented the volatilization of CO. The tensile strength, percentage elongation at break, elastic modulus, and water vapor permeability of the films indicated that microencapsulation did not affect the tensile and moisture barrier properties (P > 0.05). The results of this study suggest that effective films for the prevention of Indian meal moth invasion can be produced by the microencapsulation of CO using a large-scale film production system. Low-density polyethylene-laminated polypropylene films printed with ink incorporating microencapsulated cinnamon oil using a large-scale film production system effectively repelled Indian meal moth larvae. Without altering the tensile and moisture barrier properties of the film, microencapsulation resulted in the release of an active repellent for extended periods with a high thermal stability of cinnamon oil, enabling commercial film production at high temperatures. This anti-insect film system may have applications to other food-packaging films that use the same ink-printing platform.


The biological effects of antidepressants on the molluscs and crustaceans: a review.
Antidepressants are among the most commonly detected human pharmaceuticals in the aquatic environment. Since their mode of action is by modulating the neurotransmitters serotonin, dopamine, and norepinephrine, aquatic invertebrates who possess transporters and receptors sensitive to activation by these pharmaceuticals are potentially affected by them. We review the various types of antidepressants, their occurrence and concentrations in aquatic environments, and the actions of neurohormones modulated by antidepressants in molluscs and crustaceans. Recent studies on the effects of antidepressants on these two important groups show that molluscan reproductive and locomotory systems are affected by antidepressants at environmentally relevant concentrations. In particular, antidepressants affect spawning and larval release in bivalves and disrupt locomotion and reduce fecundity in snails. In crustaceans, antidepressants affect freshwater amphipod activity patterns, marine amphipod photo- and geotactic behavior, crayfish aggression, and daphnid reproduction and development. We note with interest the occurrence of non-monotonic dose responses curves in many studies on effects of antidepressants on aquatic animals, often with effects at low concentrations, but not at higher concentrations, and we suggest future experiments consider testing a broader range of concentrations. Furthermore, we consider invertebrate immune responses, genomic and transcriptomic sequencing of invertebrate genes, and the ever-present and overwhelming question of how contaminant mixtures could affect the action of neurohormones as topics for future study. In addressing the question, if antidepressants affect aquatic invertebrates at concentrations currently found in the environment, there is strong evidence to suggest the answer is yes. Furthermore, the examples highlighted in this review provide compelling evidence that the effects could be quite multifaceted across a variety of biological systems.