Rapid nongenomic estrogen signaling controls alcohol drinking behavior.

The sex steroid hormone estrogen is a key modulator of numerous physiological processes and adaptive behaviors, but it may also be co-opted to drive maladaptive behaviors. While many behavioral roles for estrogen signaling have been shown to occur through canonical genomic signaling mechanisms via nuclear receptors, estrogen can also act in a neurotransmitter-like fashion at membrane-associated estrogen receptors to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen but a causal role for estrogen in alcohol drinking has not been established. Here, we demonstrate that gonadally intact female mice consume more alcohol and display an anxiolytic phenotype when they have elevated levels of ovarian-derived estrogen across the estrous cycle. We found that rapid, nongenomic estrogen signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis (BNST) is necessary and sufficient for the pro-alcohol drinking effects of ovarian estrogen signaling, regardless of the transcriptional program of a high ovarian estrogen state. We further show that a population of corticotropin-releasing factor (CRF) BNST neurons (BNSTCRF) is a critical mediator of these effects, as high estrogen rapidly enhances synaptic excitation of BNSTCRF neurons and promotes their role in driving binge alcohol drinking. These findings show a causal role for endogenous, ovarian-derived estrogen in hormonal modulation of risky alcohol consumption and provide the first demonstration of a purely rapid, nongenomic signaling mechanism of ovarian estrogen in the brain controlling behavior in gonadally intact females.

Incidence and sociodemographic, living environment and maternal health associations with stillbirth in a tertiary healthcare setting in Kano, Northern Nigeria.

BACKGROUND: Almost two million stillbirths occur annually, most occurring in low- and middle-income countries. Nigeria is reported to have one of the highest stillbirth rates on the African continent. The aim was to identify sociodemographic, living environment, and health status factors associated with stillbirth and determine the associations between pregnancy and birth factors and stillbirth in the Murtala Mohammed Specialist Hospital, Kano, Nigeria. METHODS: A three-month single-site prospective observational feasibility study. Demographic and clinical data were collected. We fitted bivariable and multivariable models for stillbirth (yes/no) and three-category livebirth/macerated stillbirth/non-macerated stillbirth outcomes to explore their association with demographic and clinical factors. FINDINGS: 1,998 neonates and 1,926 mothers were enrolled. Higher odds of stillbirth were associated with low-levels of maternal education, a further distance to travel to the hospital, living in a shack, maternal hypertension, previous stillbirth, birthing complications, increased duration of labour, antepartum haemorrhage, prolonged or obstructed labour, vaginal breech delivery, emergency caesarean-section, and signs of trauma to the neonate following birth. INTERPRETATION: This work has obtained data on some factors influencing stillbirth. This in turn will facilitate the development of improved public health interventions to reduce preventable deaths and to progress maternal health within this site.

A qualitative focus group study concerning perceptions and experiences of Nigerian mothers on stillbirths.

OBJECTIVE: To explore the experiences and perceptions of stillbirth among mothers from a tertiary medical centre in Kano, Northern Nigeria. DESIGN: Qualitative, interpretative. SETTING: Tertiary healthcare facility, Murtala Muhammad Specialist Hospital (MMSH), Kano, Northern Nigeria. SAMPLE: Mothers who had given birth to a liveborn baby at the MMSH in the prior 6 months (n = 31). In order to capture the experiences and perception of stillbirth within this cohort we approached mothers who had in a previous pregnancy experienced a stillbirth. Of the 31 who attended 16 had a previous stillbirth. METHODS: Semi-structured Focus Group Discussions, consisting of open-ended questions about stillbirth, beliefs, experiences and influences were held in MMSH, conducted over 1 day. RESULTS: Our findings highlight that this is a resource-poor tertiary facility serving an ever-growing population, increasing strain on the hospital and healthcare workers. Many of the participants highlighted needing permission from certain family members before accessing healthcare or medical treatment. We identified that mothers generally have knowledge on self-care during pregnancy, yet certain societal factors prevented that from being their priority. Judgement and blame was a common theme, yet a complex area entwined with traditions, superstitions and the pressure to procreate with many mothers described being made to feel useless and worthless if they did not birth a live baby. CONCLUSIONS: As access to healthcare becomes easier, there are certain traditions, family and social dynamics and beliefs which conflict with scientific knowledge and act as a major barrier to uptake of healthcare services. The findings highlight the need for investment in maternity care, appropriate health education and public enlightenment; they will help inform appropriate interventions aimed at reducing stigma around stillbirth and aide in educating mothers about the importance of appropriate health seeking behaviour. Stillbirths are occurring in this area of the world unnecessarily, globally there has been extensive research conducted on stillbirth prevention. This research has highlighted some of the areas which can be tackled by modifying existing successful interventions to work towards reducing preventable stillbirths.

Rising trend of substance abuse in Pakistan: a study of sociodemographic profiles of patients admitted to rehabilitation centres.

OBJECTIVES: In Pakistan, the prevalence of drug addiction is increasing at an alarming rate. However, the risk factors, which are increasing vulnerability towards addiction, remain largely elusive. The major objective of this investigation was to study the sociodemographic variables common in addicted patients in order to identify vulnerable cohorts and risk factors, which increase predisposition towards substance abuse. STUDY DESIGN: This is a multi-site cross-sectional survey-based study. METHODS: In this study, 102 male addicted patients admitted to drug rehabilitation centres of the Islamabad/Rawalpindi and fulfilling Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for dependence, were interviewed with the help of a structured questionnaire. RESULTS: A total of 102 male patients participated in the survey. Participants mean age was 28.4 years (±9.8), whereas 14% were aged between 15 and 20 years. A large number of respondents (35%) initiated drug abuse in the teenage years. Majority of the subjects were skilled (60%) and had secondary education (47%), whereas 8% of the patients were students. Heroin was the most abused substance (48%) followed by cannabis (28%). The mean duration of substance abuse was between 1 and 5 years, whereas a significant fraction of subjects (8%) had more than 16 years of duration of abuse. Family disputes and peer pressure were the most common reasons for initiation of substance abuse. A significant fraction of patients (46%) reported to suffer from comorbid depression. CONCLUSIONS: The growing trend of abuse in highly addictive substances such as heroin in teenagers and in the skilled and educated stratum of society is of great concern and demands immediate preventive measures from the policymakers.

The volume of postoperative drainage fluid as a potential early predictor of lymphedema after lymph node excision for metastatic melanoma.

Lymphedema (LE) following lymph node dissection is a major problem for cancer patients, and radiation therapy, extended surgery, groin dissection, obesity, and older age are well-established risk factors of LE. We studied whether these risk factors are further associated with high volumes of postoperative drainage fluid after complete lymph node dissection (CLND) for melanoma metastases. Moreover, we examined whether a high amount of drainage fluid after sentinel lymph node biopsy (SLNB) can predict a high amount of drainage fluid after subsequent CLND. Using descriptive statistics and regression analyses, we analyzed the cumulative volumes of postoperative drainage fluid for 836 melanoma patients with lymph node excision in the axilla or groin. In multiple regression analyses, the well-established risk factors of LE, i.e., increased body mass index, older age, and ilioinguinal versus inguinal versus axillary dissection predicted a high drainage volume after CLND. Of note, a high drainage fluid volume after SLNB also predicted a high drainage volume after subsequent CLND. In patients with groin dissections, who are particularly susceptible to swelling, extended iliac dissection, age above 60, and a cumulative drainage volume of more than 100 ml in the preceding SLNB were predictors of the cumulative drainage volume. We find that common risk factors predict the volume of postoperative drainage fluid after CLND and postoperative LE. Further, high postoperative drainage volume may therefore function as a potential early predictor of LE following CLND.

Draft Genome Sequences of Six Different Staphylococcus epidermidis Clones, Isolated Individually from Preterm Neonates Presenting with Sepsis at Edinburgh's Royal Infirmary.

Herein, we report the draft genome sequences of six individual Staphylococcus epidermidis clones, cultivated from blood taken from different preterm neonatal sepsis patients at the Royal Infirmary, Edinburgh, Scotland, United Kingdom.

Draft Genome Sequence of a Pantoea sp. Isolated from a Preterm Neonatal Blood Sepsis Patient.

Herein, we report the draft genome sequence of Pantoea sp. ED-NGS-1003, cultivated from a blood sample taken from a neonatal sepsis patient at the Royal Infirmary, Edinburgh, Scotland, United Kingdom.

Draft Genome Sequence of a Staphylococcus aureus Isolate Taken from the Blood of a Preterm Neonatal Blood Sepsis Patient.

Herein, we report the draft genome sequence of Staphylococcus aureus ED-NGS-1006, cultivated from a blood sample taken from a neonatal sepsis patient at the Royal Infirmary in Edinburgh, Scotland, United Kingdom.

Draft Genome Sequence of an Enterococcus faecalis Strain Isolated from a Neonatal Blood Sepsis Patient.

Herein, we report the draft genome sequence of Enterococcus faecalis ED-NGS-1009, cultivated from a blood sample taken from a neonatal sepsis patient at the Royal Infirmary in Edinburgh, Scotland, United Kingdom.

Draft Genome Sequence of a Serratia marcescens Strain Isolated from a Preterm Neonatal Blood Sepsis Patient at the Royal Infirmary, Edinburgh, Scotland, United Kingdom.

Herein, we report the draft genome sequence for isolate ED-NGS-1015 of Serratia marcescens, cultivated from a blood sample obtained from a neonatal sepsis patient at the Royal Infirmary in Edinburgh, Scotland, United Kingdom.

Draft Genome Sequence of a Streptococcus agalactiae Strain Isolated from a Preterm Neonate Blood Sepsis Patient at the Royal Infirmary, Edinburgh, Scotland.

Herein, we report the draft genome sequence of Streptococcus agalactiae ED-NGS-1000, cultivated from a blood sample taken from a preterm neonate blood sepsis patient at the Royal Infirmary, Edinburgh, Scotland, United Kingdom.

Draft Genome Sequence of a Staphylococcus warneri Strain Isolated from a Preterm Neonate Blood Sepsis Patient at the Royal Infirmary, Edinburgh, Scotland.

Herein, we report the draft genome sequence of Staphylococcus warneri ED-NGS-1001, cultivated from a blood sample taken from a preterm neonate blood sepsis patient at the Royal Infirmary, Edinburgh, Scotland, United Kingdom.

Differential influence of vemurafenib and dabrafenib on patients' lymphocytes despite similar clinical efficacy in melanoma.

BACKGROUND: Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system. PATIENTS AND METHODS: Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. RESULTS: Progression-free survival (PFS) as well as overall survival (OS) were similar in patients treated with either BRAFi. High pretreatment LDH was associated with shorter PFS and OS in both groups. During therapy, peripheral lymphocytes decreased by 24.3% (median, P < 0.0001) in vemurafenib-treated patients but remained unchanged in dabrafenib-treated patients (+1.2%, P = 0.717). Differentiation of peripheral lymphocytes of vemurafenib-treated patients showed a significant decrease in CD4(+) T cells (P < 0.05). Within CD4(+) T cells obtained during treatment, an increase in CCR7(+)CD45RA(+) (naïve) and a decrease in CCR7(+)CD45RA(-) (central memory) populations were found (P < 0.01 for both). Furthermore, secretion of interferon-γ and interleukin-9 by CD4(+) T cells was significantly lower in samples obtained during vemurafenib treatment compared with baseline samples. CONCLUSION: While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4(+) T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents.

Development of a PCR-free electrochemical point of care test for clinical detection of methicillin resistant Staphylococcus aureus (MRSA).

An MRSA assay requiring neither labeling nor amplification of target DNA has been developed. Sequence specific binding of fragments of bacterial genomic DNA is detected at femtomolar concentrations using electrochemical impedance spectroscopy (EIS). This has been achieved using systematic optimisation of probe chemistry (PNA self-assembled monolayer film on gold electrode), electrode film structure (the size and nature of the chemical spacer) and DNA fragmentation, as these are found to play an important role in assay performance. These sensitivity improvements allow the elimination of the PCR step and DNA labeling and facilitate the development of a simple and rapid point of care test for MRSA. Assay performance is then evaluated and specific direct detection of the MRSA diagnostic mecA gene from genomic DNA, extracted directly from bacteria without further treatment is demonstrated for bacteria spiked into saline (10(6) cells per mL) on gold macrodisc electrodes and into human wound fluid (10(4) cells per mL) on screen printed gold electrodes. The latter detection level is particularly relevant to clinical requirements and point of care testing where the general threshold for considering a wound to be infected is 10(5) cells per mL. By eliminating the PCR step typically employed in nucleic acid assays, using screen printed electrodes and achieving sequence specific discrimination under ambient conditions, the test is extremely simple to design and engineer. In combination with a time to result of a few minutes this means the assay is well placed for use in point of care testing.

Transcriptional profiling technology for studying vaccine responses: an untapped goldmine.

There is much that we do not understand about the immune mechanisms whereby vaccines exert their specific and non-specific effects. Most studies take the reductionist approach of examining vaccine responses at the humoral or cellular level. Whole human transcriptional profiling is becoming more accessible, and provides a picture of the entire immune response to vaccination in a single 'snapshot'. The potential uses of such information are enormous, and the data mining tools are becoming more sophisticated to handle the complex data generated. We now face the exciting prospect of gaining in depth knowledge as to exactly what vaccines do to the immune system as a whole, and identifying molecular signatures and biomarkers that can predict immediate and long term outcomes of vaccination. The challenge now is to carry out the studies and generate the much needed data.

Exploiting parallel R in the cloud with SPRINT.

BACKGROUND: Advances in DNA Microarray devices and next-generation massively parallel DNA sequencing platforms have led to an exponential growth in data availability but the arising opportunities require adequate computing resources. High Performance Computing (HPC) in the Cloud offers an affordable way of meeting this need. OBJECTIVES: Bioconductor, a popular tool for high-throughput genomic data analysis, is distributed as add-on modules for the R statistical programming language but R has no native capabilities for exploiting multi-processor architectures. SPRINT is an R package that enables easy access to HPC for genomics researchers. This paper investigates: setting up and running SPRINT-enabled genomic analyses on Amazon's Elastic Compute Cloud (EC2), the advantages of submitting applications to EC2 from different parts of the world and, if resource underutilization can improve application performance. METHODS: The SPRINT parallel implementations of correlation, permutation testing, partitioning around medoids and the multi-purpose papply have been benchmarked on data sets of various size on Amazon EC2. Jobs have been submitted from both the UK and Thailand to investigate monetary differences. RESULTS: It is possible to obtain good, scalable performance but the level of improvement is dependent upon the nature of the algorithm. Resource underutilization can further improve the time to result. End-user's location impacts on costs due to factors such as local taxation. CONCLUSIONS: Although not designed to satisfy HPC requirements, Amazon EC2 and cloud computing in general provides an interesting alternative and provides new possibilities for smaller organisations with limited funds.

Nanoinformatics: developing new computing applications for nanomedicine.

Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended "nanotype" to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other -omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others.

[Multilocular pyoderma gangrenosum after uterus resection]. / Multilokuläres Pyoderma gangraenosum nach Uterusresektion.

A 71-year-old patient presented with very painful ulcers after uterus-resection with the da Vinci® Surgical System 3 months before. The anamnesis revealed that in the past 10 months similar wounds had appeared after osteosynthesis of a humerus fracture and after breast biopsy. The patient had been unsuccessfully treated with different antibiotics and wound dressings for several months for a suspected superinfected, postoperative disturbed wound healing. None of the wounds became smaller or healed completely. After exclusion of relevant differential diagnoses pyoderma gangrenosum (PG) could be diagnosed and systemic immunosuppressive therapy was initiated. The pain improved rapidly and complete wound healing was achieved. Pyoderma gangrenosum is a rarely diagnosed autoimmune disease which often occurs after physical trauma such as surgical interventions. Because a correct diagnose is usually made late it is important to be aware of this disease to treat it early and correctly.

Endometrial cysteine-rich secretory protein 3 is inhibited by human chorionic gonadotrophin, and is increased in the decidua of tubal ectopic pregnancy.

Ectopic pregnancy (EP) remains a considerable cause of morbidity and occasional mortality. Currently, there is no reliable test to differentiate ectopic from intrauterine gestation. We have previously used array technology to demonstrate that differences in gene expression in decidualized endometrium from women with ectopic and intrauterine gestations could be used to identify candidate diagnostic biomarkers for EP. The aim of this study was to further investigate the decidual gene with the highest fold increase in EP, cysteine-rich secretory protein-3 (CRISP-3). Decidualized endometrium from gestation-matched women undergoing surgical termination of pregnancy (n = 8), evacuation of uterus for miscarriage (n = 6) and surgery for EP (n = 11) was subjected to quantitative RT-PCR, morphological assessment, immunohistochemistry and western blot analysis. Sera were analysed for progesterone and human chorionic gonadotrophin (hCG) levels. Immortalized endometrial epithelial cells were cultured with physiological concentrations of hCG. CRISP-3 mRNA and protein expression were greater in endometrium from ectopic when compared with intrauterine pregnancies (P < 0.05). CRISP-3 protein was localized to epithelium and granulocytes of endometrium. CRISP-3 serum concentrations were not different in women with ectopic compared with intrauterine pregnancies. CRISP-3 expression in endometrium was not related to the degree of decidualization or to serum progesterone levels. Endometrial CRISP-3 expression was inversely proportional to serum hCG concentrations (P < 0.001). Stimulation of endometrial epithelial cells with hCG in vitro caused a reduction in CRISP-3 expression (P < 0.01). The measurement of CRISP-3 in endometrium could provide an additional tool in the diagnosis of failing early pregnancy of unknown location. The absence of a local reduction in expression of CRISP-3 in decidualized endometrium of women with EP may be due to reduced exposure to hCG due to the ectopic location of the trophoblast.