Do North Atlantic eels show parallel patterns of spatially varying selection?
The two North Atlantic eel species, the European and the American eel, represent an ideal system in which to study parallel selection patterns due to their sister species status and the presence of ongoing gene flow. A panel of 80 coding-gene SNPs previously analyzed in American eel was used to genotype European eel individuals (glass eels) from 8 sampling locations across the species distribution. We tested for single-generation signatures of spatially varying selection in European eel by searching for elevated genetic differentiation using FST-based outlier tests and by testing for significant associations between allele frequencies and environmental variables. We found signatures of possible selection at a total of 11 coding-gene SNPs. Candidate genes for local selection constituted mainly genes with a major role in metabolism as well as defense genes. Contrary to what has been found for American eel, only 2 SNPs in our study correlated with differences in temperature, which suggests that other explanatory variables may play a role. None of the genes found to be associated with explanatory variables in European eel showed any correlations with environmental factors in the previous study in American eel. The different signatures of selection between species could be due to distinct selective pressures associated with the much longer larval migration for European eel relative to American eel. The lack of parallel selection in North Atlantic eels could also be due to most phenotypic traits being polygenic, thus reducing the likelihood of selection acting on the same genes in both species.


Subacromial lipoma causing shoulder impingement syndrome.
Subacromial lipoma represents a rare cause of subacromial impingement syndrome (SIS). A 49-year-old male patient presented to clinic with progressive right shoulder pain and limited movement, ongoing for approximately 1 month. Magnetic resonance imaging (MRI) revealed a lesion, compatible with lipoma, extending through subacromial space and pressing on supraspinatus muscle. After histopathological verification of lipoma, mass was excised. Postoperatively, patient completed 1 month physical therapy and rehabilitation program. Patient was free of pain at 4-month follow-up. Subacromial lipoma should be included in differential diagnosis of SIS for patients unresponsive to conservative treatment; MRI is very useful to determine precise etiology and inform surgical treatment.


The contribution of voxel-based morphometry in staging patients with mild cognitive impairment.
To assess whether different patterns of regional gray matter loss in patients with mild cognitive impairment (MCI) are associated with different risks of conversion to Alzheimer disease (AD), using MRI and voxel-based morphometry (VBM). The authors recruited 22 patients with MCI, 22 patients with probable AD, and 20 healthy subjects (HS). T1 volumes from each subject were postprocessed according to an optimized VBM protocol. All patients were clinically followed up (mean [SD] time = 28.7 [5.7] months), and patients with MCI were reclassified into two groups (converters and nonconverters to AD). When comparing patients with AD to HS, widespread areas of reduced gray matter density were found predominantly in temporal, frontal, and parietal lobes and in the insula. Comparing MCI converters and nonconverters with HS, the converters showed more widespread areas of reduced gray matter density than nonconverters, with a pattern of abnormalities similar to that seen in patients with AD. Conversely, when comparing the same groups with patients with AD, MCI nonconverters showed a pattern of gray matter density similar to that of HS. Areas of decreased gray matter density were also found in MCI converters compared with nonconverters. Different patterns of gray matter density distribution in patients with mild cognitive impairment may be associated to different rates of conversion to Alzheimer disease.


The phosphorylation of a putative sperm microtubule-associated protein 2 (MAP2) is uniquely sensitive to regulation.
We have identified a bovine sperm phosphoprotein, pp255 (Mr = 255,000), which reacts strongly and specifically with an antibody to rat brain microtubule-associated protein 2 (MAP2). The phosphorylation state of this putative sperm MAP2 in intact bovine epididymal sperm is uniquely sensitive to regulation by intracellular pH (pHi), calcium, isobutyl-3-methylxanthine (MIX), H-8, and fluoride. Increasing pHi by approximately 0.4 units or exposure to calcium (0.1 microM with the ionophore A23187) or to the protein kinase inhibitor, H-8, decreases sperm MAP2 phosphorylation. Decreasing sperm pHi or exposure to MIX or fluoride increases MAP2 phosphorylation. Numerous other detectable sperm phosphoproteins are either unresponsive to most of these modulators or are considerably less sensitive to them. This phosphoprotein co-sediments with the particulate sperm heads during subcellular fractionation, and is not detectable in other sperm fractions. Two-dimensional electrophoresis separates sperm MAP2 into multiple species, indicative of varying degrees of phosphorylation. Sperm MAP2 is phosphorylated on serine residues, changes electrophoretic mobility slightly on one-dimensional gels with changes in phosphorylation levels, and exhibits the highest specific radioactivity of any sperm phosphoprotein observed. The phosphorylation state of sperm MAP2 can be uncoupled from sperm motility levels under several conditions. The co-localization of sperm MAP2 with the head fraction and the unique sensitivity of its phosphorylation level to modulators, which are known to regulate capacitation and the acrosome reaction, suggest that sperm MAP2 phosphorylation may be an intermediate step in the regulation of one or both of these sperm processes.


Gene expression profiling of ampullary carcinomas classifies ampullary carcinomas into biliary-like and intestinal-like subtypes that are prognostic of outcome.
Adenocarcinomas of the ampulla of Vater are classified as biliary cancers, though the exact epithelium of origin for these cancers is not known. We sought to molecularly classify ampullary adenocarcinomas in comparison to known adenocarcinomas of the pancreas, bile duct, and duodenum by gene expression analysis. We analyzed 32 fresh-frozen resected, untreated periampullary adenocarcinomas (8 pancreatic, 2 extrahepatic biliary, 8 duodenal, and 14 ampullary) using the Affymetrix U133 Plus 2.0 genome array. Unsupervised and supervised hierarchical clustering identified two subtypes of ampullary carcinomas that were molecularly and histologically characterized. Hierarchical clustering of periampullary carcinomas segregated ampullary carcinomas into two subgroups, which were distinctly different from pancreatic carcinomas. Non-pancreatic periampullary adenocarcinomas were segregated into two subgroups with differing prognoses: 5 year RFS (77% vs. 0%, p = 0.007) and 5 year OS (100% vs. 35%, p = 0.005). Unsupervised clustering analysis of the 14 ampullary samples also identified two subgroups: a good prognosis intestinal-like subgroup and a poor prognosis biliary-like subgroup with 5 year OS of 70% vs. 28%, P = 0.09. Expression of CK7+/CK20- but not CDX-2 correlated with these two subgroups. Activation of the AKT and MAPK pathways were both increased in the poor prognostic biliary-like subgroup. In an independent 80 patient ampullary validation dataset only histological subtype (intestinal vs. pancreaticobiliary) was significantly associated with OS in both univariate (p = 0.006) and multivariate analysis (P = 0.04). Gene expression analysis discriminated pancreatic adenocarcinomas from other periampullary carcinomas and identified two prognostically relevant subgroups of ampullary adenocarcinomas. Histological subtype was an independent prognostic factor in ampullary adenocarcinomas.


Frailty Is Associated With Mortality in Patients Aged 50 Years and Older.
Recent evidence indicates that increased frailty is associated with increased mortality in patients with burn over the age of 65 years. However, the effect of frailty may not be restricted to those over the age of 65 years. We hypothesize that admission frailty is associated with mortality in patients with burn ≥50 years of age. We performed a 5-year (2008-2013) retrospective review of patients with acute burn aged 50 years or older. Data collected included demographics, injury characteristics, outcomes, and discharge disposition. Frailty scores (FS) were calculated using the Canadian Study of Health and Aging Clinical Frailty Scale. Values are expressed as mean ± SD. About 502 patients with a mean age of 63.5 ± 10.7 years were ansalyzed. Mean TBSA was 11.7 ± 14.1%, 47 patients (9.4%) died, and mean FS was 3.7 ± 1.2 (7 being worst and 1 best). Multivariate logistic regression demonstrated an independent association between mortality and FS of ≥5 (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.3 to 2.8). Patients who were ≥65-years-old had significantly higher FS (4.2 ± 1.2 vs 3.5 ± 1.1), and more deaths (26 vs 21 patients). Multivariate logistic regression revealed that increased admission FS is associated with increased mortality to a greater extent in the 50- to 65-year-old group (age 50-65 years: OR, 2.5; 95% CI, 1.4 to 4.6; age ≥ 65 years: OR, 1.63; 95% CI, 1.003 to 2.7). FS on admission allow for an improved assessment of preinjury physiological condition in patients with burn aged ≥50 years. Poor preinjury physiological fitness is associated with increased risk of death in patients with burn aged ≥50 years.


Tumor boards: optimizing the structure and improving efficiency of multidisciplinary management of patients with cancer worldwide.
Multidisciplinary management tumor boards are now conducted worldwide for the management of patients with cancer. Studies evaluating their influence on decision making and patient outcome are limited; however, single-center studies have reported significant changes in diagnosis and treatment plans. A survey from Arabic countries showed widespread use and reliance on tumor boards for decision making. A recent multi-institutional survey of veteran affairs (VA) hospitals in the United States found limited association between the presence of tumor boards and care and outcomes. The Cancer Care Outcomes Research and Surveillance Consortium looked at the association between tumor board features and measures of quality of care. Results of overall survival among the patients of these physicians participating in tumor boards is ongoing, but preliminary results are outlined along with a recent ASCO survey of international members on the presence, utilization, and influence of tumor boards in this article. Tumor boards allow for implementation of clinical practice guidelines and may help capture cases for clinical trials. Efforts to improve preparations, structure, and conduct of tumor boards, research methods to monitor their performance, teamwork, and outcomes are outlined also in this article. The concept of mini-tumor boards and more efficient methods for MDM in countries with limited resources are also discussed. In suboptimal settings, such as small community hospitals, rural areas, and areas with limited resources, boundaries in diagnosis and management can be overcome, or at least improved, with tumor boards, especially with the use of video-conferencing facilities. Studies from the United Kingdom showed that special training of multidisciplinary teams (MDT) led to better team dynamics and communication, improved patient satisfaction, and improved clinical outcome. The weight of the benefits versus the time and effort spent to improve efficiency, patient care, and better time management in the United States and in the international oncology community is also reviewed in this article.


Population genetic structure of a sandstone specialist and a generalist heath species at two levels of sandstone patchiness across the Strait of Gibraltar.
Many habitat specialist species are originally composed of small, discontinuous populations because their habitats are naturally fragmented or patchy. They may have suffered the long-term effects of natural patchiness. Mediterranean heathlands, a representative habitat in the Strait of Gibraltar region, are associated with nutrient-poor, acidic sandstone soils. Sandstone soil patches in the African side of the Strait (Tangier) are, in general, smaller and more scattered than in the European side (Algeciras). In this study, we analyze the effect of this sandstone patchiness on the population genetic diversity and structure of two Erica species from these Mediterranean heathlands that differ in their edaphic specificity, E. australis, sandstone specialist, and E. arborea, generalist. Average levels of within-population genetic diversity and gene flow between populations were significantly lower in Tangier (high sandstone patchiness) than in Algeciras (low patchiness) for the sandstone specialist, whereas no differences between both sides of the Strait were detected in the edaphic generalist. Since most endemic species in Mediterranean heathlands of the Strait of Gibraltar are sandstone specialists, these results highlight an increased vulnerability to loss of genetic diversity and local extinction of the heathland endemic flora in the Tangier side of the Strait of Gibraltar.


[Psychological disorders and behavioral symptoms in dementia and differential diagnostic significance].
Dementia is one of the most common diseases in the elderly. Rapid and comprehensive diagnosis and appropriate treatment are imperatives. Over the course of the disease, psychiatric disturbances and behavioral abnormalities will frequently occur with the most variable of manifestations and forms. The burden on caregivers is immense. Patients usually respond well to a combination of milieu therapy and pharmacological management. The nature and the manifestation of the disorder can provide important clues for differential diagnosis.


[Developments in foot-and-mouth disease (FMD) vaccine production (author's transl)].
Cattle in the Netherlands are annually vaccinated with MDV-vaccine which is prepared from FMD-virus grown in 'surviving' bovine lingual epithelium. This 'Frenkel production system' which was developed in the Central Veterinary Institute during the forties and early fifties is still fully operative under practically the same conditions as those by the late Dr. Frenkel. However, recent experiments show that the method can be made more productive among others by regulating the PH. Particulary in non-European countries FMD-vaccines are prepared from virus produced in suspension cultures of a Baby-Hamster kidney (BHK) cell line. In the present author's variant of the system, virus is produced in growing BHK cells. This is possible as antibodies were removed from the serum in the culture medium by pretreatment of the serum with PEG. Virus was partly purified and concentrated by a precipation-filtration-elution (PFE) process: virus is precipated with PEG, the precipated virus is collected (with 'filter-aid') on a filter and eluted by pumping a buffer solution through the filter cake. Adequate protection of cattle was obtained with Al(OH)3-vaccines, which were prepared from these AEI-inactivated antigens. For the vaccination of pigs, satisfactory results were obtained with double-oil emulsion (W/O/W) vaccines prepared from these antigens. For long-term storage below -70 degrees C, antigen was highly concentrated (200 x) by a second PFE cycle. Purified antigen was obtained, which, if incorporated in double oil emulsion vaccines, has so far induced satisfactory protection of pigs. By this method, a strategic stock of concentrated inactivated antigen may be built up in order to make it possible to produce large amounts of vaccine in a last.minute operation.


Association of the malate dehydrogenase-citrate synthase metabolon is modulated by intermediates of the Krebs tricarboxylic acid cycle.
Mitochondrial malate dehydrogenase (MDH)-citrate synthase (CS) multi-enzyme complex is a part of the Krebs tricarboxylic acid (TCA) cycle 'metabolon' which is enzyme machinery catalyzing sequential reactions without diffusion of reaction intermediates into a bulk matrix. This complex is assumed to be a dynamic structure involved in the regulation of the cycle by enhancing metabolic flux. Microscale Thermophoresis analysis of the porcine heart MDH-CS complex revealed that substrates of the MDH and CS reactions, NAD+ and acetyl-CoA, enhance complex association while products of the reactions, NADH and citrate, weaken the affinity of the complex. Oxaloacetate enhanced the interaction only when it was present together with acetyl-CoA. Structural modeling using published CS structures suggested that the binding of these substrates can stabilize the closed format of CS which favors the MDH-CS association. Two other TCA cycle intermediates, ATP, and low pH also enhanced the association of the complex. These results suggest that dynamic formation of the MDH-CS multi-enzyme complex is modulated by metabolic factors responding to respiratory metabolism, and it may function in the feedback regulation of the cycle and adjacent metabolic pathways.


Contemporary teaching strategies of exemplary community preceptors--is technology helping?
Many schools rely upon community preceptors for office-based education of medical students. These preceptors struggle to balance clinical care with the learning needs of students. We aim to gain a deeper understanding of the teaching rewards and challenges of current community preceptors. Five schools' family medicine clerkship directors conducted in-depth interviews of two exemplary preceptors at each of their programs. Following qualitative analysis of the interviews, three directors conducted one focus group at their school. The individual and group interviews were recorded, transcribed, and analyzed using grounded theory. Exemplary community preceptors described strategies to improve the learning environment and specific teaching approaches. Well-known teaching strategies such as role modeling, adjusting instruction to the learner's needs, and selecting patients appropriate for a specific student were used. They also described newer techniques such as co-learning and integrating technology, for example, accessing online, current practice guidelines together with the student. They detailed challenges to teaching, including time constraints and too much content to cover and provided advice about teaching tools. While challenged by clinical demands, preceptors enjoyed teaching and found it rewarding. They used time-proven teaching strategies as well as technology and online resources to facilitate ambulatory teaching. Community preceptors continue to struggle to integrate learners and the priorities of the medical school curriculum into the clinical environment. Further development of electronic tools and other resources to support the teaching needs of preceptors may contribute to learning and help minimize preceptor burden.


Chorioamnionitis-induced fetal gut injury is mediated by direct gut exposure of inflammatory mediators or by lung inflammation.
Intra-amniotic exposure to proinflammatory agonists causes chorioamnionitis and fetal gut inflammation. Fetal gut inflammation is associated with mucosal injury and impaired gut development. We tested whether this detrimental inflammatory response of the fetal gut results from a direct local (gut derived) or an indirect inflammatory response mediated by the chorioamnion/skin or lung, since these organs are also in direct contact with the amniotic fluid. The gastrointestinal tract was isolated from the respiratory tract and the amnion/skin epithelia by fetal surgery in time-mated ewes. Lipopolysaccharide (LPS) or saline (controls) was selectively infused in the gastrointestinal tract, trachea, or amniotic compartment at 2 or 6 days before preterm delivery at 124 days gestation (term 150 days). Gastrointestinal and intratracheal LPS exposure caused distinct inflammatory responses in the fetal gut. Inflammatory responses could be distinguished by the influx of leukocytes (MPO(+), CD3(+), and FoxP3(+) cells), tumor necrosis factor-α, and interferon-γ expression and differential upregulation of mRNA levels for Toll-like receptor 1, 2, 4, and 6. Fetal gut inflammation after direct intestinal LPS exposure resulted in severe loss of the tight junctional protein zonula occludens protein 1 (ZO-1) and increased mitosis of intestinal epithelial cells. Inflammation of the fetal gut after selective LPS instillation in the lungs caused only mild disruption of ZO-1, loss in epithelial cell integrity, and impaired epithelial differentiation. LPS exposure of the amnion/skin epithelia did not result in gut inflammation or morphological, structural, and functional changes. Our results indicate that the detrimental consequences of chorioamnionitis on fetal gut development are the combined result of local gut and lung-mediated inflammatory responses.


The impact of safety culture, quality of care, missed care and nurse staffing on patient falls: A multisource association study.
To examine the association between nursing unit safety culture, quality of care, missed care and nurse staffing levels, and inpatient falls using two data sources: incidence of falls and nurses' perceptions of fall frequency in their units. The study explores the association between the two sources of patient falls and identifies if nurses' perceptions of patient fall frequency reflect the actual patient falls recorded in the incident management system. Inpatient falls are associated with severe complications that result in extended hospitalisation and increased financial consequences for patients and healthcare services. A multi-source cross-sectional study guided by the STROBE guidelines. A purposive sample of 33 nursing units (619 nurses) from five hospitals completed an online survey from August to November 2021. The survey measured safety culture, quality of care, missed care, nurse staffing levels and nurses' perceptions of patient fall frequency. In addition, secondary data on falls from participating units between 2018 and 2021 were also collected. Generalised linear models were fitted to examine the association between study variables. Nursing units with strong safety climate and working conditions and lower missed care were associated with lower rates of falls using both data sources. Nurses' perceptions of the frequency of falls in their units were reflective of the actual incidence rate of falls, but the association was not statistically significant. Nursing units with a strong safety climate and better collaborations between nurses and other professionals, including physicians and pharmacists, were associated with lower incidents of patient falls. This study provided evidence for healthcare services and hospital managers to minimise patient falls. Patients who had experienced a fall, which was reported in the incident management system, from the included units in the five hospitals were part of this study.


Inference for mutually exclusive competing events through a mixture of generalized gamma distributions.
Time-to-event data with 2 or more types of endpoints are found in many epidemiologic settings. Instead of treating the times for one of the endpoints as censored observations for the other, we present an alternative approach where we treat competing events as distinct outcomes in a mixture. Our objective was to determine if and how the mixture was modified in response to an intervention. We used a mixture of generalized gamma distributions to concatenate the overall frequency and distribution of the times of 2 competing events commonly observed in critical care trials, namely (1) unassisted breathing followed by discharge home alive and (2) in-hospital death. We applied our proposed methods to data from 2 randomized clinical trials of critically ill patients. Mechanical ventilation with lower tidal volumes modified the mixture (P = 0.103) when compared with traditional tidal volumes by lowering the overall frequency of death (P = 0.005), rather than through affecting either the distributions of times to unassisted breathing (P = 0.477) or times to death (P = 0.718). Likewise, use of a conservative versus a liberal fluid management modified the mixture (P < 0.001) by achieving earlier times to unassisted breathing (P < 0.001) and not through affecting the overall frequency of death (P = 0.202) or the distribution of times to death (P = 0.693). A mixture approach to competing risks provides a means to determine the overall effect of an intervention and insights into how this intervention modifies the components of the mixture.


Liposomal Amphotericin B Fosters the Corticosteroids' Anti-inflammatory Effect on Murine Allergic Bronchopulmonary Aspergillosis Model Airways.
Fungus is an antigen for bronchial asthma causing allergic bronchopulmonary mycosis (ABPM). As a therapy other than corticosteroids, itraconazole (ITCZ) is known to suppress the allergic inflammation induced by Aspergillus fumigatus (Af). However, the efficacy of liposomal amphotericin B (LAMB) with/without corticosteroid on ABPM is unknown. Mice sensitized to Dermatophagoides farinae (Df) allergen were intranasally infected with Af (DfAf group). After the infection, corticosteroid (dexamethasone (Dex)) was administered for 5 days (DfAf/Dex group). The effects of ITCZ or LAMB with/without Dex were also evaluated. Pathologically, Dex and LAMB combination treatment decreased the allergic inflammation evidently. The bronchoalveolar lavage fluid (BALF) concentrations of IL-5, IL-13, and MIP-2 were significantly elevated in DfAf mice compared with control mice (p < 0.05, each). In DfAf mice, ITCZ and LAMB significantly decreased the elevation of MIP-2 (p < 0.05 vs the DfAf group). The addition of both Dex and LAMB suppressed the MIP-2 elevation in DfAf mice (p < 0.05 vs the Df/Af/Dex/LAMB group), but the addition of Dex and ITCZ did not (DfAf/Dex/ITCZ group). None of Dex, ITCZ, or LAMB decreased pulmonary IL-13 concentration. It was suggested that combination of antifungal drugs and corticosteroid enhanced the suppressing effect of airway inflammations. This finding will give a hope for the treatment of severe fungus-related asthma.


Beta-endorphin-induced hyperglycemia in rabbits: effects of a glucose or arginine challenge.
The effects of beta-endorphin on glucose, insulin, and glucagon levels were studied in normal fasted adult male rabbits. An intravenous bolus of glucose (0.7 g/kg body wt) produced a hyperglycemic state (peak plasma glucose 306 +/- 22 mg/dl; means +/- SE) that lasted approximately 90 min. beta-Endorphin (31 micrograms/g body wt; iv) administered immediately prior to the glucose challenge resulted in plasma glucose levels that were significantly higher from 10 to 90 min after the glucose challenge (P less than 0.001-0.05). From 10 to 30 min, plasma insulin levels were significantly lower in the beta-endorphin group (P less than 0.001-0.05), peaking at one-half the control group levels. Glucagon levels were unchanged by the glucose bolus in either the control or beta-endorphin-treated group (means +/- SE = 102.8 +/- 4 pg/ml). In another experiment, a 30-min infusion of L-arginine (13 mg-1 X kg body wt-1 X min iv) in normal fasted rabbits produced a rapid (10 min) increase in plasma insulin and glucagon and a return to base-line levels 60 min after withdrawing the arginine stimulus. Plasma glucose levels were not altered by arginine (mean +/- SE = 94.5 +/- 1 mg/dl). Administration of beta-endorphin (31 micrograms/kg body wt iv) at the start of the arginine infusion resulted in a rapid (10 min) and long-lasting (up to 60 min) hyperglycemic effect associated with a significant decrease in insulin levels (10-20 min; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Microglial P2Y12 Receptor Regulates Seizure-Induced Neurogenesis and Immature Neuronal Projections.
Seizures are common in humans with various etiologies ranging from congenital aberrations to acute injuries that alter the normal balance of brain excitation and inhibition. A notable consequence of seizures is the induction of aberrant neurogenesis and increased immature neuronal projections. However, regulatory mechanisms governing these features during epilepsy development are not fully understood. Recent studies show that microglia, the brain's resident immune cell, contribute to normal neurogenesis and regulate seizure phenotypes. However, the role of microglia in aberrant neurogenic seizure contexts has not been adequately investigated. To address this question, we coupled the intracerebroventricular kainic acid model with current pharmacogenetic approaches to eliminate microglia in male mice. We show that microglia promote seizure-induced neurogenesis and subsequent seizure-induced immature neuronal projections above and below the pyramidal neurons between the DG and the CA3 regions. Furthermore, we identify microglial P2Y12 receptors (P2Y12R) as a participant in this neurogenic process. Together, our results implicate microglial P2Y12R signaling in epileptogenesis and provide further evidence for targeting microglia in general and microglial P2Y12R in specific to ameliorate proepileptogenic processes.SIGNIFICANCE STATEMENT Epileptogenesis is a process by which the brain develops epilepsy. Several processes have been identified that confer the brain with such epileptic characteristics, including aberrant neurogenesis and increased immature neuronal projections. Understanding the mechanisms that promote such changes is critical in developing therapies to adequately restrain epileptogenesis. We investigated the role of purinergic P2Y12 receptors selectively expressed by microglia, the resident brain immune cells. We report, for the first time, that microglia in general and microglial P2Y12 receptors in specific promote both aberrant neurogenesis and increased immature neuronal projections. These results indicate that microglia enhance epileptogenesis by promoting these processes and suggest that targeting this immune axis could be a novel therapeutic strategy in the clinic.


CTRP6 protects against ferroptosis to drive lung cancer progression and metastasis by destabilizing SOCS2 and augmenting the xCT/GPX4 pathway.
Lung cancer is a highly heterogeneous malignancy, and despite the rapid development of chemotherapy and radiotherapy, acquired drug resistance and tumor progression still occur. Thus, it is urgent to identify novel therapeutic targets. Our research aims to screen novel biomarkers associated with the prognosis of lung carcinoma patients and explore the potential regulatory mechanisms. We obtained RNA sequencing (RNA-seq) data of lung cancer patients from public databases. Clinical signature analysis, weighted gene coexpression network analysis (WGCNA) and the random forest algorithm showed that C1q/tumor necrosis factor-related protein-6 (CTRP6) is a core gene related to lung cancer prognosis, and it was determined to promote tumor proliferation and metastasis both in vivo and in vitro. Mechanistically, silencing CTRP6 was determined to promote xCT/GPX4-involved ferroptosis through functional assays related to lipid peroxidation, Fe2+ concentration and mitochondrial ultrastructure. By performing interactive proteomics analyses in lung tumor cells, we identified the interaction between CTRP6 and suppressor of cytokine signaling 2 (SOCS2) leading to SOCS2 ubiquitination degradation, subsequently enhancing the downstream xCT/GPX4 signaling pathway. Moreover, significant correlations between CTRP6-mediated SOCS2 and ferroptosis were revealed in mouse models and clinical specimens of lung cancer. As inducing ferroptosis has been gradually regarded as an alternative strategy to treat tumors, targeting CTRP6-mediated ferroptosis could be a potential strategy for lung cancer therapy.


Strain-dependence and cellular aspects of the acceleration of age-dependent shift in class-specific helper and suppressor activity in the thymus of MRL/Mp mice by the LPR gene.
Previous studies of the immunoregulatory activity of thymocytes from SJL/J mice have shown loss of suppressor activity for the antibody response by 24 weeks of age with appearance of helper activity. At the same time, suppressor cells developed which inhibit the generation of cytotoxic T lymphocytes (CTL). We now show a similar pattern of helper and suppressor activity in MRL/Mp mice. Presence of the lpr/lpr genotype significantly accelerated the onset of these changes in thymocyte activity. A similar pattern of thymocyte activity was not detected in C57B1/6 mice. In aged MRL-lpr mice, evidence of increased suppressor cell activity for the CTL response could be demonstrated in spleen, and the suppressor was sensitive to treatment with anti-thy 1.2 + complement. The magnitude of the deficiency in the CTL response in MRL-lpr mice was greater than could be accounted for by suppressor cell activity alone. Measurement of the frequency of CTL precursors (CTLP), the yield of CTL per CTLP, and the ability to produce and to respond to interleukin 2 (IL-2) indicated that a drop in CTLP frequency, subnormal generation of IL-2, and probably an intrinsic defect in the responsiveness of MRL-lpr CTLP to IL-2 was contributing to the defective CTL response. We were not able to link suppressor T cells with reduced responsiveness to IL-2. Ageing involves different patterns of change in immunoregulatory T-cell subsets in different strains of mice, depending on their genetic constitution. The general implications of this conclusion for prediction of immune dysfunction with age in genetically distinct members of an outbred population are discussed.


Intersegmental dynamics shape joint coordination during catching in typically developing children but not in children with developmental coordination disorder.
Factors shaping joint coordination during multijoint movements were studied using a one-handed ball-catching task. Typically developing (TD) boys between 9 and 12 yr of age, at which catching becomes consistently successful, and boys with developmental coordination disorder (DCD) of the same age participated in the study. The arm was initially stretched down. Catching was performed by flexing the shoulder and elbow and extending the wrist in the parasagittal plane. Catching success rate was substantially lower in children with DCD. Amplitudes and directions of joint motions were similar in both groups. Group differences were found in shoulder and elbow coordination patterns. TD children performed the movement predominantly by actively accelerating into flexion, one joint at a time-first the elbow and then the shoulder-and allowing passive interaction torque (IT) to accelerate the other joint into extension. Children with DCD tended to accelerate both joints into flexion simultaneously, suppressing IT. The results suggest that the TD joint coordination was shaped by the tendency to minimize active control of IT despite the complexity of the emergent joint kinematics. The inefficient control of IT in children with DCD points to deficiency of the internal model of intersegmental dynamics. Together, the findings advocate that joint coordination throughout a multijoint movement is a by-product of the control strategy that benefits from movement dynamics by actively accelerating a single joint and using IT for rotation of the other joint. Reduction of control-dependent noise is discussed as a possible advantage of this control strategy.


Oxytocin-augmented labor and risk for autism in males.
The use of synthetic oxytocin (OT) to induce and/or augment labor and delivery is on the rise. Maternal exposure to OT during birth may have adverse effects on the infant's development, including increased risk for autism. Yet, studies that test this biologically plausible association and whether it is modified by sex are limited and show inconsistent findings. To this end, we conducted an epidemiological analysis, including all singleton live births in Denmark between 2000 and 2009 (N = 557,040), with a follow-up through 2012. A total of 2110 children in this cohort were subsequently diagnosed with autistic disorder according to the ICD-10-DCR. Augmentation of labor with OT was modestly associated with an increased risk for autism in males (HR 1.13; 95% CI, 1.00-1.26; P = 0.04), but not in females (0.99; 0.77-1.27; P=0.95). Among males exposed to OT augmentation, 560 were subsequently diagnosed with autistic disorder, and among those not exposed, 1177 met criteria for autism (incidence rate 103.2 and 81.4 per 100,000 person-years, respectively). Our findings suggest a modest association between OT-augmented labor and risk for autism in males. However, given the known benefits of using synthetic OT during labor and delivery caution is warranted when interpreting the findings. Future studies should also investigate dose-dependent effect of OT on infant's development.


New drugs08, part 2.
In this article, you'll learn about eight new drugs, including: doripenem, an antibiotic for complicated intra-abdominal and urinary tract infections. Maraviroc, a new antiretroviral agent to treat HIV infection. Ixabepilone, a new drug for refractory metastatic breast cancer. Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult the package insert for information about each drug's safety during pregnancy and breast-feeding. Also consult a pharmacist, the package insert, or a comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions for all these drugs.


Implementing a user-driven online quality improvement toolkit for cancer care.
Peer-to-peer collaboration within integrated health systems requires a mechanism for sharing quality improvement lessons. The Veterans Health Administration (VA) developed online compendia of tools linked to specific cancer quality indicators. We evaluated awareness and use of the toolkits, variation across facilities, impact of social marketing, and factors influencing toolkit use. A diffusion of innovations conceptual framework guided the collection of user activity data from the Toolkit Series SharePoint site and an online survey of potential Lung Cancer Care Toolkit users. The VA Toolkit Series site had 5,088 unique visitors in its first 22 months; 5% of users accounted for 40% of page views. Social marketing communications were correlated with site usage. Of survey respondents (n = 355), 54% had visited the site, of whom 24% downloaded at least one tool. Respondents' awareness of the lung cancer quality performance of their facility, and facility participation in quality improvement collaboratives, were positively associated with Toolkit Series site use. Facility-level lung cancer tool implementation varied widely across tool types. The VA Toolkit Series achieved widespread use and a high degree of user engagement, although use varied widely across facilities. The most active users were aware of and active in cancer care quality improvement. Toolkit use seemed to be reinforced by other quality improvement activities. A combination of user-driven tool creation and centralized toolkit development seemed to be effective for leveraging health information technology to spread disease-specific quality improvement tools within an integrated health care system.


Anterior vaginal wall suspension procedure for moderate bladder and uterine prolapse as a method of uterine preservation.
We report our experience with anterior vaginal wall suspension for moderate anterior vaginal compartment prolapse and uterine descent less than stage 2. Data on patients who underwent anterior vaginal wall suspension with uterine preservation by hysteropexy and had a 1-year minimum followup were extracted from a long-term, prospective, institutional review board approved, surgical prolapse database. The indication for uterine preservation was uterine descent not beyond the distal third of the vagina with traction with the patient under anesthesia, and negative Pap smear and pelvic ultrasound preoperatively. The upper suture of the anterior vaginal wall suspension secures the cardinal ligament complex, allowing for uterine suspension once the suture is transferred suprapubically. Failure was defined as prolapse recurrence greater than stage 2 on physical examination or the need for reoperation for uterine descent. Outcome measures at serial intervals included validated questionnaires, physical examination, standing voiding cystourethrogram at 6 months postoperatively and complications. From May 1996 to March 2012, 52 of 739 patients met inclusion criteria. Mean followup was 55 months (range 12 to 175, median 44). Mean patient age was 62 years (range 38 to 81), mean body mass index was 26.7 kg/m(2) (range 18.3 to 49.4) and mean parity was 2.7. There were no transfusions or intraoperative complications. Overall 7 (13%) patients underwent subsequent hysterectomy for uterine prolapse recurrence at 7 months to 6 years postoperatively. The anterior vaginal wall suspension procedure offers a simple, mesh-free surgical alternative with acceptable long-term followup in patients with moderate uterine prolapse who wish for uterine preservation. However, patients should be appropriately counseled about the low risk of subsequent hysterectomy.


Failure to thrive: an update.
Failure to thrive in childhood is a state of undernutrition due to inadequate caloric intake, inadequate caloric absorption, or excessive caloric expenditure. In the United States, it is seen in 5 to 10 percent of children in primary care settings. Although failure to thrive is often defined as a weight for age that falls below the 5th percentile on multiple occasions or weight deceleration that crosses two major percentile lines on a growth chart, use of any single indicator has a low positive predictive value. Most cases of failure to thrive involve inadequate caloric intake caused by behavioral or psychosocial issues. The most important part of the outpatient evaluation is obtaining an accurate account of a child's eating habits and caloric intake. Routine laboratory testing rarely identifies a cause and is not generally recommended. Reasons to hospitalize a child for further evaluation include failure of outpatient management, suspicion of abuse or neglect, or severe psychosocial impairment of the caregiver. A multidisciplinary approach to treatment, including home nursing visits and nutritional counseling, has been shown to improve weight gain, parent-child relationships, and cognitive development. The long-term effects of failure to thrive on cognitive development and future academic performance are unclear.


Fully Integrated Ultrathin Solid Immersion Grating Microspectrometer for Handheld Visible and Near-Infrared Spectroscopic Applications.
Despite advances in microfabrication, compact spectrometers still face challenges in shrinking their size without sacrificing optical performance. Here, the solid immersion grating microspectrometer (SIG-µSPEC) for high spectral resolution in a broad operational wavelength range is reported. The spectroscopic module incorporates a silicon microslit, index-matched lens, plane mirrors, solid immersion grating (SIG), and a CMOS line sensor within a small form factor. The SIG facilitates high angular dispersion of light on a planar focal plane, resulting in an average spectral resolution of 5.8 nm, with over 76% maximum sensitivity from 400 to 800 nm. SIG-µSPEC measures the spectral reflectance of fruits at different ripening stages, clearly revealing changes in the chlorophyll absorption band. The measured spectrum is further utilized for the precise prediction of the soluble solid content (SSC) levels, achieving a high correlation (R2 = 0.91) and a ratio of prediction-to-deviation of 2.36. This compact microspectrometer holds the potential for precise and non-invasive spectral analysis across point-of-care fields.


SYMPTOMATOLOGY AND COMORBIDITY OF SOMATIZATION DISORDER AMONGST GENERAL OUTPATIENTS ATTENDING A FAMILY MEDICINE CLINIC IN SOUTH WEST NIGERIA.
Individuals with somatization may be the most difficult to manage because of the diverse and frequent complaints across many organ systems. They often use impressionistic language to describe circumstantial symptoms which though bizarre, may resemble genuine diseases. The disorder is best understood in the context "illness" behaviour, masking underlying mental disorder, manifesting solely as somatic symptoms or with comorbidity. To evaluate somatization symptoms and explore its comorbidity in order to improve the management of these patients. A cross-sectional survey of 60 somatizing patients who were part of a case-control study, selected by consecutive sampling of 2668 patients who presented at the Family Medicine Clinic of University College Hospital Ibadan, Nigeria between May-August 2009. Data was collected using the ICPC-2, WHO- Screener and Diagnostic Schedule and analysed with SPSS 16. There were at least 5 symptoms of somatization in 93.3% of the patients who were mostly females. Majority had crawling sensation, "headache", unexplained limb ache, pounding heart, lump in the throat and insomnia. The mean age at onset was 35yrs with 90% having recurrence of at least 10yrs.Approximately 54% had comorbidity with cardiovascular disease being the most prevalent. The study revealed that somatization is not a specific disease but one with a spectrum of expression. This supports proposition that features for the diagnosis of somatization could be presence of three or more vague symptoms and a chronic course lasting over two years. It is important to be conversant with pattern of symptoms and possible comorbidity for effective management of these patients.


Antitumor polycyclic acridines. 20. Search for DNA quadruplex binding selectivity in a series of 8,13-dimethylquino[4,3,2-kl]acridinium salts: telomere-targeted agents.
The growth-inhibitory activities of an extensive series of quaternized quino[4,3,2- kl]acridinium salts against tumor cell lines in vitro have been measured and their biological properties interpreted in the light of differential binding to different DNA isoforms. Selectivity for quadruplex DNA binding and stabilization by compounds were explored through an array of methods: UV absorption and fluorescence emission spectroscopy, surface plasmon resonance, and competition dialysis. Quadruplex DNA interaction was further characterized through FRET and DNA polymerase arrest assays. Telomerase inhibition, inferred from the TRAP assay, is attributed to quadruplex stabilization, supported by the strong correlation (R(2) = 0.81) across the series between quadruplex DNA binding affinity and TRAP inhibition potency. Growth inhibition potency in the NCI60 human tumor cell line panel is more marked in compounds with greater DNA duplex binding affinity (R(2) = 0.82). Quantification of relative quadruplex and duplex binding affinity constants puts some of these ligands among the most selective quadruplex DNA interactive agents reported to date.


Current therapies in hepatorenal syndrome.
Hepatorenal syndrome (HRS) is a serious complication of liver cirrhosis with critically poor prognosis. The pathophysiologic hallmark is severe renal vasoconstriction, resulting from complex changes in splanchnic and general circulations as well as systemic and renal vasoconstrictors and vasodilators. Rapid diagnosis and management are important, since recent treatment modalities including vasoconstrictor therapy can improve short-term outcome and buy time for liver transplantation, which can result in complete recovery.


The replication focus targeting sequence (RFTS) domain is a DNA-competitive inhibitor of Dnmt1.
Dnmt1 (DNA methyltransferase 1) is the principal enzyme responsible for maintenance of cytosine methylation at CpG dinucleotides in the mammalian genome. The N-terminal replication focus targeting sequence (RFTS) domain of Dnmt1 has been implicated in subcellular localization, protein association, and catalytic function. However, progress in understanding its function has been limited by the lack of assays for and a structure of this domain. Here, we show that the naked DNA- and polynucleosome-binding activities of Dnmt1 are inhibited by the RFTS domain, which functions by virtue of binding the catalytic domain to the exclusion of DNA. Kinetic analysis with a fluorogenic DNA substrate established the RFTS domain as a 600-fold inhibitor of Dnmt1 enzymatic activity. The crystal structure of the RFTS domain reveals a novel fold and supports a mechanism in which an RFTS-targeted Dnmt1-binding protein, such as Uhrf1, may activate Dnmt1 for DNA binding.


Stimulation of surfactant phospholipid biosynthesis in the lungs of rats treated with silica.
The effects of intratracheally instilled silica (10 mg/rat) on the biosynthesis of surfactant phospholipids was investigated in the lungs of rats. The sizes of the intracellular and extracellular pools of surfactant phospholipids were measured 7, 14 and 28 days after silica exposure. The ability of lung slices to incorporate [14C]choline and [3H]palmitate into surfactant phosphatidylcholine (PC) and disaturated phosphatidylcholine (DSPC) was also investigated. Both intra- and extra-cellular pools of surfactant phospholipids were increased by silica treatment. The intracellular pool increased linearly over the 28-day time period, ultimately reaching a size 62-fold greater than controls. The extracellular pool also increased, but showed a pattern different from that of the intracellular pool. The extracellular pool increased non-linearly up to 14 days, and then declined. At its maximum, the extracellular pool was increased 16-fold over the control. The ability of lung slices to incorporate phospholipid precursors into surfactant-associated PC and DSPC was elevated at all time periods. The rate of incorporation of [14C]choline into surfactant PC and DSPC was maximal at 14 days and was nearly 3-fold greater than the rate in controls. The rate of incorporation of [3H]palmitate was also maximal at 14 days, approx. 5-fold above controls for PC and 3-fold for DSPC. At this same time point, the microsomal activity of cholinephosphate cytidylyltransferase was increased 4.5-fold above controls, but cytosolic activity was not significantly affected by silica treatment. These data indicate that biosynthesis of surfactant PC is elevated after treatment of lungs with silica and that this increased biosynthesis probably underlies the expansion of the intra- and extra-cellular pools of surfactant phospholipids.


Purification, Characterization and in vitro Evaluation of Polymyxin A From Paenibacillus dendritiformis: An Underexplored Member of the Polymyxin Family.
Nosocomial infections caused by antibiotic-resistant Gram-negative pathogens are of grave concern today. Polymyxins are considered as the last resorts of therapy to treat these multi-drug resistant (MDR) bacteria. But their associated nephrotoxicity and neurotoxicity calls for the development of safer polymyxin therapy until novel and less toxic antibiotics are discovered. No other polymyxin molecule except polymyxin B and E (colistin) is explored thoroughly in literature to demonstrate its clinical relevance. In the present study, we have isolated two antimicrobial compounds named P1 and P2 from the soil isolate Paenibacillus dendritiformis strain PV3-16, which we later identified as polymyxin A2 and A1 respectively. We tested their minimum inhibitory concentrations (MICs) against MDR clinical isolates, performed membrane permeabilization assays and determined their interaction with lipopolysaccharide (LPS). Finally, we studied their toxicity against human Leukemic monocyte cell line (THP-1) and embryonic kidney cell line (HEK 293). Both compounds displayed equal efficacy when compared with standard polymyxins. P1 was 2-4 fold more active in most of the clinical strains tested. Moreover, P1 showed higher affinity toward LPS. In cytotoxicity studies, P1 had IC50 value (>1000 μg/ml) similar to colistin against HEK cells but immune cells, i.e., THP-1 cell lines were more sensitive to polymyxins. P1 showed less toxicity in THP-1 cell line than all other polymyxins checked. To sum up, P1 (polymyxin A2) possessed better efficacy than polymyxin B and E and had least toxicity to immune cells. Since polymyxin A was not investigated thoroughly, we performed the comprehensive in vitro assessment of this molecule. Moreover, this is the first report of isolation and characterization of polymyxin A from P. dendritiformis. This compound should be further investigated for its in vivo efficacy and toxicity to develop it as a drug candidate.


Effect of carboxymethylcellulose and a hyaluronate-carboxymethylcellulose membrane on healing of intestinal anastomoses in horses.
To evaluate the effect of sodium carboxymethylcellulose (SCMC) or a hyaluronate-carboxymethylcellulose membrane (HA membrane) on healing of the small intestine in horses. 18 healthy adult horses. Midline celiotomy and 2 jejunal resection-and-anastomosis surgeries were performed. In treated horses, SCMC (n = 6) or a HA membrane (6) was applied to the jejunum to cover the anastomosis. There were 6 untreated control horses. Horses were euthanatized 10 days after surgery. For each horse, 1 anastomosis was used for histologic examination, and the second was used to determine intestinal bursting strength. Intestinal bursting tension, serosal granulation tissue, serosal fibrin deposition, and width of the fibrous seal at the anastomosis were compared among groups. 3 control horses had adhesions associated with the anastomosis, but none of the treated horses had adhesions associated with the anastomosis. Mean thickness of fibrin deposited on the serosal surfaces for the SCMC and HA-membrane groups was significantly less than that for control horses. Mean thickness of serosal granulation tissue, width of fibrous seal between inverted musculature, inflammatory cell infiltrate scores, and bursting tension did not differ significantly among groups. Use of SCMC or application of a HA membrane to small intestinal anastomoses in horses resulted in fewer adhesions and decreased fibrin deposition, and it did not adversely affect anastomotic healing. In horses at increased risk for intra-abdominal adhesions, SCMC or application of HA membranes may decrease the frequency of adhesions without adversely affecting healing of small intestinal anastomoses.


Detection of Toxoplasma gondii in three common bottlenose dolphins (Tursiops truncatus); A first description from the Eastern Mediterranean Sea.
Toxoplasma gondii has been described in several marine mammals around the world including numerous species of cetaceans, yet infection and transmission mechanisms in the marine environment are not clearly defined. The Israel Marine Mammal Research and Assistance Center has been collating a database of all marine mammal stranding events along the country's national coastlines since 1993. In this study, we describe the molecular detection and characterisation of T. gondii in three common bottlenose dolphins (Tursiops truncatus) including one case of coinfection with herpesvirus. The animals were found stranded on the Mediterranean coast of Israel in May and November 2013. In one of the three cases, the dolphin was found alive and admitted to intensive care. To our knowledge, this is the first report of T. gondii infection of marine mammals in the Eastern Mediterranean Sea. As this parasite acts as an indicator for marine pollution and marine mammal health, we believe these findings add important information regarding the state of the environment in this region.


Endovascular electrocoagulation: concept, technique, and experimental results.
To evaluate the safety and efficacy of an embolotherapeutic technique that uses electrolytically detachable platinum coils and radio frequency (RF) energy to achieve rapid and distal occlusion of targeted vessels. In swine, branches of the ascending cervical artery and the hepatic artery measuring 1.5 mm or less were subjected to endovascular electrocoagulation. RF energy was delivered through modified Guglielmi detachable platinum coils that were placed in the targeted arteries. Ohmic heating generated by RF caused vessel occlusion. After the vessel occlusions were confirmed angiographically, the platinum microcoils were electrolytically detached from the delivery wire and left in the vessels as implants. All vessels were rapidly and superselectively occluded by endovascular electrocoagulation. Following use of the appropriate methods derived from this research, we did not observe rupture of the artery, dissection of the artery, unintended occlusion, or migration of the platinum microcoil. Histologic examination of treated vessels at 6 and 12 weeks revealed obliteration of the vessel lumen by the platinum microcoil surrounded by granulation tissue. Endovascular electrocoagulation is a rapid method of achieving vessel occlusion. It may be a useful and controllable embolotherapeutic technique when expeditious occlusion of small vessels and distal superselectivity are desired.


Cardioprotective Effects of Nanoemulsions Loaded with Anti-Inflammatory Nutraceuticals against Doxorubicin-Induced Cardiotoxicity.
Doxorubicin is a highly active antineoplastic agent, but its clinical use is limited because of its cardiotoxicity. Although nutraceuticals endowed with anti-inflammatory properties exert cardioprotective activity, their bioavailability and stability are inconsistent. In an attempt to address this issue, we evaluated whether bioavailable nanoemulsions loaded with nutraceuticals (curcumin and fresh and dry tomato extracts rich in lycopene) protect cardiomyoblasts (H9C2 cells) from doxorubicin-induced toxicity. Nanoemulsions were produced with a high-pressure homogenizer. H9C2 cells were incubated with nanoemulsions loaded with different nutraceuticals alone or in combination with doxorubicin. Cell viability was evaluated with a modified MTT method. The levels of the lipid peroxidation products malondialdehyde (MDA) and 4-hydroxy-2-butanone (4-HNA), and of the cardiotoxic-related interleukins IL-6, IL-8, IL-1β and IL-10, tumor necrosis factor-alpha (TNF-α), and nitric oxide were analyzed in cardiomyoblasts. The hydrodynamic size of nanoemulsions was around 100 nm. Cell viability enhancement was 35⁻40% higher in cardiomyoblasts treated with nanoemulsion + doxorubicin than in cardiomyoblasts treated with doxorubicin alone. Nanoemulsions also protected against oxidative stress as witnessed by a reduction of MDA and 4-HNA. Notably, nanoemulsions inhibited the release of IL-6, IL-8, IL-1β, TNF-α and nitric oxide by around 35⁻40% and increased IL-10 production by 25⁻27% versus cells not treated with emulsions. Of the nutraceuticals evaluated, lycopene-rich nanoemulsions had the best cardioprotective profile. In conclusion, nanoemulsions loaded with the nutraceuticals described herein protect against cardiotoxicity, by reducing inflammation and lipid oxidative stress. These results set the stage for studies in preclinical models.


Medico-legal implications of hypoxic-ischemic birth injury.
Medical malpractice litigation in the USA and much of the developed world has reached near-epidemic proportions. Brain-damaged infants are among the most costly medical malpractice lawsuits, with the average indemnity for these cases being $524,047. Hypoxic-ischemic encephalopathy (HIE) is the most common birth injury claim, generally alleging that intrapartum asphyxia led to long-term neurologic sequelae, including cerebral palsy and/or developmental delay. Timing of injury is a key element in the legal arena. The plaintiff will try to prove that injury occurred in the intrapartum period, whereas the defense may argue that it occurred prenatally. A recent American Academy of Pediatrics/American College of Obstetricians and Gynecologists Task Force on Neonatal Encephalopathy developed a checklist that needs to be fulfilled in order to establish a reasonable causal link between an intrapartum asphyxial insult and subsequent long-term neurologic disability. Therapeutic hypothermia has been shown to benefit certain infants born with moderate to severe HIE by improving neurologic outcomes. Since the advent of hypothermic neuroprotection, new malpractice allegations have arisen, including the failure to refer a baby for cooling and failure to initiate cooling in a timely manner. In all cases, documentation of the status of the baby at birth, including a thorough neurologic exam, can be extremely helpful to the later defense of a malpractice claim, which might occur years later.


Epidemiology of acute otitis media among young children: a multiple database study in Taiwan.
Acute otitis media (AOM) is a common complication of upper respiratory tract infection (URTI) among children. The purpose of this study was to evaluate the epidemiology of AOM among young children in Taiwan, including the age incidence and seasonality by combining multiple databases. Two country-based questionnaire survey studies had been conducted to evaluate the experience of otitis media (OM) among young children: one in 2007 and the other between 2005 and 2010. The number of OM cases (5% of population younger than 7 years) in 2005 and annual visiting rates for URTI from 2005 to 2010 obtained from the National Health Insurance Research Database of Taiwan were collected and comprised the third database. The fourth database comprised ambulatory visits of children with OM to a medical center in central Taiwan between 2005 and 2010. Data from a total of 1099 questionnaires were entered into Database I in 2007, and data from 9705 questionnaires between 2005 and 2010 comprised Database II. There were 86,702 children (younger than 7 years, representing 5% of the whole population for this age group) retrieved from Database III in 2007, and 5,904 cases of OM in children between 2005 and 2010 in a hospital. In Database I, 7.46% children experienced at least one episode of AOM compared with 9.21% in Database II for children aged 5 years and younger. In Database III, 13.2% children younger than 7 years had AOM in 2005. The peak season of AOM among children was from March to May (Databases III and IV). AOM was thought to be a very common disease among children; however, this comparative analysis showed that the overall prevalence of AOM among children younger than 5 years was only 20%, much lower than in other countries. AOM was more prevalent during the spring season, and still was similarly common after age 2 years.


Mobile Sensing in Environmental Health and Neighborhood Research.
Public health research has witnessed a rapid development in the use of location, environmental, behavioral, and biophysical sensors that provide high-resolution objective time-stamped data. This burgeoning field is stimulated by the development of novel multisensor devices that collect data for an increasing number of channels and algorithms that predict relevant dimensions from one or several data channels. Global positioning system (GPS) tracking, which enables geographic momentary assessment, permits researchers to assess multiplace personal exposure areas and the algorithm-based identification of trips and places visited, eventually validated and complemented using a GPS-based mobility survey. These methods open a new space-time perspective that considers the full dynamic of residential and nonresidential momentary exposures; spatially and temporally disaggregates the behavioral and health outcomes, thus replacing them in their immediate environmental context; investigates complex time sequences; explores the interplay among individual, environmental, and situational predictors; performs life-segment analyses considering infraindividual statistical units using case-crossover models; and derives recommendations for just-in-time interventions.


Untemplated nonenzymatic polymerization of 3',5'cGMP: a plausible route to 3',5'-linked oligonucleotides in primordia.
The high-energy 3',5' phosphodiester linkages conserved in 3',5' cyclic GMPs offer a genuine solution for monomer activation required by the transphosphorylation reactions that could lead to the emergence of the first simple oligonucleotide sequences on the early Earth. In this work we provide an in-depth characterization of the effect of the reaction conditions on the yield of the polymerization reaction of 3',5' cyclic GMPs both in aqueous environment as well as under dehydrating conditions. We show that the threshold temperature of the polymerization is about 30 °C lower under dehydrating conditions than in solution. In addition, we present a plausible exergonic reaction pathway for the polymerization reaction, which involves transient formation of anionic centers at the O3' positions of the participating riboses. We suggest that excess Na(+) cations inhibit the polymerization reaction because they block the anionic mechanism via neutralizing the negatively charged O3'. Our experimental findings are compatible with a prebiotic scenario, where gradual desiccation of the environment could induce polymerization of 3',5' cyclic GMPs synthesized in liquid.


Down regulation of macrophage IFNGR1 exacerbates systemic L. monocytogenes infection.
Interferons (IFNs) target macrophages to regulate inflammation and resistance to microbial infections. The type II IFN (IFNγ) acts on a cell surface receptor (IFNGR) to promote gene expression that enhance macrophage inflammatory and anti-microbial activity. Type I IFNs can dampen macrophage responsiveness to IFNγ and are associated with increased susceptibility to numerous bacterial infections. The precise mechanisms responsible for these effects remain unclear. Type I IFNs silence macrophage ifngr1 transcription and thus reduce cell surface expression of IFNGR1. To test how these events might impact macrophage activation and host resistance during bacterial infection, we developed transgenic mice that express a functional FLAG-tagged IFNGR1 (fGR1) driven by a macrophage-specific promoter. Macrophages from fGR1 mice expressed physiologic levels of cell surface IFNGR1 at steady state and responded equivalently to WT C57Bl/6 macrophages when treated with IFNγ alone. However, fGR1 macrophages retained cell surface IFNGR1 and showed enhanced responsiveness to IFNγ in the presence of type I IFNs. When fGR1 mice were infected with the bacterium Listeria monocytogenes their resistance was significantly increased, despite normal type I and II IFN production. Enhanced resistance was dependent on IFNγ and associated with increased macrophage activation and antimicrobial function. These results argue that down regulation of myeloid cell IFNGR1 is an important mechanism by which type I IFNs suppress inflammatory and anti-bacterial functions of macrophages.


Hydrodynamic Hunters.
The Gram-negative Bdellovibrio bacteriovorus (BV) is a model bacterial predator that hunts other bacteria and may serve as a living antibiotic. Despite over 50 years since its discovery, it is suggested that BV probably collides into its prey at random. It remains unclear to what degree, if any, BV uses chemical cues to target its prey. The targeted search problem by the predator for its prey in three dimensions is a difficult problem: it requires the predator to sensitively detect prey and forecast its mobile prey's future position on the basis of previously detected signal. Here instead we find that rather than chemically detecting prey, hydrodynamics forces BV into regions high in prey density, thereby improving its odds of a chance collision with prey and ultimately reducing BV's search space for prey. We do so by showing that BV's dynamics are strongly influenced by self-generated hydrodynamic flow fields forcing BV onto surfaces and, for large enough defects on surfaces, forcing BV in orbital motion around these defects. Key experimental controls and calculations recapitulate the hydrodynamic origin of these behaviors. While BV's prey (Escherichia coli) are too small to trap BV in hydrodynamic orbit, the prey are also susceptible to their own hydrodynamic fields, substantially confining them to surfaces and defects where mobile predator and prey density is now dramatically enhanced. Colocalization, driven by hydrodynamics, ultimately reduces BV's search space for prey from three to two dimensions (on surfaces) even down to a single dimension (around defects). We conclude that BV's search for individual prey remains random, as suggested in the literature, but confined, however-by generic hydrodynamic forces-to reduced dimensionality.


Development of a highly sensitive enzyme-linked immunosorbent assay (ELISA) through use of poly-protein G-expressing cell-based microplates.
The sensitivity of traditional enzyme-linked immunosorbent assays (ELISAs) is limited by the low binding avidity and heterogeneous orientation of capture antibodies coated on polystyrene-based microplates. Here, we developed a highly sensitive ELISA strategy by fixing poly-protein G-expressing cells on microplates to improve the coating amount and displayed orientation of capture antibodies. One or eight repeated fragment crystallisable (Fc) binding domains of protein G are stably expressed on the surface of BALB/c 3T3 cells (termed 1pG cells or 8pG cells), which then act as highly antibody-trapping microparticles. The 8pG cells showed higher antibody-trapping ability than the 1pG cells did. The antibody-coating amount of the 8pG cell-based microplates was 1.5-23 times and 1.2-6.8 times higher than that of traditional polystyrene-based and commercial protein G-based microplates, respectively. The 8pG cell-based microplates were then applied to an anti-IFN-α sandwich ELISA and an anti-CTLA4 competitive ELISA, respectively, and dramatically enhanced their detection sensitivity. Importantly, direct coating unpurified capture antibody produced by mammalian cells did not impair the antigen-capturing function of 8pG cell-based microplates. The 8pG cell-based microplates exhibited a significant improvement in antibody-coating amount and preserved the homogeneous orientation of capture antibodies, making them a potential replacement for traditional microplates in various formats of ELISAs.


Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison.
Indacaterol is a novel, inhaled, once-daily, ultra-long-acting β(2)-agonist bronchodilator recently approved in Europe for the treatment of chronic obstructive pulmonary disease (COPD). The aim of the present study was to investigate the efficacy and safety of indacaterol compared with placebo and the twice-daily β(2)-agonist, salmeterol, as an active control. Patients with moderate-to-severe COPD were randomised to 6 months double-blind treatment with indacaterol (150 μg once daily), salmeterol (50 μg twice daily) or placebo. The primary efficacy end-point was trough (24 h post-dose) forced expiratory volume in 1 s (FEV(1)) after 12 weeks. 1,002 patients were randomised and 838 (84%) completed the study. Indacaterol increased trough FEV(1) at week 12 by 170 mL over placebo (p<0.001) and by 60 mL over salmeterol (p<0.001). Both active treatments improved health status (St George's Respiratory Questionnaire) and dyspnoea (transition dyspnoea index) compared with placebo, with differences between them favouring indacaterol. Safety profiles were similar across the treatment groups, and both indacaterol and salmeterol were well tolerated. Once-daily treatment with 150 μg indacaterol had a significant and clinically relevant bronchodilator effect over 24 h post-dose and improved health status and dyspnoea to a greater extent than twice-daily 50 μg salmeterol. Indacaterol should prove a useful additional treatment for patients with COPD.


The role of the cysteine-rich region of the beta2 integrin subunit in the leukocyte function-associated antigen-1 (LFA-1, alphaLbeta2, CD11a/CD18) heterodimer formation and ligand binding.
The cysteine-rich region (CRR) of the beta2 integrin subunit was replaced by that of beta1 to give the chimera beta2NV1. Beta2NV1 can combine with alphaL to form a variant leukocyte-function-associated antigen (LFA)-1 on COS cell surface, suggesting that the specificity of the beta2 interaction with alphaL does not lie in the CRR. Unlike those expressing wild-type LFA-1, COS cells expressing alphaL beta2NV1 are constitutively active in intercellular adhesion molecule (ICAM)-1 adhesion. These results suggest that activation of LFA-1 involves the release of an intramolecular constraint, which is maintained, in part, by the authentic beta2 CRR.


99Tc(m) labelled HL91 versus computed tomography and biopsy for the visualization of tumour recurrence of squamous head and neck carcinoma.
This phase I pilot study reports on (1) the safety and feasibility of 99Tc(m)-HL91, an amine oxime core radioligand that has shown oxygen dependent binding, and imaging; and (2) its usefulness for the visualization of local tumour recurrence of a biopsy proven squamous cell carcinoma of the head and neck (SCCHN) as compared to spiral computed tomogaphy (CT) and biopsy. Nine men (mean age 33 years, range 34-74 years) were prospectively included. For safety measurements, vital signs were recorded and serum chemical analysis carried out, with a complete blood cell count and urine analysis, and an ECG was performed prior to injection of 99Tc(m)-HL91 and repeated during the investigation. Single photon emission computed tomography (SPECT) scans of the head and neck, and of a standard, were performed at 2 h and 4 h post-injection of 740 MBq 99Tc(m)-HL91. Tumour-to-normal tissue background (T/N) ratios and percentage uptake were measured for all 99Tc(m)-HL91 scans. Spiral CT scans were obtained using a Somaton 4+ Siemens scanner within 1 week from the 99Tc(m)-HL91 scans. Based on CT and the 99Tc(m)-HL91 scan findings guided biopsies were performed. No adverse or subjective side effects were noticed. Vital signs, ECG findings, clinical laboratory, blood and urine assays remained stable in all patients. Spiral CT suggested local recurrence in 5/9 patients accompanied by nodal involvement in three, all of which proved positive on biopsy. 99Tc(m)-HL91 scintigraphy was false positive in one patient and true positive (TP) in 3/5 local recurrences and two out of three sites of lymph node involvement depicted by spiral CT. The mean T/N ratios at 2 h and 4 h in TPs were 1.28 (range 1.1-1.66) and 1.40 (range 1.0-1.6), respectively. The corresponding absolute percentages of 99Tc(m)-HL91 lesional uptake at 2 h and 4 h were mu = 0.05% (SD = 0.03%) and mu = 0.048% (SD = 0.035%). The findings suggest 99Tc(m)-HL91 is a safe radioligand and that metabolic binding in a large fraction but not all of local SCCHN recurrences may be expected. The inference that tumour 99Tc(m)-HL91 avidity could be a non-invasive measure of tumour hypoxia deserves however independent confirmation with needle oximetry.


Dynamics of parent-adolescent communication on sexual health and HIV/AIDS in Tanzania.
Communication between parents and their adolescent children has been identified as one of the potential protective factors for adolescent sexual health. Qualitative exploration of sexual health communication with adolescents aged 12-15 (N = 114) and a sub-group of the parents (N = 20) was carried out. Four major themes emerged: reasons for parent-adolescent communications, or lack thereof; the focus of parental messages; the moral of the message; and the barriers to communication between parents and adolescents. Findings revealed similarities and discrepancies in views and perceptions between parents and adolescents. Adolescents and parents suggested that some sexual health communication was happening. Parents were reportedly likely to use fear to ensure that their children do not engage in risky sexual activities, while adolescents reported that conversations with their parents were mostly ambiguous and filled with warnings about the dangers of HIV/AIDS. Several communication barriers were reported by parents and adolescents. Parents of adolescents would benefit from HIV/AIDS specific communication skills.


[Dyslipidemia management in children and adolescents: recommendations of the Nutrition Branch of the Chilean Society of Pediatrics].
The prevalence of dyslipidemia has dramatically increased in children and adolescents, and many of these cases are associated with increased obesity. As this condition represents cardiovascular risk in the future, the bases of its treatment should be widely known. In the vast majority of patients, there will be lifestyle changes, specific diet and increased physical activity, usually all of these resulting in a favorable response. Only a minority will require drug treatment, which must be prescribed by a specialist in the context of a comprehensive cardiovascular risk assessment, including the patient and his family. The prevention of cardiovascular risk factors should be performed by all members of the health team. This article presents the recommendations of the Nutrition specialists of the Chilean Society of Pediatrics for screening, diagnosis and treatment of dyslipidemia in childhood.


Cardiovascular Risk Factors in Parents of Food-Allergic Children.
Previous studies suggest that chronic stress may induce immune system malfunction and a broad range of adverse health outcomes; however, the underlying pathways for this relationship are unclear. Our study aimed to elucidate this question by examining the relationship between parental cardiovascular risk factors including systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and waist-to-hip ratio (WHR) and maternal psychological stress score (MPSS) relative to the severity of the child's food allergy (FA) and number of affected children. SBP, DBP, BMI, and WHR were measured and calculated at the time of recruitment by trained nurses. MPSS was obtained based on self-report questionnaires covering lifestyle adjustments, perceived chronic stress, and quality of life. General linear models examined whether caregiver chronic stress was associated with FA. For mothers with children under age 5 years, SBP, DBP and number of affected children had strong and graded relationships with severity of the child's FA. MPSS was also significantly and positively associated with child FA severity (P < 0.001). However, no relationships were found between FA severity, BMI, or WHR for either parent. This was also the case for paternal SBP, DBP, and number of affected children of any age. There is a strong and graded link between cardiovascular risk and perceived stress in mothers of food-allergic children under age 5. Findings may have important implications for family-centered care of FA, may generalize to caregivers of children with chronic conditions, and extend the literature on allostatic load.


To PAPR or not to PAPR?
The present outbreak of Ebola has health care professionals seeking guidance on isolation precautions for routine care and aerosol-generating procedures (AGPs). The most recent guidelines state that during AGPs, health care professionals should wear respiratory protection at least as protective as a National Institute for Occupational Safety and Health-certified fit tested N95 filtering face piece respirator or higher; for example, a powered air-purifying respirator (PAPR). The present review discusses the advantages and disadvantages of using a PAPR versus an N95 mask, and relates the experience of the Jewish General Hospital (Montreal, Quebec) of PAPR policy implementation. Training programs on proper donning and doffing of personal protective equipment and quality control systems need to be in place. Respiratory therapists are frontline during AGPs and need to be active in the decision making of the type of equipment chosen to protect them.


Phylogeny of the Ascaridoidea (Nematoda: Ascaridida) based on three genes and morphology: hypotheses of structural and sequence evolution.
Ascaridoid nematodes parasitize the gastrointestinal tract of vertebrate definitive hosts and are represented by more than 50 described genera. We used 582 nucleotides (83% of the coding sequence) of the mitochondrial gene cytochrome oxidase subunit 2, in combination with published small- and large-subunit nuclear rDNA sequences (2,557 characters) and morphological data (20 characters), to produce a phylogenetic hypothesis for representatives of this superfamily. This combined evidence phylogeny strongly supported clades that, with 1 exception, were consistent with Fagerholm's 1991 classification. Parsimony mapping of character states on the combined evidence tree was used to develop hypotheses for the evolution of morphological, life history, and amino acid characters. This analysis of character evolution revealed that certain key features that have been used by previous workers for developing taxonomic and evolutionary hypotheses represent plesiomorphic states. Cytochrome oxidase subunit 2 nucleotides show a strong compositional bias to A+T and a substitution bias to thymine. These biases are most apparent at third positions of codons and 4-fold degenerate sites, which is consistent with the nonrandom substitution pattern of A+T pressure. Despite nucleotide bias, cytochrome oxidase amino acid sequences show conservation and retention of critical functional residues, as inferred from comparisons to other organisms.


Relative food insecurity, mental health and wellbeing in 160 countries.
Food insecurity contributes to various stress-related health problems and previous research found that its association with mental illness is stronger in more affluent countries. We hypothesised that this pattern is a function of relative deprivation whereby the severity of individual food insecurity relative to others in a reference group determines its associations with mental health and wellbeing after differences in absolute food insecurity are controlled for. Using survey data from the Gallup World Poll collected in 160 countries and a measure of relative deprivation (Yitzhaki index), we found that relative food insecurity-based on national or regional reference groups-related to more mental health symptoms, lower positive wellbeing and lower life satisfaction after controlling for absolute food insecurity, household income, and country differences. Our analysis also found that relative food insecurity was more strongly related to mental health and wellbeing where the prevalence of food insecurity was lower. The findings underscore the negative health consequences of material deprivation and unfavourable social comparisons. Consistent with relative deprivation theory, individuals who live with constant worries about not getting enough food, have to skip meals, or face chronic hunger are deprived of material and social resources that support mental health and wellbeing, especially in settings where food insecurity is less common and potentially more stigmatised. The implications of these findings for global food policy and surveillance efforts are discussed.


Mechanism of decrease of oral bioavailability of cyclosporin A during immunotherapy upon coadministration of amphotericin B.
The trough level of blood concentration of cyclosporin A (CyA) in a patient receiving immunotherapy was observed to decrease following coadministration of amphotericin B (AMB). This clinical observation was confirmed experimentally in Wistar rats intravenously given AMB (1.5 or 3.0 mg/kg) or saline (control) for 4 days, followed by CyA (10 mg/kg). The blood concentration of CyA after i.v. or p.o. administration in both AMB groups was significantly decreased compared with the control. The oral bioavailability of CyA after 1.5 or 3.0 mg/kg AMB treatment was decreased to 67% or 46%, respectively, of that of the control group. AMB treatment increased the expression levels of mdr1a and mdr1b mRNAs in the duodenum to about three times the control, and expression of CYP3A2 mRNA in the liver was increased to about twice the control. The P-gp and CYP3A2 proteins were increased significantly. These findings suggest that the oral bioavailability of CyA is reduced as a result of both increased efflux transport via P-glycoprotein in the duodenum and an increased first-pass effect of CYP3A2-mediated hepatic metabolic activity, induced by AMB. It is suggested that careful monitoring of CyA levels is necessary in the event of AMB administration to patients receiving immunotherapy with CyA.


Hospital-wide rollout of antimicrobial stewardship: a stepped-wedge randomized trial.
Our objective was to rigorously evaluate the impact of an antimicrobial stewardship audit-and-feedback intervention, via a stepped-wedge randomized trial. An effective intensive care unit (ICU) audit-and-feedback program was rolled out to 6 non-ICU services in a randomized sequence. The primary outcome was targeted antimicrobial utilization, using a negative binomial regression model to assess the impact of the intervention while accounting for secular and seasonal trends. The intervention was successfully transitioned, with high volumes of orders reviewed, suggestions made, and recommendations accepted. Among patients meeting stewardship review criteria, the intervention was associated with a large reduction in targeted antimicrobial utilization (-21%, P = .004); however, there was no significant change in targeted antibiotic use among all admitted patients (-1.2%, P = .9), and no reductions in overall costs and microbiologic outcomes. An ICU day 3 audit-and-feedback program can be successfully expanded hospital-wide, but broader benefits on non-ICU wards may require interventions earlier in the course of treatment.


Improved short-term outcomes with off-pump reoperative coronary artery bypass grafting.
Reoperative coronary surgery patients are usually sicker and older, and the procedure is more technically demanding. Comparisons between coronary surgery with (coronary artery bypass [CAB] surgery on cardiopulmonary bypass [CPB]) and without (off-pump CAB [OPCAB]) the pump have been conducted; however, few studies showed results in reoperative cases. We investigate the potential superiority of one technique over the other in redo coronary surgeries. Our institutional Society of Thoracic Surgery database was used to gather the data for 266 isolated reoperative coronary artery surgeries from January 2004 to July 2011. These were divided into the CAB surgery in CPB group (n = 204) and the OPCAB group (n = 62). Baseline characteristics of the two groups were similar, except for a significantly higher prevalence of cerebrovascular disease among the off-pump group (P = 0.01). There was also a trend toward fewer vessels bypassed among the same group (P = 0.07). Risk adjustment was done using multivariable analyses for detection of independent effects. The use of CPB was an independent predictor of increased rates of postoperative events (odds ratio, 3.9; P = 0.004) and atrial fibrillation (odds ratio, 5.9; P < 0.005) and longer intensive care unit (0.006) and hospital stay (0.004). Redo OPCAB seems to offer favorable short-term outcomes compared with redo CAB. Our results suggest a reduced rate of overall postoperative events, decreased new postoperative atrial fibrillation, reduced hours stayed in the intensive care unit, and fewer days stayed from surgery to discharge. This was not associated with an increase in morbidity and mortality. A randomized study with a larger number of patients and with a longer follow-up is needed.


[Epidemiology of in-line skate injuries: state of the art].
During the last decade, in-line skating has become an increasingly popular activity. Along with the number of reports, highlighting the number of injuries and their degree of severity, in-line skating injuries have to be considered a growing public health issue. The objective of this work is to report epidemiological knowledge about in-line skate injuries and ways of prevention. A thorough search of all reports and publications on the subject was performed through the Medline database and in references of selected publications. There are numerous case series studies and several observational ones, most of them undertaken in North America. In-line skates are used for recreation, sports, and transportation, in a variety of settings (parks, streets, bike path, etc.) and by most of age groups (5 to 71 years, median generally about 15). The most common site of injury is the wrist and forearm, although other parts of the body can be severely injured. Age, sex, physical training level, formal instruction level, lack of wearing of protective gear, skating location, may be risk factors for injury. Some preventive measures were proposed by a number of research workers (information campaigns, wearing of protective gear, instruction, laws, etc.). Several preventive attempts were undertaken but no one was appraised. In-line skates are used by all age groups and for a variety of activities. In-line skating is related to a great number of factors, such as cultural, social, geographic, urban and behavioural factors. Therefore, groups at risk for injury are very different. Emergence of an important type of injury should lead to the development of analytic epidemiological studies, based on particular groups of in-line skaters, in order to describe them, to identify and quantify risk factors and to design preventive measures, and then to appraise their efficiency.


Hepatotoxicity with High-Dose Green Tea Extract: Effect of Catechol-O-Methyltransferase and Uridine 5'-Diphospho-glucuronosyltransferase 1A4 Genotypes.
The predominant catechin in green tea, epigallocatechin gallate (EGCG), may be hepatotoxic in high doses. Our objective was to investigate the influence of catechol-O-methyltransferase (COMT) and uridine 5'-diphospho-glucuronosyltransferase 1A4 (UGT1A4) genotypes on changes in liver injury biomarkers in response to long-term, high-dose green tea extract (GTE) supplementation among postmenopausal women. A secondary analysis was conducted using data from the Minnesota Green Tea Trial (N = 1,075), in which participants were randomized to consume high-dose GTE (843 mg/day EGCG) or placebo capsules for 12 months. Analysis of covariance adjusting for potential confounders was performed to examine changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), AST: ALT ratio, and alkaline phosphatase from baseline to months 3, 6, 9, and 12 across COMT and UGT1A4 genotypes. Mean age and BMI within the GTE group (n = 400) were 59.8 yrs and 25.1 kg/m2, respectively, and 98% of subjects were white. From baseline to month 3, mean AST: ALT ratio change was +1.0% in the COMT (rs4680) A/G genotype versus -4.8% in the A/A genotype (p = 0.03). From baseline to months 6 and 9, respectively, mean ALT change was +78.1% and +82.1% in the UGT1A4 (rs6755571) A/C genotype versus +28.0% and +30.1% in the C/C genotype (p < 0.001 and p = 0.004, respectively). The UGT1A4 (rs6755571) A/C genotype may be an important risk factor for clinically-relevant serum transaminase elevations with 6-9 months of high-dose GTE supplementation among postmenopausal women. Understanding the genetic underpinnings of GTE-related hepatotoxicity may allow for a genetically-informed paradigm for therapeutic use of GTE.


Testing gene by community disadvantage moderation of sexual health outcomes among urban women.
We examined whether the interplay between community disadvantage and a conduct disorder polygenic risk score (CD PRS) was associated with sexual health outcomes among urban women. Participants (N = 511; 75.5% African American) were originally recruited to participate in a school-based intervention and were followed into adulthood. Community disadvantage was calculated using census data when participants were in first grade. At age 20, blood or saliva samples were collected and participants reported on their condom use, sexual partners, and sexually transmitted infections. A CD PRS was created based on a genome-wide association study conducted by Dick et al. [2010]. Higher levels of community disadvantage was associated with greater sexually transmitted infections among women with a higher CD PRS. Implications of the study findings are discussed.


Recombination-deficient mutants of Bacillus subtilis.
Two mutant strains of Bacillus subtilis Marburg, NIG43 and NIG45, were isolated. They showed high sensitivities to gamma rays, ultraviolet light (UV), and chemicals. Deficiencies in genetic recombination of these two mutants were shown by the experiments on their capacity in transformation. SPO2 transfection, and PBS1 phage transduction, as well as on their radiation and drug sensitivities and their Hcr+ capacity for UV-exposed phage M2. Some of these characteristics were compared with those of the known strains possessing the recA1 or recB2 alleles. Mapping studies revealed that the mutation rec-43 of strain NIG43 lies in the region of chromosome replication origin. The order was purA dna-8132 rec-43. Another mutation, rec-45, of strain NIG45 was found to be tightly linked to recA1. The mutation rec-43 reduced mainly the frequency of PBS1 transduction. On the other hand, the mutation rec-45 reduced the frequency of recombination involved both in transformation and PBS1 transduction. The mutation rec-43 of strain NIG43 is conditional, but rec-45 of strain NIG45 is not. The UV impairment in cellular survival of strain NIG43 was gradually reverted at higher salt or sucrose concentrations, suggesting cellular possession of a mutated gene produce whose function is conditional. In contrast to several other recombination-deficient strains, SPO2 lysogens of strain NIG43 and NIG45 were not inducible, indicating involvement of rec-43+ or rec-45+ gene product in the development of SPO2 prophage to a vegetative form. The UV-induced deoxyribonucleic acid degradation in vegetative cells was higher in rec-43 and rec-45 strains.


Neuropsychological test performance in a cognitively intact sample of older Japanese American adults.
The purpose of this paper was to present population-based data showing the effects of age on cognitive test performance in a sample of older Japanese American adults. In addition, the relative effects of education, gender, and primary spoken language were compared to effects that have been reported in the literature for majority culture older adults. Subjects included 201 non-demented Japanese American adults age 70 and older currently enrolled in the Kame Project, a prospective study of aging and dementia in King County, WA. Cognitive tests included the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological assessment battery, WAIS-R Digit Span and Digit Symbol subtests, Trail Making Test, Purdue Pegboard, and Finger Tapping. Older age was associated with significantly (p<0.05) lower scores on all tests; less than high school education was associated with lower scores on all tests except Digit Span, Finger Tapping, and the Purdue Pegboard. Women and English-speaking participants scored higher than men and Japanese speakers on various tests of memory, attention, and visuomotor ability. These data reinforce the importance of using appropriately corrected norms when interpreting results of cognitive screening tests with minority culture older adults.


Emerging and investigational drugs for premature ejaculation.
Over the past 20-30 years, the premature ejaculation (PE) treatment paradigm, previously limited to behavioural psychotherapy, has expanded to include drug treatment. Pharmacotherapy for PE predominantly targets the multiple neurotransmitters and receptors involved in the control of ejaculation which include serotonin, dopamine, oxytocin, norepinephrine, gamma amino-butyric acid (GABA) and nitric oxide (NO). The objective of this article is to review emerging PE interventions contemporary data on the treatment of PE was reviewed and critiqued using the principles of evidence-based medicine. Multiple well-controlled evidence-based studies have demonstrated the efficacy and safety of selective serotonin reuptake inhibitors (SSRIs) in delaying ejaculation, confirming their role as first-line agents for the medical treatment of lifelong and acquired PE. Daily dosing of SSRIs is likely to be associated with superior fold increases in IELT compared to on-demand SSRIs. On-demand SSRIs are less effective but may fulfill the treatment goals of many patients. Integrated pharmacotherapy and CBT may achieve superior treatment outcomes in some patients. PDE-5 inhibitors alone or in combination with SSRIs should be limited to men with acquired PE secondary to co-morbid ED. New on-demand rapid acting SSRIs, oxytocin receptor antagonists, or single agents that target multiple receptors may form the foundation of more effective future on-demand medication. Current evidence confirms the efficacy and safety of dapoxetine, off-label SSRI drugs, tramadol and topical anaesthetics drugs. Treatment with α1-adrenoceptor antagonists cannot be recommended until the results of large well-designed RCTs are published in major international peer-reviewed medical journals. As our understanding of the neurochemical control of ejaculation improves, new therapeutic targets and candidate molecules will be identified which may increase our pharmacotherapeutic armamentarium.


Basic audiological and related services in the north -- the role of a native technician.
Over an 18 month period a native technician in the James Bay area was selected, trained, and supervised in the execution of certain audiological functions including record keeping, basic testing, hearing aid "trouble shooting", taking of impressions for moulds, and follow-up. The evidence indicates that this is an effective program which can supplement the occasional services of otolaryngologists and audiologists in the James Bay area. In particular, language barriers are overcome, there is continuity of care, and there is some indication of cost benefit. Recommendations are made for the continuance and possible expansion of this type of service.