Gut hormone responses after reconstructive surgery for ulcerative colitis.
After colectomy, continent ileal reservoirs are an accepted alternative to conventional ileostomy for patients with ulcerative colitis. To assess the effect of these reservoirs on digestive function, circulating and morphologic gut endocrine responses were measured in patients with a continent ileostomy or with a pelvic pouch and compared to patients with conventional ileostomy, with active ulcerative colitis and healthy controls. Eight subjects were studied in each group. Basal and postprandial plasma gastrin, enteroglucagon, neurotensin, vasoactive intestinal polypeptide, insulin, pancreatic glucagon, and pancreatic polypeptide in both groups with ileal reservoirs were equivalent to controls. Basal plasma motilin and postprandial plasma gastric inhibitory polypeptide were raised in ileal reservoir patients, but similar changes also occurred in ulcerative colitis patients and those with conventional ileostomy. In one half of patients, cell populations of enteroglucagon, peptide YY, and neurotensin were decreased in pouch mucosa that corresponded with the presence of mucosal inflammation. On the other hand, with pouch inflammation vasoactive intestinal polypeptide immunoreactive nerves were increased and a proportion of the fibres were moderately coarsened. Mucosal concentrations of vasoactive intestinal polypeptide did not, however, exceed that of controls. After an ileal reservoir sufficient reserve remains for gut hormone release into the circulation, suggesting compensation for the presence of a reservoir and the absence of a colon; circulating hormone changes do occur but are consequent upon previous ulcerative colitis. Reservoirs may show neuromorphologic alterations that appear to be related to mucosal inflammation.


Bartenders' respiratory health after establishment of smoke-free bars and taverns.
The association between environmental tobacco smoke (ETS) exposure and respiratory symptoms has not been well established in adults. To study the respiratory health of bartenders before and after legislative prohibition of smoking in all bars and taverns by the state of California. Cohort of bartenders interviewed before and after smoking prohibition. Bartenders at a random sample of bars and taverns in San Francisco. Interviews assessed respiratory symptoms, sensory irritation symptoms, ETS exposure, personal smoking, and recent upper respiratory tract infections. Spirometric assessment included forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) measurements. Fifty-three of 67 eligible bartenders were interviewed. At baseline, all 53 bartenders reported workplace ETS exposure. After the smoking ban, self-reported ETS exposure at work declined from a median of 28 to 2 hours per week (P<.001). Thirty-nine bartenders (74%) initially reported respiratory symptoms. Of those symptomatic at baseline, 23 (59%) no longer had symptoms at follow-up (P<.001). Forty-one bartenders (77%) initially reported sensory irritation symptoms. At follow-up, 32 (78%) of these subjects had resolution of symptoms (P<.001). After prohibition of workplace smoking, we observed improvement in mean FVC (0.189 L; 95% confidence interval [CI], 0.082-0.296 L; 4.2% change) and, to a lesser extent, mean FEV1 (0.039 L; 95% CI, -0.030 to 0.107 L; 1.2% change). Complete cessation of workplace ETS exposure (compared with continued exposure) was associated with improved mean FVC (0.287 L; 95% CI, 0.088-0.486; 6.8% change) and mean FEV1 (0.142 L; 95% CI, 0.020-0.264 L; 4.5% change), after controlling for personal smoking and recent upper respiratory tract infections. Establishment of smoke-free bars and taverns was associated with a rapid improvement of respiratory health.


Genome-wide characterization of transcriptional start sites in humans by integrative transcriptome analysis.
We performed a genome-wide analysis of transcriptional start sites (TSSs) in human genes by multifaceted use of a massively parallel sequencer. By analyzing 800 million sequences that were obtained from various types of transcriptome analyses, we characterized 140 million TSS tags in 12 human cell types. Despite the large number of TSS clusters (TSCs), the number of TSCs was observed to decrease sharply with increasing expression levels. Highly expressed TSCs exhibited several characteristic features: Nucleosome-seq analysis revealed highly ordered nucleosome structures, ChIP-seq analysis detected clear RNA polymerase II binding signals in their surrounding regions, evaluations of previously sequenced and newly shotgun-sequenced complete cDNA sequences showed that they encode preferable transcripts for protein translation, and RNA-seq analysis of polysome-incorporated RNAs yielded direct evidence that those transcripts are actually translated into proteins. We also demonstrate that integrative interpretation of transcriptome data is essential for the selection of putative alternative promoter TSCs, two of which also have protein consequences. Furthermore, discriminative chromatin features that separate TSCs at different expression levels were found for both genic TSCs and intergenic TSCs. The collected integrative information should provide a useful basis for future biological characterization of TSCs.


RNA-Seq analysis discloses early senescence and nucleolar dysfunction triggered by Tdp1α depletion in Medicago truncatula.
An intron-spliced hairpin RNA approach was used for the targeted silencing of the MtTdp1α gene encoding the αisoform of tyrosyl-DNA phosphodiesterase 1 in Medicago truncatula Gaertn. Tyrosyl-DNA phosphodiesterase 1, involved in the repair of DNA topoisomerase I-mediated DNA damage, has been poorly investigated in plants. RNA-Seq analysis, carried out in the MtTdp1α-depleted plants, revealed different levels of transcriptional modulation (up- and down-regulation, alternative splicing, activation of alternative promoter) in genes involved in DNA damage sensing, DNA repair, and chromatin remodelling. It is suggested that the MtTdp1α gene has new, previously undetected roles in maintaining genome integrity. Up-regulation of senescence-associated genes and telomere shortening were observed. Moreover, impaired ribosome biogenesis indicated that the MtTdp1α gene is required for the nucleolar function. In agreement with the RNA-Seq data, transmission electron microscopy detected an altered nucleolar architecture in the MtTdp1α-depleted cells. Based on the reported data, a working hypothesis related to the occurrence of a nucleolar checkpoint in plant cells is proposed.


Effects of dimethyl sulfoxide on renal function in man.
To ascertain the clinical significance of dimethyl sulfoxide-induced pigmenturia, we evaluated renal function and indicators of systemic hemolysis in stable quadriplegic patients receiving the drug intravenously (IV) for spinal cord injury. Despite a dose-dependent transient hemolysis with resultant hemoglobinuria, no alteration of renal function could be appreciated. Other than the presence of urinary hemoglobin, there were no changes from baseline in the urinary sediment and all patients remained without severe hematuria. Our results indicate that patients treated with IV dimethyl sulfoxide for severe cerebral edema could serve as donors for renal transplantation.


Decreased Motor Neuron Support by SMA Astrocytes due to Diminished MCP1 Secretion.
Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by severe, often fatal muscle weakness due to loss of motor neurons. SMA patients have deletions and other mutations of the survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein. Astrocytes are the primary support cells of the CNS and are responsible for glutamate clearance, metabolic support, response to injury, and regulation of signal transmission. Astrocytes have been implicated in SMA as in in other neurodegenerative disorders. Astrocyte-specific rescue of SMN protein levels has been shown to mitigate disease manifestations in mice. However, the mechanism by which SMN deficiency in astrocytes may contribute to SMA is unclear and what aspect of astrocyte activity is lacking is unknown. Therefore, it is worthwhile to identify defects in SMN-deficient astrocytes that compromise normal function. We show here that SMA astrocyte cultures derived from mouse spinal cord of both sexes are deficient in supporting both WT and SMN-deficient motor neurons derived from male, female, and mixed-sex sources and that this deficiency may be mitigated with secreted factors. In particular, SMN-deficient astrocytes have decreased levels of monocyte chemoactive protein 1 (MCP1) secretion compared with controls and MCP1 restoration stimulates outgrowth of neurites from cultured motor neurons. Correction of MCP1 deficiency may thus be a new therapeutic approach to SMA.SIGNIFICANCE STATEMENT Spinal muscular atrophy (SMA) is caused by the loss of motor neurons, but astrocyte dysfunction also contributes to the disease in mouse models. Monocyte chemoactive protein 1 (MCP1) has been shown to be neuroprotective and is released by astrocytes. Here, we report that MCP1 levels are decreased in SMA mice and that replacement of deficient MCP1 increases differentiation and neurite length of WT and SMN-deficient motor-neuron-like cells in cell culture. This study reveals a novel aspect of astrocyte dysfunction in SMA and indicates a possible approach for improving motor neuron growth and survival in this disease.


Allogeneic hematopoietic cell transplantation in human immunodeficiency virus-positive patients with hematologic disorders: a report from the center for international blood and marrow transplant research.
The role of allogeneic hematopoietic cell transplantation (alloHCT) in human immunodeficiency virus (HIV)-positive patients is not known. Using the Center for International Blood and Marrow Transplant Research database, we retrospectively evaluated 23 HIV-positive patients undergoing matched sibling donor (n = 19) or unrelated donor (n = 4) alloHCT between 1987 and 2003. The median age at alloHCT was 32 years. Indications for alloHCT were diverse and included malignant (n = 21) and nonmalignant (n = 2) hematologic disorders. Nine patients (39%) underwent transplantation after 1996, the approximate year that highly active antiretroviral therapy became standard treatment. The median time to neutrophil engraftment was 16 days (range, 7 to 30 days), and the cumulative incidences of grade II-IV acute graft-versus-host disease (aGVHD) at 100 days, chronic GVHD (cGVHD), and survival at 2 years were 30% (95% confidence interval [CI] = 14% to 50%), 28% (95% CI = 12% to 48%), and 30% (95% CI = 14% to 50%), respectively. At a median follow-up of 59 months, 6 patients were alive. Survival appears to be better in the patients undergoing alloHCT after 1996; 4 of these 9 patients survived, compared with only 2 of 14 those undergoing transplantation before 1996. These data suggest that alloHCT is feasible for selected HIV-positive patients with malignant and nonmalignant disorders. Prospective studies are needed to evaluate the safety and efficacy of this modality in specific diseases in these patients.


Protocolized use of Factor Eight Inhibitor Bypassing Activity (FEIBA) for the reversal of warfarin induced coagulopathy.
Coagulopathy due to warfarin in patients with major bleeding was traditionally reversed with fresh frozen plasma and intravenous (IV) vitamin K, but prothrombin complex concentrates (PCC) are increasingly used in the treatment of these patients. Factor Eight Inhibitor Bypassing Activity (FEIBA) is an activated four-factor PCC most commonly used in patients with hemophilia. We aimed to evaluate the efficacy and safety of FEIBA and IV vitamin K for the reversal of warfarin-associated coagulopathy in patients with major bleeding, by measuring the percentage of patients who achieved target INR ≤ 1.5 and the incidence of thrombotic adverse events (TAE). In this prospective observational study, we enrolled patients presenting to the Emergency Department (ED) with warfarin associated coagulopathy (INR > 1.5) and major bleeding. Patients received FEIBA using an INR based dosing strategy and IV vitamin K. In 43 patients, median initial INR was 4.0 (2.7, 7.3 interquartile range (IQR)). Median time to result the second INR was 45 min (38, 55 IQR) and the median INR was 1.4 (1.3, 1.6 IQR). Out of the 43 patients, 93% achieved the target INR of ≤1.5. In-hospital mortality was 40% (17 patients). There were 11 TAEs in 6 patients (14%); 4 events in 2 patients (5%) were attributed to FEIBA. A protocolized use of FEIBA and IV vitamin K resulted in the efficacious reversal of warfarin-induced coagulopathy in patients with major bleeding. TAEs occurred in 14% of patients and were attributed to FEIBA in 5% of patients.


Design and Characterization of a Singly Labeled Fluorescent Smart Probe for In Vitro Detection of miR-21.
A sensitive hairpin smart probe (SP) has been developed and tested for its sequence-specificity and sensitivity for detecting microRNAs (miRNAs). The loop sequence of this SP is perfectly complementary to microRNA-21 (miR-21) sequence. This miRNA regulates certain biological processes and has been implicated in certain forms of cancer. The stem of the new SP consists of a fluorophore on one end and multiple guanine bases on the opposing end are used as quenchers. The fluorescence of the SP is significantly quenched by the guanine bases at room temperature and in the absence of the miR-21 target. The presence of miR-21 switches on the fluorescence due to spontaneous hybridization of the SP with this target, which also forces the stem hybrid of the SP apart. This new SP successfully discriminated between the perfect miR-21 target and two closely similar single-base mismatch sequences. When the SP was incubated with the miR-21 at 37 ℃, the hybridization kinetics increased seven times, compared to room temperature hybridization. Overall, this new SP shows good detection sensitivity and gives a limit of detection and limit of quantitation of 14.0 nM and 46.7 nM, respectively. This detection platform represents a simple, fast, mix-and-read homogeneous assay for sequence-specific detection of miR-21, and it can be adapted for other related diagnostic applications.


Beer, wine, and spirits differentially influence body composition in older white adults-a United Kingdom Biobank study.
Aging is characterized by body composition alterations, including increased visceral adiposity accumulation and bone loss. Alcohol consumption may partially drive these alterations, but findings are mixed. This study primarily aimed to investigate whether different alcohol types (beer/cider, red wine, white wine/Champagne, spirits) differentially associated with body composition. The longitudinal UK Biobank study leveraged 1869 White participants (40-80 years; 59% male). Participants self-reported demographic, alcohol/dietary consumption, and lifestyle factors using a touchscreen questionnaire. Anthropometrics and serum for proteomics were collected. Body composition was obtained via dual-energy X-ray absorptiometry. Structural equation modeling was used to probe direct/indirect associations between alcohol types, cardiometabolic biomarkers, and body composition. Greater beer/spirit consumptions were associated with greater visceral adiposity (β = 0.069, p < 0.001 and β = 0.014, p < 0.001, respectively), which was driven by dyslipidemia and insulin resistance. In contrast, drinking more red wine was associated with less visceral adipose mass (β = -0.023, p < 0.001), which was driven by reduced inflammation and elevated high-density lipoproteins. White wine consumption predicted greater bone density (β = 0.051, p < 0.005). Beer/spirits may partially contribute to the "empty calorie" hypothesis related to adipogenesis, while red wine may help protect against adipogenesis due to anti-inflammatory/eulipidemic effects. Furthermore, white wine may benefit bone health in older White adults.1.


Primary intestinal lymphangiectasia in an elderly female patient: A case report on a rare cause of secondary immunodeficiency.
Protein loss via the gut can be caused by a number of gastrointestinal disorders, among which intestinal lymphangiectasia has been described to not only lead to a loss of proteins but also to a loss of lymphocytes, resembling secondary immunodeficiency. We are reporting on a 75-year-old female patient who came to our hospital because of a minor stroke. She had no history of serious infections. During the diagnostic work-up, we detected an apparent immunodeficiency syndrome associated with primary intestinal lymphangiectasia. Trying to characterize the alterations of the immune system, we not only found hypogammaglobulinemia and lymphopenia primarily affecting CD4+, and also CD8+ T cells, but also marked hypocomplementemia affecting levels of complement C4, C2, and C3. The loss of components of the immune system most likely was due to a chronic loss of immune cells and proteins via the intestinal lymphangiectasia, with levels of complement components following the pattern of protein electrophoresis. Thus, intestinal lymphangiectasia should not only be considered as a potential cause of secondary immune defects in an elderly patient, but can also be associated with additional hypocomplementemia.


The evolution of bet hedging in response to local ecological conditions.
Genotypes that hedge their bets can be favored by selection in an unpredictably varying environment. Bet hedging can be achieved by systematically expressing several phenotypes, such as one that readily attempts to reproduce and one that procrastinates in a dormant stage. But how much of each phenotype should a genotype express? Theory predicts that evolving bet-hedging strategies depend on local environmental variation, on how the population is regulated, and on exchanges with neighboring populations. Empirically, however, it remains unknown whether bet hedging can evolve to cope with the ecological conditions experienced by populations. Here we study the evolution of bet-hedging dormancy frequencies in two neighboring populations of the chestnut weevil, Curculio elephas. We estimate the temporal distribution of demographic parameters together with the form of the relationship between fecundity and population density and use both to parameterize models that predict the bet-hedging dormancy frequency expected to evolve in each population. Strikingly, the observed dormancy frequencies closely match predictions in their respective localities. We also found that dormancy frequencies vary randomly across generations, likely due to environmental perturbations of the underlying physiological mechanism. Using a model that includes these constraints, we predict the whole distribution of dormancy frequencies whose mean and shape agree with our observed data. Overall, our results suggest that dormancy frequencies have evolved according to local ecological conditions and physiological constraints.


Drug repurposing approaches to fight Dengue virus infection and related diseases.
Dengue is a mosquito-borne viral disease caused by four antigenically distinct serotypes of Dengue Virus (DENV), namely DENV1-4 and is currently considered the most important arthropod-born viral disease in the world. An effective antiviral therapy to treat Dengue Virus infection is still missing and a number of replicative cycle inhibitors are currently under study. Considering the rapid spreading of DENV and the common timeframe required for bringing a new drug on the market, the repurposing of approved drugs used for different diseases to identify novel inhibitors of this pathogen represents an attractive approach for a rapid therapeutic intervention. Herein, we will describe the most recent drug repurposing approaches to fight DENV infection and their implications in antiviral drug-discovery.


A Comparison of Simulation-Based Education and Problem-Based Learning in Pre-Clinical Medical Undergraduates.
This article was migrated. The article was marked as recommended. Introduction: Despite the increasing popularity of high-fidelity simulation (SIM), few studies compare the effectiveness of SIM with established small-group modalities such as problem-based learning (PBL) for factual learning among pre-clinical medical undergraduates. Methods: 162 second-year medical students were randomized to two groups. The first group encountered teaching points related to the management of hypertensive emergency during a traditional PBL session, while the second group covered the same teaching points through SIM. Both groups then completed a post-test. The students were subsequently crossed-over to the opposite modality and assessed on teaching points related to the management of chronic obstructive pulmonary disease exacerbations. Results: A total of 162 students participated in the study. For the hypertension case, the average proportion of correct questions for the SIM intervention was 83% compared to 70% for the PBL intervention (OR = 3.1, 95% CI [1.3, 7.2], p=0.009). For the COPD case, the average proportion of correct questions for the SIM intervention was 73% compared to 51% for the PBL intervention (OR = 2.6, 95% CI [1.8, 3.8], p < 0.001). Conclusion:Students scored significantly higher with SIM in both cases, indicating that SIM may be superior to PBL for factual learning among students with limited clinical exposure.


Fibromyalgia and the rheumatisms. Common sense and sensibility.
Chronic musculoskeletal pain syndromes are common problems, but the etiology, pathogenesis, and pathology of many of them are very poorly understood. Because the currently used nomenclature suggests an understanding that we do not have, I propose that names like "myofascial pain," "tension myalgia," and "FM" be abandoned in favor of the more indefinite (but more honest) terms like "regional" and "generalized rheumatism." No matter what we rheumatologists call it, however, the condition of chronic generalized musculoskeletal pain probably is only one part of an even more generalized condition that includes IBS, chronic headaches, regional migratory numbness, TMJ syndrome, and a whole host of other somatic pain syndromes. The same patients end up seeing many specialists who themselves feel frustrated with the labels at their disposal, and these specialists end up resembling the blind men confronting the elephant. In this regard, the new ACR criteria for the diagnosis of fibrositis, by emphasizing tenderness and ignoring the presence of these other syndromes, are too circumscribed and represent a step backward in our attempts to understand. Although the chronic rheumatisms are problems difficult to manage and frustrating for both the patient and the physician, when patience can be applied and confidence achieved, a positive relationship can result and the patient can be helped.


Perfluorooctanesulfonic Acid and Perfluorooctanoic Acid Promote Migration of Three-Dimensional Colorectal Cancer Spheroids.
Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are persistent environmental contaminants that are of increasing public concern worldwide. However, their relationship with colorectal cancer (CRC) is poorly understood. This study aims to comprehensively investigate the effect of PFOS and PFOA on the development and progression of CRC in vitro using a series of biological techniques and metabolic profiling. Herein, the migration of three-dimensional (3D) spheroids of two CRC cell lines, SW48 KRAS wide-type (WT) and SW48 KRAS G12A, were observed after exposure to PFOS and PFOA at 2 μM and 10 μM for 7 days. The time and dose-dependent migration phenotype induced by 10 μM PFOS and PFOA was further confirmed by wound healing and trans-well migration assays. To investigate the mechanism of action, derivatization-mass spectrometry-based metabolic profiles were examined from 3D spheroids of SW48 cell lines exposed to PFOS and PFOA (2 μM and 10 μM). Our findings revealed this exposure altered epithelial-mesenchymal transition related metabolic pathways, including fatty acid β-oxidation and synthesis of proteins, nucleotides, and lipids. Furthermore, this phenotype was confirmed by the downregulation of E-cadherin and upregulation of N-cadherin and vimentin. These findings show novel insight into the relationship between PFOS, PFOA, and CRC.


[Congenital myoblastoma (a clinical case)].
A congenital myoblastoma in a newborn boy is described, developing on the maxillary gingiva. Histological examination showed it to be a myoma of myoblasts, Abrikosov's tumor. Examination after 2 years did not reveal a relapse of the tumor.


Treading the path of least resistance: HIV/AIDS and social inequalities a South African case study.
This paper outlines aspects of the HIV/AIDS epidemic scenario and the complexities associated with it. It reveals the socio-epidemiological patterns of the epidemic and in doing so identifies the populations with the greatest and fastest growing rates of infection. From the data presented it is evident that the pattern of HIV/AIDS in developing countries in sub-Saharan Africa in particular is unique. The pattern emerging in South Africa follows closely. The features of this pattern are as follows: the epidemic is mainly a heterosexual epidemic, the rates of infection in the general population are very high and the percentage of HIV-positive women is greater than men. An additional unique feature is the young age of onset of infection for women. These data demonstrate the need to focus our attention on young African women and the factors underpinning their predicament. In order to understand their position we examine the long standing relationship between social inequalities and health in general and further invoke the concepts of vulnerability and social capital to shed light on the position of women in the epidemic. Within the constraints of limited and problematic statistical data, the paper argues that a mixture and complex interaction of material, social, cultural and behavioural factors shape the nature, process and outcome of the epidemic in South Africa. It concludes with recommendations for the way forward.


Interventions to reduce readmissions: can complex adaptive system theory explain the heterogeneity in effectiveness? A systematic review.
Successfully transitioning patients from hospital to home is a complex, often uncertain task. Despite significant efforts to improve the effectiveness of care transitions, they remain a challenge across health care systems. The lens of complex adaptive systems (CAS) provides a theoretical approach for studying care transition interventions, with potential implications for intervention effectiveness. The aim of this study is to examine whether care transition interventions that are congruent with the complexity of the processes and conditions they are trying to improve will have better outcomes. We identified a convenience sample of high-quality care transition intervention studies included in a care transition synthesis report by Kansagara and colleagues. After excluding studies that did not meet our criteria, we scored each study based on (1) the presence or absence of 5 CAS characteristics (learning, interconnections, self-organization, co-evolution, and emergence), as well as system-level interdependencies (resources and processes) in the intervention design, and (2) scored study readmission-related outcomes for effectiveness. Forty-four of the 154 reviewed articles met our inclusion criteria; these studies reported on 46 interventions. Nearly all the interventions involved a change in interconnections between people compared with care as usual (96% of interventions), and added resources (98%) and processes (98%). Most contained elements impacting learning (67%) and self-organization (69%). No intervention reflected either co-evolution or emergence. Almost 40% of interventions were rated as effective in terms of impact on hospital readmissions. Chi square testing for an association between outcomes and CAS characteristics was not significant for learning or self-organization, however interventions rated as effective were significantly more likely to have both of these characteristics (78%) than interventions rated as having no effect (32%, p = 0.005). Interventions with components that influenced learning and self-organization were associated with a significant improvement in hospital readmissions-related outcomes. Learning alone might be necessary but not be sufficient for improving transitions. However, building self-organization into the intervention might help people effectively respond to problems and adapt in uncertain situations to reduce the likelihood of readmission.


Transgender Women's Experiences with Stigma, Trauma, and Attempted Suicide in the Dominican Republic.
Studies on attempted suicide in transgender populations, particularly those in resource-limited settings, are scarce. We examined the relationships between stigma, trauma, and suicide attempts in a national sample of transgender women from the Dominican Republic. Bivariate analysis examined differences between suicide attempters and nonattempters (n = 298). Multivariate analysis reported odds ratios with attempted suicide as the outcome (n = 260). About a quarter of respondents (23.9%) experienced sexual abuse, 12.3% were tortured, and 20.3% experienced a murder attempt. More than a quarter reported using illegal drugs. Independent sample t tests found significant differences between suicide attempters and nonattempters. Attempters were more likely to have experienced sexual abuse, psychological abuse, torture, and a murder attempt (p < .001 for all). Respondents who experienced psychological abuse had over three times higher odds of attempting suicide, compared to respondents who had not (OR = 3.203, p < .01). Experience with torture and attempted murder were associated with higher odds of attempting suicide (OR = 2.967, p < .05 and OR = 2.894, p < .05, respectively). Although some nations have implemented antidiscrimination policies protecting transgender citizens, these policies are often not consistently enforced. Eliminating stigmatizing policies may reduce rates of negative health outcomes and subsequently improving population health.


[Vulvar intraepithelial neoplasm].
Vulvar intraepithelial neoplasia is a challenge for the physician as it is asymptomatic and it can evolve to malignant disease. A high suspicion index, as well as some biopsies are necessary, provided an early invasive disease can exist. To establish the patient's characteristics with vulvar intraepithelial neoplasia, seen at the Clinica de Especialidades de la Mujer, SEDENA. An observational and retrospective analysis was done from February 1st, 1990 to December 31st, 2004. We used the data base of the Hospital Central Militar and of the Clinica de Especialidades de la Mujer, SEDENA. We identified patients with vulvar intraepithelial neoplasia or in situ vulvar cancer diagnosis. We assessed the following variables: patient's age, intraepithelial neoplasia or history of cervical cancer, acuminated vagina or condylomas, prescribed treatment and current health state. We identified 38 patients with ages between 49 and 82 years old. Patients with intraepithelial neoplasia I were the youngest, except one, whom at the moment of the diagnosis had 58 years old. The histopathological diagnosis was of intraepithelial neoplasia type I (koilocytotic atypia) in 10 cases, type II in 10 more, and type III in 18 of them. Treatment should be individual for each patient. In most of the cases and due to the high recurrence rates we prefer the conservative treatments.


Activation of beta 2-adrenergic receptors on mouse anterior pituitary tumor cells increases cyclic adenosine 3':5'-monophosphate synthesis and adrenocorticotropin release.
AtT-20 cells comprise a mouse anterior pituitary tumor cell line that synthesizes and secretes adrenocorticotropin hormone (ACTH). beta-Adrenergic receptors were characterized on AtT-20 cells using receptor binding methodology and the ability of beta-receptor agonists to stimulate intracellular cyclic adenosine 3':5'-monophosphate (cAMP) formation and the release of ACTH immunoreactivity. The density of beta-receptors on membrane preparations of these cells is 64 fmol/mg of protein and their affinity constant (KD value) for tritiated dihydroalprenolol is 11 nM. The binding of [3H] dihydroalprenolol to AtT-20 cells is stereoselectively inhibited by propranolol and isoproterenol but is not affected by phentolamine. The beta-receptors on these cells appear to be of the beta 2-receptor subtype since a selective beta 2-receptor agonist, salmefamol, can inhibit [3H]dihydroalprenolol binding, whereas practolol, a beta 1-receptor blocker, is ineffective. (-)-Isoproterenol stimulates cAMP formation in AtT-20 cells and this effect is blocked by dl-propranolol. Both l-epinephrine and l-norepinephrine induce dose-dependent increases in cAMP formation with the former agonist being more potent. Salmefamol also stimulates cAMP formation in these cells. The secretion of ACTH from AtT-20 cells is induced by (-)-isoproterenol as well as by other adrenergic agonists. The isoproterenol effect on ACTH release is stereoselective, calcium dependent, and blocked by dl-propranolol but not by phentolamine or practolol.


Stimulation of circular muscle motility of the isolated perfused canine ileum: relationship to VIP output.
Perfusion of ileal segments with tetrodotoxin; opioids, Met-enkephalin and dynorphin; and alpha 2 adrenoceptor agonist, BHT920, increased motility concomitant with the decreased VIP output into the venous effluent reported previously. This suggested that increased motility resulted from release of the muscle from tonic inhibition when VIP output was reduced sufficiently. However, blockade of nicotinic receptors also reduced VIP output but did not induce motility. Thus release of myogenic activity from inhibition is not a sufficient explanation for increased motility and a further excitatory mediator is required. Field stimulation of nerves increased VIP output and delayed distal contractions, suggesting that VIP does participate in the canine ileal distal inhibition reflex.


A Novel Prognostic Marker for Primary CNS Lymphoma: Lactate Dehydrogenase-to-Lymphocyte Ratio Improves Stratification of Patients Within the Low and Intermediate MSKCC Risk Groups.
Primary central nervous system lymphoma (PCNSL) is a highly aggressive and rare extranodal non-Hodgkin lymphoma (NHL). The MSKCC and the IELSG scores represent the most widely used prognostic models, but many changes have occurred in therapeutic protocols since their development. Moreover, many PCNSL patients cannot be classified using the IELSG score. We thus aimed to create a novel, effective and feasible prognostic model for PCNSL. We included 248 PCNSL patients diagnosed with PCNSL. Our primary endpoint was the overall survival (OS) and we used the receiver operating characteristic (ROC) analysis to determine the optimal prognostic cut-off value for LLR (lactate dehydrogenase-to-lymphocyte ratio), neutrophil-to-lymphocyte ratio (NLR) and derived neutrophil-to-lymphocyte ratio (dNLR). Variable associated with OS were evaluated by univariate and multivariate analyses. 124 out of 248 patients were randomly selected as the internal validation cohort. By univariate analysis, an age >60 years, Eastern Cooperative Oncology Group performance status (ECOG PS) >1, treatment with radiotherapy alone, high-risk groups of Memorial Sloan Kettering Cancer Center (MSKCC) score, NLR >4.74, dNLR >3.29, and LLR >166.8 were significantly associated with a worse OS. By multivariate analysis, the MSKCC score and LLR were confirmed as independent prognostic parameters for poorer OS. OS, however, was not significantly different between low- and intermediate-risk groups according to the MSKCC score, while LLR proved to be prognostically relevant and was thus used to develop a novel, effective three-tier PCNSL scoring system. Of 124 patients, 84 patients with survival data and LLR data were successfully validated by newly established PCNSL LLR scoring system. In the present study, we demonstrate that a high LLR represents an independent unfavorable prognostic parameter in PCNSL patients which can be integrated into an effective prognostic model.


Treatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96.
To evaluate therapeutic options for recurrent malignant sacrococcygeal germ cell tumors (GCT) following three-agent, cisplatinum-based, first-line chemotherapy and tumor resection. Twenty-two patients were evaluated in 22 first-, 14 second-, five third-, and two fourth-relapse situations. One patient, who relapsed with pure teratoma, was excluded from the analysis of adjuvant treatment. Seventeen patients presented with an isolated local recurrence, two patients showed a distant relapse, and three patients suffered from a combined local and distant recurrence. Twelve patients achieved complete remission (CR) after surgery (n = 12) and adjuvant platinum chemotherapy (n = 10). Seven of these patients remain in continuous CR, and five patients relapsed. All patients who achieved only a partial remission developed a second relapse. Three of 14 patients could be cured after a second (or further) relapse. Altogether, 10 patients survived disease free, and 12 patients died as a result of tumor progression (n = 11) or therapy-related complications (n = 1). The completeness of salvage surgery and clinical remission status after first salvage treatment were the most important prognostic parameters. In addition, patients in first or second relapse with locally advanced or poorly responding tumors benefited from preoperative chemotherapy in combination with regional hyperthermia (RHT). In some patients after microscopically incomplete resection, irradiation at doses > 45 Gy contributed to a favorable outcome. The complete resection of the local recurrence represents the cornerstone of salvage treatment. Preoperative platinum-based chemotherapy, combined with RHT in some patients, facilitates complete tumor resection. Radiotherapy should be reserved for those patients with microscopically incomplete tumor resection. As the chance of cure decreases with further relapses, it is important to establish a stringent therapeutic strategy to avoid significant treatment delays and, most importantly, insufficient local therapy.


[Perceptions of nulliparous women about prematurity].
This study was made in a neonatal intensive care unit in a school hospital at Porto Alegre/RS, trying to identify the reactions of nuliparous mothers about prematurity. Ten (10) interviews with mothers of premature infants was made. The most commonly reactions were: fear, guilty, anxiety, negation, angry and depression. The mother's feeling about the team, are also observed, and classified in: positive (tranquility, safety, trust, regardless) and negative (doubt, indifference, guilty, envy and fear). A plane of nursing care was made to mothers of premature infants in neonatal intensive care unit (NICU), with the objective of humanization and improving the assistance.


Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells.
Despite recent insights into mucosal human immunodeficiency virus (HIV) transmission, the route used by primate lentiviruses to traverse the stratified squamous epithelium of mucosal surfaces remains undefined. To determine if dendritic cells (DC) are used by primate lentiviruses to traverse the epithelial barrier of the genital tract, rhesus macaques were intravaginally exposed to cell-free simian immunodeficiency virus SIVmac251. We examined formalin-fixed tissues and HLA-DR(+)-enriched cell suspensions to identify the cells containing SIV RNA in the genital tract and draining lymph nodes within the first 24 h of infection. Using SIV-specific fluorescent in situ hybridization combined with immunofluorescent antibody labeling of lineage-specific cell markers, numerous SIV RNA(+) DC were documented in cell suspensions from the vaginal epithelium 18 h after vaginal inoculation. In addition, we determined the minimum time that the SIV inoculum must remain in contact with the genital mucosa for the virus to move from the vaginal lumen into the mucosa. We now show that SIV enters the vaginal mucosa within 60 min of intravaginal exposure, infecting primarily intraepithelial DC and that SIV-infected cells are located in draining lymph nodes within 18 h of intravaginal SIV exposure. The speed with which primate lentiviruses penetrate mucosal surfaces, infect DC, and disseminate to draining lymph nodes poses a serious challenge to HIV vaccine development.


Regulatory T cells and immune tolerance in the intestine.
A fundamental role of the mammalian immune system is to eradicate pathogens while minimizing immunopathology. Instigating and maintaining immunological tolerance within the intestine represents a unique challenge to the mucosal immune system. Regulatory T cells are critical for continued immune tolerance in the intestine through active control of innate and adaptive immune responses. Dynamic adaptation of regulatory T-cell populations to the intestinal tissue microenvironment is key in this process. Here, we discuss specialization of regulatory T-cell responses in the intestine, and how a breakdown in these processes can lead to chronic intestinal inflammation.


Activation of caspase-12 by endoplasmic reticulum stress induced by transient middle cerebral artery occlusion in mice.
We sought to clarify the involvement of caspase-12, a representative molecule related to endoplasmic reticulum (ER) stress-induced cell-death signaling pathways, in neuronal death resulting from ischemia/reperfusion in mice. Transient focal cerebral ischemia (1 h) was produced by intraluminal occlusion of the middle cerebral artery (MCA). We assessed the expression patterns of caspase-12, Bip/GRP78, an ER-resident molecular chaperone whose expression serves as a good marker of ER stress, and caspase-7 by Western blotting and/or immunohistochemistry. Double-fluorescent staining of caspase-12 immunohistochemistry and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling (TUNEL) method was performed to clarify the involvement of caspase-12 in cell death. We confirmed that ER stress was induced during reperfusion in our model, as witnessed by up-regulated Bip/GRP78 expression in the MCA territory. Western blot analysis revealed that caspase-12 activation occurred at 5-23 h of reperfusion, and immunoreactivity for caspase-12 was enhanced mainly in striatal neurons on the ischemic side at the same time points. We found the co-localization of caspase-12 immunoreactivity and DNA fragmentation detectable by the TUNEL method. We did not detect the presence of caspase-7 in the ER fraction at the period of caspase-12 cleavage. Our results imply that cerebral ischemia/reperfusion induces ER stress and that caspase-12 activation concurred with ER stress. Caspase-12 seems to be involved in neuronal death induced by ischemia/reperfusion. Caspase-7 is not likely to contribute to the cleavage of caspase-12 in our experimental model.


Resource utilization in primary repair of cleft lip.
To determine national variations in resource utilization for primary repair of cleft lip, identify patient and institutional factors associated with high resource use, and estimate the current incidence of cleft lip in the United States. Retrospective analysis of a national, pediatric database (2009 Kids' Inpatient Database [KID]). Patients aged 1 year and younger were selected using international classification of disease codes for cleft lip and procedure codes for cleft lip repair. A number of demographic variables were analyzed, and hospital charges were considered as a measure of resource utilization. There were 1318 patients identified. The national incidence was 0.09%, with a male to female ratio of 1.8:1. Regional incidence varied from 0.07% (Northeast) to 0.10% (West). The mean age at surgery was 4.2 months. The average length of stay was 1.4 days. The national average hospital charge was $20,147, ranging from $14,635 (South) to $23,663 (West). Teaching hospitals charge an average of $9764 higher than nonteaching hospitals. The strongest predictor of charge was length of stay, increasing charge by $8102 for every additional hospital day (P < .01). Regional variations exist in resource utilization for primary cleft lip repair. Resource use is higher in the West and among teaching hospitals.


Splenectomy in patients with chronic myelomonocytic leukemia: Indications, histopathological findings and clinical outcomes in a single institutional series of thirty-nine patients.
In a 28-year period, 39 (7%) patients with chronic myelomonocytic leukemia (CMML) (median age 66 years, 64% male) underwent a splenectomy at our institution. Primary indications for splenectomy were refractory thrombocytopenia (36%), progressive spleen related symptoms (33%), emergent splenectomy for splenic rupture (21%), refractory anemia (8%), and prior to allogeneic stem cell transplant (3%). Eleven (28%) patients had anemia at the time of splenectomy, of which 3 (27%) were autoimmune. The median time to splenectomy from CMML diagnosis was 6 months (0-40); perioperative morbidity and mortality rates were 43% and 13%, while the median postsplenectomy survival was 25 months (11-38). Durable remission in spleen related symptoms, thrombocytopenia, complications from splenic rupture, and anemia were achieved in 85%, 50%, 62%, and 21% of patients, respectively. Perioperative morbidity (n = 30) included infections/sepsis in 6 (20%), intraabdominal bleeding in 4 (13%), venous thromboembolism (VTE) in 3 (10%), and acute lung injury in 2 (7%) patients. The median duration of hospital stay was 6 days (1-25), with 5 deaths occurring secondary to respiratory failure (n = 2), multiorgan dysfunction (n = 2) and hemorrhagic shock (n = 1). There was no difference in overall survival between CMML patients that underwent splenectomy, in comparison to those that did not. Unlike in myelofibrosis, portal hypertension was not an indication for splenectomy and no patients developed post-splenectomy thrombocytosis. In conclusion, apart from being a lifesaving emergent modality in the event of splenic rupture, splenectomy has an important palliative role in patients with CMML, with significant and durable improvements in spleen related symptoms and refractory cytopenias.


Hypothalamic/pituitary function following high-dose conformal radiotherapy to the base of skull: demonstration of a dose-effect relationship using dose-volume histogram analysis.
To evaluate the incidence and pattern of hypopituitarism from hypothalamic (HT) and pituitary gland (PG) damage following high-dose conformal fractionated proton-photon beam radiotherapy (PPRT) to the base of skull (BOS) region in adults. The relationship between dose, volume, and PG function is explored. Between May 1982 to October 1997, 107 adults with non-PG and non-HT neoplasms (predominantly chordoma and chondrosarcomas) of the BOS were treated with PPRT after subtotal resection(s). The median age was 41.2 years (range, 17-75) with 58 males and 49 females. Median prescribed target dose was 68.4 cobalt gray equivalent (CGE) (range, 55.8-79 CGE) at 1.80-1.92 CGE per fraction per day (where CGE = proton Gy x 1.1). The HT and PG were outlined on planning CT scans to allow dose-volume histograms (DVH) analysis. All patients had baseline and follow-up clinical testing of anterior and posterior pituitary function including biochemical assessment of thyroid, adrenal, and gonadal function, and prolactin secretion. The 10-year actuarial overall survival rate was 87%, with median endocrine follow-up time of 5.5 years, thus the majority of patients were available for long-term follow-up. Five-year actuarial rates of endocrinopathy were as follows: 72% for hyperprolactinemia, 30% for hypothyroidism, 29% for hypogonadism, and 19% for hypoadrenalism. The respective 10-year endocrinopathy rates were 84%, 63%, 36%, and 28%. No patient developed diabetes insipidus (vasopressin deficiency). Growth hormone deficiency was not routinely followed in this study. Minimum target dose (Dmin) to the PG was found to be predictive of endocrinopathy: patients receiving 50 CGE or greater at Dmin to the PG experiencing a higher incidence and severity (defined as the number of endocrinopathies occurring per patient) of endocrine dysfunction. Dmax of 70 CGE or greater to the PG and Dmax of 50 CGE or greater to the HT were also predictive of higher rates of endocrine dysfunction. Radiation-induced damage to the HT & PG occurs frequently after high-dose PPRT to the BOS and is manifested by anterior pituitary gland dysfunction. Hyperprolactinemia was detected in the majority of patients. Posterior pituitary dysfunction, represented by vasopressin activity with diabetes insipidus, was not observed in this dose range. Limiting the dose to the HT and PG when feasible should reduce the risk of developing clinical hypopituitarism.


Analyses of pattern quality in roll-to-roll digital maskless lithography with positional errors.
In roll-to-roll digital maskless lithography (R2R DML) equipment, it is difficult to achieve high quality, owing to surface deformation that affects the pattern position. To address this issue, we simulated the patterning results of R2R DML to analyze the relationship between positional errors and pattern quality. Errors perpendicular to the pattern direction exhibited a 1.3-2 times greater effect on the linewidth and line edge roughness compared to those parallel to this direction. We confirmed that positioning errors could lead to defects in which the photoresists were not fully exposed. Finally, through simulations, we found that the effect of positional errors could be reduced by controlling the array spot separation length.


Optical activation of lateral amygdala pyramidal cells instructs associative fear learning.
Humans and animals can learn that specific sensory cues in the environment predict aversive events through a form of associative learning termed fear conditioning. This learning occurs when the sensory cues are paired with an aversive event occurring in close temporal proximity. Activation of lateral amygdala (LA) pyramidal neurons by aversive stimuli is thought to drive the formation of these associative fear memories; yet, there have been no direct tests of this hypothesis. Here we demonstrate that viral-targeted, tissue-specific expression of the light-activated channelrhodopsin (ChR2) in LA pyramidal cells permitted optical control of LA neuronal activity. Using this approach we then paired an auditory sensory cue with optical stimulation of LA pyramidal neurons instead of an aversive stimulus. Subsequently presentation of the tone alone produced behavioral fear responses. These results demonstrate in vivo optogenetic control of LA neurons and provide compelling support for the idea that fear learning is instructed by aversive stimulus-induced activation of LA pyramidal cells.


[Effect of cyclic nucleotides and hormones of homologous methylation in nuclear homogenates of rat bone marrow].
In vitro and in vivo studies showed that methylation of homologous DNA in nuclear homogenates of rat bone marrow is controlled by cyclic nucleotides and some hormones. The cyclic nucleotides and their dibutyryl analogs inhibited homologous methylation of DNA in the presence and absence of phosphodiesterase inhibitors. In the presence of Ca2+ the inhibiting effect of the nucleotides was more pronounced. Prostaglandins inhibited DNA methylation in a weaker degree while insulin and erythropoietin had a stronger effect in comparison with the nucleotides. Histamine stimulated DNA methylation, whereas acute hypoxic hypoxia caused a reduction in the rate of DNA methylation.


Verteporfin treatment controls morphology, phenotype, and global gene expression for cells of the human nucleus pulposus.
Cells of the nucleus pulposus (NP) are essential contributors to extracellular matrix synthesis and function of the intervertebral disc. With age and degeneration, the NP becomes stiffer and more dehydrated, which is associated with a loss of phenotype and biosynthetic function for its resident NP cells. Also, with aging, the NP cell undergoes substantial morphological changes from a rounded shape with pronounced vacuoles in the neonate and juvenile, to one that is more flattened and spread with a loss of vacuoles. Here, we make use of the clinically relevant pharmacological treatment verteporfin (VP), previously identified as a disruptor of yes-associated protein-TEA domain family member-binding domain (TEAD) signaling, to promote morphological changes in adult human NP cells in order to study variations in gene expression related to differences in cell shape. Treatment of adult, degenerative human NP cells with VP caused a shift in morphology from a spread, fibroblastic-like shape to a rounded, clustered morphology with decreased transcriptional activity of TEAD and serum-response factor. These changes were accompanied by an increased expression of vacuoles, NP-specific gene markers, and biosynthetic activity. The contemporaneous observation of VP-induced changes in cell shape and prominent, time-dependent changes within the transcriptome of NP cells occurred over all timepoints in culture. Enriched gene sets with the transition to VP-induced cell rounding suggest a major role for cell adhesion, cytoskeletal remodeling, vacuolar lumen, and MAPK activity in the NP phenotypic and functional response to changes in cell shape.


Life After College: Employment, Social, and Community Outcomes for Young Deaf Adults.
While most research on transition outcomes focuses on education and employment, the transition to adulthood also includes social outcomes, such as group involvement and community service. The present study examined a broader set of outcomes for young deaf adults after postsecondary education. A secondary analysis of a large-scale data set, the National Longitudinal Transition Study (NLTS2), was conducted to compare the employment, income assistance, and social/community outcomes of three postsecondary education cohorts: graduates, noncompleters, and nonattendees. The findings indicate that young deaf adults with more postsecondary education have more positive outcomes, e.g., higher employment rates, higher wages, and greater civic and social participation. These findings further demonstrate the importance of postsecondary education for young deaf adults and can be used to inform transition planning for deaf students, supporting the need to consider exploration of various career pathways available through college or postsecondary career/technical education.


The Influence of Smoking on the Variations in Carboxyhemoglobin and Methemoglobin During Urologic Surgery.
Surgery is supposed to modulate the production of carbon monoxide by the reduction of heme oxygenase activity or transcriptional regulation of inducible heme oxygenase. On the other hand, the inhalation of tobacco smoke can substantially raise the level of carboxyhemoglobin in the blood. Furthermore, methemoglobin is maintained at a constant level. However, excessive production of methemoglobin relative to total methemoglobin reductase activity results in methemoglobin increase. The aim of our study was to investigate the perioperative variations of carboxyhemoglobin and methemoglobin during urologic surgeries, and at the same time to evaluate the changes in methemoglobin as a possible indicator of nitric oxide generation. Our second aim was to evaluate the effect of preoxygenation on the level of carboxyhemoglobin and methemoglobin and the influence of blood transfusion on their changes. The study included 30 patients scheduled for urologic surgery under general endotracheal anesthesia, aged 18-60 years without any history of respiratory disease, divided into two groups. The study group comprised patients who were smoking cigarettes or tobacco pipe, while the control group included non-smokers. In both groups carboxyhemoglobin (COHb) and methemoglobin (MetHb) levels were determined preoperatively, after preoxygenation, and postoperatively. COHb levels were decreased postoperatively in both groups. The average values of COHb between the two groups were statistically significantly different (p=0.00). MetHb levels increased postoperatively in the group of smokers and decreased in the group of non-smokers. There were no statistically significant differences in the average postoperative MetHb levels between the two groups. Changes in carboxyhemoglobin and methemoglobin concentrations in arterial blood occur during urologic surgery, although these amplitudes are small when compared with carbon monoxide intoxication and methemoglobinemia. It is likely that organ perfusion and functions are affected by these monoxide gas mediators during urologic surgery.


Effect of translational signals on mRNA decay in Bacillus subtilis.
A 254-nucleotide model mRNA, designated deltaermC mRNA, was used to study the effects of translational signals and ribosome transit on mRNA decay in Bacillus subtilis. DeltaermC mRNA features a strong ribosome-binding site (RBS) and a 62-amino-acid-encoding open reading frame, followed by a transcription terminator structure. Inactivation of the RBS or the start codon resulted in a fourfold decrease in the mRNA half-life, demonstrating the importance of ternary complex formation for mRNA stability. Data for the decay of deltaermC mRNAs with stop codons at positions increasingly proximal to the translational start site showed that actual translation--even the formation of the first peptide bond--was not important for stability. The half-life of an untranslated 3.2-kb deltaermC-lacZ fusion RNA was similar to that of a translated deltaermC-lacZ mRNA, indicating that the translation of even a longer RNA was not required for wild-type stability. The data are consistent with a model in which ribosome binding and the formation of the ternary complex interfere with a 5'-end-dependent activity, possibly a 5'-binding endonuclease, which is required for the initiation of mRNA decay. This model is supported by the finding that increasing the distance from the 5' end to the start codon resulted in a 2.5-fold decrease in the mRNA half-life. These results underscore the importance of the 5' end to mRNA stability in B. subtilis.


Increase in intracellular sodium ion activity during stimulation in mammalian cardiac muscle.
Changes in stimulation rate alter the electrical and mechanical characteristics of myocardial cells. We have investigated the possibility that intracellular sodium activity (aiNa) changes with stimulation and correlates with changes in contraction strength. Two kinds of liquid membrane Na+-selective microelectrodes were used to measure aiNa in guinea pig and sheep ventricular muscle and in sheep Purkinje strands. Stimulation produced a rate- and time-dependent elevation of aiNa. Small increases in aiNa were seen at stimulation rates as slow as 0.2 Hz, and faster rates of stimulation elevated aiNa by over 30%. The changes seen in Purkinje strands and ventricular muscle were similar. Following a period of stimulation, aiNa and Vm returned to their pre-stimulus levels with the same time courses. This is consistent with the suggestion that the post-stimulation hyperpolarization is the result of an increased rate of electrogenic Na+ extrusion. The effects of stimulation on aiNa and tension were compared with those of ouabain. The comparison suggests that rapid stimulation could produce increased contraction strength as the result of a substantial gain in intracellular calcium via a Na-Ca exchange mechanism, but that this is only one of several factors determining the force-frequency relationship.


[Chronic rhinosinusitis: epidemiology, classification, etiology, and pathogenesis. The current view of the problem].
The study of chronic rhinosinusitis is a challenging problem bearing in mind the ever-increasing morbidity and the lack of generally accepted criteria for diagnostics and treatment of this pathology. There is a great variety of factors predisposing to the development of chronic rhinosinusitis whereas its etiology remains controversial. Moreover, the pathogenetic mechanisms of chronic rhinosinusitis remain to be elucidated despite a wealth of publications devoted to this problem The results of many evidence-based investigations are different and even conflicting. Both diagnostic techniques and characteristics of chronic rhinosinusitis vary in a broad range depending on the standards adopted in different countries.


Trajectory of right ventricular indices is an early predictor of outcomes in hypoplastic left heart syndrome.
Children with hypoplastic left heart syndrome (HLHS) have risk for mortality and/or transplantation. Previous studies have associated right ventricular (RV) indices in a single echocardiogram with survival, but none have related serial measurements to outcomes. This study sought to determine whether the trajectory of RV indices in the first year of life was associated with transplant-free survival to stage 3 palliation (S3P). HLHS patients at a single center who underwent stage 1 palliation (S1P) between 2000 and 2015 were reviewed. Echocardiographic indices of RV size and function were obtained before and following S1P and stage 2 palliation (S2P). The association between these indices and transplant-free survival to S3P was examined. There were 61 patients enrolled in the study with 51 undergoing S2P, 20 S3P, and 18 awaiting S3P. In the stage 1 perioperative period, indexed RV end-systolic area increased in patients who died or needed transplant following S2P, and changed little in those surviving to S3P (3.37 vs -0.04 cm2 /m2 , P = .017). Increased indexed RV end-systolic area was associated with worse transplant-free survival. (OR = 0.815, P = .042). In the interstage period, indexed RV end-diastolic area increased less in those surviving to S3P (3.6 vs 9.2, P = .03). Change in indexed RV end-systolic area through the stage 1 perioperative period was associated with transplant-free survival to S3P. Neither the prestage nor poststage 1 indexed RV end-systolic area was associated with transplant-free survival to S3P. Patients with death or transplant before S3P had a greater increase in indexed RV end-diastolic area during the interstage period. This suggests earlier serial changes in RV size which may provide prognostic information beyond RV indices in a single study.


The attachment system in fledgling relationships: an activating role for attachment anxiety.
Is it sensible to study attachment dynamics between potential romantic partners before they share a full-fledged attachment bond? The present data indicate that such an approach may reveal novel insights about initial attraction processes. Four studies suggest that the state-like experience of attachment anxiety has functional implications within fledgling (i.e., desired or undeveloped) romantic relationships, well before the formation of an attachment bond. Studies 1 and 3 reveal that attachment anxiety directed toward a particular romantic interest is elevated before (in comparison with after) participants report being in an established relationship. Studies 2 and 3 demonstrate that such partner-specific attachment anxiety predicts attachment-relevant outcomes in fledgling relationships, including proximity seeking, safe haven, secure base, passionate love, and other approach behaviors. These associations were reliable above and beyond (and were typically as strong as or stronger than) the effect of sexual desire. Finally, Study 4 presents evidence that partner-specific attachment anxiety may cause several of these attachment-relevant outcomes. Attachment anxiety seems to be a normative experience and may signal the activation of the attachment system during the earliest stages of romantic relationships.


PDIM and SL1 accumulation in Mycobacterium tuberculosis is associated with mce4A expression.
Lipid metabolism forms the heart and soul of Mycobacterium tuberculosis life cycle. Starting from macrophage invasion at cholesterol rich micro-domains to a sustainable survival for infection by utilizing cholesterol, Mycobacterium displays the nexus of metabolic pathways around host derived lipids. mce4 operon acts as cholesterol import system in M. tuberculosis and here we demonstrate role of mce4A gene of this operon in cholesterol catabolism. Here M. tuberculosis H37Rv overexpressing Rv3499c (mce4A) recombinant was used as a model to decipher the metabolic flux during intake and utilization of host lipids by mycobacteria. We analysed the impact of mce4A expression on carbon shift initiated during cholesterol utilization necessary for long term survival of mycobacterium. Through transcriptional analysis, upregulation in methylcitrate cycle (MCC) and methylmalonyl pathway (MMP) genes was observed in Rv3499c overexpressing recombinants of M. tuberculosis H37Rv. Up-regulation of methylmalonyl pathway associated enzyme encoding genes increased accumulation of virulence associated mycobacterial lipids phthiocerol dimycocerates (PDIM) and sulfolipid (SL1). We demonstrate that MCC and MMP associated enzyme encoding genes are upregulated upon mce4A overexpression and lead to enhanced accumulation of PDIM and SL1 which are responsible for pathogenicity of M. tuberculosis.


Mechanism of induction of transforming growth factor-beta type II receptor gene expression by v-Src in murine myeloid cells.
Transforming growth factor (TGF)-beta1 plays an important role during hematopoiesis. Previously, we had shown that the growth of a v-Src-transformed myeloid cell line was markedly more inhibited by TGF-beta treatment when compared with the wild-type myeloid cell line. To investigate the increased growth sensitivity of the v-Src-transformed myeloid cell line, 32D-src, to TGF-beta, we examined expression of the TGF-beta type II receptor (TGF-beta RII) gene in myeloid cell lines. Northem blot analysis showed that expression of approximately 8- and 6-kb species of TGF-beta RII transcripts was markedly increased in the 32D-src cell line. The expression of the TGF-beta RII promoter linked to a reporter gene was increased 23-fold by v-Src. DNA transfection and electrophoretic mobility shift assay revealed that v-Src induces TGF-beta RII promoter activity through an AP1/ATF2-like sequence (-219 to -172), ETS binding sites (+1 to +36), and the inverted CCAAT box (-81 to -77). Novel DNA-protein complexes with ETS binding sites are significantly increased in v-src-transformed cell lines compared with the control cell line. These results suggest that v-Src induces activity of the TGF-beta RII promoter through multiple elements by inducing expression of nuclear proteins interacting with these elements.


Evaluation of Etest method for determining isavuconazole MICs against Cryptococcus gattii and Cryptococcus neoformans.
We compared Etest with broth microdilution testing for isavuconazole activity against 92 Cryptococcus isolates. A 97.8% agreement was found between these methods, without major discrepancies (>2-well dilution difference). Our findings support the use of the Etest methodology as a reliable method for the determination of MICs against Cryptococcus spp.


Linear and nonlinear contributions to the visual sensitivity of neurons in primate lateral geniculate nucleus.
Several parallel pathways convey retinal signals to the visual cortex of primates. The signals of the parvocellular (P) and magnocellular (M) pathways are well characterized; the properties of other rarely encountered cell types are distinctive in many ways, but it is not clear that they can provide signals with the same fidelity. Here we study this by characterizing the temporal receptive field of neurons in the lateral geniculate nucleus of anesthetized marmosets. For each neuron, we measured the response to a flickering uniform field, and, from this, estimated the linear and nonlinear receptive fields using spike-triggered average (STA) and spike-triggered covariance (STC) analyses. As expected the response of most P-cells was dominated by the STA, but the response of most M-cells required additional nonlinear components, and these usually acted to suppress cell responses. The STC analysis showed stronger suppressive axes in suppressed-by-contrast cells, and both suppressive and excitatory axes in on-off cells. Together, the STA and the STC analyses form a model of the temporal response to a large uniform field: under this model, the information that was provided by suppressed-by-contrast cells or on-off cells approached that provided by the P- and M-cells. However, whereas P- and M-cells provided more information about luminance, the nonlinear cells provided more information about the contrast energy. This suggests that the nonlinear cells provide complimentary signals to those of P- and M-cells, with reasonably high fidelity, and may play an important role in normal visual processing.


The relationship between work engagement and psychological distress of hospital nurses and the perceived communication behaviors of their nurse managers: A cross-sectional survey.
Communication between nurse managers and nurses is important for mental health of hospital nurses. The aim of the present study was to investigate the relationship between managers' communication behaviors toward nurses, and work engagement and psychological distress among hospital nurses using a multilevel model. The present study was a cross-sectional questionnaire survey. The participants were nurses working at three hospitals in Japan. A total of 906 nurses from 38 units participated in the present study. The units with small staff sizes and participants with missing entries in the questionnaire were excluded. The data for 789 nurses from 36 questionnaire survey units were analyzed. A survey using a self-administered questionnaire was conducted. The questionnaire asked staff nurses about communication behaviors of their immediate manager and their own levels of work engagement, psychological distress, and other covariates. Three types of manager communication behaviors (i.e., direction-giving, empathetic, and meaning-making language) were assessed using the Motivating Language scale; and the scores of the respondents were averaged for each unit to calculate unit-level scores. Work engagement and psychological distress were measured using the Utrecht Work Engagement Scale and the K6 scale, respectively. The association of communication behaviors by unit-level managers with work engagement and psychological distress among nurses was analyzed using two-level hierarchical linear modeling. The unit-level scores for all three of the manager communication behaviors were significantly and positively associated with work engagement among nurses (p<0.05). This association was smaller and non-significant after adjusting for the psychosocial work environment. The individual levels of all three of the manager communication behaviors were also significantly and positively associated with work engagement (p<0.05). None of the three manager communication behaviors was significantly associated with psychological distress (p>0.05). Motivating language by unit-level managers might be positively associated with work engagement among hospital nurses, which is mediated through the better psychosocial work environment of the unit.


Factors associated with self-reported adherence to antiretroviral therapy in a Tanzanian setting.
This study aimed to determine the level of antiretroviral adherence and factors associated with adherence among patients receiving free antiretroviral therapy (ART) at one clinic in Tanzania. Adult patients were recruited into the cross-sectional study and completed a survey that included self-reported adherence over four days and over one month. Less than 95% adherence on either measure was considered "poor." Factors associated with adherence in unadjusted analyses (alpha = 0.10) were included in a logistic regression model. A total of 340 patients participated in the study, and 5.9% (20/340) reported poor adherence. The final model found poor adherence associated with: being young (odds ratio (OR) = 4.03) or old (OR = 6.68); having lower perceived quality of patient-provider interaction (OR = 2.75); and ever missing a clinic appointment (OR = 3.13). Results highlight good adherence, but suggest the importance of addressing: (1) age-specific challenges of adherence through counseling and support; (2) client-focused care and quality of patient-provider interaction; and (3) clinic appointment reminder systems.


L-band erbium-doped fiber laser with coupling-ratio controlled wavelength tunability.
By controlling the output coupling ratio, we demonstrate a novel wavelength-tunable L-band Erbium-doped fiber laser (EDFL) with a maximum tuning range up to 58 nm (from 1567 to 1625 nm) by controlling its output coupling ratio between 1% and 99%. The L-band EDFL is configured by using a bi-directionally dual-wavelength pumped EDFA in close-loop with an output coupler of tunable coupling ratio and an air-gap inserted FC/PC connector pair. Such an EDFL exhibits a quantum efficiency of 42% and an ultra-high power conversion efficiency of 37% under optimized pumping scheme, providing the small-signal gain and output power of ~34 dB and 91 mW, respectively. Low variation of <1.2 dB on channel power, power fluctuation of 0.04% and a narrow linewidth of 0.03 nm are obtained.


[The individual health of male teenagers studying at secondary school].
Mental health, physical development, physiological constants, somatic health and chronic case rates were studied in graduating-class schoolboys aged 16 (n = 63) and 17 (n = 82) years. The prevailing temperament in 17-year-old teenagers was hyperthymic and that in 16-year-olds was labile and introverted. The majority of the surveyed young men were extroverts, emotionally stable with a moderate useful level of situational and personal anxiety. More than 70.0% of the young men showed high social adaptation and low autonomic lability. 17-year-old young men had retarded processes as shown by moderate-low and moderate rates ofphysical development and disharmony. The most of teenagers had moderate and above-moderate levels of somatic health and a vital index that characterizes good functional, adaptive capacities of the cardiorespiratory system.


Complexity of localised coherent structures in a boundary-layer flow.
We study numerically transitional coherent structures in a boundary-layer flow with homogeneous suction at the wall (the so-called asymptotic suction boundary layer ASBL). The dynamics restricted to the laminar-turbulent separatrix is investigated in a spanwise-extended domain that allows for robust localisation of all edge states. We work at fixed Reynolds number and study the edge states as a function of the streamwise period. We demonstrate the complex spatio-temporal dynamics of these localised states, which exhibits multistability and undergoes complex bifurcations leading from periodic to chaotic regimes. It is argued that in all regimes the dynamics restricted to the edge is essentially low-dimensional and non-extensive.


[To resuscitate or not? Discuss timely with all chronically ill patients].
In-hospital adult cardiopulmonary resuscitation is successful in only approximately 20% of cases and may result in permanent neurological damage. Two reasons justify not commencing resuscitation: either the patient does not want to be resuscitated, or resuscitation is considered medically futile by the doctor. This subject should be discussed timely with all chronically ill patients who are likely to be admitted to hospital, preferably in the outpatient clinic setting, and results must be communicated with all doctors involved (e.g. general practitioners). Here we describe 3 cases that demonstrate the need to discuss possible restrictions on cardiopulmonary resuscitation with all chronically ill patients, regardless of their age. The first was a 45-year-old HIV-positive male with chronic clinical depression who refused ICU care, the second a 75-year-old patient whose initial 'do no resuscitate' order was reversed based on the wishes of her daughter and the third a 45-year-old female with sickle cell disease who expressed a sustained wish not to be treated in the ICU or to be resuscitated.


Conjugative Transfer of IncP-9 Catabolic Plasmids Requires a Previously Uncharacterized Gene, mpfK, Whose Homologs Are Conserved in Various MPFT-Type Plasmids.
Conjugative transfer of bacterial plasmids to recipient cells is often mediated by type IV secretion machinery. Experimental investigations into the minimal gene sets required for efficient conjugative transfer suggest that such gene sets are variable, depending on plasmids. We have been analyzing the conjugative transfer of Pseudomonas-derived and IncP-9 plasmids, NAH7 and pWW0, whose conjugation systems belong to the MPFT type. Our deletion analysis and synthetic biology analysis in this study showed that these plasmids require previously uncharacterized genes, mpfK (formerly orf34) and its functional homolog, kikA, respectively, for their efficient conjugative transfer. MpfK was localized in periplasm and had four cysteine residues whose intramolecular or intermolecular disulfide bond formation was suggested to be important for efficient conjugative transfer. The mpfK homologs were specifically carried by many MPFT-type plasmids, including non-IncP-9 plasmids, such as R388 and R751. Intriguingly, the mpfK homologs from the two non-IncP-9 plasmids were not required for conjugation of their plasmids, but were able to complement efficiently the transfer defect of the NAH7 mpfK mutant. Our results suggested the importance of the mpfK homologs for conjugative transfer of MPFT-type plasmids.IMPORTANCE IncP-9 plasmids are important mobile genetic elements for the degradation of various aromatic hydrocarbons. Elucidation of conjugative transfer of such plasmids is expected to greatly contribute to our understanding of its role in the bioremediation of polluted environments. The present study mainly focused on the conjugation system of NAH7, a well-studied and naphthalene-catabolic IncP-9 plasmid. Our analysis showed that the NAH7 conjugation system uniquely requires, in addition to the conserved components of the type IV secretion system (T4SS), a previously uncharacterized periplasmic protein, MpfK, for successful conjugation. Our findings collectively revealed a unique type of T4SS-associated conjugation system in the IncP-9 plasmids.


Hospital-acquired pressure ulcer prevention: a burn surgeon's team approach.
Hospital-acquired pressure ulcers (HAPUs) are a problem that has been under increased scrutiny in recent years. To help reduce the incidence of HAPUs and to improve their management, a burn unit-centered wound care team was established. The team decided to pursue two goals: to identify opportunities for improvement that may help prevent HAPUs and to evaluate all available support surfaces to identify those that might best help with pressure redistribution. To identify opportunities for improvement, the team studied each new case of HAPUs throughout our hospital with a forensic chart review for a 3-year period. To identify the best support surfaces to help reduce the incidence of pressure ulcers, we evaluated all support surfaces available at our institution by pressure mapping in healthy volunteers. From 3 years of collecting and reporting data for quality improvement, we identified 23 patients with HAPUs and obtained more than 800 data sets from pressure mapping in healthy volunteers. Most (23/24; 96%) patients with HAPUs identified in this series had undergone a surgical procedure. The results of the quality improvement studies are presented. We conclude that prevention planning of HAPUs needs to be improved in patients undergoing surgery, in particular. No single support surface can prevent pressure ulcers, but use of overlays may help reduce peak pressures over bony prominences.


Oestrogen receptor beta: role in neurohypophyseal neurones.
The robust expression of oestrogen receptor beta (ER-beta) in magnocellular vasopressin neurones has focused attention on the role of this receptor and the gonadal steroids in the regulation of vasopressin secretion. Although the effects of gonadal steroids on vasopressin secretion have been the subject of many studies, there is no consensus in the literature as to their role. Possible reasons for the diverse findings are discussed, including diversity in the types, site and level of expression of steroid receptors across species, gender and physiological conditions. The physiological regulation of expression is of particular interest because ER-beta mRNA expression in vasopressin neurones is inversely correlated to the osmotic state of the animal. Chronic hyperosmolality inhibits ER-beta mRNA expression in magnocellular vasopressin neurones, while chronic hypo-osmolality enhances expression. This is consistent with an inhibitory role for ER-beta because hyperosmolality is a potent stimulus for vasopressin secretion, whereas vasopressin secretion is maximally inhibited by chronic hypo-osmolality. An inhibitory role is also indicated by in vitro experiments demonstrating inhibition of osmotically stimulated vasopressin secretion by oestrogen and testosterone, and ER-beta mediated inhibition of NMDA-stimulated vasopressin secretion. The challenge remains to elucidate the mechanism of this inhibition, and to understand its significance for maintenance of whole-body fluid and electrolyte homeostasis.


CXCR6 predicts poor prognosis in gastric cancer and promotes tumor metastasis through epithelial-mesenchymal transition.
Chemokines and their receptors have been confirmed to be involved in several types of cancer. However, little is known concerning the role of CXCL16 and its receptor CXCR6 in gastric cancer (GC) progression and metastasis. In the present study, expression of CXCL16 and CXCR6 in GC tumor and peritumoral tissues was detected by immunohistochemistry (IHC) in a cohort of 352 GC patients who underwent gastrectomy, and the correlation between CXCL16/CXCR6 expression and clinicopathological characteristics was further analyzed. To evaluate the function of CXCR6, we overexpressed and knocked down CXCR6 in GC cell lines. Results showed that expression of CXCR6, but not CXCL16, was significantly upregulated in GC tumor tissues, and was significantly correlated with lymph node and distant metastases, and advanced clinical stage in the GC patients. Survival analysis showed that large tumor size (>5 cm), elevated preoperative serum carcinoembryonic antigen (CEA) level, advanced TNM stage and high CXCR6 expression indicated worse overall survival (OS) and disease-free survival (DFS) in GC, and CXCR6 was an independent predictor for both OS and DFS in GC. In vitro experiments showed that CXCR6 overexpression induced cell migration and invasion ability, and promoted epithelial-mesenchymal transition of GC cells by upregulation of mesenchymal markers and inhibition of epithelial markers. In contrast, knockdown of CXCR6 in GC cells resulted in inhibition of cell proliferation, migration and invasion ability, and reversal of epithelial-mesenchymal transition (EMT) phenomenon. Our results demonstrated that CXCR6 is an independent prognostic factor for poor survival in GC patients, and may promote GC metastasis through EMT.


Variation in mitochondrial DNA reveals multiple distant glacial refugia in black spruce (Picea mariana), a transcontinental North American conifer.
Range-wide genetic variation of black spruce (Picea mariana) was studied using polymerase chain reaction-random fragment length polymorphism markers of the mitochondrial genome. Four polymorphic mitochondrial DNA (mtDNA) loci were surveyed and two or three alleles were detected at each locus, resulting in 10 multilocus mtDNA types or mitotypes. A significant subdivision of population genetic diversity was detected (GST = 0.671; NST = 0.726), suggesting low levels of gene flow among populations. The distribution of mitotypes was not random (NST > GST; P < 0.05) and revealed four partially overlapping zones, presumably representative of different glacial populations. Comparison of the genetic structure derived from mtDNA markers and the colonization paths previously deduced from the fossil and pollen records allow us to infer at least three southern and one northeastern glacial populations for black spruce. The patterns revealed in this study suggest that black spruce shares its biogeographical history with other forest-associated North American species.


The Influence of Closing the Abdominal Donor-Site Superficial Fascial System in Deep Inferior Epigastric Perforator Flap Breast Reconstruction.
The superficial fascial system is routinely closed to alleviate tension at the abdominal donor site after harvest of the deep inferior epigastric artery perforator flap (DIEP) for breast reconstruction. This is thought to decrease rates of wound dehiscence and improve contour postoperatively. There has been no comparative analysis on closure of the superficial fascial system and its effect on donor-site outcomes. The authors retrospectively evaluated outcomes of DIEP flap breast reconstructions performed between 2017 and 2019. After May of 2018, the surgeons collectively agreed to stop closure of the superficial fascial system. All subsequent patients underwent closure of rectus abdominis fascia followed by skin closure. Patient demographic data and abdominal donor-site comorbidities were recorded between the superficial fascial system closure and no-superficial fascial system closure groups. Representative photographs of patients from the two groups were blindly assessed for scar appearance and contour using previously published grading scales. The results were compared. DIEP flap breast reconstruction was performed in 103 consecutive women. Among patients with abdominal donor-site reconstruction, 66 had superficial fascial system closure and 37 did not. There was not a significant difference in fat necrosis or wound dehiscence between the two groups (p = 0.29 and p = 0.39, respectively). Postoperative abdominal scar and contour were evaluated by 10 independent raters and showed no significant difference between the two groups. Omission of superficial fascial system closure resulted in no difference in wound dehiscence or fat necrosis rates and aesthetic appearance of the abdominal scar and contour. Therapeutic, III.


Efficacy and safety of cerivastatin for type 2 diabetes and hypercholesterolaemia. Hyperlipidaemia in Diabetes Mellitus investigators.
The prevalence of coronary heart disease (CHD) is markedly increased in diabetic patients compared with non-diabetic individuals, and its prognosis is less good. Serum total and low-density lipoprotein (LDL) cholesterol concentrations have been shown to be powerful predictors of CHD morbidity and mortality in patients with type 2 diabetes. The available data suggest that the target cholesterol concentration in patients with diabetes should be similar to that in non-diabetic individuals with a previous myocardial infarction. This led us to investigate the efficacy, tolerability and safety of a new, highly potent statin, cerivastatin, in diabetic hyperlipidaemia. This was a multinational, multicentre, double-blind, randomized study in type 2 diabetic patients with hypercholesterolaemia (LDL cholesterol >3.35 mmol/l; triglycerides <4.56 mmol/l). Eligible patients were randomly assigned to groups to receive cerivastatin 0.1 mg or 0.3 mg or placebo in a ratio of 2:2:1 for 12 weeks. They were monitored in the clinic every 4 weeks. Of the 453 patients screened, 265 were allocated to the study groups. Fifty-one received placebo and 107 patients were assigned to each active treatment group (0.1 mg and 0.3 mg cerivastatin). At the close of the study, total cholesterol had decreased by 13.7% and 23.5%, LDL cholesterol decreased by 20.2% and 33.8%, and triglyceride concentrations decreased by 3.9% and 12.3% in the cerivastatin 0.1 mg and 0.3 mg groups, respectively. There was no significant difference between the groups in haemoglobin A1c, adverse events or increases in liver and muscle enzymes during the study period. Hypercholesterolaemic patients with type 2 diabetes had a significant reduction in LDL cholesterol and total cholesterol concentrations after cerivastatin treatment once daily. The dose of 0.3 mg cerivastatin is effective in diabetic hypercholesterolaemia, with co-reduction of triglyceride concentrations. The effect of cerivastatin on coronary morbidity and mortality is currently being investigated in clinical trials.


Megacystis-microcolon-intestinal hypoperistalsis syndrome in a newborn after clomiphene ingestion during pregnancy.
A case of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) in a newborn after clomiphene ingestion during pregnancy is described. Review of the literature revealed no other MMIHS associated with maternal clomiphene ingestion.


Low-dose nitroglycerin improves microcirculation in hospitalized patients with acute heart failure.
Impaired tissue perfusion is often observed in patients with acute heart failure. We tested whether low-dose nitroglycerin (NTG) improves microcirculatory perfusion in patients admitted for acute heart failure. In 20 acute heart failure patients, NTG was given as intravenous infusion at a fixed dose of 33 microg/min. Using Sidestream Dark Field (SDF) imaging, sublingual microvascular perfusion was evaluated before (T0, average of two baseline measurements) and 15 min after initiation of NTG (T1). In a subgroup of seven patients, SDF measurements were repeated after NTG had been stopped for 20 min. Capillaries were defined as microvessels with a diameter of <20 microm. Perfused capillary density (PCD) was determined as the parameter of tissue perfusion. Values are expressed as median and interquartile range (P25; P75). The median age of the subjects was 60 (52; 73) years, and 65% were male. Patients were stable before starting NTG. Nitroglycerin decreased central venous pressure [17 (13; 19) mmHg at T0 vs. 16 (13; 17) mmHg at T1, P = 0.03] and pulmonary capillary wedge pressure [23 (18; 31) mmHg at T0 vs. 19 (16; 25) mmHg at T1, P = 0.03]. It increased PCD [10.7 (9.9; 12.5) mm mm(-2) at T0 vs. 12.4 (11.4; 13.6) mm mm(-2) at T1, P = 0.01]. After cessation of NTG, PCD returned to baseline values (P = 0.04). Low-dose NTG significantly reduces cardiac filling pressures and improves microvascular perfusion in patients admitted for acute heart failure.


Relationship between the effective attenuation coefficient of spaceborne lidar signal and the IOPs of seawater.
Multiple scattering is an inevitable effect in spaceborne oceanic lidar because of the large footprint size and the high optical density of seawater. The effective attenuation coefficient klidar in the oceanic lidar equation, which indicates the influence of the multiple scattering effect on the formation of lidar returns, is an important parameter in the retrieval of inherent optical properties (IOPs) of seawater. In this paper, the relationships between klidar of the spaceborne lidar signal and the IOPs of seawater are investigated by solving the radiative transfer equation with an improved semianalytic Monte Carlo model. Apart from the geometric loss factors, klidar is found to decrease exponentially with the increase of depth in homogeneous waters. klidar is given as an exponential function of depth and IOPs of seawater. The mean percentage errors between klidar calculated by the exponential function and the simulated ones in three typical stratified waters are within 0.5%, proving the effectiveness and applicability of this klidar-IOPs function. The results in this paper can help researchers have a better understanding of the multiple scattering effect of spaceborne lidar and improve the retrieval accuracy of the IOPs and the chlorophyll concentration of case 1 water from spaceborne lidar measurements.


New Insights and Enhanced Human Norovirus Cultivation in Human Intestinal Enteroids.
Human noroviruses (HuNoVs) are the leading cause of epidemic and sporadic acute gastroenteritis worldwide. We previously demonstrated human intestinal stem cell-derived enteroids (HIEs) support cultivation of several HuNoV strains. However, HIEs did not support virus replication from every HuNoV-positive stool sample, which led us to test and optimize new medium conditions, identify characteristics of stool samples that allow replication, and evaluate consistency of replication over time. Optimization of our HIE-HuNoV culture system has shown the following: (i) a new HIE culture medium made with conditioned medium from a single cell line and commercial media promotes robust replication of HuNoV strains that replicated poorly in HIEs grown in our original culture medium made with conditioned media from 3 separate cell lines; (ii) GI.1, 11 GII genotypes (GII.1, GII.2, GII.3, GII.4, GII.6, GII.7, GII.8, GII.12, GII.13, GII.14, and GII.17), and six GII.4 variants can be cultivated in HIEs; (iii) successful replication is more likely with virus in stools with higher virus titers; (iv) GII.4_Sydney_2012 virus replication was reproducible over 3 years; and (v) HuNoV infection is restricted to the small intestine, based on replication of two viral strains in duodenal and ileal HIEs, but not colonoids, from two susceptible donors. These results improve the HIE culture system for HuNoV replication. Use of HIEs by several laboratories worldwide to study the molecular mechanisms that regulate HuNoV replication confirms the usefulness of this culture system, and our optimized methods for virus replication will advance the development of effective therapies and methods for virus control.IMPORTANCE Human noroviruses (HuNoVs) are highly contagious and cause acute and sporadic diarrheal illness in all age groups. In addition, chronic infections occur in immunocompromised cancer and transplant patients. These viruses are antigenically and genetically diverse, and there are strain-specific differences in binding to cellular attachment factors. In addition, new discoveries are being made on strain-specific differences in virus entry and replication and the epithelial cell response to infection in human intestinal enteroids. Human intestinal enteroids are a biologically relevant model to study HuNoVs; however, not all strains can be cultivated at this time. A complete understanding of HuNoV biology thus requires cultivation conditions that will allow the replication of multiple strains. We report optimization of HuNoV cultivation in human intestinal enteroid cultures to increase the numbers of cultivatable strains and the magnitude of replication, which is critical for testing antivirals, neutralizing antibodies, and methods of virus inactivation.


The relationships between sex hormones and sexual function in middle-aged and older European men.
Limited data are available exploring the associations between sex hormones, multiple domains of sexual functioning, and sexual function-related distress in nonpatient samples in Europe. The aim of the study was to investigate the relationships between serum testosterone (T), estradiol (E2), and dihydrotestosterone (DHT) and sexual function in a multicenter population-based study of aging in men. Using stratified random sampling, 2838 men aged 40-79 yr completed the European Male Ageing Study-Sexual Function Questionnaire and provided a blood sample for hormone measurements. T, E2, and DHT were measured using gas chromatography-mass spectrometry. We conducted a community-based population survey in eight European centers. Self-reported sexual function (overall sexual function, sexual function-related distress, erectile dysfunction, masturbation) was measured. Total and free T, but not E2 or DHT, was associated with overall sexual function in middle-aged and older men. E2 was the only hormone associated with sexual function-related distress such that higher levels were related to greater distress. Free T levels were associated with masturbation frequency and erectile dysfunction in the fully adjusted models, such that higher T was associated with less dysfunction and greater frequency. Moreover, there was a T threshold for the relationship between total T, sexual function, and erectile dysfunction. At T concentrations of 8 nmol/liter or less, T was associated with worse sexual functioning, whereas at T levels over 8 nmol/liter, the relationship came to a plateau. These findings suggest that different hormonal mechanisms may regulate sexual functioning (T) vs. the psychological aspects (E2) of male sexual behavior. Moreover, there was a T threshold for overall sexual function such that at levels greater than 8 nmol/liter the relationship between T and sexual function did not become stronger.