[Evidence that periplacentary leukocytes subpopulations of term pregnancy have functional properties associated with labor induction].
The rise of cholagenolitic activity in fetal membranes, associated to premature rupture, have been related to abnormal activity of the extracellular matrix metalloproteinases discharged to the extracellular space as inactive enzymes that have to be activated to selectively degrade its components. To analyze the functional properties of leukocytes subpopulations coming from the placental circulation. Biomedical experimental study in which placental and outlying blood leukocytes were cultivated during 96 hours, from women with pregnancy to term without labor. Leukocytes subpopulations were stained by flow cytometry. Culture media were analyzed with zymography and enzymatic activity profile was evaluated in presence of proteases inhibitors. Placental leukocytes are composed of T-, NK- and B-lymphocytes, and monocytes; it was documented a progressive increase of inactive MMP-9 secretion (92 kDa), accompanied by an 82 kDa form MMP-9 activation since 48 hours. Enzymatic profile mainly showed metalloproteasas. Placental blood leukocytes showed functional capacities different from those that circulate in pregnant women's outlying circulation. Placental leukocytes, mainly T-lymphocytes, are characterized by the specific capacity to secrete and activate MMP-9; an enzyme that participates in fetal membranes degradation. It suggests that in placental surroundings are recruited cells specialized in labor changes induction.


Benzodiazepine use among opiate-dependent subjects in buprenorphine maintenance treatment: correlates of use, abuse and dependence.
Previous studies from North America, Europe and Australia have reported high levels of benzodiazepine use among opiate-dependent patients in opiate maintenance treatment. However, to date, there are no available data on patterns of abuse and dependence on benzodiazepines according to DSM criteria among these patients. To describe the independent correlates of use, abuse and dependence on benzodiazepines among buprenorphine patients selected from standard treatment settings. Cross-sectional study in France between June 2001 and June 2004. Buprenorphine patients treated for over 3 months were recruited via physicians prescribing buprenorphine. Patients answered a self-administered questionnaire, the DSM-IV criteria for benzodiazepine abuse and dependence, the Beck Anxiety and Depression Inventories (BAI, BDI) and the Nottingham Health Profile (NHP). Main outcome was modalities of benzodiazepine use: no use vs. simple use vs. problematic use (abuse or dependence according to DSM-IV). 170 patients were recruited. 54% did not use benzodiazepines during the previous month, 15% were simple users and 31% were problematic users. Benzodiazepine use (all modalities) was associated with poly-use of psychotropics. Simple users of benzodiazepines were not statistically different from non-users for the other factors explored. Problematic users of benzodiazepines had higher depression and anxiety levels, correlated with quality of life impairment and precariousness. They used higher dosages of benzodiazepines than simple users. Characteristics of simple benzodiazepine users were distinct from problematic users but not from non-users in this sample of buprenorphine patients. This should be taken into account in the clinical management of benzodiazepine use among buprenorphine patients.


Our way of being: Infant and Early Childhood Mental Health workforce development in Tennessee.
The optimal relational experiences of infants and young children demand a cross-sector workforce informed by Infant and Early Childhood Mental Health (IECMH) principles and practices. A recent review by the Alliance for the Advancement of Infant Mental Health, Inc identified seven themes that help define "What makes an IECMH association strong?": (1) Identity, (2) Cross-Systems Collaborations, (3) Sound Organizational Structure, (4) Competency-Informed Training, (5) Reflective Supervision Capacity, (6) Policy, and (7) Higher Education. The present paper documents the story of the Association of Infant Mental Health in Tennessee (AIMHiTN) and the role of the Endorsement for Culturally Sensitive, Relationship-Focused Practice Promoting IECMH in that growth across those seven themes with the additional themes of (8) Funding and, (9) Diversity, Equity, Inclusion, and Belonging. First, foundational literature is reviewed to summarize IECMH-informed workforce development. Next, AIMHiTN's story of workforce development is mapped onto the nine themes and challenges and lessons learned are summarized. The article aims to serve as a roadmap for other states, provinces, territories, or nations hoping to develop their own Association for Infant Mental Health (AIMH) as well as a guide for those with existing AIMHs for promoting continued growth and sustainability.


Analysis of genotype-phenotype correlation in Walker-Warburg syndrome with a novel CRPPA mutation in different clinical manifestations.
Walker-Warburg syndrome (WWS) is a rare autosomal recessive disorder characterized by congenital muscular dystrophy and severe brain and eye malformations. This study aims to analyze genotype-phenotype correlations in WWS with a novel cytidine diphosphate-l-ribitol pyrophosphorylase A (CRPPA) mutation in different clinical manifestations. We report a girl with a presentation of multiple brain and ocular anomalies. Her ophthalmological evaluation showed a shallow anterior chamber, cortical cataract, iris hypoplasia, persistent hyperplastic primary vitreous in the right eye, punctate cataract, iris hypoplasia, primary congenital glaucoma, and a widespread loss of fundus pigmentation in the left eye. She was hypotonic, and her deep tendon reflexes were absent. Laboratory investigations showed high serum levels of serum creatine kinase. Brain magnetic resonance imaging demonstrated hydrocephalus, agenesis of the corpus callosum, retrocerebellar cyst, cerebellar dysplasia and hypoplasia, cobblestone lissencephaly, and hypoplastic brainstem. Whole exome sequencing revealed a novel homozygous nonsense mutation in the first exon of the CRPPA gene (NM_001101426.4, c.217G>T, p.Glu73Ter). The study findings expand the phenotypic variability of the ocular manifestations in the CRPPA gene-related WWS. Iris hypoplasia can be a part of clinical manifestations of the CRPPA gene-related WWS. The uncovering of the genes associated with ocular features can provide preventative methods, early diagnosis, and improved therapeutic strategies.


Can the municipalities prevent medication of mental diseases?
In extension of a large municipality reform in 2007, which reduced the number of Danish municipalities from 275 to 98, it was the intention that the municipalities should assume responsibility for a part of the expenditure connected to secondary sector health care treatment. Furthermore, the municipalities were assigned the responsibility for--and equipped with a number of opportunities for--exerting primary preventive initiatives. To investigate, whether the municipalities by applying these opportunities have been able to prevent medication of mental diseases. Specifically, this is resolved by analysing whether there are significant relationships between measures of municipal policy opportunities and the proportion of population medicated for mental diseases. We apply a variety of statistical regression models. Initially, simple linear regression is applied. Next, a Seemingly Unrelated Regression approach, which accounts for intra-municipal behavioural correlation, is brought in play. Finally, this approach is extended to regressions which are adjusted for spatial spillover effects. The initial simple linear specification indicates a potential significant relationship between municipal policy opportunities and medication. However, when applying a specification which is adjusted for intra-municipal correlation, this relationship vanishes. Finally, there seem to be indications of spatial spillover effects. Thus, the relationship between municipal preventive initiatives and medication seems to be a structural, intra-municipal relationship, rather than a cause-response effect. Our results show that potential linkages between municipal preventive initiatives and medication for mental diseases are not of a simple nature. Specifically, sophisticated and targeted interventions are needed rather than broad and general public health initiatives. Though the approach is promising, the data underlying the study is at present relatively weak. Future studies should involve more variables as well as longer times series in order to obtain proper understandings of the potential linkages between municipal policy efforts and medication.


Robotic Stereotactic Body Radiation Therapy in Patients With Recurrent or Metastatic Abdominopelvic Tumors: A Single Institute Experience.
The aim of this study was to evaluate the efficacy and toxicity of robotic CyberKnife (Accuray Incorporated, Sunnyvale, California)-based stereotactic body radiation therapy (SBRT) in patients with recurrent or metastatic abdominopelvic tumors. A total of 69 patients treated between May 2008 and January 2011 were evaluated retrospectively. Indication for SBRT was persistent disease in 3 (4%) patients, local recurrence in 29 (42%) patients, regional recurrence in 13 (19%) patients, and oligometastatic disease in 24 (35%) patients. Forty-two (61%) patients were previously irradiated to the same region and 27 (39%) patients were treated for the first time. The median age was 59 years (range, 24-86 years). There were 31 (45%) male and 38 (55%) female patients. The median total dose was 30 Gy (range, 15-60 Gy) delivered with a median 3 fractions (range, 2-5 fractions). The tumor response to treatment was assessed by computed tomography, magnetic resonance imaging, or positron emission tomography. At the 12-month (range, 2-44 months) median follow-up, local control was 65% and median overall survival (OS) was 20 months. A larger gross tumor volume (≥ 67 cm(3)) was significantly correlated with worse 1-year OS (81% vs 48%, P = .03). The patients with local recurrence occurring <11 months had a significantly shorter 1-year local control rate than patients with ≥ 11 months (31% vs 91%, P < .001). Grade 3-4 acute and late toxicities were seen in 7% and 15% of patients, respectively. The patients with previous radiotherapy history had significantly higher rate of acute toxicity (19% vs 0%, P = .019). Late toxicity was significantly higher in pelvic tumors than in abdominal tumors (3% vs 28%, P = .004). The SBRT seems to be feasible and resulted in good treatment outcomes in patients with recurrent or metastatic abdominopelvic tumors.


Translational repression of Ccl5 and Cxcl10 by 4E-BP1 and 4E-BP2 restrains the ability of mouse macrophages to induce migration of activated T cells.
Signaling through the mechanistic target of rapamycin complex 1 (mTORC1) is a major regulatory node of pro-inflammatory mediator production by macrophages (MΦs). However, it is still unclear whether such regulation relies on selective translational control by two of the main mTORC1 effectors, the eIF4E-binding proteins 1 and 2 (4E-BP1/2). By comparing translational efficiencies of immune-related transcripts of MΦs from WT and 4E-BP1/2 double-KO (DKO) mice, we found that translation of mRNAs encoding the pro-inflammatory chemokines CCL5 and CXCL10 is controlled by 4E-BP1/2. Macrophages deficient in 4E-BP1/2 produced higher levels of CCL5 and CXCL10 upon LPS stimulation, which enhanced chemoattraction of activated T cells. Consistent with this, treatment of WT cells with mTORC1 inhibitors promoted the activation of 4E-BP1/2 and reduced CCL5 and CXCL10 secretion. In contrast, the phosphorylation status of eIF4E did not affect the synthesis of these chemokines since MΦs derived from mice harboring a non-phosphorylatable form of the protein produced similar levels of CCL5 and CXCL10 to WT counterparts. These data provide evidence that the mTORC1-4E-BP1/2 axis contributes to regulate the production of chemoattractants by MΦs by limiting translation efficiency of Ccl5 and Cxcl10 mRNAs, and suggest that 4E-BP1/2 act as immunological safeguards by fine-tuning inflammatory responses in MΦs.


[Regulation of Metabolism and the Role of Redox Factors in the Energy Control of Quiescence and Proliferation of Hematopoietic Cells].
One of the key regulators of hematopoietic stem cell (HSC) maintenance is cellular metabolism. Resting HSCs use anaerobic glycolysis as the main source of energy. During expansion and differentiation under conditions of steady state hematopoiesis, the energy needs of activated HSCs increase by many fold. To meet the increased demands, cells switch to mitochondrial oxidative phosphorylation, which is accompanied by an increase in reactive oxygen species (ROS) production. Here, the molecular mechanisms maintaining glycolysis in HSCs, as well as the factors determining the increase in metabolic activity and the transition to mitochondrial biogenesis during HSC activation are discussed. We focus on the role of HIF (hypoxia-inducible factor) proteins as key mediators of the cellular response to hypoxia, and also consider the phenomenon of extraphysiological oxygen shock (EPHOSS), leading to the forced differentiation of HSCs as well as methods of overcoming it. Finally, the role of fatty acid oxidation (FAO) in hematopoiesis is discussed. Understanding the metabolic needs of normal HSCs and precursors is crucial for the development of new treatments for diseases related to the hematopoietic and immune systems.


Identifying patients harboring extended-spectrum-beta-lactamase-producing Enterobacteriaceae on hospital admission: derivation and validation of a scoring system.
Increases in community-acquired infections caused by extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae have important implications for hospital infection control and empirical antibiotic therapy protocols. We developed and validated a tool for identifying patients harboring these organisms at hospital admission. We retrospectively analyzed chart data for 849 adult inpatients. The derivation cohort included 339 patients admitted to a large hospital in Rome during 2008, with (n = 113) or without (n = 226) culture positivity for ESBL-producing Escherichia coli, Klebsiella spp., or Proteus mirabilis within 48 h after admission. Logistic-regression-based prediction scores were calculated based on variables independently associated with the outcome. The model was validated in a second cohort (n = 510) selected with identical criteria in hospitals in Genoa and Turin during 2009. Prediction scores were based on the following six variables (reported with odds ratio for study outcome and the 95% confidence intervals in brackets): recent (≤ 12 months before admission) hospitalization (5.69 [2.94 to 10.99]), transfer from another health care facility (5.61 [1.65 to 19.08]), Charlson comorbidity score ≥ 4 (3.80 [1.90 to 7.59]), recent (≤ 3 months before admission) β-lactam and/or fluoroquinolone treatment (3.68 [1.96 to 6.91]), recent urinary catheterization (3.52 [1.96 to 6.91]), and age ≥ 70 years (3.20 [1.79 to 5.70]). The model displayed good calibration and good-to-excellent discrimination in the derivation and validation sets (Hosmer-Lemshow χ(2) = 15.28 and 14.07; P = 0.17 and 0.23; areas under the receiver-operating characteristic curve, 0.83 and 0.92). It reliably identified patients likely to be harboring ESBL-producing Enterobacteriaceae at hospital admission who may need special infection control measures. Further study is needed to confirm this model's potential as a guide for prescribing empirical antibiotic therapy.


Antigenic site II of the rabies virus glycoprotein: structure and role in viral virulence.
Twelve monoclonal antibodies neutralizing the CVS strain of rabies virus were used to characterize antigenic site II of the viral glycoprotein. Nineteen antigenic mutants resistant to neutralization by some of these antibodies were selected; some continued to normally or partially bind the antibody, whereas others did not. Mutations conferring resistance to neutralization by site II-specific monoclonal antibodies were localized into two clusters, the first between amino acids 34 and 42 (seven groups of mutants) and the second at amino acids 198 and 200 (three groups of mutants). Two intermediate mutations were identified at positions 147 and 184. Four mutations resulted in reduced pathogenicity after intramuscular inoculation of the virus in adult mice. One of the mutants, M23, was 300 times and the others were 10 to 30 times less pathogenic than CVS. In three cases the attenuated phenotype was related to an important modification of antigenic site II, whereas the other known antigenic sites were unchanged.


Effect of prolonged restraint on glycogen content and activities of four enzymes of carbohydrate metabolism in the liver of rats.
Triphasic changes in glycogen content and activities of four enzymes of carbohydrate metabolism (glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, hexokinase, and glucose-6-phosphate dehydrogenase) were studied in the liver of male Wistar rats exposed to 1, 5, 10, 15, 20, 30, 45, 60, 70 and 90-day movement restrain in pencil cases. It was assumed that these three phases corresponded to the alarm, resistance and exhaustion stages of Selye's general adaptation syndrome. In hypokinetic rats, however, a transition of the alarm reaction to the resistance stage was registered later, and hepatic glycogen accumulation was reduced in comparison with the standard pattern observed in chronic stress.


Phonon optics and phonon propagation in semiconductors.
Recent experiments involving the propagation of extremely high frequency, short-wavelength acoustic phonons in semiconductors are described. Such phonons, which play an important role in thermal energy transpor and nonradiative recombination processes, can be used as sensitive microscopic probes of electronic, defect, and interface states. Experiments on phonon transmission thrugh epitaxially grown bulk material as well as thin-film superlattice structures in the semiconductor gallium arsenide are described. Such thin-film periodic structures can be used to build frequency-selective phonon filters and reflectors, which can in turn be used to manipulate phonon diagnostic beams in technologically important materials.


Prisoners at ultra-high-risk for psychosis: a cross-sectional study.
The definition of ultra-high risk (UHR) for psychosis was derived from community-based help-seeking populations. Prisoners have high rates of psychosis and other severe mental health (MH) problems. They also have high rates of risk factors for psychiatric morbidity and yet they are among the populations who are less likely to seek help in the community. Despite a policy of equivalence of care for individuals in prison there are no early intervention services for psychosis in prisons in the UK. This was a study exploring feasibility of introducing such a service into a local London prison. This paper discusses the differences in MH profile of prisoners who met criteria for at-risk mental state compared with those who did not. A two-stage procedure was used. Participants in a local London prison were routinely screened in the first week of arrival in prison with the Prodrome Questionnaire - Brief Version (PQ-B; Loewy et al. 2011). Those that screened positive as well as a small sample of those who screened negative underwent a further semi-structured assessment to see whether they met criteria for UHR state. Data on self-harm and suicide attempt, family psychiatric history, and anxiety and depression was also collected. A total of 891 prisoners were screened, 44% of whom screened positive. A total of 354 underwent second stage assessment, 60 of whom had screened negative. Four groups were identified: those that had no MH problems, a group experiencing First Episode Psychosis, those at UHR of psychosis and a group with other MH problems. The UHR state and Psychotic groups had very similar MH profiles of symptoms and distress. Prisoners with no MH problems were at the other end of the spectrum with few symptoms and little distress. The Other group fell in between this group and the psychotic spectrum group in terms of symptomology and distress. This study is the first to examine risk for psychosis in an adult male prison population. We identified a broad spectrum of MH disorder for which there is little current service provision in prisons. Screening early in the custodial process has the potential to identify unmet MH need and has implications for keeping individuals safe in custody. A long-term strategic approach is required to address MH need in prisons.


In vitro culture medium influences the vaccine efficacy of Mycobacterium bovis BCG.
The varied rates of protection induced by Mycobacterium bovis BCG vaccine against tuberculosis has been attributed to many factors such as genetic variability among BCG strains, rapid clearance of BCG in some populations, and different levels of previous exposure of vaccinated populations to environmental mycobacteria. However, the methods and conditions employed to prepare this vaccine for human usage by various manufacturers have not been investigated as potential factors contributing to the variation in vaccine efficacy. A review of the literature indicates discrepancies between the approach for growing BCG vaccine in the laboratory to assess immune responses and protective ability in animal models, and that employed for production of the vaccine for administration to humans. One of the major differences is in the growth medium used for routine propagation in the laboratory and the one used for bulk vaccine production by manufacturers. Here we compared the immunogenicity of the BCG vaccine grown in Middlebrook 7H9 medium, the most commonly used medium in laboratory studies, against that grown in Sauton medium, which is used for growing BCG by most manufacturers. Our results showed clear differences in the behavior of BCG grown in these different culture media. Compared to BCG grown in Middlebrook 7H9 medium, BCG grown in Sauton media was more persistent inside macrophages, more effective at inhibiting apoptosis of infected cells, induced stronger inflammatory responses and stimulated less effective immunity against aerosol challenge with a virulent Mtb strain. These findings suggested that the growth medium used for producing BCG vaccine is an important factor that deserves increased scrutiny in ongoing efforts to produce more consistently effective vaccines against Mtb.


The renin-angiotensin system: the role of inhibitors, blockers, and genetic polymorphisms in the treatment and prevention of heart failure.
The renin-angiotensin system (RAS) plays an important role in the pathogenesis and worsening of heart failure (HF). Blocking this system with angiotensin converting enzyme (ACE) inhibitors in patients with HF and left ventricular dysfunction reduces mortality and morbidity and these drugs are currently recommended as standard therapy. A more recently developed class of drug, angiotensin receptor blockers (ARBs) block the RAS at the receptor level, and may therefore provide more complete blockade. ARBs, either singly or in combination with ACE inhibitors, are currently being compared to either ACE inhibitor therapy alone or to placebo in randomized trials of patients with or at high risk of developing HF. With respect to large trials published to date directly comparing ARB versus ACE inhibitor therapy, neither the Losartan Heart Failure Survival Study (ELITE II) nor the Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) found differences in mortality or morbidity between the treatment groups. As regards combination ARB/ACE inhibitor therapy versus ACE inhibitor therapy alone, one completed study, the Valsartan Heart Failure Trial (Val-HeFT), found no differences in mortality but a decrease in HF-related hospitalizations in the combined therapy group. Four additional long-term trials (VALIANT, CHARM, ONTARGET, and TRANSCEND) should complete the totality of evidence regarding the role of ARBs in the treatment of HF. Since genetic polymorphisms affecting drug metabolizing enzymes or drug receptors are known to influence responses to drugs, exploration of these effects on treatment responses to ARBs and ACE inhibitors may provide for more targeted treatment of HF.


Preaching to the choir? Sociodemographic differences in medical students' evaluation of an undergraduate diversity training module.
This article was migrated. The article was marked as recommended. Introduction: Patients with diverse cultural backgrounds experience barriers in access to care, and do not always receive the care they need. To prepare future doctors to provide high quality care for all patients, adequate diversity education is essential. At VUmc School of Medical Sciences, we therefore developed a bachelor second year module on Care ethics and Diversity using an arts-based approach. The aim of this study was to evaluate the module from the students' perspective, and to gain insight in the relationship between evaluation outcomes and student sociodemographic characteristics. Methods: Design: cross-sectional evaluation study. Module content: after watching three short film fragments, students engaged in a structured dialogue about diversity in relation to care and care giving. Data collection: in 2015 and 2016, a questionnaire containing 12 evaluation items based on module learning outcomes were administered to second year medical students (N=287) immediately after receiving the module. Overall satisfaction with the module was measured using a 1-10 scale (with 1 indicating a very poor, and 10 indicating an excellent evaluation score); learning objective-related items were measured using a 5-point Likert scale. Results were analyzed using multiple linear regression, Pearson's correlation and Chi-square tests. Results: The average overall satisfaction score was 7.3. We found a strong positive correlation between the overall satisfaction score and the score of the item that measured students' level of interest (r=.70). Multiple linear regression showed a significant positive effect of identifying as non-native Dutch on multiple evaluation outcomes. Students with non-native Dutch backgrounds reported higher satisfaction with the module, perceived the module as more interesting and more personally relevant, and had higher scores on four of the six learning objective items. Discussion: Our findings indicate that students with non-native Dutch backgrounds were more satisfied with the module and reported more learning than their native Dutch peers. This might be explained by the fact that diversity education acknowledges Dutch students' lived experiences and builds on preexisting embodied diversity knowledge. Conversely, (white) native Dutch students might not always perceive diversity knowledge as legitimate or consider diversity as something that does not concern them. Conclusion: Non-native Dutch students reported more overall satisfaction with diversity education and more diversity learning than majority students. To secure and advance high quality health care for all patients, medical schools should invest in researching and developing diversity content that engages all students.


Identification of the sources of nitrous oxide produced by oxidative and reductive processes in Nitrosomonas europaea.
1. Cells of Nitrosomonas europaea produced N(2)O during the oxidation of ammonia and hydroxylamine. 2. The end-product of ammonia oxidation, nitrite, was the predominant source of N(2)O in cells. 3. Cells also produced N(2)O, but not N(2) gas, by the reduction of nitrite under anaerobic conditions. 4. Hydroxylamine was oxidized by cell-free extracts to yield nitrite and N(2)O aerobically, but to yield N(2)O and NO anaerobically. 5. Cell extracts reduced nitrite both aerobically and anaerobically to NO and N(2)O with hydroxylamine as an electron donor. 6. The relative amounts of NO and N(2)O produced during hydroxylamine oxidation and/or nitrite reduction are dependent on the type of artificial electron acceptor utilized. 7. Partially purified hydroxylamine oxidase retained nitrite reductase activity but cytochrome oxidase was absent. 8. There is a close association of hydroxylamine oxidase and nitrite reductase activities in purified preparations.


Gender, AIDS, and bereavement: a comparison of women and men living with HIV.
The purpose of this study was to examine the bereavement experience, psychiatric morbidity, and suicidality in bereaved men and women living with HIV. HIV+ women (n = 31) who reported a loss in the recent 12 months were case matched to bereaved HIV+ men (n = 62) on the basis of lifetime histories of major depression. Study participants were examined for grief reactions, psychiatric morbidity, mood symptomatology, and suicidality using the Texas Revised Inventory of Grief Revised, Structured Clinical Interview for DSM-III-R, the Hamilton Depression and Anxiety Rating, and the Diagnostic Interview Schedule for Suicide. Bereaved HIV+ women presented with intensified bereavement responses, a higher prevalence of current generalized anxiety disorder, and elevated thoughts and gestures of suicide and when compared to HIV+ men. In conclusion, bereaved women living with HIV may be at increased risk for bereavement complicated with psychiatric morbidity and thoughts of suicide. It is critical that adequate mental health support services be available to this growing risk group of bereaved individuals.


Olfactory cues from different plant species in host selection by female pea moths.
In herbivorous insects specialized on few plant species, attraction to host odor may be mediated by volatiles common to all host species, by specific compounds, or combinations of both. The pea moth Cydia nigricana is an important pest of the pea. Volatile signatures of four host plant species were studied to identify compounds involved in pea moth host selection and to improve previously reported attractive volatile blends. P. sativum and alternative Fabaceae host species were compared regarding female attraction, oviposition, and larval performance. Pea moth females were strongly attracted to the sweet pea Lathyrus odoratus, but larval performance on that species was moderate. Chemical analyses of sweet pea odor and electrophysiological responses of moth antennae led to identification of seven sweet-pea-specific compounds and ten compounds common to all tested host species. Blends of these specific and common cues were highly attractive to mated pea moth females in wind tunnel and field experiments.


Safety and tolerability of donepezil in mild cognitive impairment: open-label extension study.
Following a 48-week, double-blind, randomized, placebo-controlled trial of donepezil in 821 patients with amnestic mild cognitive impairment (aMCI), safety and tolerability of donepezil (10 mg) were further evaluated in a 28-week extension study. Of 499 participants who completed the double-blind phase, 145 enrolled in the open-label study. Adverse events (AEs) were recorded throughout. Overall, 57.4% of participants in the donepezil/donepezil group and 62.3% in the placebo/donepezil group experienced an AE, with the most frequent treatment-emergent AEs being diarrhea, muscle spasms, insomnia, and nausea. Most were mild to moderate in severity and were more common in the first several weeks after treatment initiation. More participants in the placebo/donepezil group (22.1%) discontinued donepezil due to an AE compared with the donepezil/donepezil group (10.3%). These findings support the safety of donepezil in patients with aMCI. When compared with other studies, however, the data suggest that patients with Alzheimer's tolerate donepezil better than patients with MCI.


DNA phylogeny reveals polyphyly of Phoma section Peyronellaea and multiple taxonomic novelties.
Species of the anamorph genus Phoma are commonly isolated from a wide range of ecological niches. They are notoriously difficult to identify due to the paucity of morphological features and the plasticity of these when cultivated on agar media. Species linked to Phoma section Peyronellaea are typified by the production of dictyochlamydospores and thus have additional characters to use in taxon delineation. However, the taxonomy of this section is still not fully understood. Furthermore the production of such chlamydospores also is known in some other sections of Phoma. DNA sequences were generated from three loci, namely ITS, actin, and 3-tubulin, to clarify the phylogeny of Phoma taxa that produce dictyochlamydospores. Results were unable to support section Peyronellaea as a taxonomic entity. Dictyochlamydospore formation appears to be a feature that developed, or was lost, many times during the evolution of Phoma. Furthermore, based on the multigene analyses, five new Phoma species could be delineated while a further five required taxonomic revision to be consistent with the genetic variation observed.


Clomipramine challenge responses covary with Tridimensional Personality Questionnaire scores in healthy subjects.
Cloninger's Unified Biosocial Theory of Personality postulates a relationship between the relative functional activity of central serotonergic, dopaminergic, and noradrenergic neurotransmitter systems, and the strength of three elemental dimensions of personality. These dimensions are Harm Avoidance, Novelty Seeking, and Reward Dependence, respectively. Accordingly, we predicted that neuroendocrine responses to serotonergic challenge would correlate with Harm Avoidance scores, but not with Novelty Seeking or Reward Dependence scores. We examined the relationship between the prolactin and cortisol responses to a 12.5-mg intravenous clomipramine challenge and these personality dimensions as measured by Cloninger's Tridimensional Personality Questionnaire in 32 healthy subjects. The cortisol response correlated only with Harm Avoidance scores, as predicted; however, prolactin response did not correlate with Harm Avoidance scores. Instead, it demonstrated an inverse relationship with Novelty Seeking scores. There was a positive relationship of baseline prolactin with Harm Avoidance in a post hoc analysis. Cortisol response to serotonergic challenge may be a better indicator for responsivity of serotonergic systems as they relate to the personality dimension of Harm Avoidance than is prolactin. Prolactin responses may be overly affected by dopaminergic influences; however, baseline prolactin may still be a valid indicator of serotonergic tone.


Molecular biology of familial and sporadic vestibular schwannomas: implications for novel therapeutics.
Vestibular schwannomas (VSs) are benign tumors arising from the sheath of cranial nerve VIII. The pathogenesis underlying most familial and sporadic VSs has been linked to a mutation in a single gene, the neurofibromin 2 (NF2) gene located on chromosome 22, band q11-13.1. In this review, the authors summarized what is known about the epidemiology of NF2 mutations and patients with VSs. The authors also discuss the function of the NF2 gene product, merlin, and describe the known and hypothetical effects of genetic mutations that lead to merlin dysfunction on a broad variety of cellular and histological end points. A better understanding of the molecular pathobiology of VSs may lead to novel therapeutics to augment current modalities of treatment while minimizing morbidity.


Pharmacological management of malignant hypertension.
According to current guidelines, malignant hypertension is one of the emergencies in hypertension. The definition requires the presence of bilateral retinal hemorrhages or exudates, with or without papilledema, acute heart failure and acute deterioration in renal function in severe hypertension. Patients with malignant hypertension are characterized by pronounced target organ damage, including structural and functional cardiac abnormalities and renal insufficiency. Knowledge of the available treatment options is extremely important as we know that we only have a limited time to reduce blood pressure. There are only four drugs dedicated to immediate blood pressure lowering in patients with malignant hypertension, including 'first-line' and alternative drugs. Our review aims to discuss all those drugs and gives practical suggestions on how to properly use them. The decision of which drug to use depends on numerous factors including the clinical indications, pharmacokinetics, toxicity and drug interactions. Furthermore, frequently, more than one of the recommended drugs is required for the successful lowering of the patient's blood pressure.


Moving in extreme environments: what's extreme and who decides?
Humans work, rest and play in immensely varied extreme environments. The term 'extreme' typically refers to insufficiency or excess of one or more stressors, such as thermal energy or gravity. Individuals' behavioural and physiological capacity to endure and enjoy such environments varies immensely. Adverse effects of acute exposure to these environments are readily identifiable (e.g. heat stroke or bone fracture), whereas adverse effects of chronic exposure (e.g. stress fractures or osteoporosis) may be as important but much less discernable. Modern societies have increasingly sought to protect people from such stressors and, in that way, minimise their adverse effects. Regulations are thus established, and advice is provided on what is 'acceptable' exposure. Examples include work/rest cycles in the heat, hydration regimes, rates of ascent to and duration of stay at altitude and diving depth. While usually valuable and well intentioned, it is important to realise the breadth and importance of limitations associated with such guidelines. Regulations and advisories leave less room for self-determination, learning and perhaps adaptation. Regulations based on stress (e.g. work/rest cycles relative to WBGT) are more practical but less direct than those based on strain (e.g. core temperature), but even the latter can be substantively limited (e.g. by lack of criterion validation and allowance for behavioural regulation in the research on which they are based). Extreme Physiology & Medicine is publishing a series of reviews aimed at critically examining the issues involved with self- versus regulation-controlled human movement acutely and chronically in extreme environments. These papers, arising from a research symposium in 2013, are about the impact of people engaging in such environments and the effect of rules and guidelines on their safety, enjoyment, autonomy and productivity. The reviews will cover occupational heat stress, sporting heat stress, hydration, diving, extreme loading, chronic unloading and high altitude. Ramifications include factors such as health and safety, productivity, enjoyment and autonomy, acute and chronic protection and optimising adaptation.


Circulating FGF21 Concentration, Fasting Plasma Glucose, and the Risk of Type 2 Diabetes: Results From the PREVEND Study.
Fibroblast growth factor 21 (FGF21) is a peptide hormone synthesized by several organs and regulates, among others, energy homeostasis. In obesity, insulin resistance and type 2 diabetes (T2D), higher circulating FGF21 concentrations have been found. Temporal analyses in murine studies demonstrate that FGF21 increases before insulin resistance occurs. The current study aims to investigate in time-to-event analyses whether FGF21 may be an early biomarker in the development of T2D. Circulating FGF21 was measured using an immunoassay of the Mesoscale U-PLEX assay platform. The study outcome was incident T2D. Associations of circulating FGF21 concentration with T2D were quantified using Cox proportional hazards models with adjustments for potential confounders. We included 5244 participants aged 52 ± 12 years, of whom 50% were male. Median [interquartile range] circulating FGF21 concentration was 860 [525-1329] pg/mL. During 7.3 [6.1-7.7] years of follow-up, 299 (5.7%) participants developed T2D. In fully adjusted analyses, higher circulating FGF21 concentration was associated with an increased risk of incident T2D (hazard ratio per doubling: 1.26 [95% CI, 1.06-1.51]; P = 0.008), with effect modification by fasting plasma glucose, consistent with strengthening of the association at lower fasting glucose (interaction coefficient: -0.12; P = 0.022). Higher circulating FGF21 concentrations are independently associated with an increased risk of incident T2D in participants with a low fasting plasma glucose, making circulating FGF21 concentration a potential early biomarker for type 2 diabetes.


Neutron spin echo monitoring of segmental-like diffusion of water confined in the cores of carbon nanotubes.
Following the stream of increasing scientific interest in condensed-matter systems under ultra-hydrophobic confinement, the present work reports the first incoherent neutron spin echo assessment of the dynamics of water axially confined inside single-wall carbon nanotubes of diameter d∼ 1.4 nm. At the time scale of nanoseconds, two water populations are retrieved, whose relative proportion matches the one expected for a concentric shell + chain arrangement with cylindrical symmetry. The time dependence of the mean square displacement related to the external component is found to be subdiffusive, with peculiar resemblance to segmental diffusion typical of entangled polymeric systems.


Bladder diary measurements in asymptomatic females: functional bladder capacity, frequency, and 24-hr volume.
To study the effects of age and 24-h volume (V(24)) on bladder diary measurements of voiding frequency (F(24)) and functional bladder capacity (FBC) from an asymptomatic female population. Also, to use these data to develop clinical reference values. (We use FBC as a generic term for bladder diary volume-per-void measurements.) Computer-processed 3-day bladder diaries were collected from 161 females (median age: 46.6 years; range = 19.6-81.8 years) claiming no urological symptoms, previous pelvic surgery and diseases and medications effecting urologic function. Regression analysis was used to investigate relationships among age, FBC and V(24). Both FBC and F(24) increase as V(24) increases (P < 0.0005). With aging, F(24) increases (P = 0.026) and FBC may decrease slightly (P = 0.02-0.08). There is a concave downward, curvilinear relationship between age and V(24). We used multiple regression to generate tables of FBC and F(24) "normal limits" adjusted for these simultaneous influences of V(24) and age. Removing their relationships to age reduces the variability of FBC and F(24) reference values by 50% and 20%, respectively. Our finding, supported by others, that, with increasing V(24), FBC increases more than F(24) suggests an adaptive mechanism that adjusts FBC to urine production to minimize changes in voiding frequency. We illustrate adjustment of reference values for age and V(24) by calculating traditional clinical "normal limits." However, the probable large overlap between "normal" and "abnormal" suggests that it may be more useful to report bladder diary measurements as reference population percentiles rather than to designate them "normal" or "abnormal".


Finger microvascular responses to deep inspiratory gasp assessed and quantified using wavelet analysis.
The physiological changes following a deep inspiratory gasp (DIG) manoeuvre have been described in the literature. However, the lack of a reliable signal processing technique to visualize and quantify these physiological changes has so far limited the applicability of the test to the clinical setting. The main aim of this study was to assess the feasibility of using wavelet analysis to quantify the pulse arrival time (PAT) and its changes during the DIG manoeuvre. Vascular responses were extracted from cardiac (electrocardiogram, ECG) and peripheral pulse (photoplethysmography, PPG) waveforms. Wavelet analysis characterized their cardiovascular responses in healthy adult subjects in the time-frequency space, and for the ECG-PPG inter-relationship in terms of the PAT. PAT showed a characteristic biphasic response to gasp, with an increase of 59 ± 59 ms (p = 0.001) compared to the maximum value reached during quiet breathing, and a decrease of -38 ± 55 ms (p < 0.01) compared to the minimum value during quiet breathing. The response measures were repeatable. This pilot study has successfully shown the feasibility of using wavelet analysis to characterize the cardiovascular waveforms and quantify their changes with DIG.


Diagnostic and public health investigation of Mycobacterium tuberculosis infection in a dog in Ontario, Canada.
A 4-y-old, female mixed-breed dog was presented to the Ontario Veterinary College for further evaluation of multiple pulmonary and hepatic masses, intrathoracic lymphadenitis, and recent development of a pyogranulomatous pleural effusion. Along with other comprehensive tests, a thoracic lymph node biopsy was performed, and Mycobacterium tuberculosis complex infection was confirmed by real-time PCR. The dog's condition declined post-operatively, and euthanasia was elected. Postmortem examination confirmed severe granulomatous pneumonia, hepatitis, intrathoracic and intraabdominal lymphadenitis, omentitis, and nephritis. Line-probe assays performed on samples collected postmortem confirmed the species as M. tuberculosis. 24-loci MIRU-VNTR genotyping, spoligotyping, and whole-genome sequencing revealed relations to known human isolates, but no epidemiologic link to these cases was investigated. Given the concern for potential human exposure during this animal's disease course, a public health investigation was initiated; 45 individuals were tested for M. tuberculosis exposure, and no subsequent human infections related to this animal were identified. Our case highlights the need for more readily available, minimally invasive testing for the diagnosis of canine mycobacteriosis, and highlights the ability of canid species to act as potential contributors to the epidemiology of M. tuberculosis infections.


Unilateral macular oedema secondary to retinal venous congestion without occlusion in patients with diabetes mellitus.
To identify fundus characteristics associated with intraocular and intra-individual variations in the distribution of macular oedema in patients with diabetes. A review was carried out of fundus photographs and fluorescein angiograms from 226 diabetes patients who received photocoagulation treatment for macular oedema. Cases with strictly unilateral clinically significant macular oedema were identified. Strictly unilateral macular oedema was identified in five patients with non-proliferative diabetic retinopathy, three of whom demonstrated angiographic leakage confined to a single venous drainage unit, and two of whom demonstrated leakage confined to two adjacent venous drainage units opposing one another on either side of the temporal circulatory watershed. Involved drainage units were delimited by arteriovenous crossings displaying signs of venous compression. Affected eyes had more frequent and more severe crossing signs involving macular drainage than fellow eyes. Although all patients had been examined regularly, no patient had had branch retinal vein occlusion and no patient developed such occlusion during 5 years of follow-up. In the present study, unilateral macular oedema in patients with diabetes was associated with angiographic leakage from venous drainage units where compression signs indicated a higher than normal likelihood of upstream congestion being present. Presumably, a modest increase in venous pressure induced macular oedema because of an underlying abnormal vascular vulnerability induced by diabetes.


[Diagnostic value of spinal fluid immunoglobulins in cerebral arachnoiditis].
The authors believe that the deficiency of immunoglobulins A in the cerebrospinal fluid (CSF) of patients with arachnoiditis may be explained by an increase in their consumption due to antigenic aggression in relation to the meninges, which results in extremely low values of the circulating immunoglobulins A. The absence of immunoglobulins A in the CSF of patients with cerebral arachnoiditis is one of the components of its pathogenesis owing to impairment of permeability of the blood brain barrier and fixation of antigens in the tissues of the brain and meninges.


Body burden of aluminum in relation to central nervous system function among metal inert-gas welders.
The relationship between elevated internal aluminum loads and central nervous system function was studied among aluminum welders, and the threshold level for adverse effect was defined. For 65 aluminum welders and 25 current mild steel welders body burden was estimated, and the aluminum concentrations in serum (S-Al) and urine (U-Al) were analyzed with graphite furnace atomic absorption spectrometry with Zeeman background correction. Referents and low-exposure and high-exposure groups were defined according to an aggregated measure of aluminum body burden, the group median S-Al levels being 0.08, 0.14, and 0.46 micromol/l, respectively, and the corresponding values for U-Al being 0.4, 1.8, and 7.1 micromol/l. Central nervous system functions were assessed with a neuropsychological test battery, symptom and mood questionnaires, a visual and quantitative analysis of electroencephalography (EEG), and P3 event-related potentials with pitch and duration paradigms. Subjective symptoms showed exposure-related increases in fatigue, mild depression, and memory and concentration problems. Neuropsychological testing revealed a circumscribed effect of aluminum, mainly in tasks demanding complex attention and the processing of information in the working memory system and in the analysis and recall of abstract visual patterns. The visual EEG analysis revealed pathological findings only for aluminum welders. Mild, diffuse abnormalities were found in 17% of the low-exposure group and 27% of the high-exposure group, and mild to moderate epileptiform abnormalities at a frequency of 7% and 17%, respectively. Both objective neurophysiological and neuropsychological measures and subjective symptomatology indicated mild but unequivocal findings dose-dependently associated with increased aluminum body burden. The study indicates that the body burden threshold for adverse effect approximates an U-Al value of 4-6 micromol/l and an S-Al value of 0.25-0.35 micromol/l among aluminum welders.


Fourier domain mode locking at 1050 nm for ultra-high-speed optical coherence tomography of the human retina at 236,000 axial scans per second.
A Fourier domain mode-locked (FDML) laser at 1050 nm for ultra-high-speed optical coherence tomography (OCT) imaging of the human retina is demonstrated. Achievable performance, physical limitations, design rules, and scaling principles for FDML operation and component choice in this wavelength range are discussed. The fiber-based FDML laser operates at a sweep rate of 236 kHz over a 63 nm tuning range, with 7 mW average output power. Ultra-high-speed retinal imaging is demonstrated at 236,000 axial scans per second. This represents a speed improvement of approximately10x over typical high-speed OCT systems, paving the way for densely sampled volumetric data sets and new imaging protocols.


Protein-Protein Interactions in Candida albicans.
Despite being one of the most important human fungal pathogens, Candida albicans has not been studied extensively at the level of protein-protein interactions (PPIs) and data on PPIs are not readily available in online databases. In January 2018, the database called "Biological General Repository for Interaction Datasets (BioGRID)" that contains the most PPIs for C. albicans, only documented 188 physical or direct PPIs (release 3.4.156) while several more can be found in the literature. Other databases such as the String database, the Molecular INTeraction Database (MINT), and the Database for Interacting Proteins (DIP) database contain even fewer interactions or do not even include C. albicans as a searchable term. Because of the non-canonical codon usage of C. albicans where CUG is translated as serine rather than leucine, it is often problematic to use the yeast two-hybrid system in Saccharomyces cerevisiae to study C. albicans PPIs. However, studying PPIs is crucial to gain a thorough understanding of the function of proteins, biological processes and pathways. PPIs can also be potential drug targets. To aid in creating PPI networks and updating the BioGRID, we performed an exhaustive literature search in order to provide, in an accessible format, a more extensive list of known PPIs in C. albicans.


A new nuclear protease with cathepsin L properties is present in HeLa and Caco-2 cells.
Recently many authors have reported that cathepsin L can be found in the nucleus of mammalian cells with important functions in cell-cycle progression. In previous research, we have demonstrated that a cysteine protease (SpH-protease) participates in male chromatin remodeling and in cell-cycle progression in sea urchins embryos. The gene that encodes this protease was cloned. It presents a high identity sequence with cathepsin L family. The active form associated to chromatin has a molecular weight of 60 kDa, which is higher than the active form of cathepsin L described until now, which range between 25 and 35 kDa. Another difference is that the zymogen present in sea urchin has a molecular weight of 75 and 90 kDa whereas for human procathepsin L has a molecular weight of 38-42 kDa. Based on these results and using a polyclonal antibody available in our laboratory that recognizes the active form of the 60 kDa nuclear cysteine protease of sea urchin, ortholog to human cathepsin L, we investigated the presence of this enzyme in HeLa and Caco-2 cells. We have identified a new nuclear protease, type cathepsin L, with a molecular size of 60 kDa, whose cathepsin activity increases after a partial purification by FPLC and degrade in vitro histone H1. This protease associates to the mitotic spindle during mitosis, remains in the nuclei in binuclear cells and also translocates to the cytoplasm in non-proliferative cells.


Johne's disease in a free-ranging white-tailed deer from Virginia and subsequent surveillance for Mycobacterium avium subspecies paratuberculosis.
Johne's disease (paratuberculosis) was diagnosed in a 2-yr-old, male, free-ranging white-tailed deer (Odocoileus virginianus) from Fauquier County, Virginia, USA, based on histopathology and culture for Mycobacterium avium subspecies paratuberculosis. Clinical and pathologic findings included emaciation; loss of body fat; chronic diarrhea; severe, chronic, diffuse granulomatous colitis with intrahistiocytic acid-fast bacilli; moderate, chronic granulomatous lymphadenitis with intrahistiocytic acid-fast bacilli; as well as moderate chronic, multifocal, lymphoplasmacytic hepatitis. These findings are consistent with previous reports of Johne's disease in cervids. Subsequent targeted surveillance of 10 emaciated deer with diarrhea, as well as sampling of 72 asymptomatic deer for M. avium subsp. paratuberculosis using culture of multiple tissue types, as well as serology using an enzyme-linked immunosorbent assay (ELISA) optimized for cervid antibody detection, did not reveal any additional cases of infection in this geographic region. To date, this appears to be an isolated case of Johne's disease in a free-ranging white-tailed deer, and infection with the causative agent for Johne's disease appears to be an infrequent occurrence in deer from this region. The origin of infection was most likely domestic ruminants. This is the first report of clinical Johne's disease in a free-ranging white-tailed deer outside of the Florida Keys, USA. Stressors, such as high deer population density and low selenium levels, may have contributed to the development of clinical disease in this case and warrant further investigation.


Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice.
Antibiotics and dietary habits can affect the gut microbial community, thus influencing disease susceptibility. Although the effect of microbiota on the postnatal environment has been well documented, much less is known regarding the impact of gut microbiota at the embryonic stage. Here we show that maternal microbiota shapes the metabolic system of offspring in mice. During pregnancy, short-chain fatty acids produced by the maternal microbiota dictate the differentiation of neural, intestinal, and pancreatic cells through embryonic GPR41 and GPR43. This developmental process helps maintain postnatal energy homeostasis, as evidenced by the fact that offspring from germ-free mothers are highly susceptible to metabolic syndrome, even when reared under conventional conditions. Thus, our findings elaborate on a link between the maternal gut environment and the developmental origin of metabolic syndrome.


Pediatric Weight Errors and Resultant Medication Dosing Errors in the Emergency Department.
An accurate weight is critical for dosing medications in children. Weight errors can lead to medication-dosing errors. This study examined the frequency and consequences of weight errors occurring at 1 children's hospital and 2 general hospitals. Using an electronic medical record database, 79,000 emergency department encounters of children younger than 5 years were analyzed. Extreme weights were first identified using weight percentiles. Encounters with potential weight errors were further evaluated using a retrospective chart review to determine whether a weight error and medication-dosing error occurred. The percentage of weight errors of total encounters at all 3 institutions was low (0.63% on average), but a large proportion of weight errors led to subsequent medication-dosing errors (34% on average). The children's hospital did not have clinically significantly lower occurrences of weight errors or weight-based medication errors. Common weight errors included the weight in pounds being substituted for the weight in kilograms and decimal placement errors. Weight errors were uncommon at the 3 emergency departments that we studied, but they led to weight-based medication-dosing errors that had the potential to cause harm.


An Examination of an Iconic Trap-Neuter-Return Program: The Newburyport, Massachusetts Case Study.
The use of trap-neuter-return (TNR) as a humane alternative to the lethal management of free-roaming cats has been on the rise for several decades in the United States; however a relative paucity of data from TNR programs exists. An iconic community-wide TNR effort; initiated in 1992 and renowned for having eliminated hundreds of free-roaming cats from the Newburyport; Massachusetts waterfront; is cited repeatedly; yet few details appear in the literature. Although the presence of feline population data was quite limited; a detailed narrative emerged from an examination of contemporaneous reports; extant TNR program documents; and stakeholder testimony. Available evidence indicates that an estimated 300 free-roaming cats were essentially unmanaged prior to the commencement of the TNR program; a quick reduction of up to one-third of the cats on the waterfront was attributed to the adoption of sociable cats and kittens; the elimination of the remaining population; over a 17-year period; was ascribed to attrition. These findings illuminate the potential effectiveness of TNR as a management practice; as well as call attention to the need for broad adoption of systematic data collection and assessment protocols.


Amyloid in the islets of Langerhans: thoughts and some historical aspects.
Deposition of amyloid, derived from the polypeptide hormone islet amyloid polypeptide (IAPP; 'amylin') is the single most typical islet alteration in type 2 diabetes. Islet amyloid was described as hyalinization already in 1901, but not until 1986 was it understood that it is a polymerization product of a novel β-cell regulatory product. The subject of this focused review deals with the pathogenesis and importance of the islet amyloid itself, not with the biological effect of the polypeptide. Similar to the situation in Alzheimer's disease, it has been argued that the amyloid may not be of importance since there is no strict correlation between the degree of islet amyloid infiltration and the disease. However, it is hardly discussable that the amyloid is important in subjects where islets have been destroyed by pronounced islet amyloid deposits. Even when there is less islet amyloid the deposits are widely spread, and β-cells show ultrastructural signs of cell membrane destruction. It is suggested that type 2 diabetes is heterogeneous and that in one major subtype aggregation of IAPP into amyloid fibrils is determining the progressive loss of β-cells. Interestingly, development of islet amyloid may be an important event in the loss of β-cell function after islet transplantation into type 1 diabetic subjects.


The impact of hepatitis C on labor force participation, absenteeism, presenteeism and non-work activities.
Between 2.7 and 3.9 million people are currently infected with the hepatitis C virus (HCV) in the United States. Although many studies have investigated the impact of HCV on direct healthcare costs, few studies have estimated the indirect costs associated with the virus using a nationally-representative dataset. Using data from the 2009 United States (US) National Health and Wellness Survey, patients who reported a hepatitis C diagnosis (n = 695) were compared to controls on labor force participation, productivity loss, and activity impairment after adjusting for demographics, health risk behaviors, and comorbidities. All analyses applied sampling weights to project to the population. Patients with HCV were significantly less likely to be in the labor force than controls and reported significantly higher levels of absenteeism (4.88 vs. 3.03%), presenteeism (16.69 vs. 13.50%), overall work impairment (19.40 vs.15.35%), and activity impairment (25.01 vs. 21.78%). A propensity score matching methodology replicated many of these findings. While much of the work on HCV has focused on direct costs, our results suggest indirect costs should not be ignored when quantifying the societal burden of HCV. To our knowledge, this is the first study which has utilized a large, nationally-representative data source for identifying the impact of HCV on labor force participation and work and activity impairment using both a propensity-score matching and a regression modeling framework. All data were patient-reported (including HCV diagnosis and work productivity), which could have introduced some subjective biases.


Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest.
There is limited information on genetic factors associated with sudden cardiac arrest (SCA). To assess the association of common variation in genes in fatty acid pathways with SCA risk. We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases. Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (95% confidence interval -21% to -5%) in the discovery phase and 9% lower SCA risk (95% confidence interval -16% to -1%) in the replication phase. While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.


Comparative genomics reveals adaptive evolution of Asian tapeworm in switching to a new intermediate host.
Taenia saginata, Taenia solium and Taenia asiatica (beef, pork and Asian tapeworms, respectively) are parasitic flatworms of major public health and food safety importance. Among them, T. asiatica is a newly recognized species that split from T. saginata via an intermediate host switch ∼1.14 Myr ago. Here we report the 169- and 168-Mb draft genomes of T. saginata and T. asiatica. Comparative analysis reveals that high rates of gene duplications and functional diversifications might have partially driven the divergence between T. asiatica and T. saginata. We observe accelerated evolutionary rates, adaptive evolutions in homeostasis regulation, tegument maintenance and lipid uptakes, and differential/specialized gene family expansions in T. asiatica that may favour its hepatotropism in the new intermediate host. We also identify potential targets for developing diagnostic or intervention tools against human tapeworms. These data provide new insights into the evolution of Taenia parasites, particularly the recent speciation of T. asiatica.


Improved scaling of time-evolving block-decimation algorithm through reduced-rank randomized singular value decomposition.
When the amount of entanglement in a quantum system is limited, the relevant dynamics of the system is restricted to a very small part of the state space. When restricted to this subspace the description of the system becomes efficient in the system size. A class of algorithms, exemplified by the time-evolving block-decimation (TEBD) algorithm, make use of this observation by selecting the relevant subspace through a decimation technique relying on the singular value decomposition (SVD). In these algorithms, the complexity of each time-evolution step is dominated by the SVD. Here we show that, by applying a randomized version of the SVD routine (RRSVD), the power law governing the computational complexity of TEBD is lowered by one degree, resulting in a considerable speed-up. We exemplify the potential gains in efficiency at the hand of some real world examples to which TEBD can be successfully applied and demonstrate that for those systems RRSVD delivers results as accurate as state-of-the-art deterministic SVD routines.


The effect of phosphatidylserine administration on memory and symptoms of attention-deficit hyperactivity disorder: a randomised, double-blind, placebo-controlled clinical trial.
Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed behavioural disorder of childhood, affecting 3-5% of school-age children. The present study investigated whether the supplementation of soy-derived phosphatidylserine (PS), a naturally occurring phospholipid, improves ADHD symptoms in children. Thirty six children, aged 4-14 years, who had not previously received any drug treatment related to ADHD, received placebo (n = 17) or 200 mg day(-1) PS (n = 19) for 2 months in a randomised, double-blind manner. Main outcome measures included: (i) ADHD symptoms based on DSM-IV-TR; (ii) short-term auditory memory and working memory using the Digit Span Test of the Wechsler Intelligence Scale for Children; and (iii) mental performance to visual stimuli (GO/NO GO task). PS supplementation resulted in significant improvements in: (i) ADHD (P < 0.01), AD (P < 0.01) and HD (P < 0.01); (ii) short-term auditory memory (P < 0.05); and (iii) inattention (differentiation and reverse differentiation, P < 0.05) and inattention and impulsivity (P < 0.05). No significant differences were observed in other measurements and in the placebo group. PS was well-tolerated and showed no adverse effects. PS significantly improved ADHD symptoms and short-term auditory memory in children. PS supplementation might be a safe and natural nutritional strategy for improving mental performance in young children suffering from ADHD.


Risk factors for ineffective therapy in patients with bloodstream infection.
Infections occurring among outpatients having recent contact with the health care system have been termed health care-associated infections. The objective of this study was to analyze the impact of health care-associated status on effectiveness of initial therapy in hospitalized patients with bloodstream infections. Prospective cohort study of adults with bloodstream infections at 3 North Carolina hospitals. Bloodstream infection was defined as health care-associated if it occurred within the first 48 hours after hospitalization and if patients had 1 of the following characteristics: had received home health services, outpatient intravenous therapy, or outpatient renal dialysis in the 30 days prior to hospital admission; had been hospitalized within 90 days prior to admission; or lived in a long-term care facility. Of 466 bloodstream infections, 132 (28%) were community-acquired, 178 (38%) were health care-associated, and 156 (33%) were nosocomial. Multivariable logistic regression using community-acquired status as a reference identified health care-associated status (odds ratio, 3.1; 95% confidence interval, 1.6-6.1) and nosocomial status (odds ratio, 4.3; 95% confidence interval, 2.2-8.3) as independent predictors of ineffective initial antibiotic therapy. Among health care-associated characteristics, hospitalization in the 90 days prior to admission was independently associated with ineffective initial therapy (odds ratio, 2.4; 95% confidence interval, 1.4-4.2). Among patients treated in the hospital for bloodstream infection, health care-associated status was an independent predictor of ineffective initial antibiotic therapy. Hospitalization within 90 days prior to hospital admission was the component of health care-associated status most strongly associated with ineffective initial therapy.


In vivo detoxification of endotoxin by the reticuloendothelial system.
Evidence is presented that The normal RES extracts endotoxin from the circulation and inactivates it very rapidly. When the RES has been damaged, whether by a blockading agent, such as thorotrast, or by a reversible degree of hemorrhagic shock, it cannot extract more than a small per cent of the amount of the endotoxin the normal system can extract. Of that fraction of endotoxin which is extracted, very little is detoxified. An organ like the kidney, which does not contain a significant amount of RE tissue, does not extract more than an insignificant percentage of the injected amount, and therefore does not detoxify endotoxin. Since dephosphorylation is a process concurrent with detoxification, and does not occur in an organ which does not extract or inactivate a significant amount of injected endotoxin, it is probable that this process is an indirect index of detoxification. Within the time limits of these experiments, plasma alone does not inactivate endotoxin.


[Medicolegal analysis of ARD mass cases occurred in servicemen].
The article presents the analysis of causes and outcomes of ARD and pneumonia incidence among the servicemen in one of the military units during the period 2002-2003. 95 forensic medical examinations were analyzed. The terms of disease occurrence, complications, unfavorable outcomes are presented. The defects in medical care rendering are shown. The recommendations on prophylaxis of such cases are shown.


Effect of a single dose of dexamethasone on glucose homeostasis in healthy horses by using the combined intravenous glucose and insulin test.
Sustained dexamethasone administration to horses results in insulin resistance, which may predispose them to laminitis. A single dose of dexamethasone is commonly used as a diagnostic aid, yet the effect of a single dose of dexamethasone on glucose homeostasis in horses is not well defined. The objective of this study was to characterize the change in glucose dynamics over time in response to a single dose of dexamethasone. A combined glucose-insulin tolerance test (CGIT) was performed on 6 adult geldings before and at 2, 24, and 72 h postdexamethasone (40 microg/kg of BW, i.v.); a minimum of 1 wk of rest was allowed between treatments. Before any treatment, the CGIT resulted in a hyperglycemic phase followed by a hypoglycemic phase. Dexamethasone affected glucose dynamics in 3 ways: 1) at 2 h, dexamethasone shortened the ascending branch of the negative phase (P < 0.001) of the test, indicating moderate insulin resistance; 2) at 24 h, dexamethasone impaired glucose clearance by extending the positive phase and eliminating the negative phase while insulin was elevated before the CGIT, indicating a decreased response to insulin; and 3) at 72 h, dexamethasone caused a deeper nadir value (P < 0.001) compared with predexamethasone, indicating an increased response to insulin. It was concluded that dexamethasone decreased the response to insulin as early as 2 h and maximally at 24 h. At 72 h, dexamethasone caused an increased response to insulin, which was unexpected.


Participatory Assessment of Factors Influencing Nutrition and Livelihoods in Rural Ethiopia: Implications for Measuring Impacts of Multisector Nutrition Programs.
Agricultural interventions more effectively improve nutrition when they are adapted to local contexts and engage multiple sectors. However, evidence is limited for how to design and measure the impacts of such interventions. We piloted a participatory methodology to collect community feedback to inform the design and selection of measures for a multisector nutrition intervention in Ethiopia. Study participants were purposively recruited from 6 rural districts in Tigray and the Southern Nations, Nationalities, and Peoples' regions. Qualitative data were collected from 12 focus group discussions with smallholder farmers (men and women) participating in a nutrition-sensitive agriculture intervention. The Sustainable Livelihoods Approach (SLA) combined with an ecological systems model informed the survey tool and analyses. Analyses revealed 3 key findings. First, there were regional differences in how communities defined assets important for nutrition. Second, when asked to prioritize which assets were most important, communities selected every SLA capital category; however, the types of assets within each category differed by region. Third, the most commonly reported barriers to good nutrition were traditional feeding behaviors (eg, men eating before women) and lack of nutrition knowledge. How households use assets to enhance nutrition is influenced by diverse and dynamic cultural, social, economic, and ecological factors. The participatory methods piloted in this study present a novel approach to identify contextually relevant household, community, and institutional assets used to support food and nutrition security.


Osteoclast stimulation factor 1 (Ostf1) KNOCKOUT increases trabecular bone mass in mice.
Osteoclast stimulation factor 1 (OSTF1) is an SH3-domain containing protein that was initially identified as a factor involved in the indirect activation of osteoclasts. It has been linked to spinal muscular atrophy in humans through its interaction with SMN1, and is one of six genes deleted in a human developmental microdeletion syndrome. To investigate the function of OSTF1, we generated an Ostf1 knockout mouse model, with exons 3 and 4 of Ostf1 replaced by a LacZ orf. Extensive X-Gal staining was performed to examine the developmental and adult expression pattern, followed by phenotyping. We show widespread expression of the gene in the vasculature of most organs and in a number of cell types in adult and embryonic mouse tissues. Furthermore, whilst SHIRPA testing revealed no behavioural defects, we demonstrate increased trabecular mass in the long bones, confirming a role for OSTF1 in bone development.


Single-crystal organic charge-transfer interfaces probed using Schottky-gated heterostructures.
Organic semiconductors based on small conjugated molecules generally behave as insulators when undoped, but the heterointerfaces of two such materials can show electrical conductivity as large as in a metal. Although charge transfer is commonly invoked to explain the phenomenon, the details of the process and the nature of the interfacial charge carriers remain largely unexplored. Here we use Schottky-gated heterostructures to probe the conducting layer at the interface between rubrene and PDIF-CN(2) single crystals. Gate-modulated conductivity measurements demonstrate that interfacial transport is due to electrons, whose mobility exhibits band-like behaviour from room temperature to ~150 K, and remains as high as ~1 cm(2) V(-1) s(-1) at 30 K for the best devices. The electron density decreases linearly with decreasing temperature, an observation that can be explained quantitatively on the basis of the heterostructure band diagram. These results elucidate the electronic structure of rubrene/PDIF-CN(2) interfaces and show the potential of Schottky-gated organic heterostructures for the investigation of transport in molecular semiconductors.


Risks of cataract in Nigerian metal arc welders.
Occupational exposure to ultraviolet (UV) radiation from welding is considered a risk factor for cataract and other eye disorders, but the evidence for such effects is limited. To identify any increased risk of developing cataract from metal arc welding and to investigate the associated risk factors. A cross-sectional study was carried out on male welders and control subjects (not engaged in welding) from five fabrication and construction companies in Port Harcourt, Nigeria. A questionnaire was used to gather information regarding their demography and lifestyle, along with their occupational, medical and ocular histories. Cataract was identified by external examination and ophthalmoscopy. A total of 117 welders and 105 controls participated. There was no statistically significant increase in the risk of cataract in welders after adjusting for age, smoking status, family history of cataract, outdoor work and history of eye injury. There was a strong association between work-related eye-injury history and cataract. Only 60% of welders were wearing eye protection when the eye injury occurred. The majority of the eye injuries (72%) occurred during welding and grinding operations. The findings of this study suggest that the main occupational risk factor for cataract was a history of eye injuries. The role of UV (or optical) radiation appeared to be less important than impact eye injuries associated with welding-allied processes. It is therefore important that welders are provided with different types of eye protection and are informed about which type should be used, and when, so that they can be protected against optical and impact injuries.


Phonon and Raman scattering of two-dimensional transition metal dichalcogenides from monolayer, multilayer to bulk material.
Two-dimensional (2D) transition metal dichalcogenide (TMD) nanosheets exhibit remarkable electronic and optical properties. The 2D features, sizable bandgaps and recent advances in the synthesis, characterization and device fabrication of the representative MoS2, WS2, WSe2 and MoSe2 TMDs make TMDs very attractive in nanoelectronics and optoelectronics. Similar to graphite and graphene, the atoms within each layer in 2D TMDs are joined together by covalent bonds, while van der Waals interactions keep the layers together. This makes the physical and chemical properties of 2D TMDs layer-dependent. In this review, we discuss the basic lattice vibrations of 2D TMDs from monolayer, multilayer to bulk material, including high-frequency optical phonons, interlayer shear and layer breathing phonons, the Raman selection rule, layer-number evolution of phonons, multiple phonon replica and phonons at the edge of the Brillouin zone. The extensive capabilities of Raman spectroscopy in investigating the properties of TMDs are discussed, such as interlayer coupling, spin-orbit splitting and external perturbations. The interlayer vibrational modes are used in rapid and substrate-free characterization of the layer number of multilayer TMDs and in probing interface coupling in TMD heterostructures. The success of Raman spectroscopy in investigating TMD nanosheets paves the way for experiments on other 2D crystals and related van der Waals heterostructures.


Desmoplakin expression and organization at human umbilical vein endothelial cell-to-cell junctions.
Desmoplakin is an intracellular component of desmosomes which plays a role in the anchorage of intermediate filaments to these structures. We report here that, despite the absence of desmosomes, cultured endothelial cells from human umbilical vein express desmoplakin I and II both at mRNA and protein level. Desmoplakin I/II are found only in the detergent insoluble fraction suggesting that most of the protein is linked to the cytoskeleton. Desmoplakin I/II could be detected by western blot only in long confluent cells even if desmoplakin mRNA levels are unchanged by cell confluency. This suggests that desmoplakin might be stabilized at protein level by its association with junctional components. Immunofluorescence confocal microscopy showed that desmoplakin codistributes with VE-cadherin and plakoglobin along the lateral cell membrane. In contrast, desmoplakin localization was distinct from that of PECAM, an endothelial specific junctional protein localized outside adherence junctions. Endothelial cells do not have keratins but they express vimentin. In confluent cells vimentin forms peripheral filaments which attach to the cell membrane in areas at desmoplakin localization. These data suggest that desmoplakin may participate in the molecular organization of interendothelial junctions by interacting with VE-cadherin and promoting vimentin anchorage. This new type of intercellular junction seems to correspond to the "complexus adhaerentes' described in vivo in lymphatic endothelium.


Comparison and validation of genomic predictors for anticancer drug sensitivity.
An enduring challenge in personalized medicine lies in selecting the right drug for each individual patient. While testing of drugs on patients in large trials is the only way to assess their clinical efficacy and toxicity, we dramatically lack resources to test the hundreds of drugs currently under development. Therefore the use of preclinical model systems has been intensively investigated as this approach enables response to hundreds of drugs to be tested in multiple cell lines in parallel. Two large-scale pharmacogenomic studies recently screened multiple anticancer drugs on over 1000 cell lines. We propose to combine these datasets to build and robustly validate genomic predictors of drug response. We compared five different approaches for building predictors of increasing complexity. We assessed their performance in cross-validation and in two large validation sets, one containing the same cell lines present in the training set and another dataset composed of cell lines that have never been used during the training phase. Sixteen drugs were found in common between the datasets. We were able to validate multivariate predictors for three out of the 16 tested drugs, namely irinotecan, PD-0325901, and PLX4720. Moreover, we observed that response to 17-AAG, an inhibitor of Hsp90, could be efficiently predicted by the expression level of a single gene, NQO1. These results suggest that genomic predictors could be robustly validated for specific drugs. If successfully validated in patients' tumor cells, and subsequently in clinical trials, they could act as companion tests for the corresponding drugs and play an important role in personalized medicine.


Democratic governance and global science: A longitudinal analysis of the international research collaboration network.
The democracy-science relationship has traditionally been examined through philosophical conjecture and country case studies. There remains limited global-scale empirical research on the topic. This study explores country-level factors related to the dynamics of the global research collaboration network, focusing on structural associations between democratic governance and the strength of international research collaboration ties. This study combines longitudinal data on 170 countries between 2008 and 2017 from the Varieties of Democracy Institute, World Bank Indicators, Scopus, and Web of Science bibliometric data. Methods include descriptive network analysis, temporal exponential random graph models (TERGM), and valued exponential random graph models (VERGM). The results suggest significant positive effects of democratic governance on the formation and strength of international research collaboration ties and homophily between countries with similar levels of democratic governance. The results also show the importance of exogenous factors, such as GDP, population size, and geographical distance, as well as endogenous network factors, including preferential attachment and transitivity.


Visible light mediated cyclization of tertiary anilines with maleimides using nickel(II) oxide surface-modified titanium dioxide catalyst.
Surface-modified titanium dioxides by highly dispersed NiO particles have an extended absorption in the visible light region and a reduced hole-electron pair recombination than unmodified TiO2. They have now been successfully applied as highly active heterogeneous photocatalysts in the visible light mediated direct cyclization of tertiary anilines with maleimides to give tetrahydroquinoline products in moderate to high yields at ambient temperature. In contrast with unmodified titanium dioxide catalysts that are conventionally used in a stoichiometric amount in combination with UVA light, only a catalytic amount (1 mol %) of the surface-modified TiO2 catalyst is needed along with visible light to efficiently catalyze the reaction. Compared with transition-metal complexes such as Ru(bpy)3Cl2 or Ir(ppy)2(dtbbpy)PF6, advantages of these surface-modified titanium dioxides as photocatalyst include high catalytic activity, low cost, ease of recovering, and being able to be used for at least nine times without significant decay of catalytic activity.


Distribution of anionic sites on surface of B cell granule and plasma membranes: a study using cationic ferritin.
The distribution of anionic sites on the membranes of rat pancreatic B cells and of their storage granules has been studied by the use of a visual probe of cationic ferritin. Membranes of isolated storage granules possessed a net negative charge which was apparently evenly distributed; the number of anionic sites was not markedly altered by prior incubation of the granules with neuraminidase or with 10(-5) to 2 X 10(-3) M calcium chloride. Distribution of charges along B cell plasma membranes was less uniform but was similarly unaffected by alterations of calcium concentration, or by neuraminidase treatment. However, during the fusion of plasma membrane and granule membrane which occurs in exocytosis, the emerging granule membrane was found to be devoid of anionic sites. The implications of these findings for the regulation of insulin secretion by exocytosis are discussed.


The mental health impacts of the COVID-19 pandemic among individuals with depressive, anxiety, and stressor-related disorders: A scoping review.
A scoping review of studies published in the first year of the COVID-19 pandemic focused on individuals with pre-existing symptoms of depression, anxiety, and specified stressor-related disorders, with the objective of mapping the research conducted. (1) direct study of individuals with pre-existing depressive, anxiety, and/or specified stressor-related (i.e., posttraumatic stress, acute stress) disorders/issues; (2) focus on mental health-related pandemic effects, and; (3) direct study of mental health symptoms related to depression, anxiety, or psychological distress. Database-specific subject headings and natural language keywords were searched in Medline, Embase, APA PsycInfo, and Cumulative Index to Nursing & Allied Health Literature (CINAHL) up to March 3, 2021. Review of potentially relevant studies was conducted by two independent reviewers and proceeded in two stages: (1) title and abstract review, and; (2) full paper review. Study details (i.e., location, design and methodology, sample or population, outcome measures, and key findings) were extracted from included studies by one reviewer and confirmed by the Principal Investigator. 66 relevant articles from 26 countries were identified. Most studies adopted a cross-sectional design and were conducted via online survey. About half relied on general population samples, with the remainder assessing special populations, primarily mental health patients. The most commonly reported pre-existing category of disorders or symptoms was depression, followed closely by anxiety. Most studies included depressive and anxiety symptoms as outcome measures and demonstrated increased vulnerability to mental health symptoms among individuals with a pre-existing mental health issue. These findings suggest that improved mental health supports are needed during the pandemic and point to future research needs, including reviews of other diagnostic categories and reviews of research published in subsequent years of the pandemic.


Dose-dependent increase in intratesticular testosterone by very low-dose human chorionic gonadotropin in normal men with experimental gonadotropin deficiency.
In men with infertility secondary to gonadotropin deficiency, treatment with relatively high dosages of human chorionic gonadotropin (hCG) stimulates intratesticular testosterone (IT-T) biosynthesis and spermatogenesis. Previously we found that lower dosages of hCG stimulated IT-T to normal. However, the minimal dose of hCG needed to stimulate IT-T and the dose-response relationship between very low doses of hCG and IT-T and serum testosterone in normal men is unknown. We induced experimental gonadotropin deficiency in 37 normal men with the GnRH antagonist acyline and randomized them to receive one of four low doses of hCG: 0, 15, 60, or 125 IU sc every other day or 7.5 g daily testosterone gel for 10 d. Testicular fluid was obtained by percutaneous aspiration for steroid measurements at baseline and after 10 d of treatment and correlated with contemporaneous serum hormone measurements. Median (25th, 75th percentile) baseline IT-T was 2508 nmol/liter (1753, 3502 nmol/liter). IT-T concentrations increased in a dose-dependent manner with very low-dosage hCG administration from 77 nmol/liter (40, 122 nmol/liter) to 923 nmol/liter (894, 1017 nmol/liter) in the 0- and 125-IU groups, respectively (P<0.001). Moreover, serum hCG was significantly correlated with both IT-T and serum testosterone (P<0.01). Doses of hCG far lower than those used clinically increase IT-T concentrations in a dose-dependent manner in normal men with experimental gonadotropin deficiency. Assessment of IT-T provides a valuable tool to investigate the hormonal regulation of spermatogenesis in man.


Augmentation of the cardiac natriuretic peptides by beta-receptor antagonism: evidence from a population-based study.
The present retrospective analysis of data derived from a population-based study examined the relationship between intake of beta-receptor antagonists and plasma concentrations of the cardiac natriuretic peptides and their second messenger. Beta-receptor antagonists are widely used for treatment of cardiovascular disease. In addition to direct effects on heart rate and cardiac contractility, recent evidence suggests that beta-receptor antagonists may also modulate the cross talk between the sympathetic nervous system and the cardiac natriuretic peptide system. Plasma concentrations of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and their second messenger cyclic guanosine monophosphate (cGMP) were assessed in addition to anthropometric, hemodynamic and echocardiographic parameters in a population-based sample (n = 672), of which 80 subjects used beta-receptor antagonists. Compared to subjects without medication, subjects receiving beta-receptor antagonists were characterized by substantially elevated ANP, BNP and cGMP plasma concentrations (plus 32%, 89% and 18%, respectively, p < 0.01 each). Analysis of subgroups revealed that this effect was highly consistent and present even in the absence of hypertension, left atrial enlargement, left ventricular hypertrophy or left ventricular dysfunction. The most prominent increase was observed in a subgroup with increased left ventricular mass index. By multivariate analysis, a statistically significant and independent association between beta-receptor antagonism and ANP, BNP and cGMP concentrations was confirmed. Such an association could not be demonstrated for other antihypertensive agents such as angiotensin-converting enzyme inhibitors or diuretics. Beta-receptor antagonists appear to augment plasma ANP, BNP and cGMP concentrations. The current observation suggests an important contribution of the cardiac natriuretic peptide system to the therapeutic mechanism of beta-receptor antagonists.


Ventilatory threshold is related to walking tolerance in patients with intermittent claudication.
This study assessed the relationship between lower limb hemodynamics and metabolic parameters with walking tolerance in patients with intermittent claudication (IC). Resting ankle-brachial index (ABI), baseline blood flow (BF), BF response to reactive hyperemia (BFRH), oxygen uptake (VO2), initial claudication distance (ICD) and total walking distance (TWD) were measured in 28 IC patients. Pearson and Spearman correlations were calculated. ABI, baseline BF and BF response to RH did not correlate with ICD or TWD. VO2 at first ventilatory threshold and VO2peak were significantly and positively correlated with ICD (r = 0.41 and 0.54, respectively) and TWD (r = 0.65 and 0.71, respectively). VO2peak and VO2 at first ventilatory threshold, but not ABI, baseline BF and BFHR were associated with walking tolerance in IC patients. These results suggest that VO2 at first ventilatory threshold may be useful to evaluate walking tolerance and improvements in IC patients.


Study design and statistical analysis of data in human population studies with the micronucleus assay.
The most common study design performed in population studies based on the micronucleus (MN) assay, is the cross-sectional study, which is largely performed to evaluate the DNA damaging effects of exposure to genotoxic agents in the workplace, in the environment, as well as from diet or lifestyle factors. Sample size is still a critical issue in the design of MN studies since most recent studies considering gene-environment interaction, often require a sample size of several hundred subjects, which is in many cases difficult to achieve. The control of confounding is another major threat to the validity of causal inference. The most popular confounders considered in population studies using MN are age, gender and smoking habit. Extensive attention is given to the assessment of effect modification, given the increasing inclusion of biomarkers of genetic susceptibility in the study design. Selected issues concerning the statistical treatment of data have been addressed in this mini-review, starting from data description, which is a critical step of statistical analysis, since it allows to detect possible errors in the dataset to be analysed and to check the validity of assumptions required for more complex analyses. Basic issues dealing with statistical analysis of biomarkers are extensively evaluated, including methods to explore the dose-response relationship among two continuous variables and inferential analysis. A critical approach to the use of parametric and non-parametric methods is presented, before addressing the issue of most suitable multivariate models to fit MN data. In the last decade, the quality of statistical analysis of MN data has certainly evolved, although even nowadays only a small number of studies apply the Poisson model, which is the most suitable method for the analysis of MN data.


[Follow-up of drug administration through nasogastric tube: development of a practice guideline].
To carry out a study of how medication is administered by catheter in daily practice in our hospital. To prepare a practical guide for the administration of medication by catheter. in-patients using enteral feeding tubes, except ICU. Study duration: 2 months. Through a single-dose medication distribution system, the nutrition team's pharmacist prospectively collects the data on the medication of patients subjected to enteral feeding through a catheter and compares these data with the nursing record and, if the medication has been incorrectly handled, makes the pertinent recommendations. Using the information obtained from the pharmaceutical industry and a review of the literature, a guide is drawn up for the medicines used with catheters. The study was carried out with 25 patients receiving enteral nutrition. A total of 55 different pharmaceutical preparations were used. Administration was correct in 116 of the 123 medicines prescribed (91%); the other 5 drugs (9%) were incorrectly handled. A total of 16 alterations were recommended in 25 patients (64 recommendations/100 patients), of which 9 involved a change of pharmaceutical form from solid to liquid, 4 were due to incorrect handling of the solid form, 2 because of interaction between the medication and enteral nutrition and 1 because of interaction between concomitant medications. A guide was drawn up for the administration of medication by catheter, covering a total of 179 active substances and 197 pharmaceutical products. The presence of a pharmacist in clinical units facilitates the detection and solution of problems associated with the administration of medication via catheters. The preparation of a handbook as a tool for the intra-catheter administration of medicines is a useful starting point for improving the use of medication and facilitating nursing tasks.