Mechanisms subserving the physiological nocturnal relative hypoprolactinemia of healthy older men: dual decline in prolactin secretory burst mass and basal release with preservation of pulse duration, frequency, and interpulse interval--a General Clinical Research Center study.
Increasing age is accompanied by decrements in randomly obtained, fasting, or frequently sampled serum PRL concentrations. The precise neuroendocrine mechanisms underlying such relative hypoprolactinemia in aging are incompletely understood. In the present study, we sampled blood at 2.5-min intervals overnight in 11 young (aged 21-34 yr) and 8 older (aged 62-72 yr) healthy men for subsequent chemiluminescence-based assay of serum PRL concentrations. The mean (+/- SEM) serum PRL concentration was significantly reduced at 4.3 +/- 0.78 microg/L in older men compared with 9.5 +/- 1.2 microg/L in young volunteers (P = 0.0049). PRL concentrations correlated with serum testosterone (r = 0.473; P = 0.041), dehydroepiandrosteroen sulfate (r = +0.455, P = 0.05), and insulin-like growth factor I (r = 0.494; P = 0.032) levels. Deconvolution analysis was used to evaluate combined pulsatile and basal modes of PRL secretion. In older men, discrete PRL secretory bursts were marked by a significantly (2.4-fold) attenuated mass of hormone secreted per burst (amount of PRL secreted per unit distribution volume), viz. 1.6 +/- 0.23 (older) vs. 3.9 +/- 0.57 microg/L (young; P < 0.01). In contrast, PRL secretory burst frequency, interpulse interval, and pulse duration were invariant of age. Concomitantly, basal PRL secretion was reduced by 2-fold in older subjects, namely to 0.00030 +/- 0.00027 (older) vs. 0.00065 +/- 0.0002 microg/L/min (young; P < 0.01). The amount of total PRL secretion that was pulsatile averaged 82 +/- 5.3% in young and 99 +/- 0.13% in older men (P = 0.012), indicating preferential loss of the basal mode of PRL release in aging. Assuming that basal PRL secretion mirrors functional pituitary lactotroph cell secretory mass, whereas pulsatile PRL release reflects effective (net) intermittent hypothalamic drive to responsive lactotroph cells, then our results suggest both an attrition in lactotroph cell mass and an impoverishment of net positive hypothalamic (agonistic) input to lactotrophs in older men. Given the multiple roles of PRL reported in experimental animals (e.g. on the one hand to support immune function and adrenal androgen biosynthesis and on the other hand to activate intraprostatic growth factors), we suggest that the nocturnal relative hypoprolactinemia observed in healthy aging men may have both adaptive and maladaptive clinical implications to target tissues.


Elemental balances during intravenous hyperalimentation of underweight adult subjects.
Intravenous hyperalimentation was done in 11 underweight adults whose body weight (body wt) was less than 85 percent of ideal. For the first 6 days, "complete formula" was infused furnishing per kilogram ideal body wt per day: 15 g glucose, 0.40 g N, 0.018 g P, 2.4 meq K, 3.0 meq Na, 2.3 meq C1, 0.5 meq Mg, 0.45 meq Ca, and 50 ml H20. Patients gained weight at an average rate of 9.0 g/kg ideal body wt/day and showed average balances/kilogram ideal body wt/day as follows: plus 0.14 g N; plus 0.012 g P; plus 0.43 meq K; plus 0.49 meq Na; plus 0.37 meq Cl; and plus 0.085 meq Ca. Application of standard equations to the elemental balances indicated weight gain consisted of 35-50 percent protoplasm, 35-50 percent extracellular fluid, 5-25 percent adipose tissus, and less than 1 percent bone. Withdrawas of N, P, Na, or K impaired or abolished retention of other elements. Removal of N halted retention P, K, Na and C1; withdrawal of K stopped retention of N and P; and removal of Na or P interrupted retention of all other elements. Weight gain continued at a rate of 1.4-3.1 g/kg ideal body wt/day despite zero or negative elemental balances of N, K, P, and sometimes Na and C1. Calculations showed that weight gain during infusion of fluids lacking N, P, K, or Na consisted largely of adipose tissue, with little or no contribution by protoplasm or extracellular fluid. Data show that repletion of protoplasm and extracellular fluid of wasted adults by intravenous hyperalimentation is retarded or abolished if N, P, Na, or K is lacking. Repletion of bone mineral does not occur in absence of Na or P but proceeds in absence of N, P, K, or Na. Thus, quality of weight gained by underfed adult patients during hyperalimentation depends on elemental composition of the infusate.


Native Low-Density Lipoproteins Act in Synergy with Lipopolysaccharide to Alter the Balance of Human Monocyte Subsets and Their Ability to Produce IL-1 Beta, CCR2, and CX3CR1 In Vitro and In Vivo: Implications in Atherogenesis.
Increasing evidence has demonstrated that oxidized low-density lipoproteins (oxLDL) and lipopolysaccharide (LPS) enhance accumulation of interleukin (IL)-1 beta-producing macrophages in atherosclerotic lesions. However, the potential synergistic effect of native LDL (nLDL) and LPS on the inflammatory ability and migration pattern of monocyte subpopulations remains elusive and is examined here. In vitro, whole blood cells from healthy donors (n = 20) were incubated with 100 μg/mL nLDL, 10 ng/mL LPS, or nLDL + LPS for 9 h. Flow cytometry assays revealed that nLDL significantly decreases the classical monocyte (CM) percentage and increases the non-classical monocyte (NCM) subset. While nLDL + LPS significantly increased the number of NCMs expressing IL-1 beta and the C-C chemokine receptor type 2 (CCR2), the amount of NCMs expressing the CX3C chemokine receptor 1 (CX3CR1) decreased. In vivo, patients (n = 85) with serum LDL-cholesterol (LDL-C) >100 mg/dL showed an increase in NCM, IL-1 beta, LPS-binding protein (LBP), and Castelli's atherogenic risk index as compared to controls (n = 65) with optimal LDL-C concentrations (≤100 mg/dL). This work demonstrates for the first time that nLDL acts in synergy with LPS to alter the balance of human monocyte subsets and their ability to produce inflammatory cytokines and chemokine receptors with prominent roles in atherogenesis.


[Treatment of synchronized K562 cells by tetrafluoroaluminate does not modulate the fluorescence of ethidium bromide and 4'6-diamidine-2-phenylindole in case of the binding with nucleoid DNA].
Earlier we showed that 4-hours treatment of cells K562 with the GTP-binding protein activator AlF4- (10 mM NaF + 20 microM AlCl3) increased the DNA fragmentation on an average to 5% of the total 3H-thymidine-labeled DNA. The viability of cells under these conditions did not change. It has been suggested that gene toxic action of AlF4- is a result of cell proliferation block induced by AlF4-. In the present work we tried to determine possible changes in the ethidium bromide and 4',6-diamidine-2-phenylindole (DAPI) fluorescence when they bind with nucleoid DNA of synchronized cells K562 treated with AlF4-. Cells K562 were incubated for synchronization with 2 mM thymidine during 15 hours. Under these conditions DNA synthesis (3H-thymidine uptake) was suppressed by 94-99%. It has been found that the treatment of "cool" thymidine-incubated cells K562 with AlF4- did not change the fluorescence of either ethidium or DAPI. The presence of phorbol-12-myristate-13-acetate (PMA) in the incubation medium did not influence the results. On the other, hand the rat thymocytes incubated with dexametazone (2 microM) during 4 hours (positive control of DNA fragmentation) demonstrated the increase in both parameters. PMA decreased the ethidium fluorescence that correspond to its (PMA) ability to suppress fragmentation of thymocyte DNA. On the base of the results we suggested that AlF4- did not induce DNA fragmentation in the cells K562 with the blocked DNA synthesis.


Adhesion pathway proteins and risk of atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis.
The cellular adhesion pathway has been suggested as playing an important role in the pathogenesis of atrial fibrillation (AF). However, prior studies that have investigated the role of adhesion pathway proteins in risk of AF have been limited in the number of proteins that were studied and in the ethnic and racial diversity of the study population. Therefore we aimed to study the associations of fifteen adhesion pathway proteins with incident AF in a large, diverse population. Multi-Ethnic Study of Atherosclerosis participants from four races/ethnicities (n = 2504) with protein levels measured were followed for incident AF (n = 253). HGF protein was measured on Exam 1 samples (N = 6669; AF n = 851). Cox proportional hazards regression was used to assess the association of AF with 15 adhesion pathway proteins. Bonferroni correction was applied to account for multiple comparisons. After adjusting for potential confounding variables (age, sex, race/ethnicity, height, body mass index, systolic blood pressure, antihypertension therapy, diabetes status, current smoker, current alcohol use, and total and HDL cholesterol), and accounting for multiple testing (P < 0.05/15 = 0.0033), circulating levels of the following proteins were positively associated with a higher risk of AF: MMP-2 (HR per standard deviation increment, 1.27; 95% CI 1.11‒1.45), TIMP-2 (HR 1.28; 95% CI 1.12‒1.46), VCAM-1 (HR 1.32; 95% CI 1.16‒1.50), and SLPI (HR 1.22; 95% CI 1.07‒1.38). The association between proteins and AF did not differ by race/ethnicity. Circulating levels of MMP-2, TIMP-2, VCAM-1, and SLPI were positively associated with an increased risk of incident AF in a diverse population. Our findings suggest that adhesion pathway proteins may be important risk predictors of AF.


Psychological and Pain Sensitization Characteristics Are Associated With Patellofemoral Osteoarthritis Symptoms: The Multicenter Osteoarthritis Study.
Determine the relation of symptomatic and structural features of patellofemoral osteoarthritis (PFOA) to psychological characteristics and measures of pain sensitization, in older adults with or at risk of knee osteoarthritis (OA). This study included 1112 participants from the Multicenter Osteoarthritis Study (713 females, mean age 66.8 ± SD 7.6 yrs, body mass index 29.5 ± 4.8 kg/m2). Participants were grouped based on the presence of PFOA symptoms (anterior knee pain and pain on stairs) and magnetic resonance imaging (MRI) PFOA (full-thickness cartilage lesion with bone marrow lesion): (1) patellofemoral (PF) symptoms with MRI PFOA; (2) PF symptoms without MRI PFOA; (3) MRI PFOA without PF symptoms; and (4) no PF symptoms or MRI PFOA (no PFOA). Relation of PFOA classification to depressive symptoms, catastrophizing, temporal summation (TS) and pressure pain thresholds (PPT) was evaluated using logistic (categorical variables) and linear regression (continuous variables). Compared with no PFOA, those with PF symptoms with or without MRI PFOA had significantly greater odds of depressive symptoms, catastrophizing, and patellar TS (OR range 1.5-2.01), and those with PF symptoms without MRI PFOA had significantly greater odds of wrist TS (OR 1.66). Males with PF symptoms without MRI PFOA had significantly lower pressure PPT at the patella compared with no PFOA and those with MRI PFOA only (no symptoms). There were no significant differences at the wrist for males, or the patella or wrist for females. Persons with PFOA symptoms, regardless of MRI PFOA status, are more likely to demonstrate depressive symptoms, catastrophizing, and TS. Males with PFOA symptoms without MRI PFOA demonstrate local hyperalgesia.


Identification of differentially expressed proteins in human malignant pleural effusions.
A high protein concentration in a pleural effusion makes it more likely to be a malignant than a transudative effusion. However, the variability in protein composition between these two forms of pleural effusion is not well understood. In order to compare their protein compositions, the proteomic profiles of 14 malignant and 13 transudative pleural effusions were studied using two-dimensional gel electrophoresis. Protein spots with differential expression were identified by matrix-assisted laser desorption/ionisation quadrupole time-of-flight mass spectrometry and liquid chromatography/tandem mass spectrometry. Targeted proteins were further examined by ELISA and Western immunoassay in all samples. Two-dimensional gel electrophoresis revealed seven spots whose expression was reduced in malignant pleural effusions. Four of the abnormal spots were identified as fibrinogen gamma-chain precursor, two as fibrinogen beta-chain precursor and one as pigment epithelium-derived factor. ELISA and Western immunoassay showed that pigment epithelium-derived factor levels were significantly lower in malignant than in transudative pleural effusions. It has been demonstrated that proteomic technologies may help in the elucidation of variable expression of proteins with particular functions. By applying these technologies, the level of pigment epithelium-derived factor, a potent anti-angiogenic factor, was found to be significantly lower in malignant than in transudative pleural effusions. This finding allows for further exploration regarding how underexpression of pigment epithelium-derived factor may relate to the pathogenesis of malignant pleural effusions.


Malaria Screening Using Front-Line Loop-Mediated Isothermal Amplification.
We implemented front-line loop-mediated isothermal amplification (LAMP)-based malaria screening in our nonendemic multicenter health region to reduce reliance on microscopy without sacrificing diagnostic efficiency. We aimed to evaluate changes in test volumes, positivity rates, turnaround times, and approximate labor time savings resulting from implementation of LAMP-based malaria testing to assess the efficacy of the novel testing algorithm in our regional hub-and-spoke testing model. We reviewed data generated from institutional malaria testing between 2016 and 2019, having implemented LAMP in October 2018 as a front-line screening test for all malaria investigations from our hub facility and investigations from satellite facilities with negative rapid diagnostic tests (RDTs) and microscopy. Blood film microscopy and RDT workloads decreased substantially in the year following LAMP implementation (by 90% and 46%, respectively,) despite similar numbers of patients tested and positivity rates for malaria compared with historical data. LAMP turnaround times (TATs) were comparable to historical TATs for RDTs, and TATs for RDTs and thick films did not increase with the change in workflow. LAMP was successfully implemented in our multicenter health region malaria diagnostic algorithm, significantly reducing reliance on microscopic evaluations and RDT and providing substantial labor time savings without compromising TATs.


Homer Wheelon, M.D., physiologist, artist, and poet: origins of the tailpieces in journals of the American Physiological Society.
Since 1953, illustrations have been inserted as "tailpieces" at the ends of articles in The American Journal of Physiology and The Journal of Applied Physiology. The drawings were made by Homer Wheelon, a member of the American Physiological Society from 1919 until his death in 1960. Forty-five years after his death, Wheelon is unknown, but he contributed 32 publications to the medical literature and trained J. Earl Thomas, an important 20th century gastrointestinal physiologist. Wheelon was born into poverty in 1883 to itinerant Methodist preachers, circumstances that guided his education and career choices. Throughout his life, Wheelon exhibited a fondness and talent for art and photography and an unusual breadth of intellectual interests and knowledge. Wheelon received a bachelor's degree from the University of Washington, then studied at the University of Oregon, Northwestern University, and St. Louis University. Earning his M.D. from St. Louis University and assuming a faculty position there, Wheelon and his graduate student, Thomas, conducted widely recognized gastrointestinal research. Returning to Seattle in 1921, Wheelon became a highly respected physician and hospital administrator, but he also found time to indulge his interest in visual art and poetry. In 1933, inspired by observing a rabbit being used in a pregnancy test, Wheelon began to write and illustrate an epic, 322-page poem, Rabbit No. 202, illustrations from which became the journals' tailpieces. The present study traces Wheelon's personal life and scientific career in an attempt to understand this complex man and the origins of his unusual poem and its drawings.


Description of Riemerella columbipharyngis sp. nov., isolated from the pharynx of healthy domestic pigeons (Columba livia f. domestica), and emended descriptions of the genus Riemerella, Riemerella anatipestifer and Riemerella columbina.
A group of 11 bacterial strains was isolated during microbiological investigations of pharyngeal swabs collected from domestic pigeons (Columba livia f. domestica). Phenotypic properties of the isolates closely resembled those of members of the genus Riemerella within the family Flavobacteriaceae. The genus presently contains two species, Riemerella anatipestifer and Riemerella columbina. The pigeon isolates differed from R. columbina by their lack of pigment production and negative CAMP co-haemolysis reaction. They grew more slowly at 37 °C under microaerobic conditions and showed reduced viability during storage under aerobic conditions at different temperatures, compared with both Riemerella species. Comparisons of protein profiles with matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) MS analysis allowed differentiation between the new pigeon isolates and both R. anatipestifer and R. columbina. Phylogenetic analysis based on 16S rRNA gene and rpoB gene (encoding RNA polymerase beta subunit) sequences supported the affiliation of the 11 strains to a novel species within the genus Riemerella, for which we propose the name Riemerella columbipharyngis sp. nov. The type strain is 8151(T) (=DSM 24015(T) = LMG 26094(T)). Emended descriptions of the genus Riemerella and of its species Riemerella anatipestifer and Riemerella columbina are also presented.


Mobility of DNA sequence recognition domains in DNA methyltransferases suggests epigenetics-driven adaptive evolution.
DNA methylation is one of the best studied epigenetic modifications observed in prokaryotes as well as eukaryotes. It affects nearby gene expression. Most DNA methylation reactions in prokaryotes are catalyzed by a DNA methyltransferase, the modification enzyme of a restriction-modification (RM) system. Its target recognition domain (TRD) recognizes a specific DNA sequence for methylation. In this commentary, we review recent evidence for movement of TRDs between non-orthologous genes and movement within a gene. These movements are likely mediated by DNA recombination machinery, and are expected to alter the methylation status of a genome. Such alterations potentially lead to changes in global gene expression pattern and various phenotypes. The targets of natural selection in adaptive evolution might be these diverse methylomes rather than diverse genome sequences, the target according to the current paradigm in biology. This "epigenetics-driven adaptive evolution" hypothesis can explain several observations in the evolution of prokaryotes and eukaryotes.


A cost-effective technique for generating preservable biomass smoke extract and measuring its effect on cell receptor expression in human bronchial epithelial cells.
Nearly half of the world's population uses biomass fuel for the purposes of cooking and heating. Smoke derived from biomass increases the risk of the development of lung diseases, including pneumonia, chronic obstructive pulmonary disease, airway tract infections, and lung cancer. Despite the evidence linking biomass smoke exposure to pulmonary disease, only a small number of experimental studies have been conducted on the impact of biomass smoke on airway epithelial cells. This is in part due to the lack of a standard and easily accessible procedure for the preparation of biomass smoke. Here, we describe a cost-effective and reproducible method for the generation of different smoke extracts, in particular, cow dung smoke extract (CDSE) and wood smoke extract (WSE) for use in a range of biological applications. We examined the effect of the biomass smoke extracts on human bronchial epithelial cell expression of a known responder to cigarette smoke exposure (CSE), the platelet-activating factor receptor (PAFR). Similar to the treatment with CSE, we observed a dose-dependent increase in PAFR expression on human airway epithelial cells that were exposed to CDSE and WSE. This method provides biomass smoke in a re-usable form for cell and molecular bioscience studies on the pathogenesis of chronic lung disease.


Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis.
Macroautophagy selectively degrades dysfunctional mitochondria by a process known as mitophagy. Here we demonstrate the involvement of transglutaminase 2 (TG2) in the turnover and degradation of damaged mitochondria. In TG2-ablated cells we observed the presence of a large number of fragmented mitochondria that display decreased membrane potential, downregulation of IF1 along with increased Drp1 and PINK1 levels, two key proteins regulating the mitochondrial fission. Of note, we demonstrate that in healthy mitochondria, TG2 interacts with the dynamic proteins Drp1 and Fis1; interestingly, their interaction is largely reduced upon induction of the fission process by carbonyl cyanide m-chlorophenyl hydrazine (CCCP). In keeping with these findings, mitochondria lacking TG2 are more susceptible to CCCP treatment. As a consequence of accumulation of damaged mitochondria, cells lacking TG2 increased their aerobic glycolysis and became sensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). In contrast, TG2-proficient cells are more resistant to 2-DG-induced apoptosis as the caspase 3 is inactivated through the enzyme's crosslinking activity. The data presented in this study show that TG2 plays a key role in cellular dynamics and consequently influences the energetic metabolism.


Prognostic Value of Pericardial Effusion on Serial Echocardiograms in Pulmonary Arterial Hypertension.
Pericardial effusion in pulmonary arterial hypertension (PAH) is an indicator of right heart failure and poor prognosis; its significance on serial transthoracic echocardiograms (TTE) is not clear. Baseline and follow-up TTE (1.0 ± 0.5 years), clinical parameters, and outcomes were studied (N = 200) in consecutive patients with PAH who underwent TTE at our center between October 1999 and November 2007. Study baseline TTE was 2.8 ± 4.0 years from initial PAH diagnosis. Over median follow-up of 3.6 ± 2.6 years from baseline TTE, 106 patients (53%) died. Pericardial effusion was present in 20% at baseline, and at any time during the study in 29%. Patients with any pericardial effusion during follow-up were more likely to have underlying connective tissue disease. They also had significantly higher mean right atrial pressure and pulmonary vascular resistance, had lower cardiac output by invasive hemodynamic studies, had higher serum creatinine, and were more likely to be treated with prostanoids. Patients were also significantly likely to have more echocardiographic right atrial dilation and right ventricular dilation and dysfunction, and worse tricuspid regurgitation with higher peak velocity. During follow-up, there was significantly increased use of prostanoids (58% vs. 28%) and combination therapy (8% vs. 2%) compared to baseline. Persistence of pericardial effusion on both baseline and follow-up TTE was associated with worse outcome, and an independent predictor of survival after adjusting for age, creatinine, functional class, and hemodynamics (P < 0.01). Persistence of pericardial effusion in PAH despite vasoactive therapy predicts worse outcomes; absence or resolution of pericardial effusion with therapy suggests better prognosis.


A solid tissue phantom for photon migration studies.
A solid tissue phantom made of agar, Intralipid and black ink is described and characterized. The preparation procedure is fast and easily implemented with standard laboratory equipment. An instrumentation for time-resolved transmittance measurements was used to determine the optical properties of the phantom. The absorption and the reduced scattering coefficients are linear with the ink and Intralipid concentrations, respectively. A systematic decrease of the reduced scattering coefficient dependent on the agar content is observed, but can easily be managed. The phantom is highly homogeneous and shows good repeatability among different preparations. Moreover, agar inclusions can be easily embedded in either solid or liquid matrixes, and no artefacts are caused by the solid-solid or solid-liquid interfaces. This allows one to produce reliable and realistic inhomogeneous phantoms with known optical properties, particularly interesting for studies on optical imaging through turbid media.


Labour induction with prostaglandins: a systematic review and network meta-analysis.
To assess the effectiveness and safety of prostaglandins used for labour induction. Systematic review with Bayesian network meta-analysis The Cochrane Pregnancy and Childbirth Group's Database of Trials (which incorporates the results of a broad generic search for all pregnancy and postpartum trials). Sources included are CENTRAL, Medline, Embase, NHS Economic Evaluation Database, CINAHL, relevant journals, conference proceedings, and registries of ongoing trials. Randomised clinical trials of prostaglandin or prostaglandin analogues used for third trimester cervical ripening or labour induction versus placebo or no treatment, alternative prostaglandin dose or administration, or a different type of prostaglandin. We included studies recruiting women with a viable fetus, but had no other restrictions relating to indication for labour induction or language of publication. Outcomes assessed were serious neonatal morbidity (trialist defined) or perinatal death; serious maternal morbidity (trialist defined) or death; vaginal delivery not achieved within 24 hours, caesarean section, and uterine hyperstimulation with fetal heart rate changes. 280 randomised clinical trials were included (48 068 women) in the review. Maternal and neonatal mortality and serious morbidity were rarely reported and are summarized narratively. Unresolved inconsistency was observed for the hyperstimulation outcome. Relative to placebo, the odds of failing to achieve a vaginal delivery were lowest for vaginal misoprostol (≥50 µg) (odds ratio 0.06 (95% credible interval 0.02 to 0.12)), with a 39% absolute probability of event (95% credible interval 1% to 94%). Compared with placebo, odds of caesarean section were lowest for titrated oral misoprostol solution (<50 µg) (odds ratio 0.65 (0.49 to 0.83)), with an absolute probability of event of 15% (3% to 40%). Low dose(<50 µg) titrated oral misoprostol solution had the lowest probability of caesarean section, whereas vaginal misprostol (≥50 µg) had the highest probability of achieving a vaginal delivery within 24 hours. These findings have important implications for a series of current national and international guidelines for induction of labour and future research in this area. PROSPERO 2013:CRD42013005116.


Identifying genetic loci associated with antidepressant drug response with drug-gene interaction models in a population-based study.
It has been difficult to identify genes affecting drug response to Selective Serotonin Reuptake Inhibitors (SSRIs). We used multiple cross-sectional assessments of depressive symptoms in a population-based study to identify potential genetic interactions with SSRIs as a model to study genetic variants associated with SSRI response. This study, embedded in the prospective Rotterdam Study, included all successfully genotyped participants with data on depressive symptoms (CES-D scores). We used repeated measurement models to test multiplicative interaction between genetic variants and use of SSRIs on repeated CESD scores. Besides a genome-wide analysis, we also performed an analysis which was restricted to genes related to the serotonergic signaling pathway. A total of 273 out of 14,937 assessments of depressive symptoms in 6443 participants, use of an SSRI was recorded. After correction for multiple testing, no plausible loci were identified in the genome-wide analysis. However, among the top 10 independent loci with the lowest p-values, findings within two genes (FSHR and HMGB4) might be of interest. Among 26 genes related to the serotonergic signaling pathway, the rs6108160 polymorphism in the PLCB1 gene reached statistical significance after Bonferroni correction (p-value = 8.1e-5). Also, the widely replicated 102C > T polymorphism in the HTR2A gene showed a statistically significant drug-gene interaction with SSRI use. Therefore, the present study suggests that drug-gene interaction models on (repeated) cross-sectional assessments of depressive symptoms in a population-based study can identify potential loci that may influence SSRI response.


Synthesis and Characterization of pH-Sensitive Inulin Conjugate of Isoniazid for Monocyte-Targeted Delivery.
The use of particles for monocyte-mediated delivery could be a more efficient strategy and approach to achieve intracellular targeting and delivery of antitubercular drugs to host macrophages. In this study, the potential of inulin microparticles to serve as a drug vehicle in the treatment of chronic tuberculosis using a monocytes-mediated drug targeting approach was evaluated. Isoniazid (INH) was conjugated to inulin via hydrazone linkage in order to obtain a pH-sensitive inulin-INH conjugate. The conjugate was then characterized using proton nuclear magnetic resonance (1HNMR), Fourier transform infrared spectroscopy (FTIR) as well as in vitro, cellular uptake and intracellular Mycobacterium tuberculosis (Mtb) antibacterial efficacy. The acid-labile hydrazone linkage conferred pH sensitivity to the inulin-INH conjugate with ~95, 77 and 65% of the drug released after 5 h at pH 4.5, 5.2, and 6.0 respectively. Cellular uptake studies confirm that RAW 264.7 monocytic cells efficiently internalized the inulin conjugates into endocytic compartments through endocytosis. The intracellular efficacy studies demonstrate that the inulin conjugates possess a dose-dependent targeting effect against Mtb-infected monocytes. This was through efficient internalization and cleavage of the hydrazone bond by the acidic environment of the lysosome, which subsequently released the isoniazid intracellularly to the Mtb reservoir. These results clearly suggest that inulin conjugates can serve as a pH-sensitive intracellular drug delivery system for TB treatment.


[Studies on the roles of insulin-like growth factor-1 (IGF-1)/somatomedin C (SMC) during pregnancy].
Studies in human as well as animal experiments have proved that IGF-1/SMC, which shows mitogenic activities in a wide variety of cell types, stimulates growth in vitro and in vivo. The aim of this study was to investigate the roles of IGF-1/SMC on fetal growth during pregnancy by measuring IGF-1/SMC, insulin, C-peptide, human placental lactogen (hPL), and GH and PRL concentrations in maternal and fetal plasma, and by clarifying the changes of IGF receptor in human fetal liver microsomal membranes during pregnancy. Maternal plasma IGF-1/SMC concentrations were not distinguishable from those of nonpregnant women (9.2 +/- 1.7 nmol/l) in the 1st and 2nd trimester of gestation; however, they showed a gradual increase after the 30th week of gestation, reaching 12.7 +/- 5.4 at term. They possessed a significant positive correlation with hPL (r = 0.45, p less than 0.05) and PRL (r = 0.38, p less than 0.05) but not with GH (r = 0.39, NS). On the other hand, IGF-1/SMC in cord plasma could be first detected in the 30th week of gestation, and it increased gradually until term but had no significant correlation with that in maternal plasma. Furthermore, it possessed an intimate correlation with C-peptide (r = 0.30, p less than 0.05) but not with GH or PRL. Additionally, IGF-1/SMC in cord plasma had a positive correlation with birth weight (r = 0.60, p less than 0.005). On the other hand, specific binding of 125I-IGF-1 and -II to liver microsomal membranes which was also displaced by nonlabeled insulin could be detected in human fetuses at various gestational ages. Scatchard analyses indicated that the binding affinity, which was 0.14 +/- 0.05(x 10(9)M-1) in the fetal liver before the 19th week of gestation, increased after the 19th week of gestation (0.58 +/- 0.12); conversely, the binding capacity was lower after the 19th week of gestation (0.15 +/- 0.08 x 10(-12) moles/mg protein) compared with that before the 19th week (0.51 +/- 0.25). These results suggest that (1) plasma IGF-1/SMC might be produced in fetal sites and its regulating mechanism is different from that in maternal sites, and that (2) IGFs might play an important role in human fetal growth and development by its affect via IGF or insulin receptors on the human fetal liver.


Employee conscientiousness, agreeableness, and supervisor justice rule compliance: A three-study investigation.
Researchers have paid limited attention to what makes organizational authority figures decide to treat their employees either justly or unjustly. Drawing from the actor-focused model of justice, as well as the stereotype content model, we argue that employee conscientiousness and agreeableness can impact the extent to which supervisors adhere to normative rules for distributive, procedural, informational, and interpersonal justice, as a result of supervisors' evaluations of their employees' effort and their liking of the employees. Supervisory compliance with justice rules may, in turn, impact the extent to which employees judge themselves to be treated either justly or unjustly. We tested these possibilities in 3 studies. In Study 1, we utilized a meta-analysis to demonstrate positive relationships between employees' conscientiousness, agreeableness, and their justice perceptions. In Study 2, we conducted 3 experiments to test the causal relationship between employee personality and supervisor intentions to comply with justice rules. In Study 3, we conducted an employee-supervisor dyadic field survey to examine the entire mediation model. Results are discussed in terms of the potential roles that both employees and supervisors may play in shaping employees' justice perceptions. (PsycINFO Database Record


A parasite vector-host epidemic model for TSE propagation.
Transmissible spongiform encephalopathies (TSEs) are a family of diseases that infect mammals. They are explained by cross-contamination through an unknown route or from infection of food contaminated with prion proteins (PrPs), natural proteins that take an infectious form contributing to the slow destruction of the animal brain. While the extreme resistance of PrPs to denaturation and proteolysis accounts for a route from the mouth to the brain, the possible role of another route of contamination is explored here. Many diseases are spread by vectors, as seen in plague, typhus, malaria, or dengue. The situation where PrPs would be transmitted by a vector and, from the characteristics of outbreaks, proposed hypotheses about the biological nature of such vectors are explored. The nontrivial situation where contamination by the vector prevents infection by making the host immune to further vector contamination was analyzed. To investigate the nature of a possible vector, the spread of a disease in a closed population of hosts and vectors where the number of hosts is constant and the vectors multiply in the host was modeled mathematically. In this model, the disease is caused by an infective agent and is spread by a vector, while direct host-to-host spread is not permitted. Concrete values of the parameters of the model were computed from simulation of the BSE outbreak in the UK as a possible example of the process. Microbial vector-borne diseases might play an unexpected role in the spread of epidemics, warranting further exploration.


Mapping the Terrain of Moral Suffering.
This essay explores what to make of the various kinds of moral distress and moral injury increasingly discussed in multiple disciplines and fields of work. It argues for transdisciplinary cooperation and inquiry and proposes a common name "moral suffering" to embrace the diversity of morally fracturing experiences that negatively impact those in health care and other helping professions. The authors offer important insights into the phenomenological relationship between moral conscience and traumatic experience, presenting questions and offering a possible hypothesis for those who want to pursue this discussion further. The essay reviews the diversity of theories regarding moral distress and moral injury advanced by health-care researchers, military clinicians, and educators. It names questions that transdisciplinary engagement can help address, such as what do the disciplines of health humanities, psychology, and education have to teach each other about prevention of moral harm and the healing of invisible wounds?


Regulation of blood flow in the retinal trilaminar vascular network.
Light stimulation evokes neuronal activity in the retina, resulting in the dilation of retinal blood vessels and increased blood flow. This response, named functional hyperemia, brings oxygen and nutrients to active neurons. However, it remains unclear which vessels mediate functional hyperemia. We have characterized blood flow regulation in the rat retina in vivo by measuring changes in retinal vessel diameter and red blood cell (RBC) flux evoked by a flickering light stimulus. We found that, in first- and second-order arterioles, flicker evoked large (7.5 and 5.0%), rapid (0.73 and 0.70 s), and consistent dilations. Flicker-evoked dilations in capillaries were smaller (2.0%) and tended to have a slower onset (0.97 s), whereas dilations in venules were smaller (1.0%) and slower (1.06 s) still. The proximity of pericyte somata did not predict capillary dilation amplitude. Expression of the contractile protein α-smooth muscle actin was high in arterioles and low in capillaries. Unexpectedly, we found that blood flow in the three vascular layers was differentially regulated. Flicker stimulation evoked far larger dilations and RBC flux increases in the intermediate layer capillaries than in the superficial and deep layer capillaries (2.6 vs 0.9 and 0.7% dilation; 25.7 vs 0.8 and 11.3% RBC flux increase). These results indicate that functional hyperemia in the retina is driven primarily by active dilation of arterioles. The dilation of intermediate layer capillaries is likely mediated by active mechanisms as well. The physiological consequences of differential regulation in the three vascular layers are discussed.


The instability of Brucella abortus strain 45/20 and a note on significance of using an unstable rough strain in the diagnosis of bovine brucellosis.
The serum agglutinin titres of six heifers experimentally inoculated with live Br. abortus strain 45/20 were similar to those produced in six bullocks inoculated with virulent Br. abortus strain 544. However, the agglutinin response appeared slowly and disappeared earlier in the heifers than in the bullocks. It is concluded that Br. abortus strain 45/20 is an unstable strain, could revert to the smooth form and become highly agglutinogenic in non-pregnant heifers. The significance of using an unstable rough strain of Br. abortus vaccine in the diagnosis of bovine brucellosis is briefly discussed.


Design, synthesis and pharmacology of aortic-selective acyl-CoA: Cholesterol O-acyltransferase (ACAT/SOAT) inhibitors.
We describe our molecular design of aortic-selective acyl-coenzyme A:cholesterol O-acyltransferase (ACAT, also abbreviated as SOAT) inhibitors, their structure-activity relationships (SARs) and their pharmacokinetic (PK) and pharmacological profiles. The connection of two weak ligands-N-(2,6-diisopropylphenyl)acetamide (50% inhibitory concentration [IC50] = 8.6 μM) and 2-(methylthio)benzo[d]oxazole (IC50 = 31 μM)-via a linker comprising a 6 methylene group chains yielded a highly potent molecule, 9-(benzo[d]oxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide (3h) that exhibited high potency (IC50 = 0.004 μM) toward aortic ACAT. This head-to-tail design made it possible to markedly enhance the activity to 2150- to 7750-fold and to discriminate the isoform-selectivity based on the double-induced fit mechanism. At doses of 1 and 3 mg/kg, 3h significantly decreased the lipid-accumulation areas in the aortic arch to 74 and 69%, respectively without reducing the plasma total cholesterol level in high fat- and cholesterol-fed F1B hamsters. Here, we demonstrate the antiatherosclerotic effect of 3hin vivo via its direct action on aortic ACAT and its powerful modulator of cholesterol level. This molecule is a potential therapeutic agent for the treatment of diseases involving ACAT-1 overexpression.


A combined subcision approach with either fractional CO2 laser (10,600 nm) or cross-linked hyaluronic acid versus subcision alone in atrophic post-acne scar treatment.
Different treatment options for post-acne scars exist, but with varying clinical efficacy, side effects, and prolonged downtime. This study aims to compare the efficacy and safety of combined subcision with either fractional CO2 laser or cross-linked hyaluronic acid filler (HA) versus subcision alone in the treatment of facial atrophic post-acne scars. Forty patients with atrophic post-acne scars were subjected to subcision on both sides of the face, then were randomly divided into three groups. Group I (20 patients): subcision combined with cross-linked HA filler injection at one side of the face; group II (20 patients): subcision followed by fractional CO2 at the other side of the face; and group III (20 patients): with subcision only as a control group. Treatment sessions were every month until clinical improvement or for maximum three sessions. The treatment's efficacy was assessed by Goodman and Baron's qualitative and quantitative grading systems. The two blinded investigator scores showed significant improvement in both the filler side versus subcision (p value = 0.015), and the fractional laser side versus subcision (p value < 0.001), with no statistically significant difference between both sides (p value = 0.171). Qualitative grading by Goodman and Baron scores showed that the percentage of patients with excellent improvement was higher in group 1 and group 2 than in group 3 with p value = 0.031; also the mean percentage of reduction in quantitative grading was higher in group 1 and group 2 than in group 3 with p value < 0.00. Either combined subcision with fractional CO2 laser or with cross-linked HA filler achieved superior improvement in facial atrophic post acne scars treatment with no serious side effects in this study. However, subcision only by blunt canula also had modest improvement.


Clustering preference data in the presence of response-style bias.
Preference data, such as Likert scale data, are often obtained in questionnaire-based surveys. Clustering respondents based on survey items is useful for discovering latent structures. However, cluster analysis of preference data may be affected by response styles, that is, a respondent's systematic response tendencies irrespective of the item content. For example, some respondents may tend to select ratings at the ends of the scale, which is called an 'extreme response style'. A cluster of respondents with an extreme response style can be mistakenly identified as a content-based cluster. To address this problem, we propose a novel method of clustering respondents based on their indicated preferences for a set of items while correcting for response-style bias. We first introduce a new framework to detect, and correct for, response styles by generalizing the definition of response styles used in constrained dual scaling. We then simultaneously correct for response styles and perform a cluster analysis based on the corrected preference data. A simulation study shows that the proposed method yields better clustering accuracy than the existing methods do. We apply the method to empirical data from four different countries concerning social values.


The utility of the radionuclide probe in parathyroidectomy for primary hyperparathyroidism.
INTRODUCTION Parathyroidectomy is the definitive treatment for primary hyperparathyroidism but the intraoperative identification of adenomas is challenging. The aim of this study was to evaluate the utility of a radionuclide probe (RNP) in addition to intraoperative parathyroid hormone ( IOPTH) measurement as an intraoperative diagnostic adjunct in patients undergoing parathyroidectomy for primary hyperparathyroidism. METHODS This was a retrospective cohort study of patients treated between 2004 and 2015 in a university affiliated teaching hospital. Patients were grouped into those with RNP use (RNP+) and those without (RNP-). The primary outcome measure was rate of operative failure, which included false positives. The diagnostic sensitivity and positive predictive value of both RNP and IOPTH were also evaluated. RESULTS A total of 298 patients were included in the study, 127 (42.6%) being in the RNP+ group and 171 (57.4%) in the RNP- group. The false positive rate for the RNP+ patients was 1.6% compared with 9.4% for RNP- patients (p=0.006, hazard ratio [HR]: 6.45). The rates of operative failure were 6.3% and 11.7% respectively (p=0.159, HR: 1.97). RNP use had a sensitivity of 92.0% and a positive predictive value of 98.3% compared with 78.6% and 95.2% respectively for IOPTH monitoring. CONCLUSIONS RNP use is associated with fewer false positives and reduced operative failure than IOPTH measurement. It also has a higher sensitivity and positive predictive value. RNP use is recommended in centres that have the required facilities.


Diffusional solute flux during osmotic water flow across the human red cell membrane.
The effect of solvent drag on the unidirectional efflux of labeled water, urea, and chloride from human red cells was studied by means of the continuous flow tube method under conditions of osmotic equilibrium and net volume flow. Solvent (water) flow out of cells was created by mixing cells equilibrated in 100 mM salt solution with a 200-mM or 250-mM salt solution, while flow of water into cells was obtained by equilibrating the cells in the higher concentration and mixing them with the 100-mM solution. Control experiments constitute measurements of efflux of [14C]ethanol in normal cells and 3H2O in cells treated with p-chloromercuribenzosulfonate under the conditions described above. In both instances, the solute is known to penetrate the membrane through nonporous pathways. As anticipated, the tracer flux of neither urea nor chloride showed any dependence on net solvent flow, regardless of the direction. If one assumes the recently reported reflection coefficient for urea of 0.7, the urea tracer flux should change by at least 24% under volume flow conditions. Since such changes would be easily detected with our method, we conclude that the pathways for water, for urea, and for chloride are functionally separated.


Irrigation frequencies and corn (Zea mays L.) yield relation in northern Turkey.
A field experiment was conducted during summer season of 2005 at the Research Station (altitude 180 m above sea level, 41 degrees 21' N and 36 degrees 15'E) Faculty of Agriculture, Ondokuz Mayis University, Samsun, Turkey. Experiment consisted of three irrigation levels and a non-irrigation level. Drip irrigation treatments consisted of three soil water deficits in the 90 cm soil profile depth was replenished to field capacity. Irrigation treatments were A: no irrigation, B: irrigation at 50% of available soil water capacity, C: irrigation at 30% of available soil water capacity, D: irrigation at 15% of available soil water capacity. The average seasonal water use values ranged from 257.14 to 285.71 mm in corn treatments. Irrigation frequencies (intervals) significantly affected corn crop yields. The average corn grain yields varied from 7.98 to 29.16 t ha(-1). The treatment D was recorded significantly higher corn grain yield 29.16 t ha(-1) compared to B (21.59 t ha(-1)); C (19.15 t ha(-1)) and A (7.98 t ha(-1)), respectively. According to research results, the maximum corn grain yield was obtained when the corn plants were irrigated at 15% of available soil water capacity to field capacity.


Selective delivery of 2-hydroxy APA to Trypanosoma brucei using the melamine motif.
Trypanosoma brucei, the parasite that causes human African trypanosomiasis, is auxotrophic for purines and has specialist nucleoside transporters to import these metabolites. In particular, the P2 aminopurine transporter can also selectively accumulate melamine derivatives. In this Letter, we report the coupling of the melamine moiety to 2-hydroxy APA, a potent ornithine decarboxylase inhibitor, with the aim of selectively delivering this compound to the parasite. The best compound described here shows an increased in vitro trypanocidal activity compared with the parent.


Insulin and growth factors stimulate the phosphorylation of a Mr-22000 protein in 3T3-L1 adipocytes.
Insulin, epidermal growth factor (EGF), platelet-derived growth factor, multiplication-stimulating activity and 10% foetal-calf serum each stimulated the phosphorylation of a cytosolic Mr-22000 acidic heat-stable protein in Swiss mouse 3T3-L1 adipocytes. Phosphorylation of this protein was not stimulated by isoprenaline or dibutyryl cyclic AMP. The effect of insulin was maximal (3-fold increase) by 10 min; half-maximal stimulation was observed at 70 pM-insulin. Both [32P]phosphoserine and [32P]phosphothreonine residues were present in the Mr-22000 protein after insulin- and growth-factor-stimulated phosphorylation, but no [32P]phosphotyrosine. The major site of insulin- and EGF-stimulated phosphorylation appeared to be a threonine residue, in contrast with previously studied insulin-stimulated phosphorylation of serine residues. Insulin treatment appeared to result in a shift of the protein toward the anode on isoelectric focusing. Insulin and EGF present simultaneously did not lead to phosphorylation beyond that seen with each hormone singly. We surmise that insulin, EGF and perhaps other growth factors may activate a common protein kinase or inhibit a common protein phosphatase in 3T3-L1 adipocytes which acts on the Mr-22000 protein.


Differential associations between sensory loss and neuropsychiatric symptoms in adults with and without a neurocognitive disorder.
To investigate the differential associations between sensory loss and neuropsychiatric symptoms among older adults with and without diagnosed neurocognitive disorder. The sample comprised 1,393 adults (52.3% men) aged between 72 and 79 years from a community-based cohort study. There were 213 cases of mild and 64 cases of major neurocognitive disorders. The main outcome was number of informant reported symptoms on the Neuropsychiatric Inventory (NPI). Sensory loss was defined by visual acuity worse the 0.3 logMAR (6/12 or 20/40) and self-reported hearing problems. Clinically relevant NPI symptoms were reported in 182 (13.1%) participants, but no individual symptom occurred in more than 5% of the total sample. Among participants diagnosed with a major neurocognitive disorder, those with any sensory loss had over three times (95%CI: 1.72-11.78) greater rates of NPI symptoms than those with unimpaired levels of sensory functioning. There were no differences in the number of neuropsychiatric symptoms by type of sensory loss, and no additional risk associated with a dual sensory loss compared to a single sensory loss. There was no evidence of an association between sensory loss and number of neuropsychiatric symptoms among cognitively healthy adults. The extent to which this association is the result of underlying neuropathology, unmet need, or interpersonal factors is unclear. These findings have significant implications for dementia care settings, including hospitals and respite care, as patients with sensory loss are at increased risk of neuropsychiatric symptoms and may require additional psychosocial support. Interventions to manage sensory loss and reduce the impact of sensory limitations on neuropsychiatric symptoms are needed.


Wastage of standardised parenteral nutrition solution - a challenge for neonatal units.
Background: Standardised parental nutrition (PN) has been used in many neonatal intensive care unit (NICU). Easy accessibility, better provision of nutrients, reduced prescription errors and cost savings are some of its benefits. Fixed large volume (e.g. 750-1000 mL) and short expiry limit (48 hrs) along with changing metabolic needs of neonates leads to significant wastage of PN solution. Objective: To evaluate wastage of PN solution in our 22-bedded NICU. Methods: The audit was conducted over 21-month period (July 2015-April 2017). Data on PN use (e.g. type, duration, infused volume, residual after use) was obtained from hospital records. The discarded volume of PN was estimated after subtracting the administered volume based on the rate of infusion from the total volume in the bag. Cumulative "discarded" volume as percentage of the total "supplied" volume was calculated. Results: A total of 305-PN bags (Standardised: Preterm: 222, Term: 83) were used. The estimated total used, discarded, and percentage discarded volumes for standard preterm and term PN were 78.1, 88 L, 53% and 33.5, 49.7 L, and 59.8%, respectively. Conclusions: There was more than 50% wastage of PN solution in our NICU. The estimated cost of this PN wastage was around 21,000 AUD over 21 months. Strategies such as minipack should be explored to prevent such losses.


Pre-packaged food products Business to Consumer (B2C) distance selling and information obligations in Italian mass market retailers.
The supply and sale of food online are on the rise. The value of e-commerce in Europe has been estimated in 602 billion euros in 2017, 324 million people in the old continent purchase online. In the European area, the Netherlands and Italy are the countries where the e-commerce market grew faster in the last five years. Nevertheless, in Italy the spread of online shopping has reached the 89.9% of the population between 11 and 74 years old. The access to the Internet, as declared by 43 million Italians, it is carried out from fixed or mobile locations. In terms of revenues the food sector recorded a +24% among the different sectors facing one of the higher grows in terms of percentages. The regulatory framework that disciplines the food products distance selling can be traced back to two fundamental pillars: the European legislation on e-commerce on the one side and the food information to consumers on the other side. Under article 14 of the Regulation (EU) No. 1169/2011, the European legislator states that the mandatory information, as indicated in article 9, shall be available to the consumer before the purchase is concluded and when the product is delivered. The study aims at verifying: the level of compliance by Italians MMR with the information regulation about food products distance selling in relation to (a) the fulfillment of the obligation concerning mandatory provisions and (b) the fulfillment of the obligations concerning availability and readability of the information provided. The research has been conducted analyzing the websites of the ten largest Italian MMR and in particular: if the mandatory information were provided, the availability of the information according to the Regulation (EU) 1169/2011; the number of clicks needed to identify the food product in the website and the number of clicks required to obtain all the information. The observation testified a substantial compliance with the information obligations according to the European regulation. Differently, when considering the availability and readability of the information, from the analysis emerged that consumers have to follow a path that is not immediate and intuitive. Conclusions are provided in relation to the presented research.


Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer.
To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and efficacy of gemcitabine combined with fluorouracil (5-FU) in patients with pancreatic cancer. Patients with measurable, locally advanced, nonresectable or metastatic pancreatic cancer were candidates for the study. 5-FU was given via protracted venous infusion (PVI) at a fixed dosage of 200 mg/m2/d, and gemcitabine was administered weekly for 3 consecutive weeks every 4 weeks. The initial dose of gemcitabine was 700 mg/m2 and was escalated in increments of 100 mg/m2/wk until the appearance of severe toxicity. Measurements of efficacy included the following: response rate; clinical benefit response, which is a composite measurement of pain, performance status, and weight loss; time to disease progression; and survival. Twenty-six patients received a total of 109 courses. Dose-limiting toxicity, which consisted of grade 4 neutropenia with fever (one patient) and grade 4 thrombocytopenia (one patient), was observed in two of three patients treated with 1,100 mg/m2/wk of gemcitabine. On the basis of these results, the MTD of gemcitabine with 5-FU via PVI on this schedule was 1,000 mg/m2. Sixteen patients developed grade 3-4 neutropenia, and three patients developed grade 3-4 thrombocytopenia. Grade 3-4 nonhematologic toxicity consisted of diarrhea (two patients) and cutaneous toxicity, asthenia, edema, mucositis, and nausea and vomiting (one patient each). The delivered dose-intensity of gemcitabine was similar at the 1,000 mg/m2 dose level (599 mg/m2/wk) as at the 900 mg/m2 (601 mg/m2/wk) dose level. For this reason, the recommended dose of gemcitabine for phase II evaluation on this schedule was 900 mg/m2. Five patients had objective responses (one complete response and four partial responses; response rate, 19.2%; 95% confidence interval [CI], 6.5 to 39.3), and 10 patients had improvement of disease-related symptoms (45%; 95% CI, 24 to 67). After a median follow-up of 17.7 months (range, 7.8 to 24.8 months), the median progression-free survival and overall survival times were 7.4 months (95% CI, 3.3 to 11.4) and 10.3 months (95% CI, 8.1 to 12.5), respectively. The MTD of gemcitabine when combined with 5-FU via PVI on this schedule was 1,000 mg/m2/ wk; however, on the basis of administered dose-intensity, the recommended dose for additional investigation is 900 mg/m2. This combination chemotherapy regimen was well tolerated and showed promising antitumor activity in the treatment of pancreatic cancer.


Hypercapnic acidosis attenuates pressure-dependent increase in whole-lung filtration coefficient (Kf).
Hypercapnic acidosis (HCA) has beneficial effects in experimental models of lung injury by attenuating inflammation and decreasing pulmonary edema. However, HCA increases pulmonary vascular pressure that will increase fluid filtration and worsen edema development. To reconcile these disparate effects, we tested the hypothesis that HCA inhibits endothelial mechanotransduction and protects against pressure-dependent increases in the whole lung filtration coefficient (Kf). Isolated perfused rat lung preparation was used to measure whole lung filtration coefficient (Kf) at two levels of left atrial pressure (PLA = 7.5 versus 15 cm H2O) and at low tidal volume (LVt) versus standard tidal volume (STVt) ventilation. The ratio of Kf2/Kf1 was used as the index of whole lung permeability. Double occlusion pressure, pulmonary artery pressure, pulmonary capillary pressures, and zonal characteristics (ZC) were measured to assess effects of HCA on hemodynamics and their relationship to Kf2/Kf1. An increase in PLA2 from 7.5 to 15 cm H2O resulted in a 4.9-fold increase in Kf2/Kf1 during LVt and a 4.8-fold increase during STVt. During LVt, HCA reduced Kf2/Kf1 by 2.7-fold and reduced STVt Kf2/Kf1 by 5.2-fold. Analysis of pulmonary hemodynamics revealed no significant differences in filtration forces in response to HCA. HCA interferes with lung vascular mechanotransduction and prevents pressure-dependent increases in whole lung filtration coefficient. These results contribute to a further understanding of the lung protective effects of HCA.


Functional interfacing of Rhodospirillum rubrum chromatophores to a conducting support for capture and conversion of solar energy.
Owing to the considerable current interest in replacing fossil fuels with solar radiation as a clean, renewable, and secure energy source, light-driven electron transport in natural photosynthetic systems offers a valuable blueprint for conversion of sunlight to useful energy forms. In particular, intracytoplasmic membrane vesicles (chromatophores) from the purple bacterium Rhodospirillum rubrum provide a fully functional and robust photosynthetic apparatus, ideal for biophysical investigations of energy transduction and incorporation into biohybrid photoelectrochemical devices. These vesicular organelles, which arise by invagination of the cytoplasmic membrane, are the sites of the photochemical reaction centers and the light harvesting 1 (LH1) complex. The LH1 protein is responsible for collecting visible and near-IR radiant energy and funneling these excitations to the reaction center for conversion into a transmembrane charge separation. Here, we have investigated the morphology, fluorescence kinetics and photocurrent generation of chromatophores from Rsp. rubrum deposited directly onto gold surfaces in the absence of chemical surface modifications. Atomic force microscopy showed a significant coverage of the gold electrode surface by Rsp. rubrum chromatophores. By in situ fluorescence induction/relaxation measurements, a high retention of the quantum yield of photochemistry was demonstrated in the photoactive films. Chronoamperometric measurements showed that the assembled bioelectrodes were capable of generating sustained photocurrent under white light illumination at 220 mW/cm(2) with a maximum current of 1.5 μA/cm(2), which slowly declines in about 1 week. This study demonstrates the possibility of photoelectrochemical control of robust chromatophore preparations from Rsp. rubrum that paves the way for future incorporation into functional solar cells.


Tritium isotope effects in the measurement of the glycerol phosphate and dihydroxyacetone phosphate pathways of glycerolipid biosynthesis in rat liver.
1. Rat liver slices were employed to study the relative rates of incorporation of a mixture of [2-(3)H]- or [1,3-(3)H]-glycerol and [1-(14)C]glycerol into lipids. 2. With 0.1mm-glycerol approx. 82% of the newly synthesized lipid, calculated from (14)C incorporation, was present as neutral lipid, 13% as phosphatidylcholine and 5% as phosphatidylethanolamine. Increasing the glycerol concentration to 40mm caused a decrease in the percentage of neutral lipid to 59% and a corresponding increase in the percentage of phosphatidylcholine to 36% of the newly synthesized lipid. 3. The (d.p.m. of 2-(3)H)/(d.p.m. of 1-(14)C) ratio in glycerolipid was considerably higher than that in precursor glycerol throughout the range of experimental conditions. In contrast the incorporation of a mixture of [1,3-(3)H]glycerol and [1-(14)C]glycerol into lipid occurred with little or no change in the (3)H/(14)C ratio. 4. Respiring rat liver mitochondria were found to oxidize a mixture of sn-[2-(3)H]- and sn-[1-(14)C]-glycerol 3-phosphate with a resultant increase in the (3)H/(14)C ratio of the remaining sn-glycerol 3-phosphate. This increase is due to a (3)H isotope effect of the mitochondrial sn-glycerol 3-phosphate dehydrogenase (EC 220.127.116.11), which discriminates against sn-[2-(3)H]glycerol 3-phosphate during oxidation. 5. A method is described for the simultaneous determination of the relative contributions of the glycerol phosphate and dihydroxyacetone phosphate pathways of glycerolipid biosynthesis in rat liver slices. The method involves measurement of the (d.p.m. of 2-(3)H)/(d.p.m. of 1-(14)C) ratio in both sn-glycerol 3-phosphate and glycerolipid after incubation of rat liver slices with a mixture of [2-(3)H]glycerol and [1-(14)C]glycerol for various times. 6. By using this method it was shown that 40-50% of the glycerol incorporated into lipid by rat liver slices proceeded via the sn-glycerol 3-phosphate pathway and 50-60% was incorporated via dihydroxyacetone phosphate.


Molecular characterisation of rough variants of Vibrio cholerae isolated from hospitalised patients with diarrhoea.
Seven rough isolates of Vibrio cholerae isolated as the sole infecting agent from patients with cholera-like diarrhoea were examined for the presence of the regulatory element toxR and certain virulence-associated genes of the CTX genetic element and V. cholerae pathogenicity island (VPI). Multiplex PCR analysis with wb-specific genes of either O1 or O139 origin showed that six of the seven isolates produced an O1 wb-specific amplicon and the remaining isolate produced an O139-specific amplicon. Analysis of lipopolysaccharide profiles of smooth variants of V. cholerae revealed the presence of long repeated units of 'O' polysaccharide side chains but all the rough variants appeared to be devoid of the latter and possessed only core oligosaccharide. PCR amplification with primers specific to the ctxA, ctxB, tcpA, tagA, int, aldA, toxT, LJ, RJ and toxR genes revealed that six of the seven rough isolates were positive for these genes. One isolate was found to be negative for tagA and RJ, indicating the presence of an altered VPI. Each of these isolates showed media-dependent expression of cholera toxin (CT) and produced more toxin than the reference V. cholerae O1 El Tor strain VC20 or O139 strain SG24 under comparable conditions. Studies on the clonality of these isolates by the analysis of rRNA genes indicated their relatedness to strains of V. cholerae O1 El Tor or O139, isolated during the same time period.


Thyroid hormone receptor beta gene mutation (P453A) in a family producing resistance to thyroid hormone.
Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome characterized by decreased responsiveness of target tissues to thyroid hormone. Two members of a Turkish family, a mother and son, had thyroid function tests suggestive of resistance to thyroid hormone (RTH). The clinical presentation was, however, different. The mother (proposita) had palpitation, weakness, tiredness, nervousness, dry mouth and was misdiagnosed as having multinodular toxic goiter which was treated with antithyroid drugs and partial thyroidectomy. Her younger son had attention deficit hyperactivity disorder and primary encopresis, but normal intellectual quotient. Both had elevated serum iodothyronine levels with nonsuppressed thyrotropin. A mutation in one allele of the thyroid hormone receptor beta gene (P453A) was identified, providing a genetic confirmation for the diagnosis of RTH. Mutational analysis of the TRss gene allows definitive diagnosis of RTH, potentially avoiding the need for protracted and expensive pituitary function testing.


TMB-Hunt: an amino acid composition based method to screen proteomes for beta-barrel transmembrane proteins.
Beta-barrel transmembrane (bbtm) proteins are a functionally important and diverse group of proteins expressed in the outer membranes of bacteria (both gram negative and acid fast gram positive), mitochondria and chloroplasts. Despite recent publications describing reasonable levels of accuracy for discriminating between bbtm proteins and other proteins, screening of entire genomes remains troublesome as these molecules only constitute a small fraction of the sequences screened. Therefore, novel methods are still required capable of detecting new families of bbtm protein in diverse genomes. We present TMB-Hunt, a program that uses a k-Nearest Neighbour (k-NN) algorithm to discriminate between bbtm and non-bbtm proteins on the basis of their amino acid composition. By including differentially weighted amino acids, evolutionary information and by calibrating the scoring, an accuracy of 92.5% was achieved, with 91% sensitivity and 93.8% positive predictive value (PPV), using a rigorous cross-validation procedure. A major advantage of this approach is that because it does not rely on beta-strand detection, it does not require resolved structures and thus larger, more representative, training sets could be used. It is therefore believed that this approach will be invaluable in complementing other, physicochemical and homology based methods. This was demonstrated by the correct reassignment of a number of proteins which other predictors failed to classify. We have used the algorithm to screen several genomes and have discussed our findings. TMB-Hunt achieves a prediction accuracy level better than other approaches published to date. Results were significantly enhanced by use of evolutionary information and a system for calibrating k-NN scoring. Because the program uses a distinct approach to that of other discriminators and thus suffers different liabilities, we believe it will make a significant contribution to the development of a consensus approach for bbtm protein detection.


Sleep hygiene training program for patients on hemodialysis.
The high prevalence of sleep disorders highlights the importance of its treatment in hemodialysis patients. Due to complications of hypnotic medications, considering effective nonpharmacological methods to improve sleep quality is important. This study has conducted to determine the effect of a sleep hygiene training program on sleep quality of hemodialysis patients. In a randomized controlled clinical trial, 82 hemodialysis patients were randomly selected and allocated to the intervention (n = 41) and control (n = 41) groups. A 1-month sleep hygiene program was provided to the intervention group within 6 sessions, and the sleep quality was assessed by the Pittsburgh Sleep Quality Index before and after the intervention. The global and components scores were compared between the two groups. The mean global scores and component scores of sleep quality were not significantly different between the two groups before the intervention. The mean global score of sleep quality of the intervention group significantly reduced after sleep hygiene education, as compared to the baseline values. The mean global score of the intervention group was significantly lower than that of the control group after the intervention (intervention, 9.92 +/- 3.80 versus control, 13.05 +/- 4.28). Also, the mean scores subjective sleep quality, sleep latency, sleep disturbances, and daytime dysfunction were significantly lower in the intervention group. The findings of this study suggest that nursing and physicians team should consider reducing sleep problems of hemodialysis patients by training sleep hygiene.


Residual serologic reactivity in children with resolved Lyme arthritis.
To define the pattern of persistent antibody response in children with resolved Lyme arthritis. From a cohort of 67 children with Lyme arthritis followed in our department since 1989, 19 were selected using these criteria: All patients (1) were asymptomatic; (2) had an ELISA titer < or = 1:160; (3) had been in treatment a minimum of 6 months. Their initial and late samples were assessed by Western blot and the pattern of reactivity was analyzed. The mean interval between treatment and last sample was 9.6 months (6-23). Analysis of the last sample showed that only 5/19 were negative by ELISA and 4/19 were at the cutoff limit (1:80). Only 6 patients had fewer than 4 reactive bands, 4 had 4 bands, and 9 had 5-11 bands on Western blot. The 41, 39, and 60 kDa were the most commonly observed reactive bands at last evaluation. 31 and 34 kDa bands, while relatively common in initial samples (36%), became uncommon (5%) on late samples. A significant finding was the absence of IgM reactivity in 18/19: 1/19 had 41 kDa reactivity. Only 4 patients had both ELISA (< 1:80) and Western blot tests negative (< 5 reactive bands). All patients with resolved Lyme arthritis continue to show serologic reactivity beyond 6 months of therapy. 68% of the patients satisfy Western blot criteria for positivity in our laboratory. IgM reactivity to any antigen was minimal and IgG reactivity against the 41 kDa antigen, considered diagnostic of infection in initial samples by some laboratories, is very common (16/19).


Prevention of hepatitis B and C transmission during pregnancy and the first year of life.
Hepatitis B (HBV) infection is readily transmitted from infected mothers to their infants at birth. An estimated 22,000 HBV carriers give birth in the United States annually. HBV infection is more than 95% preventable if exposed infants receive hepatitis B immune globulin and HBV vaccine at birth. Current guidelines recommend testing of all pregnant women for hepatitis B surface antigen to detect infection and ensure prophylaxis of infants. The risk of perinatal transmission of hepatitis C (HCV) infection appears to be small, except in women coinfected with human immunodeficiency virus or with high viral titers. Currently, there is no licensed vaccine against HCV, although several are in development. Postexposure treatment with immunoglobulin is of no proven benefit in preventing HCV infection.


The Golden Hour: Sustainability and Clinical Outcomes of Adequate Time to Antibiotic Administration in Children with Cancer and Febrile Neutropenia in Northwestern Mexico.
Time to antibiotic administration (TTA) is a commonly used standard of care in pediatric cancer settings in high-income countries. Effective interventions to improve outcomes in cancer patients with febrile neutropenia (FN) often address timely and appropriate antibiotic administration. We assessed the effectiveness of a locally adapted multimodal strategy in decreasing TTA in a resource-constrained pediatric cancer center in Mexico. We conducted a prospective observational study between January 2014 and April 2019. A three-phase (phase I: execution, phase II: consolidation, phase III: sustainability) multimodal improvement strategy that combined system change, FN guideline development, education, auditing and monitoring, mentoring, and dissemination was implemented to decrease TTA in inpatient and ambulatory areas. Sustainability factors were measured by using a validated tool during phases I and III. Our population included 105 children with cancer with 204 FN events. The baseline assessment revealed that only 50% of patients received antibiotics within 60 minutes of prescription (median time: inpatient, 75 minutes; ambulatory, 65 minutes). After implementing our improvement strategy, the percentage of patients receiving antibiotics within 60 minutes of prescription increased to 88%. We significantly decreased median TTA in both clinical areas during the three phases of the study. In phase III (sustainability), the median TTA was 40 minutes (P = .023) in the inpatient area and 30 minutes (P = .012) in the ambulatory area. The proportion of patients with sepsis decreased from 30% (baseline) to 5% (phase III) (P = .001). Our results demonstrate that locally adapted multimodal interventions can reduce TTA in resource-constrained settings. Mentoring and dissemination were novel components of the multimodal strategy to improve FN-associated clinical outcomes. Improving local infrastructure, ongoing monitoring systems, and leadership engagement have been key factors to achieving sustainability during the 5-year period.


Statistical and practical problems of cohort study design: occupational hazards in the health care industry.
Many populations are exposed to health hazards, particularly workers in the health care industry. Yet practical reasons make it impossible or unfeasible for investigators to meet the technical requirements of the cohort method. One such experience is detailed of hospital workers who were members of a large health care workers' union. Given the fact of exposure to known or suspected hazards, two strategies are urged: 1) projection of work toward adoption of rules regarding organizational settings that would make cohort investigation practical when necessary, and 2) development of alternate means by which work can be assessed when cohort analysis cannot be realistically conducted.


Understanding Independence: Board of Directors and CSR.
On August Business Roundtable (2019), the Business Roundtable redefined the purpose and social responsibility of the corporation. Yet, this statement must be followed by substantial changes in the business models of corporations for it to avoid becoming empty rhetoric. We believe that the figure of the independent director may be one of the catalysts needed for this change of paradigm for corporations. In spite of the positive correlation between Corporate Social Responsibility (CSR) and board independence, the development of the independence of boards during the last decade has not lead to the expected CSR results. Academics and regulators point to a weak definition and the non-standardized measurement of both independence and board independence (BI) as one possible explanation, and agree that a broader definition is needed. This paper aims to contribute to this debate. We develop a second-generation definition of independence based on a positive approximation to the concept by integrating an Aristotelian perspective of virtue ethics with the best practices of corporate governance. Thus, we define independence as a virtue guided by practical wisdom, that implies autonomy and autarky and which enables a person to act with integrity, fairness and truthfulness. In the context of corporate governance, independence is associated with an honest disposition to serve. Our proposal has political implications for supervisors that make decisions relating to the suitability of board members.


Please and no, thank you: politeness norms alter compliance more when refusing than when making or acquiescing to a request.
Research indicates that using polite words does not enhance compliance. However, this work focuses on requests, not responses, which also are compliance-relevant behaviors that might depend on politeness. In 12 experiments (4 preregistered), we examined the role of politeness in compliance by manipulating the politeness of people's requests and responses. Polite requests increased compliance relative to what people wanted to do, d = .95. Adding a polite word to a request, however, did not significantly increase compliance, d = .11. In terms of responses, polite acceptances did not increase compliance, d = .08, but polite declines mattered. Respondents were sooner to decline a request if they could reply with "No, thank you" rather than a less polite "No," d = -.34. These data indicate that politeness norms shape compliance, but the key norm might not be whether people comply with polite others, but rather whether people can politely decline the request.


Optimum receiver array design for magnetic induction tomography.
Magnetic induction tomography (MIT) is an imaging modality that aims at mapping the distribution of the electrical conductivity inside the body. Eddy currents are induced in the body by magnetic induction and the resulting fields are measured by an array of receiver coils. In MIT, the location of the receivers affects the quality of the image reconstruction. In this paper, a fast deterministic algorithm was applied to obtain optimum receiver array designs for a given specific excitation. The design strategy is based on the iterative exclusion of receiver locations, which yield poor conductivity information, from the space spanning all possible locations until a feasible design is reached. The applicability of "regionally focused" MIT designs that increase the image resolution at a particular region was demonstrated. Currently used design geometries and the corresponding reconstructed images were compared to the images obtained by optimized designs. The eigenvalue analysis of the Hessian matrix showed that the algorithm tends to maintain identical conductivity information content sensed by the receivers. Although the method does not guarantee finding the optimum design globally, the results demonstrate the practical usability of this algorithm in MIT experimental designs.


A neutralizing epitope on human rhinovirus type 2 includes amino acid residues between 153 and 164 of virus capsid protein VP2.
Use has been made of a monoclonal antibody (designated 8F5) to map a neutralizing epitope on the viral capsid protein VP2 of human rhinovirus 2 (HRV2). This antibody which was raised against the native virus, neutralizes HRV2 and is also capable of recognizing denatured VP2 on Western blots. To examine the binding site of 8F5, VP2 of HRV2 was expressed in Escherichia coli. Deletions starting at the 3' end were then introduced into the gene for VP2 using Bal-31 nuclease. Polypeptides shortened at the carboxy terminus of VP2 were obtained from the deletions and were blotted onto nitrocellulose. The samples were then probed with monoclonal antibody 8F5. Recognition by 8F5 was maintained as long as the expressed polypeptide contained the VP2 sequence up to amino acid 164 or beyond. However, when the VP2 sequence was truncated to amino acid 153 or less 8F5 was no longer able to bind. The neutralization epitope (or part of it) recognized by 8F5 on VP2 is therefore located between amino acids 153 and 164.


The autophagy/lysosome pathway is impaired in SCA7 patients and SCA7 knock-in mice.
There is still no treatment for polyglutamine disorders, but clearance of mutant proteins might represent a potential therapeutic strategy. Autophagy, the major pathway for organelle and protein turnover, has been implicated in these diseases. To determine whether the autophagy/lysosome system contributes to the pathogenesis of spinocerebellar ataxia type 7 (SCA7), caused by expansion of a polyglutamine tract in the ataxin-7 protein, we looked for biochemical, histological and transcriptomic abnormalities in components of the autophagy/lysosome pathway in a knock-in mouse model of the disease, postmortem brain and peripheral blood mononuclear cells (PBMC) from patients. In the mouse model, mutant ataxin-7 accumulated in inclusions immunoreactive for the autophagy-associated proteins mTOR, beclin-1, p62 and ubiquitin. Atypical accumulations of the autophagosome/lysosome markers LC3, LAMP-1, LAMP2 and cathepsin-D were also found in the cerebellum of the SCA7 knock-in mice. In patients, abnormal accumulations of autophagy markers were detected in the cerebellum and cerebral cortex of patients, but not in the striatum that is spared in SCA7, suggesting that autophagy might be impaired by the selective accumulation of mutant ataxin-7. In vitro studies demonstrated that the autophagic flux was impaired in cells overexpressing full-length mutant ataxin-7. Interestingly, the expression of the early autophagy-associated gene ATG12 was increased in PBMC from SCA7 patients in correlation with disease severity. These results provide evidence that the autophagy/lysosome pathway is impaired in neurons undergoing degeneration in SCA7. Autophagy/lysosome-associated molecules might, therefore, be useful markers for monitoring the effects of potential therapeutic approaches using modulators of autophagy in SCA7 and other autophagy/lysosome-associated neurodegenerative disorders.


Biological properties of anti-CD4 autoantibodies purified from HIV-infected patients.
We have previously reported the detection of anti-CD4 autoantibodies in the sera of approximately 10% of HIV-1-infected patients. These antibodies recognized epitopes located on the V3V4 domains of the soluble recombinant CD4 molecule but did not recognize CD4 in its native conformation on the cell membrane. To analyse further the biological properties of these antibodies, we have purified them from the sera of six patients using affinity chromatography. We demonstrate that purified and concentrated anti-CD4 antibodies still cannot recognize CD4 either in its native conformation or after the binding of HIV gp120. They also cannot mediate antibody-dependent cellular cytotoxicity on CD4+ or HIV-coated CD4+ cells. In one patient, however, we could detect a minor fraction of anti-CD4 antibodies directed to the V1V2 domains of CD4.


Ethnic heterogeneity and prostate cancer mortality in Hispanic/Latino men: a population-based study.
Few studies focus on prostate cancer (PCa) outcomes in Hispanic/Latino men. Our study explores whether Hispanic/Latino subgroups demonstrate significantly different prostate cancer-specific mortality (PCSM) relative to Non-Hispanic White (NHW) and Non-Hispanic Black (NHB) men. We extracted a population-based cohort of men diagnosed with local-regional PCa from 2000-2013 (n= 486,865). PCSM was measured in racial/ethnic groups: NHW (n=352,886), NHB (n= 70,983), Hispanic/Latino (n= 40,462), and Asian American/Pacific Islander (n= 22,534). PCSM was also measured in Hispanic/Latino subgroups: Mexican (n= 8,077), Puerto Rican (n= 1,284), South or Central American (n= 3,021), Cuban (n= 788), and Dominican (n= 300). We conducted univariable and multivariable analyses (MVA) to compare risk for PCSM. Compared to NHW men, results showed worse outcomes for NHB men with similar outcomes for Hispanic/Latino men. In MVA with NHW men as a reference, NHB (HR= 1.15, p <0.001) men had significantly worse PCSM and Hispanic/Latino (HR= 1.02, p= 0.534) men did not show a significant difference. In a second MVA, Puerto Rican (HR= 1.71, p <0.001) and Mexican (HR= 1.21, p= 0.008) men had significantly higher PCSM. With NHB men as a reference, the MVA showed Puerto Rican (HR= 1.50, p= 0.006) men with higher PCSM and Mexican (HR= 1.08, p= 0.307) men with no significant difference. Our findings indicate previously unknown disparities in PCSM for Puerto Rican and Mexican American men.


Acute and short-term beetroot juice nitrate-rich ingestion enhances cardiovascular responses following aerobic exercise in postmenopausal women with arterial hypertension: A triple-blinded randomized controlled trial.
The increase in blood pressure (BP) levels in the postmenopausal period can be partly explained by the decrease in nitric oxide synthases (NOS). To investigate the acute and one-week effects of beetroot juice nitrate-rich (BRJ-NO3-rich) ingestion on cardiovascular and autonomic performance in response to submaximal aerobic exercise in postmenopausal women with systemic arterial hypertension (SAH) who are physically inactive. Fourteen postmenopausal women with SAH [mean (SD) age: 59(4) y; BMI (kg/m2): 29.2(3.1)] completed submaximal aerobic exercise bouts after an acute and a one-week intervention with BRJ in a placebo-controlled, randomized, triple-blind, crossover design. Participants ingested either BRJ (800 mg of NO3-) or placebo acutely and drank either BRJ (400 mg of NO3-) or placebo every day for the next six days. After two and ½ hours, they performed a session of aerobic submaximal aerobic exercise, and their systolic BP (SBP) and diastolic BP (DBP), flow-mediated dilation (FMD), heart rate (HR) recovery, and HR variability were measured. In the post-exercise recovery period, SBP dropped significantly in the BRJ-NO3-rich group (-9.28 mmHg [95%CI: -1.68 to -16.88] ES: -0.65, p = 0.019) compared to placebo after acute ingestion. The FMD values increased after acute BRJ-NO3-rich on post-exercise (3.18 % [0.36 to 5.99] ES: 0.87, p = 0.031). After the one-week intervention, FMD values were higher in the BRJ-NO3-rich group before (4.5 % [1.62 to 7.37] ES: 1.21, p = 0.005) and post-exercise measurements (4.2 % [1.52 to 6.87] ES: 1.22, p = 0.004) vs. placebo. HRV indices with remarkable parasympathetic modulation to heart recovered faster on the BRJ-NO3-rich group than placebo group. No between-group differences were identified in values of HR post-exercise recovery in the 30s, 60s, 120s, 180s, and 300s. Acute and short-term BRJ-NO3-rich ingestion may enhance cardiovascular and autonomic behavior in response to aerobic exercise in postmenopausal women diagnosed with SAH. https://clinicaltrials.gov/ct2/show/NCT05384340.


Fibre reinforced composites--alternative for lost teeth replacement.
The loss of an anterior tooth can affect a patient psychologically and socially. This trauma can be minimized by the immediate replacement of the lost tooth, preferably using a fixed prosthesis. This paper describes the immediate replacement of anterior lost teeth by using fibre reinforced composite materials, although these techniques can be employed very successfully in the replacement of posterior teeth as well. The abutment teeth can be conserved, with little or no preparation, making this procedure truly minimally invasive and keeping the technique reversible. Additional advantages are that the procedure is completed at the chairside in a single visit, thereby avoiding laboratory costs and saving time while waiting for the finished prosthesis. This technique can be used as an interim measure or as a permanent prosthesis.


Oocyte and embryo donation in IVF programmes.
We have described a cyclic steroid replacement regimen of oestradiol and progesterone which is able to produce physiological concentrations of these steroids in plasma indicative of a normal menstrual cycle. The stimulation of a secretory endometrium at the appropriate time in this artificial menstrual cycle bears testament to the suitability of the treatment and has led to the establishment of pregnancy in three women with complete ovarian failure or ovarian agenesis when used in combination with the established techniques of in vitro fertilization and embryo transfer. The steroid replacement regimen can easily be adjusted to maintain pregnancy until the time of luteoplacental shift, based on the close monitoring of the plasma steroid and hCG levels in the pregnant individual. The implications of this form of treatment for other disease states and for our understanding of the mechanisms involved in ovarian hormone action, pregnancy maintenance and parturition are immense.


[Modeling of hole transfer dynamics in tetramer GAGG].
The hole transfer in the nucleotide sequence GAGG, where guanine G is a donor and the guanine doublet GG is an acceptor, was considered. It was shown that the relaxation of the hole on the acceptor is accompanied by rapid oscillations of the hole between the donor and the acceptor with an oscillation period of a few picoseconds. The calculated slow relaxation of the hole on the acceptor over a period of 2 ns was compared with experimental data.


Congenital nephrosis as a cause of elevated alpha-fetoprotein.
Two cases of congenital nephrosis were detected through routine maternal serum alpha-fetoprotein (MSAFP) screening of 95,135 patients. No other cases of congenital nephrosis from this group were reported, resulting in an incidence of approximately one in 47,500 in this low-risk population. In both of these cases, similar to other reported cases of congenital nephrosis having MSAFP screening, the protein concentrations were greater than or equal to 10 multiples of the median (MOM). Therefore, in the case of an MSAFP over 10 MOM and a normal ultrasound examination, congenital nephrosis should be included in counseling regarding the possibility of undetected malformations. Furthermore, in the case of a pregnancy with elevated amniotic fluid AFP with negative acetylcholinesterase and normal ultrasound, the possibility of congenital nephrosis should be mentioned, regardless of family history or ancestry. When a pregnancy is terminated because of these biochemical findings, special and immediate attention to the fetal kidneys using electron microscopy is necessary to evaluate properly the possibility of congenital nephrosis.


Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation.
Oxidative tissue injury often accompanies viral infection, yet there is little understanding of how it influences virus replication. We show that multiple hepatitis C virus (HCV) genotypes are exquisitely sensitive to oxidative membrane damage, a property distinguishing them from other pathogenic RNA viruses. Lipid peroxidation, regulated in part through sphingosine kinase-2, severely restricts HCV replication in Huh-7 cells and primary human hepatoblasts. Endogenous oxidative membrane damage lowers the 50% effective concentration of direct-acting antivirals in vitro, suggesting critical regulation of the conformation of the NS3-4A protease and the NS5B polymerase, membrane-bound HCV replicase components. Resistance to lipid peroxidation maps genetically to transmembrane and membrane-proximal residues within these proteins and is essential for robust replication in cell culture, as exemplified by the atypical JFH1 strain of HCV. Thus, the typical, wild-type HCV replicase is uniquely regulated by lipid peroxidation, providing a mechanism for attenuating replication in stressed tissue and possibly facilitating long-term viral persistence.


Tenotomy and postoperative brace treatment for muscular torticollis.
A postoperative corrective brace for congenital muscular torticollis is introduced and the results and indications for its use are presented. Thirty-three of 55 patients who underwent open tenotomy of the sternocleidomastoid muscle with application of the brace following surgery were evaluated in follow-up. Tenotomy was performed at the sternoclavicular origin of the muscle. The mean age at operation was six years; the mean follow-up period was seven years. The results were good in 21 patients (64%), fair in seven (21%), and poor in five (15%). Facial asymmetry remained in all patients over the age of ten who underwent operation. Alopecia, one of the complications of the brace, was found only in patients under age five. This combined treatment with tenotomy and postoperative brace is considered best indicated for patients between six and ten years of age.


Anesthesia for patients with ischemic heart disease.
The suggested anesthetic management of patients with potentially ischemic myocardium is as follows: 1. Careful work-up before proceeding if angina is present preoperatively. 2. Heavy premedication, attention to factors of preoperative anxiety, and avoidance of unnecessary painful procedures in the awake patient. Do not stop propranolol. 3. Monitoring of ST segments via V5 lead during anesthesia. Do not permit large fluctuations in systolic blood pressure or large increases in heart rate. 4. Maintenance of patient's temperature to obviate postoperative shivering. 5. Treatment of increased heart rate and ST segment changes with propranolol in 0.25-mg I.V. increments every 1 to 3 minutes until improvement noted (reasonable acute dose limit is 2 to 3 mg). 6. Treatment of ventricular arrhythmias with lidocaine bolus (50 to 100 mg) and infusion if more than one bolus is required (1 to 2 mg/70 kg/min), plus usual blood gases and electrolytes.


Improvement on image transform coding by reducing interblock correlation.
We try to improve transform coding efficiency by alleviating the interblock correlation due to the small size of the block. The proposed method needs minor modification from conventional transform coding techniques such as JPEG, and reduces the information loss in the coding procedure for a given bit rate. Simulation results demonstrate that the method drastically diminishes the blocking effects and enhances the subjective visual quality compared with such existing algorithms as JPEG and LOT.


A new approach for diffusive sampling based on SPME for occupational exposure assessment.
Passive sampling is a well-established methodology for the evaluation of exposures to environmental volatile organic compounds (VOCs). The solid-phase microextraction (SPME) technique is a reliable means of sampling VOCs in air. SPME is also being applied as a passive sampler to determine time-weighted average exposure. The use of SPME as a diffusive sampler was evaluated. The passive sampler is based on the use of a cylindrical diffusion cell (porous hydrophobic polyethylene) with an 80 μm carboxen/polydimethylsiloxane fiber to obtain radial diffusion of the analytes to the sorbent. Standard atmospheres of organic vapors in air were used to determine the experimental uptake rates for toluene and chlorobenzene. Toluene concentrations between 2 and 38 mg/m(3) with sampling times between 15 and 60 min were evaluated, as well as chlorobenzene concentrations between 2 and 47 mg/m(3) with sampling times between 30 and 60 min. The mean diffusive uptake rate was 2.14 mL/min for toluene and 2.57 mL/min for chlorobenzene, and no statistical significant effects of concentration and sampling time were observed under the studied conditions for the two compounds. Relative standard deviation ranged from 2.6 to 6.5%. The performance of the sampler under varying concentrations of toluene was also tested, showing that the sampler reflects the average exposure concentration. Effects of temperature, relative humidity, velocity of the air, back diffusion, competitive adsorption, and the stability of chlorobenzene in the sampler were also studied. Sampler behavior was tested in gas stations, and the results were successfully compared with a 3M-3500 diffusive sampler. The results are promising for using this new SPME device for diffusive monitoring for occupational exposure assessment.


The C proteins of heterogeneous nuclear ribonucleoprotein complexes interact with RNA sequences downstream of polyadenylation cleavage sites.
The heterogeneous nuclear ribonucleoprotein C1 and C2 proteins were preferentially cross-linked by treatment with UV light in nuclear extracts to RNAs containing six different polyadenylation signals. The domain required for the interaction was located downstream of the poly(A) cleavage site, since deletion of this segment from several polyadenylation substrate RNAs greatly reduced cross-linking efficiency. In addition, RNAs containing only downstream sequences were efficiently cross-linked to C proteins, while fully processed, polyadenylated RNAs were not. Analysis of mutated variants of the simian virus 40 late polyadenylation signal showed that uridylate-rich sequences located in the region between 30 and 55 nucleotides downstream of the cleavage site were required for efficient cross-linking of C proteins. This downstream domain of the simian virus 40 late poly(A) addition signal has been shown to influence the efficiency of the polyadenylation reaction. However, there was not a strict correlation between cross-linking of C proteins and the efficiency of polyadenylation.