In silico pharmacophore modeling and simulation studies for searching potent antileishmanials targeted against Leishmania donovani nicotinamidase.
Nicotinamidase is a key enzyme for the salvage pathway catalyzing the first step for the conversion of nicotinamide (NAm) to nicotinic acid (NA) required for the synthesis of Nicotinamide Adenine Dinucleotide (NAD+) in the subsequent steps. Leishmania protozoan parasites are NAD+ auxotrophs and need precursors (nicotinamide, nicotinic acid, nicotinamide riboside) from their host environment to synthesize NAD+ for their survival. Interestingly, absence of this enzyme in higher eukaryotes and its absolute requirement in the developmental cycle of Leishmania has led nicotinamidase an attractive drug target towards leishmaniasis. Hence, we report some potential inhibitors for nicotinamidase screened based on 3-D pharmacophore model consisting of "ML", "Hyd|Aro", "Acc" and "Excl vol" features. Subsequently, dynamics simulation studies validate the proposed pharmacophore model suggesting its reliability for future studies. Furthermore, these essential site-specific features will help in enhancing the inhibition of nicotinamidase activity. Results of our study suggest that blocking of active site of nicotinamidase by the identified lead inhibitor will have major impact on the infectious processes and the survival of the parasite. Furthermore, due to the structural homology in the enzyme among L. donovani, L. infantum, L. major, we anticipate that our study would help to design more potent drug candidates against leshmaniasis for these three species.


[Saving motives in young, middle-aged, and older adults. Preliminary results of a new inventory for exploring lifespan saving motives].
There is some research on personal reasons for saving money in the economic sciences. However, not much is known about the age differences of saving motives. In this vein, the future time perspective (FTP) is known to play a critical role for motivation across the life span. In this study, we introduce a new Saving Motive Inventory (SMI), which also covers saving goals after retirement. Furthermore, it is argued that additional saving motives that are not based on economic models of life-cycle saving also exist. In accordance with the socio-emotional selectivity theory, we explored age differences in an online survey with 496 participants from young (19-44 years), middle-aged (45-64 years), and older (65-86 years) adulthood, who completed a questionnaire on saving motives, personality, and future-related thinking (e.g., Future Time Perspective Scale, Life Orientation Test). Results of the explorative Factor Analysis (EFA) are consistent with the theoretical expectations. The factors are generativity, educational investment, consumption, indifference, and provision for death and dying. Together these five factors account for 67% of the variance. In general, the inventory is reliable and valid with respect to the expected internal and external criteria. It contributes to better understanding of saving motives over the lifespan, especially with respect to effects of the future time perspective.


The impact of menopause on work ability in women with severe menopausal symptoms.
To measure the impact of menopause on work ability in women with severe menopausal symptoms. This cross-sectional study compared the work ability of a sample of otherwise healthy employed Dutch women (n=205) with that of a sample of first-time attendees of a menopause clinic (n=60); both groups were aged 44-60 years. Self-reported questionnaire data assessing work ability (Work Ability Index; WAI) and menopausal symptoms (Greene Climacteric Scale; GCS) were used. Logistic regression analyses were used to examine whether women with severe menopausal symptoms were more likely to have low work ability (defined as a score <37.0 points on the WAI) than were women in the reference group, after adjustment for individual and lifestyle factors. Symptomatic women had significantly higher total GCS scores (mean 26.7 vs 14.2, t=10.8, P<0.001) and significantly lower WAI scores (median 32.0 vs 40.0, U=2380, P<0.001) than the reference group. They were 8.4 times more likely to report low work ability than their healthy counterparts: 76.7% versus 30.2% (OR 8.4, 95% CI 4.1-17.2). Over three-quarters of symptomatic menopausal women report serious problems in dealing with the physical and mental demands of their work (recorded here as low work ability); hence these women might be at risk of prolonged sickness absence from work.


Manganese as a calcium probe: electron paramagnetic resonance and nuclear magnetic resonance spectroscopy of intact cells.
When Lettree cells are exposed to Mn2+, the cation becomes associated with cells in two ways: in a relatively loose and mobile manner that gives a six-line EPR spectrum designated Mnb*, and in an immobile, relatively tight manner that gives no detectable EPR specrtum, designated Mnb. Mnb* is probably on the surface of cells; most Mnb is probably inside cells. NMR measurements of Lettree cell suspensions show two water proton relaxation rates and confirm the existence of cell-associated Mn. Human erythrocytes, on the other hand, bind no Mn2+ under these conditions, as judged by EPR and NMR measurements. Virally-treated Lettree cells show an increase in Mnb (but not in Mnb*). They also show a third water proton relaxation rate.


Moderate alcohol consumption is associated with impaired insulin secretion and fasting glucose in non-obese non-diabetic men.
A low insulin secretion capacity has been implicated in the high prevalence of non-obese diabetes in East Asians. As alcohol consumption alters insulin and glucose metabolism, we tested the hypothesis that alcohol consumption contributes to impaired insulin secretion and glucose intolerance in lean/normal-weight non-diabetic Japanese men. This cross-sectional study was undertaken among the residents of Shika town, Japan, between 2011 and 2017. A total of 402 non-diabetic men, including participants with normal fasting plasma glucose (FPG) and impaired FPG (FPG 5.6-6.9 mmol/L), and aged ≥40 years, were examined. FPG, the homeostasis model assessment of insulin secretion capacity (HOMA-B) and alcohol consumption were evaluated and compared between the body mass index (BMI) <25 and BMI ≥25 groups. HOMA-B levels were lower in the BMI <25 group than in the BMI ≥25 group. Alcohol consumption correlated with a low HOMA-B level regardless of BMI, and, thus, the HOMA-B levels of alcohol drinkers were significantly lower in the BMI <25 group. A multivariable logistic regression analysis showed that alcohol consumption, even light-to-moderate consumption (1-25 g/day), was associated with significantly low levels of HOMA-B and impaired FPG in the BMI <25 group. Among participants with impaired FPG, a low level of HOMA-B was observed in alcohol drinkers, but not in non-drinkers. In contrast, light-to-moderate alcohol consumption was not related to HOMA-B or FPG in the BMI ≥25-group. Alcohol consumption, even a small amount, might contribute to reductions in HOMA-B levels and impaired FPG in lean/normal-weight Japanese men.


Comparison of patients with complete and partial biotinidase deficiency: biochemical studies.
Seventeen partially biotinidase-deficient patients detected by neonatal screening or family studies were compared with four patients with classical biotinidase deficiency. Using a sensitive HPLC method for biotinidase in plasma (substrate: biocytin) the patients could be divided into two groups: one with residual biotinidase activity, and the second with undetectable biotinidase activity (0-activity). Biocytin excretion, characteristically elevated in 0-activity patients, decreased rapidly with increasing residual biotinidase activity and was almost normal when residual activity exceeded 2-3% of mean normal. In one patient with classical disease (0-activity) biotin deficiency, typical organic aciduria and multiple carboxylase deficiency were found as early as at the second week of life. In contrast, 13 infants with residual activities from 1.2% to 23% had no remarkable clinical or biochemical abnormalities. However, in three 5-, 14- and 15-year-old healthy siblings with residual biotinidase activities between 2.3% and 4.2%, biotin deficiency was proven by decreased activities of the mitochondrial carboxylases in lymphocytes (30-57% of mean normal) and, in the older siblings, also by subnormal plasma biotin concentrations. In biotinidase deficiency, biotin depletion presumably occurs earlier in the brain than in other tissues and may thus first affect the central nervous system. For this reason and because of discrete biochemical abnormalities found in a patient with residual biotinidase activity of 8%, we suggest that at least all patients with residual activities below 10% should be treated with biotin.


Genetic variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2) and risk of non-Hodgkin lymphoma.
Animal studies suggest that lymphomagenesis can be induced by exposure to carcinogenic aromatic and heterocyclic amines found in diet, cigarette smoke and the environment, but human epidemiologic investigations of these exogenous exposures have yielded conflicting results. As part of our evaluation of the role of aromatic and heterocyclic amines, which are metabolized by N-acetyltransferase (NAT) enzymes, in the etiology of non-Hodgkin lymphoma (NHL), we examined NHL risk in relation to genetic variation in NAT1 and NAT2 and exposure to cigarette smoke and dietary heterocyclic amines and mutagens. We genotyped 10 common single nucleotide polymorphisms (SNPs) in NAT1 and NAT2 among 1136 cases and 922 controls from a population-based case-control study in four geographical areas of the USA. Relative risk of NHL for NAT1 and NAT2 genotypes, NAT2 acetylation phenotype, and exposure to cigarette smoke and dietary heterocyclic amines and mutagens was estimated using odds ratios (ORs) and 95% confidence intervals (CIs) derived from unconditional logistic regression models. We observed increased risk of NHL among individuals with the NAT1*10/*10 genotype compared with individuals with other NAT1 genotypes (OR = 1.60, 95% CI = 1.04-2.46, P = 0.03). We also observed increased NHL risk in a dose-dependent model among NAT2 intermediate- and rapid-acetylators compared with slow-acetylators, although only the trend was statistically significant (intermediate: OR = 1.18, 95% CI = 0.97-1.44, P = 0.1; rapid: OR = 1.43, 95% CI = 0.97-2.14, P = 0.07; P for linear trend = 0.03). Compared with non-smokers, NHL risk estimates for current cigarette smoking were increased only among NAT2 intermediate/rapid-acetylators (OR = 2.44, 95% CI = 1.15-5.20, P = 0.02). Our data provide evidence that NAT1 and NAT2 genotypes are associated with NHL risk and support a contributory role for carcinogenic aromatic and/or heterocyclic amines in the multi-factorial etiology of NHL.


Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells.
Costimulatory signals are critical to T cell activation, but how their effects are mediated remains incompletely characterized. Here, we demonstrate that locally produced C5a and C3a anaphylatoxins interacting with their G protein-coupled receptors (GPCRs), C5aR and C3aR, on APCs and T cells both upstream and downstream of CD28 and CD40L signaling are integrally involved in T cell proliferation and differentiation. Disabling these interactions reduced MHC class II and costimulatory-molecule expression and dramatically diminished T cell responses. Importantly, impaired T cell activation by Cd80-/-Cd86-/- and Cd40-/- APCs was reconstituted by added C5a or C3a. C5aR and C3aR mediated their effects via PI-3 kinase-gamma-dependent AKT phosphorylation, providing a link between GPCR signaling, CD28 costimulation, and T cell survival. These local paracrine and autocrine interactions thus operate constitutively in naive T cells to maintain viability, and their amplification by cognate APC partners thus is critical to T cell costimulation.


Characterization of natural killer cells in colorectal tumor tissue of rats fed a control diet or a high-fat diet.
Obesity is a major public health problem with an increasing prevalence reaching pandemic levels. The incidence and mortality for colorectal cancer is augmented in overweight and obese individuals. Previous studies demonstrated an impaired number, phenotype and functionality of natural killer (NK) cells under obese conditions. So far, the influence of obesity on NK cells in colorectal cancer tissue remained unclear. Therefore, the aim of the study was to investigate the occurrence and localization of NK cells in colorectal tumors of normal weight and diet-induced obese rats. Wistar rats were fed a normal-fat diet (control) or a high-fat diet (HFD) to induce obesity. In half of the experimental groups azoxymethane (AOM) was injected to induce colorectal cancer. Tumors in colon and rectum were histopathologically classified in adenomas and adenocarcinomas and immunohistologically stained with the rat NK cell marker CD161. Occurrence and localization of NK cells were analyzed and quantified in the tunica mucosa and tunica submucosa of colorectal adenomas and the tunica submucosa of colorectal adenocarcinomas. NK cells are localized in the tunica mucosa and the tunica submucosa of colorectal tumors with NK cell accumulations as follicle-like aggregates especially in regions of the lamina muscularis mucosae and the lamina propria mucosae of the tunica mucosa as well as in regions of the tunica submucosa adjacent to the lamina muscularis mucosae. Although not statistically significant, the CD161 staining was clearly reduced in the tunica mucosa of colorectal tumors of rats fed a HFD compared to rats fed a control diet. Moreover, the CD161 staining in the tunica mucosa was positively correlated with the final body weight of AOM-treated rats independent of the supplied diet. For the first time, these results provide information about the localization and quantity of NK cells in colorectal tumor tissue of rats fed a control diet or high-fat diet. The slight reduction of NK cell number in colorectal tissue of rats fed a high-fat diet may contribute to an impaired tumor defense and the increased colorectal tumor outcome in diet-induced obese rats.


Recharge of low-arsenic aquifers tapped by community wells in Araihazar, Bangladesh, inferred from environmental isotopes.
More than 100,000 community wells have been installed in the 150-300 m depth range throughout Bangladesh over the past decade to provide low-arsenic drinking water (<10 μg/L As), but little is known about how aquifers tapped by these wells are recharged. Within a 25 km2 area of Bangladesh east of Dhaka, groundwater from 65 low-As wells in the 35-240 m depth range was sampled for tritium (3H), oxygen and hydrogen isotopes of water (18O/16O and 2H/1H), carbon isotope ratios in dissolved inorganic carbon (DIC, 14C/12C and 13C/12C), noble gases, and a suite of dissolved constituents, including major cations, anions, and trace elements. At shallow depths (<90 m), 24 out of 42 wells contain detectable 3H of up to 6 TU, indicating the presence of groundwater recharged within 60 years. Radiocarbon (14C) ages in DIC range from modern to 10 kyr. In the 90-240 m depth range, however, only 5 wells shallower than 150 m contain detectable 3H (<0.3 TU) and 14C ages of DIC cluster around 10 kyr. The radiogenic helium (4He) content in groundwater increases linearly across the entire range of 14C ages at a rate of 2.5×10-12 ccSTP 4He g-1 yr-1. Within the samples from depths >90 m, systematic relationships between 18O/16O, 2H/1H, 13C/12C and 14C/12C, and variations in noble gas temperatures, suggest that changes in monsoon intensity and vegetation cover occurred at the onset of the Holocene, when the sampled water was recharged. Thus, the deeper low-As aquifers remain relatively isolated from the shallow, high-As aquifer.


A universal random DNA amplification and labeling strategy for microarray to detect multiple pathogens of aquatic animals.
Diseases caused by bacteria, fungi, and viruses pose a great threat to aquaculture. As DNA microarrays can be used to detect multiple pathogens, here we reported an array with the potential to simultaneously detect 13 bacterial and 11 viral pathogens of aquatic animals. The array included 853 oligonucleotide probes (20-40 mer) complementary to various virus-specific sequences and four chromosomal loci (16S rRNA, gyrB, dnaJ, and recA) of bacteria. Multiplex PCR, phi29 DNA polymerase, and a Klenow fragment-based method were evaluated for amplifying and labeling the nucleic acid of pathogens. While array hybridization signals were most intense using pathogen sequences amplified by multiplex PCR, the phi29 DNA polymerase method was more convenient and ideal since it did not require sequence-specific primers that could bias against detecting novel pathogens. The feasibility of the phi29 DNA polymerase-based microarray strategy was also demonstrated by detecting multiple unknown pathogens from four samples of diseased fish and shrimps.


Preconcentration and separation of Cr(III) and Cr(VI) using sawdust as a sorbent.
A simple, inexpensive method based on solid-phase extraction (SPE) on sawdust from Cedrus deodera has been developed for speciation of Cr(III) and Cr(VI) in environmental water samples. Because different exchange capacities were observed for the two forms of chromium at different pH-Cr(III) was selectively retained at pH 3 to 4 whereas Cr(VI) was retained at pH 1-complete separation of the two forms of chromium is possible. Retained species were eluted with 2.5 mL 0.1 mol L(-1) HCl and 0.1 mol L(-1) NaOH. Detection limits of 0.05 and 0.04 microg mL(-1) were achieved for Cr(III) and Cr(VI), respectively, with enrichment factors of 100 and 80. Recovery was quantitative using 250 mL sample volume for Cr(III) and 200 mL for Cr(VI). Different kinetic and thermodynamic properties that affect sorption of the chromium species on the sawdust were also determined. Metal ion concentration was measured as the Cr(VI)-diphenylcarbazide complex by UV-visible spectroscopy. The method was successfully applied for speciation of chromium in environmental and industrial water samples.


Effects of group status and victim sex on female bystanders' responses to a potential party rape.
This research examined bystander responses to 1 of 4 potential party rape scenarios. Undergraduate women (N = 249) imagined attending a party either alone or with three friends where a sober man led an intoxicated potential victim (either male or female) into a bedroom. After random assignment to conditions, participants reported on intent to help and barriers to helping the potential victim. In contrast to the classic bystander effect, bystanders in groups intended to offer more help than lone bystanders. Bystanders also intended to offer more help to potential female than male victims and experienced more barriers to helping male victims. Two of these barriers (lack of personal responsibility to help and identifying risk) explained the lower intentions to help potential male victims. Potential male victims were more likely than female victims to be perceived as gay, and bystanders reported the least intentions to help presumably gay men at risk.


Protection against DSP-4-induced neurotoxicity by deprenyl is not related to its inhibition of MAO B.
Clinical studies suggest that deprenyl may retard the progression of Parkinson's disease, an effect that may be related to its monoamine oxidase (MAO) inhibiting properties. Deprenyl also protects against the neurodegenerative effects of the noradrenergic toxin DSP-4. In this study we investigated the role of MAO B inhibition in this protection. C57BL/6 mice were given DSP-4 (50 mg/kg i.p.) 1 h. 24 h or 4 days after the administration of deprenyl (10 mg/kg i.p.) or the selective MAO B inhibitor MDL 72974 (1.25 mg/kg), and then killed 1 week later for assay of hippocampal norepinephrine. The MAO B inhibiting effects of deprenyl or MDL 72974 were also determined after these same intervals of time. Deprenyl and MDL 72974 produced comparable degrees of enzyme inhibition 1 h (greater than 95%), 24 h (greater than 90%) or 4 days (greater than 70%) after their administration. Given 1 h before, deprenyl totally blocked the norepinephrine-depleting effects of DSP-4, but this protection declined sharply when 24 h or 4 days was allowed to elapse between deprenyl and DSP-4 administration. MDL 72974 failed to protect at any time point. In vitro, we detected no activity using DSP-4 as a substrate for MAO. These findings suggest that the ability of deprenyl to protect against DSP-4-induced neuronal degeneration may not depend on its MAO B inhibiting properties.


The effect of premature rupture of the membranes on the surface activity of amniotic fluid and on the pulmonary function of the newborn.
In 30 patients with rupture of the membranes at 29 to 37 weeks gestation amniotic fluid was collected immediately and within 72 h. The concentration of lung surfactant was estimated by surface tension measurements in the Wilhelmy-balance. In 19 cases the results of the first surface tension measurement predicted lung immaturity, in 17 of these surfactant concentration increased, the last surface tension measurement being consistent with complete pulmonary maturation. None of these infants developed RDS. However, the two newborn infants, in whom serial surface tension measurements had shown no increase of surfactant concentration developed symptoms of RDS. In 11 patients with apparently mature surfactant values immediately after membrane rupture, further amniotic fluid surface tension measurements showed an increase in the concentration of surface active material. The respiratory compliance was measured in 11 healthy neonates and in the two newborn with RDS. The results reflected those of surfactant concentration obtained in amniotic fluid. Premature rupture of the membranes would seem to constitute a stimulus for fetal lung maturation.


Miniaturized Growth Inhibition Assay to Assess the Anti-blood Stage Activity of Antibodies.
While no immune correlate for blood-stage specific immunity against Plasmodium falciparum malaria has been identified, there is strong evidence that antibodies directed to various malarial antigens play a crucial role. In an effort to evaluate the role of antibodies in inhibiting growth and/or invasion of erythrocytic stages of the malaria parasite it will be necessary to test large sample sets from Phase 2a/b trials as well as epidemiological studies. The major constraints for such analyses are (1) availability of sufficient sample quantities (especially from infants and small children) and (2) the throughput of standard growth inhibition assays. The method described here assesses growth- and invasion inhibition by measuring the metabolic activity and viability of the parasite (by using a parasite lactate dehydrogenase-specific substrate) in a 384-microtiter plate format. This culture method can be extended beyond the described detection system to accommodate other techniques commonly used for growth/invasion-inhibition.


Minimally invasive carpal tunnel decompression using the KnifeLight: How I Do It.
Carpal tunnel decompression is commonly performed open or endoscopically. Carpal tunnel release using the KnifeLight instrument (Stryker, Kalamazoo, MI) is an alternative method established in 2000. The instrument has a cutting blade placed between two blunt flat tips with an integrated light source which helps to locate the tool blade by transillumination through the tissues. The instrument is inserted into an opening made in the wrist crease and transverse carpal ligament and used to divide the ligament. This is a simple, efficient, and reproducible alternative for carpal tunnel decompression.


The association between facility case volume and overall survival in patients with metastatic renal cell carcinoma in the targeted therapy era.
Improved overall survival of cancer patients treated by high-volume providers has been reported in surgical oncology and radiation oncology literature. Whether this volume-outcome association exists in medical oncology-managed metastatic solid tumors is uncertain. This study aimed to investigate the effect of facility case volume (FCV) on overall survival in patients with metastatic renal cell carcinoma (mRCC) diagnosed in the targeted therapy era. Adult patients diagnosed with mRCC between 2006 and 2015 were identified in the National Cancer Database. The primary exposure was FCV, which was defined by mRCC case volume of each treating facility. The association between FCV and all-cause mortality in mRCC was investigated in multivariable Cox regression model and validated with inverse propensity-score weighting method. Logistic regression was used to identify independent predictors for treatment at high-volume facilities. Covariates adjusted for were sociodemographics, tumor characteristics and treatment modalities. There were 31,329 mRCC patients identified. The mean follow-up time was 14.3 months. When FCV was coded as a continuous variable, each increment of 10 mRCC cases/y was associated with reduced all-cause mortality after baseline covariates adjustment [adjusted hazard ratio: 0.93, 95% confidence interval: 0.90-0.96, P value:<0.0001]. In dichotomized models, improved all-cause mortality was observed at cutoffs of 85th (4.3 cases/y), 90th (5.4 cases/y) and 95th (7.4 cases/y) but not at 50th (2.2 cases/y) and 75th (3.4 cases/y) percentiles. For illustrative purpose, 95th percentile was chosen and inverse propensity-score weighting-adjusted Kaplan-Meier curve demonstrated improved overall survival for mRCC patients treated at high-volume facilities (adjusted hazard ratio: 0.90, 95% confidence interval: 0.88-0.94, P value <0.0001; the 1-, 2-, 3-year survival rates were 41%, 26%, and 19% vs. 36%, 22%, and 16% for patients treated at high and low-volume facilities, respectively). Patients without insurance or with Medicaid status, with shorter travel distance, living in nonmetropolitan area or in area with lower averaged education level were less likely to be treated at high-volume facilities. Patients diagnosed with mRCC in the targeted therapy era have improved overall survival when treated at high mRCC-volume facilities, suggesting a volume-outcome association in medical oncology-managed metastatic solid tumors.


TP53 mutations and CDKN2A mutations/deletions are highly recurrent molecular alterations in the malignant progression of sinonasal papillomas.
Sinonasal papillomas are benign epithelial tumors of the sinonasal tract that are associated with a synchronous or metachronous sinonasal carcinoma in a subset of cases. Our group recently identified mutually exclusive EGFR mutations and human papillomavirus (HPV) infection in inverted sinonasal papillomas and frequent KRAS mutations in oncocytic sinonasal papillomas. We also demonstrated concordant mutational and HPV infection status in sinonasal papilloma-associated sinonasal carcinomas, confirming a clonal relationship between these tumors. Despite our emerging understanding of the oncogenic mechanisms driving formation of sinonasal papillomas, little is currently known about the molecular mechanisms of malignant progression to sinonasal carcinoma. In the present study, we utilized targeted next-generation DNA sequencing to characterize the molecular landscape of a large cohort of sinonasal papilloma-associated sinonasal carcinomas. As expected, EGFR or KRAS mutations were present in the vast majority of tumors. In addition, highly recurrent TP53 mutations, CDKN2A mutations, and/or CDKN2A copy-number losses were detected; overall, nearly all tumors (n = 28/29; 96.6%) harbored at least one TP53 or CDKN2A alteration. TERT copy-number gains also occurred frequently (27.6%); however, no TERT promoter mutations were identified. Other recurrent molecular alterations included NFE2L2 and PIK3CA mutations and SOX2, CCND1, MYC, FGFR1, and EGFR copy-number gains. Importantly, TP53 mutations and CDKN2A alterations were not detected in matched sinonasal papillomas, suggesting that these molecular events are associated with malignant transformation. Compared to aerodigestive tract squamous cell carcinomas from The Cancer Genome Atlas (TCGA) project, sinonasal papilloma-associated sinonasal carcinomas have a distinct molecular phenotype, including more frequent EGFR, KRAS, and CDKN2A mutations, TERT copy-number gains, and low-risk human papillomavirus (HPV) infection. These findings shed light on the molecular mechanisms of malignant progression of sinonasal papillomas and may have important diagnostic and therapeutic implications for patients with advanced sinonasal cancer.


Professionalism in Physician Assistant, Physical Therapist, Occupational Therapist, Clinical Psychology, and Biomedical Sciences Students.
Interprofessional collaboration for healthcare requires a better understanding of the commonalities and differences in student perceptions of professionalism. 217 students in five programs (PA 71, PT 46, OT 29, CP 12, and BMS 59) completed a 22-item survey (response rate 79.5%). A Likert scale grading from 1 (hardly ever) to 5 (always) was used to assess professional attitudes and behaviors. A mixed-model MANOVA, supplemented with post-hoc analyses, showed significant group by time interactions for 5 items. Sensitivity to differences and diversity of other people increased for BMS students, but decreased for PT students. Timeliness increased for BMS students, but did not change for PA students. Seeking out new learning experiences increased for BMS students, but did not change for PA or PT students. Taking a group leadership role increased for BMS students, decreased for PT students, while PA and OT students showed no change. Volunteering time to serve others decreased for OT and PA students, while BMS and BM students showed no change. It is plausible that these findings emerge from differences in program curricula and specific training objectives. The findings provide initial insight to educators on ways that attitudes and behaviors pertaining to professionalism sometimes vary among students in different health science programs.


[Mechanisms of the increased resistance to blood flow in the spontaneously hypertensive rat].
Limb perfusion in spontaneously hypertensive rats demonstrated increased vascular resistance at maximum vasodilatation which may be related to structural specifics: the development of smooth muscle hypertrophy in resistive vessels and, obviously, decreased total number of functioning arterioles. The obtained "perfusion pressure - noradrenaline dosage" curves provide further evidence to this effect. The shift to the left shown by these curves and their greater steepness in spontaneously hypertensive rats are due to increased vascular reactivity to pressor effects.


Quality of life (QOL) assessment of MIP (mitomycin, ifosfamide and cisplatin) chemotherapy in advanced non-small cell lung cancers (NSCLC).
Quality of life (QOL) assessment has emerged to measure and quantify the balance between treatment benefit and toxicity, and has a value in predicting response and overall survival in cancer patients. From July 1995 to February 1997, 38 symptomatic patients with advanced non-small cell lung cancer (NSCLC) were treated with MIP chemotherapy (mitomycin 6 mg/m2, ifosfamide 3000 mg/m2 and cisplatin 50 mg/m2 on day 1 every 3 weeks). Patients were assessed for QOL including physical well-being, general symptoms and lung cancer-specific symptoms, as well as objective response. The overall response rate was 38.9% (14/36, all were partial response) and the median duration of response was 3.5 months [95% confidence interval (CI) 2.0-4.0]. The median duration of overall survival was 7 months (95% CI 5.9-8.5). The overall improvement of QOL was 58.3% with 21 patients feeling better on treatment. The toxicity of chemotherapy was mild, mainly nausea/vomiting and minimal alopecia. Using multiple clinical predictors of survival (age, histology, stage, performance status), only change of QOL emerged significantly (P = 0.0007). MIP had an endurable response and low toxicity profile, and provided good QOL. Integral QOL data in our study provided the strong prediction of survival in advanced NSCLC. Further experienced QOL study will provide greatly enhanced outcome data in clinical trials.


Transgene expression in the vegetative tissues of apple driven by the vascular-specific rolC and CoYMV promoters.
The ability of the heterologous promoters, rolCP and CoYMVP, to drive expression of the gusA reporter gene in the vegetative tissues of apple (Malus pumila Mill.) has been studied using transgenic plants produced by Agrobacterium-mediated transformation. Replicate plants of each transgenic clone were propagated in soil to a uniform size and samples of leaf, petiole, stem, and root were taken for the measurement of beta-glucuronidase (GUS) activity by fluorometric assay. The levels of expression were compared with those in tissues of a representative clone containing the CaMV 35S promoter. These quantitative GUS data were related to the copy number of transgene loci assessed by Southern blotting. The CoYMV promoter was slightly more active than the rolC promoter, although both expressed gusA at a lower level than the CaMV 35S promoter. In clones containing the rolC promoter with multiple transgene loci, expression values were generally among the highest or lowest in the range. The precise location of GUS activity in each tissue was identified by staining of whole leaves and tissue sections with a chromogenic substrate. This analysis demonstrated that with both the rolC and CoYMV promoters the reporter gene activity was primarily localised to vascular tissues, particularly the phloem. Our results indicate that both promoters would be suitable to drive the expression of transgenes to combat pests and diseases of apple that are dependent on interaction with the phloem.


miR-205 promotes epithelial-mesenchymal transition by targeting AKT signaling in endometrial cancer cells.
AKT signaling regulates multiple biological processes and expresses in various cancers. miR-205 plays complex roles in tumorigenesis and tumor progression by acting either as a tumor suppressor or an oncogene depending on the tumor type. Here we describe the molecular mechanism of miR-205 regulating epithelial-mesenchymal transition by activation of AKT signaling in endometrial cancer cells HEC-50B and HEC-1-A. The proliferation of HEC-50B cells transfected with miR-205 mimic was assessed by WST-1 assay. The migration and invasion were evaluated by BD transwell migration and matrigel invasion assays. The EMT markers were detected by Western blot. We found that miR-205 increased the proliferation in HEC-50B cells. The migration and invasion of HEC-50B cells and HEC-1-A cells were enhanced by miR-205. When HEC-50B cells and HEC-1-A cells were treated with anti-miR-205 inhibitor, the migration and invasion were decreased as compared with the negative control. The overexpression of miR-205 inhibited E-cadherin expression and promoted Snail expression by activation of AKT and downregulation of glycogen synthase kinase 3β. However, after the HEC-50B cells and HEC-1-A cells were treated with anti-miR-205 inhibitor, E-cadherin expression was increased and Snail protein level was decreased by inhibition of AKT expression. Our data strongly suggest that miR-205 plays an important role in endometrial cancer migration and invasion by targeting the AKT pathway. Our data highlight miR-205 as a potential molecular target for endometrial cancer treatment.


MicroRNA let-7a suppresses breast cancer cell migration and invasion through downregulation of C-C chemokine receptor type 7.
C-C chemokine receptor type 7 (CCR7) plays an important role in chemotactic and metastatic responses in various cancers, including breast cancer. In the present study, the authors demonstrated that microRNA (miRNA) let-7a downregulates CCR7 expression and directly influences the migration and invasion of breast cancer cells. The expression of CCR7, its ligand CCL21, and let-7a was detected in breast cancer cell lines and in breast cancer patient tissues. Synthetic let-7a and an inhibitor of let-7a were transfected into MDA-MB-231 and MCF-7 breast cancer cells, respectively, and cell proliferation, cell migration, and invasion assays were performed. To confirm the fact that 3'UTR of CCR7 is a direct target of let-7a, a luciferase assay for the reporter gene expressing the let-7a binding sites of CCR7 3'UTR was used. An in vivo invasion animal model system using transparent zebrafish embryos was also established to determine the let-7a effect on breast cancer cell invasion. First, a higher expression of both CCR7 and CCL21 in malignant tissues than in their normal counterparts from breast cancer patients was observed. In addition, a reverse correlation in the expression of CCR7 and let-7a in breast cancer cell lines and breast cancer patient tissues was detected. Synthetic let-7a decreased breast cancer cell proliferation, migration, and invasion, as well as CCR7 protein expression in MDA-MB-231 cells. The let-7a inhibitor reversed the let-7a effects on the MCF-7 cells. The 3'UTR of CCR7 was confirmed as a direct target of let-7a by using the luciferase assay for the reporter gene expressing let-7a CCR7 3'UTR binding sites. Notably, when analyzing in vivo invasion, MDA-MB 231 cells after synthetic let-7a transfection were unable to invade the vessels in zebrafish embryos. The results from the present study suggest that targeting of CCL21-CCR7 signaling is a valid approach for breast cancer therapy and that let-7a directly binds to the 3'UTR of CCR7 and blocks its protein expression, thereby suppressing migration and invasion of human breast cancer cells. Furthermore, the present study underscores the therapeutic potential of let-7a as an antitumor and antimetastatic manager in breast cancer patients.


[Study on the active protein fractions from scorpii tegument].
Extracting the total protein from scorpii tegument, investigating its effect on immune system by transformation of T/B cell. Water-soluble protein(ST1) was extracted by distilled water method and salting-out method, while keratin(ST2) by deoxidization method. Sephadex G-50 was used to isolate the protein. The effects of components isolated by sephadex G-50 on T/B and NK cell were investigated. The protein from scorpii tegument could increase the transformation of T/B cell distinctly in vitro, while no apparent effect on NK cell. Protein from scorpii tegument could modulate the immune system, which may offer a new way for people to find protein drugs.


Low microplastic loads in riverine European eel (Anguilla anguilla) from southwest England during their marine-freshwater transition.
The microplastic loads in elvers of the critically endangered European eel Anguilla anguilla, sampled in the lower reaches of three English rivers, were very low (incidence: 3.3%, mean ± s.d.: 0.03 ± 0.18 particles) and did not vary with body length or between rivers. Particles were mostly black, polyolefins, fibres and fragments of size 101-200 μm. Current levels indicate a low contamination pressure locally and, consequently, management efforts might prioritise mitigating the effects of other stressors affecting the species.


Use of expanded temporal flaps to resurface the skin grafted forehead.
The forehead flap, whilst providing a reliable method of intra-oral reconstruction, leaves an unsightly donor defect in the skin grafted forehead. We describe a technique of resurfacing the forehead using tissue expansion. Axial pattern flaps of expanded hairless temporal scalp are transposed to the forehead. This technique is likely to have wide applications since no other satisfactory method of resurfacing the entire forehead exists.


Production of 1,3-Propanediol by Clostridium butyricum VPI 3266 in continuous cultures with high yield and productivity.
The effects of dilution rate and substrate feed concentration on continuous glycerol fermentation by Clostridium butyricum VPI 3266, a natural 1,3-propanediol producer, were evaluated in this work. A high and constant 1,3-propanediol yield (around 0.65 mol/mol), close to the theoretical value, was obtained irrespective of substrate feed concentration or dilution rate. Improvement of 1,3-propanediol volumetric productivity was achieved by increasing the dilution rate, at a fixed feed substrate concentration of 30, 60 or 70 g l(-1). Higher 1,3-propanediol final concentrations and volumetric productivities were also obtained when glycerol feed concentration was increased from 30 to 60 g l(-1), at D=0.05-0.3 h(-1), and from 60-70 g l(-1), at D=0.05 and 0.1 h(-1).30 g l(-1) of 1,3-propanediol and the highest reported value of productivity, 10.3 g l(-1) h(-1), was achieved at D=0.30 h(-1) and 60 g l(-1) of feed glycerol. A switch to an acetate/butyrate ratio higher than one was observed for 60 g l(-1) of feed glycerol and a dilution rate higher than 0.10 h(-1); moreover, at D=0.30 h(-1) 3-hydroxypropionaldehyde accumulation was observed for the first time in the fermentation broth of C. butyricum.


[Inhibition of histamine-sensitive adenylate cyclase system of human gastric mucosa by cimetidine (author's transl)].
Human gastric mucosa contains a histamin-sensitive adenylate cyclase system. The activation of this enzyme system by histamine is competititively inhibited by the H2-receptor blocking agent cimetidine. Our results underscore the rational basis for the use 0f H2-receptor antagonists in the therapy of peptic ulcer.


Developing a social prescribing local system in a European Mediterranean country: a feasibility study to promote active and healthy aging.
Social Prescribing (SP) is an innovative strategy to respond to the non-clinical health needs of the population. A Social Prescribing Local System (SPLS) can be defined as a set of joined community, health, and social organizations to foster SP-oriented activities. This study aimed to develop and assess the feasibility of an SPLS implemented in a Mediterranean country, to promote health and wellbeing and contribute to active and healthy aging. A mixed-methods approach was followed, including three sequential components: 1) Cross-sectional online survey targeting health professionals (HP) working in a primary health care cluster, Portugal's southern region; 2) Pilot study implementing an on-the-job training program for HP, designed to meet identified training needs in the survey; 3) Focus group (FG) with the HP who participated in the pilot study, two individual interviews, with an elderly patient and a community provider for assessing the satisfaction with the pilot test. Sixty-five HP completed the survey; of these, 13 completed the theoretical part of the on-the-job training program; and six (out of these 13) completed the full program. Five HP participated in the FG, one patient and one community provider were interviewed. The surveyed HP perceived as facilitators to implement SP: an automatic system of notifications to prompt the use of SP, contribute to patient satisfaction, human and community resources' stability. The survey also highlighted barriers to SP implementation: length of appointments, shortage of human resources, data records confidentiality, low patient adherence rates, bureaucratic issues, time constraints, and financial costs. Participants were satisfied with the training. Identified SPLS implementation benefits were grouped into four dimensions (from the qualitative approach): gains for patients' health and wellbeing, support for the health services, sustainability of the community resources, and HP' professional satisfaction. Our study took the first steps towards the implementation of an SPLS. Findings reinforce that training HP in SP and on-the-job training seems feasible. This approach was well received and appears to represent a suitable and sustainable strategy. It can promote professional satisfaction, support health services, contribute to the stability of community resources, improve health and promote active and healthy aging.


9-(Pyrrolidinium-1-yl)-9-boranuidabi-cyclo-[3.3.1]nona-ne.
The title compound, C12H24BN, is an adduct formed from 9-borabi-cyclo-[3.3.1]nonane (9-BBN) and pyrrolidine. It crystallizes in the triclinic space group P with three mol-ecules in the asymmetric unit, one of which has disorder of the pyrrolidine ring. The B-N bond lengths are between 1.631 (2) and 1.641 (2) Å. The boron and nitro-gen atoms are bound to one hydrogen atom each. These hydrogen atoms are in anti-periplanar orientation. Both six-membered rings of the 9-BBN unit are in a chair conformation in all three mol-ecules. Differences between the three crystallographic independent mol-ecules are found in the five-membered rings of the pyrrolidine unit. These adopt different twisted and envelope conformations.


Clinical considerations in the use of missing tissue compensators for head and neck cases.
The irregular shape or contour of the patient's surface in the treatment field can alter the dose distribution resulting in non-uniformity of dose in the treatment volume. Missing tissue compensators have been most commonly used to improve this non-uniformity, especially in head & neck, breast, lung and supraclavicular regions. Two or three dimensional compensators have been typically designed to make the dose uniform at a specific depth. This compensation shifts the dose distribution within the treatment volume so that some structures may be under or over compensated. This study will examine how various sites in head and neck cases are affected by compensators. We have also analyzed the uncertainty in compensated dose due to the daily variations in patient repositioning. Computer isodose plans using Cobalt-60 gamma rays and 6 and 18 MV x-rays were generated using coronal contours. Results show that the dose uniformity is improved for the treatment sites, especially for the thinner sites, like the larynx and the anterior cervical neck nodes. Finally, patient movement or positioning errors of +/-1.0 cm will cause a change in dose distribution.


Paralytic brachial neuritis or Parsonage-Turner syndrome anterior interosseous nerve involvement. Report of three cases.
Paralytic brachial neuritis or Parsonage-Turner syndrome principally involves the shoulder girdle, rarely muscles moving the hand and fingers. Three cases are reported. After an acute episode with severe pain in the arm and fore-arm there appeared, a palsy of flexor pollicis longus and flexor indicis profundus, due to an isolated lesion of the anterior interosseous nerve. Two cases spontaneously recovered their full function, the third incompletely. Delay in recovery may be long; more than two years. Mechanical nerve entrapement should not be confused with this syndrome.


Aberrant NSG1 Expression Promotes Esophageal Squamous Cell Carcinoma Cell EMT by the Activation of ERK Signaling Pathway.
Neuron-specific gene family member 1 (NSG1) is a 21 kDa endosomal protein that is specifically expressed in neurons. This study was to explore the expression of NSG1 and possible mechanism in Esophageal Squamous Cell Carcinoma (ESCC). The Cancer Genome Atlas (TCGA) database was consulted to analyze the expression of NSG1 in ESCC. Immunohistochemistry (IHC) staining was used to evaluate NSG1 expression in ESCC cancerous tissues and matched paracancerous tissues. The CCK-8 assay, wound-healing assay, and transwell assay were used to detect the cell viability, migration, and invasion of ESCC cells. Western blot was used to assay epithelial-mesenchymal transition (EMT)-related proteins and ERK signaling pathway protein expression. The results showed that the expression of NSG1 in ESCC cancerous tissues was higher than noncancerous tissues. Compared with negative control (NC) group, cell viability, migration. and invasion significantly increased, the expression of p-ERK in ERK signaling pathway was significantly upregulated, the expressions of mesenchymal marker Vimentin and EMT-related transcription factors including snail and slug were significantly upregulated, and the expression of epithelial marker E-cadherin was significantly downregulated in KYSE-150 cells with NSG1 overexpression. However, these effects were reversed by the ERK signaling pathway inhibitor U0126. On the other hand, TE-1 cells with NSG1 knockdown had the changes contrary to that in KYSE-150 cells with NSG1 overexpression. NSG1 plays a potential carcinogenic role on the occurrence and progression of ESCC, and aberrant NSG1 expression might promote ESCC cell EMT by the activation of ERK signaling pathway.


Amrinone loading during cardiopulmonary bypass in neonates, infants, and children.
To determine whether amrinone is bound to cardiopulmonary bypass circuits. When amrinone is administered to children during cardiopulmonary bypass, determine whether measured amrinone concentrations differ from those predicted based on a reported volume of distribution of 1.6 L/kg. In vitro study: Uptake of amrinone by cardiopulmonary bypass circuits was determined. Clinical study: Prospective, open label investigation. University-affiliated tertiary children's hospital. Clinical study: 27 children participated, including 5 neonates and 9 infants. In vitro study: Waste blood was circulated within seven pediatric cardiopulmonary circuits. Amrinone was administered, and blood was serially assayed for amrinone levels. Clinical study: Amrinone (mean dose 4.9 mg/kg) was loaded during cardiopulmonary bypass and amrinone concentrations in pump blood were determined at termination of bypass. Amrinone measured by high-performance liquid chromatography. Cardiopulmonary bypass circuit uptake reduced amrinone concentrations to 79% of predicted. After correcting for circuit uptake, serum amrinone levels in patients were significantly higher than predicted. The levels, expressed in the ratio of measured: predicted amrinone concentration, did not differ among neonates, infants, and children older than 1 year of age. When amrinone is administered to children during cardiopulmonary bypass, about 20% of the dose becomes bound to the circuit. Available drug is distributed within a smaller volume than predicted. This may be the consequence of the physiologic perturbations of hypothermic cardiopulmonary bypass.


Primary pulmonary hydatid cysts in children-a report of three cases.
Three children with a total of six primary pulmonary hydatid cysts, all of whom underwent surgical management, are presented. Of these six hydatid cysts, two were treated with thoracotomy with cyst enucleation and capittonage, three with thoracoscopy-assisted minithoracotomy with enucleation and capittonage, and one with limited resection.


Induction of cyclooxygenase (COX)-2 in human vaginal epithelial cells in response to TLR ligands and TNF-α.
Mucosal inflammation caused by infections of the female lower genital tract is considered to be an important cofactor for HIV transmission. We hypothesize that COX-2, a key inflammation-related enzyme, is involved in these responses and is upregulated by microbial ligands and pro-inflammatory cytokines. Human vaginal epithelial cells (VK-2/E6E7) and ectocervical biopsy tissues were stimulated with TLR ligands and the cytokine TNF-α, used as surrogates of vaginal infections, and assessed for COX-2 expression and activity by microarray, real-time RT-PCR, immunoblotting, immunohistochemistry, and ELISA. TLR agonists and TNF-α induce transcriptional and translational expression of COX-2 in vaginal cells. TLR ligands, MALP2, Pam3CSK4, LTA, and imiquimod induced high epithelial COX-2 expression, while zymosan and poly dI:dC induced very low enzyme expression. Induced mRNA and protein expression correlated with increased COX-2 activity, which led to increased levels of PGE(2) in the cell culture supernatant. These cell-based findings were confirmed in primary cervicovaginal tissue explants. Induction of COX-2 expression and activity and the consequent increased levels of prostaglandins are common inflammatory pathways in human cervicovaginal epithelial cells and tissues in response to diverse TLR ligands and pro-inflammatory cytokines. These findings are relevant to the understanding of genital mucosal inflammation, its potential treatment, and its possible relationship with increased tissue susceptibility to HIV-1 infection.


Nonlinear interdependence of the results of measuring anti-SARS-CoV-2 IgG levels using Abbott and Euroimmun test systems.
There are significant number of tests used to determine the level of antibodies to SARS-CoV-2 which differ both in the methods underlying testing and in the antigenic targets used and classes of measured immunoglobulins. Comparison of the results obtained using various tests reveals their significant discrepancy when converted to the WHO recommended standard unit for measuring the level of specific immunoglobulins BAU/mL. The aim of this study is a comparison of anty-SARS-CoV-2 IgG levels, measured using test systems based on different methodological platforms - EuroImmun assay and Abbott assay. Abbott uses the immunochemiluminescence method CLIA, EuroImmun uses the enzyme immunoassay method ELISA. The dependences of the measurement error on the level of antibodies for the two test systems were approximated by power functions using the least squares method. The nonlinear relation of antibody levels values measured by Abbott assay and Euroimmun assay was approximated by an asymptotic function. The study involved 112 people. Our results confirm the fallacy of using a single conversion coefficient in BAU/mL for anti-SARS-CoV-2 IgG levels measured by Abbott and EuroImmun. To describe the interdependence of anti-SARS-CoV-2 IgG Abbott and EuroImmun levels, we offer the function y = 18/π arctan(0.0009x) and a calculator that allows to easily recalculate the results obtained using these tests. The non-linear nature of the interdependence of the measured anti-SARS-CoV-2 antibodies levels on the levels magnitude is one of the main reasons for the discrepancy between the tests results when converted to BAU/mL using a single conversion coefficient.


Fluoxetine action on murine T-lymphocyte proliferation: participation of PKC activation and calcium mobilisation.
The present study was undertaken to analyse the effect of fluoxetine upon murine T-lymphocyte proliferation. We found that fluoxetine exerted a dual effect, which depended on the degree of lymphocyte activation: at mitogenic concentration (2 microg/mL) of concavalin A (Con A), we observed an inhibitory effect on cellular proliferation, whereas, on submitogenic Con A concentration (1 microg/mL), fluoxetine stimulated the cellular response. Given these facts, we studied PKC activation and calcium mobilisation in both stimulatory and inhibitory effects of fluoxetine on T-cell proliferation. We observed that fluoxetine increased PKC translocation obtained with 1 microg/mL Con A concentration, whereas PKC was degraded when 2 microg/mL was used. This mechanism is thought to be mediated by calcium mobilisation. According to our results, fluoxetine seemed to modulate calcium influx, which, in turn, would influence PKC translocation, modulating the immune response.


Association of the mitochondrial DNA 15497G/A polymorphism with obesity in a middle-aged and elderly Japanese population.
Although polymorphism of the mitochondrial DNA 15497guanine/adenine (Mt15497G-->A) leads to the Gly251Ser amino acid replacement on human cytochrome b, it is unknown whether functional alteration of the mitochondrion is induced by the Gly251Ser replacement. To see if an association exists between the Mt15497G-->A polymorphism and obesity, we examined differences in body size, body composition, and regional body fat distribution between the two genotypes in middle-aged and elderly Japanese individuals (825 women and 906 men). The Mt15497 genotype was determined with an automated colorimetric allele-specific DNA probe assay system using the polymerase chain reaction (PCR) method. The Mt15497G-->A polymorphism was detected in 3.5% ( n=60) of all subjects: 2.8% ( n=23) among women and 4.1% ( n=37) among men. After adjusting for age and smoking, we found that body weight, body mass index, waist and hip circumferences, fat mass, fat-free mass, intra-abdominal fat and triglycerides were significantly greater in women with the A allele compared with the G allele ( p=0.001-0.025). For men, waist to hip ratio was significantly greater ( p=0.032), and waist circumference, intra-abdominal fat and triglycerides had a trend to be significantly greater ( p=0.062-0.087) in subjects with the A allele compared with the G allele. These data suggest that the Mt15497 polymorphism may be associated with obesity-related variables and lipid metabolism.


Using the E-PASS scoring system to estimate the risk of emergency abdominal surgery in patients with acute gastrointestinal disease.
The Estimation of Physiologic Ability and Surgical Stress (E-PASS) scoring system, which quantifies a patient's reserve and surgical stress, is used to predict morbidity and mortality in patients before elective gastrointestinal surgery. We conducted this study to clarify whether the E-PASS scoring system is useful for assessing the risks of emergency abdominal surgery. The subjects of this retrospective study were 51 patients who underwent emergency gastrointestinal surgery at a public general hospital. The main outcomes were the E-PASS scores and the postoperative course, defined by mortality and morbidity. Postoperative complications developed in 15 of the 51 patients (29.4%). The E-PASS score was significantly higher in the patients with postoperative complications than in those without (0.61 ± 0.31 vs 0.20 ± 0.35, respectively; n = 36). The morbidity rates were significantly lower in the patients with a value less than 0.5 than in those with a value more than 0.5 (17.1% and 56.3%, respectively; P < 0.01). There were 7 operative deaths among the 16 patients with a high score, versus none among the 9 patients with a low score (P < 0.01). Three patients underwent laparoscopic-assisted bowel resection with a good postoperative course, with scores of less than 0.5. The E-PASS scoring system is useful for surgical decision making and evaluating whether patients will tolerate emergency gastrointestinal surgery. Minimally invasive therapy would assist in lowering the risk of complications.


Health-seeking behaviors of patients with acute respiratory infections during the outbreak of novel coronavirus disease 2019 in Wuhan, China.
We conducted two surveys to evaluate the health-seeking behaviors of individuals with acute respiratory infections (ARI) during the COVID-19 outbreak in Wuhan, China. Among 351 participants reporting ARI (10.3%, 351/3,411), 36.5% sought medical assistance. Children were more likely to seek medical assistance than other age-groups (66.1% vs. 28.0%-35.1%). This population-based study demonstrates that the majority of patients with ARI symptoms did not seek medical assistance during the COVID-19 outbreak in Wuhan. These findings may be used to refine the estimates of disease burden and clinical severity of COVID-19 and to plan for health resources allocation.


Photo biostimulatory effect of low dose photodynamic therapy on human mesenchymal stem cells.
Tissue engineering is one treatment to regenerate bone . Stem cell proliferation or differentiation can be stimulated by adjunctive approaches like photobiomodulation. Some studies suggested that, photodynamic therapy with low concentration of photosensitizers can stimulate cell differentiation as a photobiomodulation approach. Human bone marrow mesenchymal stem cell was isolated and then cultured in sterile medium. Two photosensitizer drugs as 5- aminolevulenic acid (1 mM) (5-ALA) and Methylene blue (1μM) (MB) were used in incubation culture media. In order to activate the photosensitizers, 630 and 660 nm wavelengths were irradiated with 1 J/cm2 energy density, respectively. Cell viability was assessed using MTT assay before and after laser irradiation, and also Alizarin red histologic test was used for calcium nodule formation. performing the MTT test before irradiation showed that, the optimum concentrations were 1 mM for 5-ALA and 1μM for MB that were optimized. After laser irradiation, ALA group showed no osseous differentiation. In contrast, there was a significant calcium nodule formation in MB group compared with the control one. Photodynamic therapy with low photosensitizer concentration and low doses of laser energy density may improve osteogenic differentiation. Accordingly, MB had stimulatory effect on bone marrow derived mesenchymal stem cells. However, 5-ALA did not show this effect.


The influence of pH on the healing-over of mammalian cardiac muscle.
The process of healing-over was followed in trabeculae from the right ventricle of guinea-pigs and in Purkinje fibres from dogs by measuring resting potential and input resistance close to a site of damage. In Ca2+-free bathing solution at pH 6.5 no signs of healing-over were found; at pH 5.5 healing-over was incomplete; at pH 5.0 and 4.0 healing-over occurred promptly. It is concluded that transformation of low-resistance nexus membranes into high-resistance membranes separating the intracellular from the extracellular compartment normally is due to Ca2+, while protons can bring about the same effect under extreme conditions.


Immunohistochemical analysis of cyclooxygenase-2 expression in premalignant and malignant esophageal glandular and squamous lesions in Cixian, China.
Increased cyclooxygenase-2 (COX-2) expression has been observed in both squamous cell carcinoma (SCC) and adenocarcinoma (AC) in Western countries, and COX-2 inhibitors have been considered as potential chemopreventive agents for esophageal cancers. Since chemoprevention often targets the premalignant lesions in high-risk population, it is worthwhile to study COX-2 expression in a spectrum of premalignant and malignant lesions obtained from the high-risk populations. In this study, biopsy samples were taken from 240 subjects identified by screening of the high-risk population in Cixian, China, including 27 normal, 29 with squamous hyperplasia, 84 with dysplasia (31 low grade and 53 high grade), 30 with carcinoma in situ, and 70 with invasive carcinoma (60 SCC and 10 AC). For comparison, tissue samples were also collected from He Lon Jiang Province, a low-risk population in China, including 10 patients with invasive SCC, 20 patients with AC, and 17 patients with Barrett's esophagus. The COX-2 protein expression was examined by immunohistochemistry. Using 10% staining as a threshold, 9 of 10 (90%) invasive SCC from low-risk population were COX-2 positive. However, no positive COX-2 staining was seen on normal, hyperplastic, dysplastic, and in situ squamous lesions from the high-risk population, and only 4 of 60 (6%) invasive SCC exhibited positive COX-2 staining. For glandular lesions, 6 of 10 (60%) AC from high-risk area and 15 of 20 (75%) from low-risk area showed positive COX-2 staining, and 12 of 17 (70%) premalignant Barrett's esophagus were also positive. Our findings show that COX-2 expression various in squamous lesions from high- and low-risk areas, but not in glandular lesions. Additional studies are needed to fully explore the mechanisms that are associated with the different COX-2 immunohistochemical staining patterns in esophageal squamous lesions from low- and high-risk populations.


Malaria among under-five children in Ethiopia: a systematic review and meta-analysis.
Globally, malaria is among the leading cause of under-five mortality and morbidity. Despite various malaria elimination strategies being implemented in the last decades, malaria remains a major public health concern, particularly in tropical and sub-tropical regions. Furthermore, there have been limited and inconclusive studies in Ethiopia to generate information for action towards malaria in under-five children. Additionally, there is a considerable disparity between the results of the existing studies. Therefore, the pooled estimate from this study will provide a more conclusive result to take evidence-based interventional measures against under-five malaria. The protocol of this review is registered at PROSPERO with registration number CRD42020157886. All appropriate databases and grey literature were searched to find relevant articles. Studies reporting the prevalence or risk factors of malaria among under-five children were included. The quality of each study was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). Data was extracted using Microsoft Excel 2016 and analysis was done using STATA 16.0 statistical software. The pooled prevalence and its associated factors of malaria were determined using a random effect model. Heterogeneity between studies was assessed using the Cochrane Q-test statistics and I2 test. Furthermore, publication bias was checked by the visual inspection of the funnel plot and using Egger's and Begg's statistical tests. Twelve studies with 34,842 under-five children were included. The pooled prevalence of under-five malaria was 22.03% (95% CI 12.25%, 31.80%). Lack of insecticide-treated mosquito net utilization (AOR: 5.67, 95% CI 3.6, 7.74), poor knowledge of child caretakers towards malaria transmission (AOR: 2.79, 95% CI 1.70, 3.89), and living near mosquito breeding sites (AOR: 5.05, 95% CI 2.92, 7.19) were risk factors of under-five malaria. More than one in five children aged under five years were infected with malaria. This suggests the rate of under-five malaria is far off the 2030 national malaria elimination programme of Ethiopia. The Government should strengthen malaria control strategies such as disseminating insecticide-treated mosquito nets (ITNs), advocating the utilization of ITNs, and raising community awareness regarding malaria transmission.


[Is rheumatoid arthritis connected with a digestive tract parasitosis? (author's transl)].
The comparison of blood eosinophil counts and stool parasites in two groups of patients--twenty one suffering from rheumatoid arthritis and twenty one from other various diseases--did not show any significant difference in favour of a parasitological etiology in rheumatoid arthritis, an hypothesis which had to be considered because of the efficacy of levamisole in the treatment of this disease.


Characterization of gastric cancer models from different cell lines orthotopically constructed using improved implantation techniques.
To develop orthotopic gastric cancer mouse models from different cell lines and characterize the tumor features to assist further in preclinical trials and clinical treatment strategies. Human gastric cancer SGC-7901 and BGC-823 cell suspensions were injected subcutaneously into nude mice to develop solid tumors, and tumor tissue pieces were then implanted under the serous coat of the stomach. An autopsy was performed on all animals of the SGC-7901 and BGC-823 models to observe the primary tumor growth and metastases using pathological and immunohistochemical methods. Both models showed large tumors in situ resulting in pressure and infiltration of the adjacent organs. The gastric cavity became smaller, along with stenosis of the cardia or pylorus. There were biological and statistical differences between the two models. The metastasis rate in involved organs (lymph nodes, kidney, spleen, testis) was significantly higher in the BGC-823 model compared to the SGC-7901 model (P < 0.05 or P < 0.01). The median survival of the BGC-823 model was shorter than that of SGC-7901 (23 d vs 84 d, P < 0.05). Histopathologically, the primary tumor and metastatic lesions of the two models showed obvious atypia and mucus in the cytoplasm. Compared with the SGC-7901 model, BGC-823 appeared more poorly differentiated (absence of adenoid structure), had a smaller volume, and richer capillary structure. Immunohistochemical staining revealed cytokeratin 20 and epithelial membrane antigen expression was positive in the SGC-7901 tumors, while negative in BGC-823 ones. Models using the SGC-7901 and BGC-823 cell lines were established which could function in gastric cancer research on carcinogenesis mechanism and drug discovery. The two models showed different tumor behavior and the latter was more malignant than the former.


Factors associated with tuberculosis disease among children who are household contacts of tuberculosis cases in an urban setting in Malaysia.
With the rise in prevalence of childhood tuberculosis (TB) globally, contact tracing should be a powerful strategy for early diagnosis and management, especially in children who are household contacts of active TB cases. Here, we aimed to determine the prevalence and factors associated with TB disease in children who are household contacts of TB cases. We used a cross-sectional study with data from the Malaysian TB Information System (TBIS) recorded from 1 January 2014 to 31 December 2017. All children aged 0-14 years who were registered in the TBIS with at least one household contact of TB cases were included in the study. Multiple logistic regression analysis was performed to calculate the adjusted odds ratio (adj. OR) and for adjusting the confounding factors. A total of 2793 children were included in the study. The prevalence of active TB was 1.5% (95% confidence interval [CI]: 1.31, 1.77%). Children aged < 5 years [adj. OR 9.48 (95% CI: 3.41, 26.36) p < 0.001] with positive tuberculin skin test [adj. OR 395.73 (95% CI: 134.17, 1167.13), p < 0.001] and investigation period of > 6 weeks [adj. OR 7.48 (95% CI: 2.88, 19.43), p < 0.001] had significantly higher odds for TB disease. The prevalence of TB disease in children who were household contacts of TB cases is relatively low. However, contact tracing programmes should not only focus on children aged < 5 years and with positive tuberculin skin test results, but also be empowered to reduce the investigation period.


Is laparoscopic excision for superficial peritoneal endometriosis helpful or harmful? Protocol for a double-blinded, randomised, placebo-controlled, three-armed surgical trial.
Placebo-controlled surgical designs are recommended to ascertain treatment effects for elective surgeries when there is genuine doubt about the effectiveness of the surgery. Some elective surgeries for pain have been unable to show an effect beyond sham surgery, suggesting contributions from contextual factors. However, the nature of contextual factors in elective surgery is largely unexplored. Further, methodological difficulties in placebo-controlled surgical trials impact the ability to estimate the effectiveness of a surgical procedure. These include an overall lack of testing the success of blinding, absence of comparison to a no-surgery control group and dearth of test for neuropathic pain.For women with peritoneal endometriosis, there is uncertainty regarding the pain-relieving effect of surgery. Surgery may put patients at risk of complications such as postsurgical neuropathic pain, without guarantees of sufficient pelvic pain relief. The planned placebo-controlled trial aims to examine the effect of surgery on pelvic pain, widespread pain and neuropathic pain symptoms in women with peritoneal endometriosis, and to test the contribution of contextual factors to pain relief. One hundred women with peritoneal endometriosis will be randomised to either diagnostic laparoscopy with excision of endometrial tissue (active surgery), purely diagnostic laparoscopy (sham surgery) or delayed surgery (no-surgery control group). Outcomes include pelvic pain relief, widespread pain, neuropathic pain symptoms and quality of life. Contextual factors are also assessed. Assessments will be obtained at baseline and 1, 3 and 6 months postrandomisation. Mixed linear models will be used to compare groups over time on all outcome variables. The trial is approved by the Regional Ethics Committee in the Central Denmark Region (1-10-72-152-20). The trial is funded by a PhD scholarship from Aarhus University, and supported by a grant from 'Helsefonden' (20-B-0448). Findings will be published in international peer-reviewed journals and disseminated at international conferences. NCT05162794.


Assessment of two volumetrically different concentration approaches to improve sensitivities for SARS-CoV-2 detection during wastewater monitoring.
Wastewater monitoring for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the virus responsible for the global coronavirus disease 2019 (COVID-19) pandemic, has highlighted the need for methodologies capable of assessing viral prevalence during periods of low population infection. To address this need, two volumetrically different, methodologically similar concentration approaches were compared for their abilities to detect viral nucleic acid and infectious SARS-CoV-2 signal from primary influent samples. For Method 1, 2 L of SARS-CoV-2 seeded wastewater was evaluated using a dead-end hollow fiber ultrafilter (D-HFUF) for primary concentration, followed by the CP Select™ for secondary concentration. For Method 2, 100 mL of SARS-CoV-2 seeded wastewater was evaluated using the CP Select™ procedure. Following D-HFUF concentration (Method 1), significantly lower levels of infectious SARS-CoV-2 were lost (P value range: 0.0398-0.0027) compared to viral gene copy (GC) levels detected by the US Centers for Disease Control (CDC) N1 and N2 reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) assays. Subsamples at different steps in the concentration process were also taken to better characterize the losses of SARS-CoV-2 during the concentration process. During the centrifugation step (prior to CP Select™ concentration), significantly higher losses (P value range: 0.0003 to <0.0001) occurred for SARS-CoV-2 GC levels compared to infectious virus for Method 1, while between the methods, significantly higher infectious viral losses were observed for Method 2 (P = 0.0002). When analyzing overall recovery of endogenous SARS-CoV-2 in wastewater samples, application of Method 1 improved assay sensitivities (P = <0.0001) compared with Method 2; this was especially evident during periods of lower COVID-19 case rates within the sewershed. This study describes a method which can successfully concentrate infectious SARS-CoV-2 and viral RNA from wastewater. Moreover, we demonstrated that large volume wastewater concentration provides additional sensitivity needed to improve SARS-CoV-2 detection, especially during low levels of community disease prevalence.


Ontology-driven and weakly supervised rare disease identification from clinical notes.
Computational text phenotyping is the practice of identifying patients with certain disorders and traits from clinical notes. Rare diseases are challenging to be identified due to few cases available for machine learning and the need for data annotation from domain experts. We propose a method using ontologies and weak supervision, with recent pre-trained contextual representations from Bi-directional Transformers (e.g. BERT). The ontology-driven framework includes two steps: (i) Text-to-UMLS, extracting phenotypes by contextually linking mentions to concepts in Unified Medical Language System (UMLS), with a Named Entity Recognition and Linking (NER+L) tool, SemEHR, and weak supervision with customised rules and contextual mention representation; (ii) UMLS-to-ORDO, matching UMLS concepts to rare diseases in Orphanet Rare Disease Ontology (ORDO). The weakly supervised approach is proposed to learn a phenotype confirmation model to improve Text-to-UMLS linking, without annotated data from domain experts. We evaluated the approach on three clinical datasets, MIMIC-III discharge summaries, MIMIC-III radiology reports, and NHS Tayside brain imaging reports from two institutions in the US and the UK, with annotations. The improvements in the precision were pronounced (by over 30% to 50% absolute score for Text-to-UMLS linking), with almost no loss of recall compared to the existing NER+L tool, SemEHR. Results on radiology reports from MIMIC-III and NHS Tayside were consistent with the discharge summaries. The overall pipeline processing clinical notes can extract rare disease cases, mostly uncaptured in structured data (manually assigned ICD codes). The study provides empirical evidence for the task by applying a weakly supervised NLP pipeline on clinical notes. The proposed weak supervised deep learning approach requires no human annotation except for validation and testing, by leveraging ontologies, NER+L tools, and contextual representations. The study also demonstrates that Natural Language Processing (NLP) can complement traditional ICD-based approaches to better estimate rare diseases in clinical notes. We discuss the usefulness and limitations of the weak supervision approach and propose directions for future studies.


Everolimus in Metastatic Breast Cancer: Clinical Experience as a Late Treatment Line.
Everolimus (Afinitor®) plus exemestane are indicated for hormone receptor-positive, HER2/neu-negative metastatic breast cancer (MBC), in menopausal women without symptomatic visceral disease after recurrence or progression following aromatase inhibitors. But everolimus efficacy as late treatment has not been explored. Sixty-three MBC patients progressing under hormonotherapy (HT; n = 30) or after chemotherapy (CT; n = 32) received everolimus plus HT (EHT) and were analyzed for safety, efficacy and overall survival (OS). This cohort was compared with our previous 530 MBC patients stratified by line (PMID 21852136). The median duration of EHT was 27.8 weeks at 5-10 mg/day until clinical progression or toxicity. Median OS was not reached (median follow-up 18 months). Twelve-month survival was 100, 79 and 49% for patients treated with 0 (n = 13), 1-2 (n = 18) and >3 CT (n = 32), respectively. Median time-to-treatment failure was 6.4 months. In 62 EHT patients randomly matched 1:7 with 421 previous patients for age and number of CT, OS improved compared with patients receiving a new CT (p = 0.062). In patients pretreated with <2 CT, EHT gave a better OS than in those with a new CT (p = 0.026). These results may support the use of EHT whatever the number of previous lines.


Isolation, identification and characterization of Bacillus subtilis ZJB-063, a versatile nitrile-converting bacterium.
Strain ZJB-063, a versatile nitrile-amide-degrading strain, was newly isolated from soil in this study. Based on morphology, physiological tests, Biolog and the 16S rDNA sequence, strain ZJB-063 was identified as Bacillus subtilis. ZJB-063 exhibited nitrilase activity without addition of inducers, indicating that the nitrilase in B. subtilis ZJB-063 is constitutive. Interestingly, the strain exhibited nitrile hydratase and amidase activity with the addition of epsilon-caprolactam. Moreover, the substrate spectrum altered with the alteration of enzyme systems due to the addition of epsilon-caprolactam. The constitutive nitrilase was highly specific for arylacetonitriles, while the nitrile hydratase/amidase in B. subtilis ZJB-063 could not only hydrolyze arylacetonitriles but also other nitriles including some aliphatic nitriles and heterocyclic nitriles. Despite comparatively low activity, the amidase of hydratase/amidase system was effective in converting amides to acids. The versatility of this strain in the hydrolysis of various nitriles and amides makes it a potential biocatalyst in organic synthesis.


Limitations of AIDS reporting under favorable circumstances.
To assess completeness of acquired immunodeficiency syndrome (AIDS) reporting by a consortium of Philadelphia physicians, we compared the consortium's patient data base to AIDS case reports received by the Philadelphia Department of Public Health (PDPH). Several circumstances favored better than ordinary reporting. Consortium physicians were highly motivated, specialized in the care of patients with human immunodeficiency virus disease, had worked with PDPH physicians for years, and knew beforehand about the plan to compare data bases. Of 295 patients in the consortium data base diagnosed with AIDS at least nine months prior to this study, 267 (90.5%) had been reported to the PDPH and 28 (9.5%) had not. Only two of the missed reports were deliberately withheld, each in response to the patient's request. Reporting completeness increased with the time elapsed since diagnosis, varied by practice from 70% to 100%, and was unrelated to patient demographic, insurance status, or occupational characteristics. AIDS reporting for patients in health care occupations (11/13 = 85% reported) was not significantly different from reporting for patients in other occupations (256/282 = 91% reported). We conclude that, under conditions favorable to reporting, approximately 10% of AIDS patients are not reported; the only patient characteristic that predicts reporting is the time elapsed since diagnosis; and nearly all reporting failures are inadvertent.


Comparative Analysis of Palliative Care Needs Identified in Inpatient Rehabilitation and Skilled Nursing Facilities by Multidisciplinary Team Members.
Assess access to, need for, and beliefs surrounding specialized palliative care (PC). Observational, comparative analysis needs assessment survey. Four inpatient rehabilitation facilities (IRFs) or skilled nursing facilities with long-term care (SNFs/LTC) that provide subacute rehabilitation within 1 tertiary care system. Allied health professionals, physicians, nursing, case managers, social workers, spiritual care (n=198). Not applicable. Frequency of patient needs, attitudes about current systems, individual beliefs, and barriers to PC. Confidence in management, communicating, and navigating primary PC competencies among clinical pathway employees. Of 198 respondents, 37% said PC was available at their facility. Those in IRF reported higher frequencies of grief/unmet spiritual needs of patients compared with SNF/LTC (P≤.001). Conversely, SNF/LTC reported higher frequencies of agitation, poor appetite, and end-of-life care (P≤.003). Respondents in SNF/LTC felt more confident managing end-of-life care, explaining what hospice and PC are and appropriateness for referral to each, discussing advance directives, determining appropriate decision-makers, and navigating ethical decisions than in IRFs (P≤.007). SNF/LTC participants reported higher effectiveness of their current system involving PC and ease of hospice transition compared with IRFs (P≤.008). A majority agreed that PC does not take away patient hope, could prevent recurrent hospitalizations, improve symptom management, communication, and patient and family satisfaction. The most common reported barriers to PC consultation were (1) attitudes and beliefs of staff or patients and families, (2) system issues with access, cost, or prognosis communication, and (3) lack of understanding of PC role. A gap exists in PC access in IRF and SNF/LTC despite patient needs and staff beliefs. Future studies should focus on identifying which patients should be referred to PC in the post-acute setting and what outcomes can be used as a guide to meet the needs of this growing area of practice.


Signal transduction pathways involved in particulate matter induced relaxation in rat aorta--spontaneous hypertensive versus Wistar Kyoto rats.
Previously we reported that in vivo exposure to ambient particulate matter (PM) induces vasodilatation in rat aorta. The purpose of the current study was to investigate the intracellular messengers involved in PM-elicited vasodilatation in aortas from spontaneous hypertensive (SHR) and normotensive (WKY) rats. The contribution of three different intracellular pathways, i.e. (1) the NO-cGMP pathway, (2) prostanoids signaling and (3) endothelial hyperpolarisation factors were evaluated by using specific inhibitors (NS2028, Diclofenac and high K-concentration/17-ODYA, respectively). Using antagonists of capsaicin- or histamine receptors we tested potential interactions of PM with these receptors. Particle suspensions (EHC-93), particle filtrates (particle-free) and Cu(2+)- or Zn(2+)-containing solutions were used to obtain cumulative dose-response curves of relaxation in normal and endothelium-denuded rings. Our present data confirm that PM and its soluble components elicit an endothelium-independent vasodilatation in rat aorta rings. The response is mainly linked to the activation of soluble guanylate cyclase (sGC), since its inhibition by NS2028 almost abolished relaxation. Indeed PM suspensions stimulated cGMP production in purified isolated sGC. Neither the receptor nor their signaling pathways played a significant role in the direct relaxation by PM or metals. Vasodilatation responses were significantly higher in SHR than WKY control rats. Our data demonstrate that PM elicits a dose-dependent vasodilatation via activation of sGC in vascular smooth muscles. PM components, including soluble transition metals play a major role in this response. The stronger effect in SHR rats is in accordance with the observation that acute effects of PM are mainly seen in patients with underlying cardiovascular diseases.


Suppurative inflammation of vas deferens: an unusual groin mass.
We report a case of suppurative vasitis that presented as an inguinal mass in a young man. Inflammation of the vas deferens may occur as a manifestation of genital tuberculosis or other genitourinary tract infection. A granulomatous vasitis, vasitis nodosa, is usually associated with previous trauma or surgery. Suppuration is rare. We report a case that represents a rare cause of an inguinal mass.


Characterization of palytoxin-induced catecholamine secretion from cultured bovine adrenal chromaffin cells. Effects of Na(+)- and Ca(2+)-channel blockers.
The effect of palytoxin (PTX), a potent marine toxin, on catecholamine (CA) secretion from cultured bovine adrenal chromaffin cells was examined. PTX at concentrations of over 10(-10) M induced CA secretion concentration-dependently. About 40-50% of the total cellular CA was secreted during 20-min incubation with 3 x 10(-8) M PTX. PTX-induced CA secretion was dependent on both extracellular Na+ and Ca2+. PTX caused increases in [22Na](+)- and [45Ca](2+)-influxes into the cells. Increase in [22Na](+)-influx was observed at concentrations of over 10(-11) M PTX and was maximal at 10(-10) M PTX and then gradually decreased at higher concentrations that induced [45Ca](2+)-influx and CA secretion. On the other hand, increase in [45Ca](2+)-influx was observed at concentrations of over 10(-10) M PTX and increased with increase in concentration of PTX. This concentration-response curve for PTX-induced [45Ca](2+)-influx was similar to that for PTX-induced CA secretion. The CA secretion and [22Na](+)- and [45Ca](2+)-influxes induced by PTX were not affected by tetrodotoxin (TTX), but were significantly inhibited by quinidine and aprindine(mexiletine), antiarrythmic drugs known to block Na(+)-channels. Ca(2+)-channel blockers such as nifedipine, verapamil, Co2+, Cd2+, inhibited both CA secretion and [45Ca](2+)-influx induced by PTX. These results indicate that PTX-induced CA secretion is mediated by activation of Na(+)-dependent, TTX-insensitive voltage-dependent Ca(2+)-channels, and is inhibited by quinidine and aprindine through their inhibitory effects on the Na(+)- and Ca(2+)-influxes into the cells induced by PTX.


Mild dehydration modifies the cerebrovascular response to the cold pressor test.
The cold pressor test (CPT) is widely used in clinical practice and physiological research. It is characterized by a robust autonomic response, with associated increases in heart rate (HR), mean arterial pressure (MAP) and mean middle cerebral artery blood flow velocity (MCAv(mean)). Hydration status is not commonly reported when conducting this test, yet blood viscosity alone can modulate MCAv(mean), potentially modifying the MCAv(mean) response to the CPT. We investigated the effect of mild dehydration on the physiological response to the CPT in 10 healthy men (mean ± SD: age 28 ± 5 years; body mass 83 ± 5 kg). All participants completed two CPTs, cold water (0°C) immersion of both feet for 90 s, with the order of the euhydration and dehydration trials counterbalanced. Beat-to-beat MCAv, MAP, HR and breath-by-breath partial pressure of end-tidal CO2 (P(ET,CO2)) were measured continuously. Participants' pain perception was measured 1 min into the CPT using a visual analog scale (no pain = 0; maximal pain = 10). Dehydration significantly elevated plasma osmolality and urine specific gravity and reduced body mass (all P < 0.01). The MAP and HR responses were not different between treatments (both P > 0.05). After 90 s of immersion, the change in MCAv(mean) from baseline was less in the dehydration compared with the euhydration trial (change 0 ± 5 versus 7 ± 7 cm s(-1), P = 0.01), as was P(ET,CO2) (change -3 ± 2 versus 0 ± 3 mmHg, P = 0.02). Dehydration was associated with greater relative pain sensation during the CPT (7.0 ± 1.3 vs 5.8 ± 1.8, P = 0.02). Our results demonstrate that mild dehydration can modify the cerebrovascular response to the CPT, with dehydration increasing perceived pain, lowering P ET ,CO2 and, ultimately, blunting the MCAv(mean) response.


Role of Health Equity Research and Policy for Diverse Populations Requiring Hand Surgery Care.
Health equity requires allocation of resources to eliminate the systematic disparities in health, imposed on marginalized groups, which adversely impact outcomes. A socioecological approach is implemented to elucidate the role of health equity research and policy for underrepresented minority and socioeconomically disadvantaged populations. Through investigation of the individual, community, institution, and public policy, we investigate problems and propose solutions to ensure fair and just treatment of all patients requiring hand surgery.


[Blockade of the anti-influenza specific proliferative response of cloned cell lines restricted either by HLA-DR7 or HLA-DR1 molecules or by a still-unknown molecule].
Four different continuous cell lines of T lymphocytes are described, three of them were obtained by cloning. Their activity is restricted in three cases by a histocompatibility antigen undistinguishable from HLA-DR. The last one is restricted by an autologous unidentified structure. The first three lines are specific for a viral antigen corresponding to a subtype of the H3 hemagglutinin. The fourth line seems to react with an hitherto undescribed antigen shared by type A and type B influenza viruses.


Agreement between obstructive airways disease diagnoses from self-report questionnaires and medical records.
To evaluate agreement between self-reported obstructive airways disease (OAD) diagnoses of asthma, bronchitis, and chronic obstructive pulmonary disease (COPD)/emphysema obtained from the New York City Fire Department (FDNY) monitoring questionnaires with physician diagnoses from FDNY medical records. We measured sensitivity, specificity, and agreement between self-report and physician OAD diagnoses in FDNY members enrolled in the World Trade Center (WTC) monitoring program who completed a questionnaire between 8/2005-1/2012. Using logistic models, we identified characteristics of those who self-report a physician diagnosis that is also reported by FDNY physicians. 20.3% of the study population (N=14,615) self-reported OAD, while 15.1% received FDNY physician OAD diagnoses. Self-reported asthma had the highest sensitivity (68.7%) and overall agreement (91.9%) between sources. Non-asthma OAD had the lowest sensitivity (32.1%). Multivariate analyses showed that among those with an OAD diagnosis from FDNY medical records, inhaler use (OR=4.90, 95% CI=3.84-6.26) and respiratory symptoms (OR=1.55 [95% CI=1.25-1.92]-1.77 [95% CI=1.37-2.27]) were associated with self-reported OAD diagnoses. Among participants in the WTC monitoring program, sensitivity for self-reported OAD diagnoses ranges from good to poor and improves by considering inhaler use. These findings highlight the need for improved patient communication and education, especially for bronchitis or COPD/emphysema.


Bretschneider's histidine-buffered cardioplegic solution and the calcium paradox.
Reperfusion of an isolated heart with calcium-containing solution after a short period of calcium-free perfusion may result in irreversible cell damage (calcium paradox). Experiments were undertaken to determine whether rat hearts could be predisposed to the calcium paradox by perfusion with Bretschneider's calcium-free histidine-buffered cardioplegic solution. Creatine kinase (CK) release during the reperfusion phase was used to quantitate cell damage. Perfusion with cardioplegic solution was performed at 37 degrees and 20 degrees C. Reperfusion after 10 minutes of perfusion with this solution at 37 degrees C resulted in a full calcium paradox. After 120 minutes of perfusion with cardioplegic solution at 20 degrees C, CK release during reperfusion amounted to 30% of the release during a full calcium paradox. This CK release could be further reduced by lowering the coronary flow rate or by adding 50 mumol X L-1 CaCl2 to the cardioplegic solution. It is concluded that a combination of hypothermia, a low coronary flow rate, and a limited duration of exposure to Bretschneider's histidine-buffered cardioplegic solution will minimize the risk of evoking the calcium paradox.


Tobacco industry litigation to deter local public health ordinances: the industry usually loses in court.
The tobacco industry uses claims of state preemption or violations of the US Constitution in litigation to overturn local tobacco control ordinances. Collection of lawsuits filed or threatened against local governments in the USA; review of previously secret tobacco industry documents; interviews with key informants. The industry is most likely to prevail when a court holds that there is explicit preemption language by the state legislature to exclusively regulate tobacco. The industry has a much weaker record on claims of implied preemption and has lost all challenges brought under equal protection claims in the cases we located. Although the tobacco industry is willing to spend substantial amounts of money on these lawsuits, it never won on constitutional equal protection grounds and lost or dropped 60% (16/27) of the cases it brought claiming implied state preemption. Municipalities should continue to pass ordinances and be prepared to defend them against claims of implied preemption or on constitutional grounds. If the ordinance is properly prepared they will likely prevail. Health advocates should be prepared to assist in this process.


Co-microencapsulation of human umbilical cord-derived mesenchymal stem and pancreatic islet-derived insulin producing cells in experimental type 1 diabetes.
Post-partum umbilical cord Wharton Jelly-derived adult mesenchymal stem cells (hUCMS) hold anti-inflammatory and immunosuppressive properties. Human pancreatic islet-derived progenitor cells (hIDC) may de-differentiate, and subsequently re-differentiate into insulin producing cells. The two cell types share common molecules that facilitate their synergistic interaction and possibly crosstalk, likely useful for the cell therapy of type 1 diabetes (T1D). Upon microencapsulation in sodium alginate (AG), hUCMS and hIDC were able to form cell co-aggregates that looked well integrated and viable. We then grafted microencapsulated hUCMS/hIDC co-aggregates into non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice, and observed an acquired ability of cells to produce and store hormones. Finally, we transplanted these biohybrid constructs into NOD mice with recent onset, spontaneous overt diabetes, observing a decline of blood glucose levels. In vitro, we have shown that hUCMS inhibited proliferation of allogeneic polymorphonuclear blood cells from patients with T1D, while promoting expansion of FoxP3+ Tregs. Reversal of hyperglycemia in diabetic NODs seems to suggest that hUCMS and hIDC, upon co-microencapsulation, anatomically and functionally synergized to accomplish two goals: maintain tracer insulin output by hIDC, while exploting the immunoregulatory properties of hUCMS. We have gathered preliminary evidence that the two adult stem cell types within AG microcapsules, may synergistically promote tracer insulin production, while "freezing" the autoimmune disease process, and help reversal of the recent onset hyperglycemia in a spontaneous, autoimmune rodent model of diabetes, the NOD mouse, with no need for pharmacologic immunosuppression.


Differential sensitivity of integrity criteria as indicators of cadmium-induced cell damage.
The reliability of the stainability by Trypan Blue (TB) to detect membrane damage in hepatocyte suspensions of different TB stainability and in freshly isolated cells exposed to 50 microM cadmium (Cd) for 60 min was assessed by comparison with the leakage of lactate dehydrogenase (LDH) and NADH-oxidation. The cellular nitrophenyl-phosphate (NPP) uptake and the digitonin-induced fluorescence of 8-anilinonaphthalene-sulfonate-1 (dig-ANS-F) were introduced as integrity parameters of hepatocytes and compared with TB stainability. Cd was without effect on all these parameters. LDH-leakage was a poor criterion, whereas NADH-oxidation and dig-ANS-F were as sensitive as TB stainability. The NPP-uptake was more sensitive than TB stainability to indicate toxic Cd-effects when the plasma membrane still seemed to be intact. Because of the enhanced extracellular NPP-degradation, which resulted from the release of alkaline phosphatase, NPP-uptake was useful as a measure of Cd-induced damage only under certain conditions. These results confirm TB stainability as a simple and reliable criterion for plasma membrane integrity and therefore viability of hepatocytes also in Cd-toxicity.


Apg-2 has a chaperone-like activity similar to Hsp110 and is overexpressed in hepatocellular carcinomas.
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. We constructed subtracted cDNA libraries enriched with genes overexpressed in HCCs. Among the 17 genes identified were molecular chaperones, Hsp110, Hsp90B, and Hsp70-1. Expression of the Hsp110 family members was further analyzed, and increased transcript levels of Hsp110 and Apg-2, but not Apg-1, were found in 12 and 14, respectively, of 18 HCCs. Immunohistochemical analysis demonstrated the overexpression of the proteins in tumor cells. Apg-2 had chaperone ability similar to Hsp110 in a thermal denaturation assay using luciferase, and showed anti-apoptotic activity. These results suggest that the Hsp110 family members play important roles in hepatocarcinogenesis through their chaperoning activities.