24(S),25-Epoxycholesterol. Evidence consistent with a role in the regulation of hepatic cholesterogenesis.
Previously we showed that 24(S),25-epoxycholesterol is formed from acetate, via squalene 2,3(S),22(S),23-dioxide and 24(S),25-oxidolanosterol, during the normal course of cholesterol biosynthesis in S10 rat liver homogenate (Nelson, J. A., Steckbeck, S. R., and Spencer, T. A. (1981) J. Biol. Chem. 256, 1067-1068; Nelson, J. A., Steckbeck, S. R., and Spencer, T. A. (1981) J. Am. Chem. Soc. 103, 6974-6975). Herein we demonstrate that the nonsaponifiable extract from human liver tissue contains 24(S),25-epoxycholesterol in an amount approximately 10(-3) relative to cholesterol. We show that 24(S),25-epoxycholesterol, like many other oxygenated sterols, represses hydroxymethylglutaryl-CoA reductase activity in cultured cells and binds to the cytosolic oxysterol-binding protein. Furthermore, we show that this epoxide is not rapidly metabolized in cultured cells. These results suggest that 24(S),25-epoxycholesterol may participate in the regulation of hepatic cholesterol metabolism in vivo.


Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia.
Central core disease (CCD) of muscle is an inherited myopathy which is closely associated with malignant hyperthermia (MH) in humans. CCD has recently been shown to be tightly linked to the ryanodine receptor gene (RYR1) and mutations in this gene are known to be present in MH. Mutation screening of RYR1 has led to the identification of two previously undescribed mutations in different CCD pedigrees. One of these mutations was also detected in an unrelated MH pedigree whose members are asymptomatic of CCD. The data suggest a model to explain how a single mutation may result in two apparently distinct clinical phenotypes.


The effect of active and passive maternal smoking before and during pregnancy on neonatal weight at birth.
Smoking during pregnancy is a risk factor for adverse pregnancy outcomes. Data on the correlation between passive maternal smoking and pregnancy outcomes remain limited. We investigated the effect of active smoking and environmental tobacco smoke (ETS) during pregnancy on neonatal birthweight, including the risk for low birthweight (LBW). The study was conducted between 2010 and 2012. A group of 8625 women were surveyed during postpartum hospitalization. Outcome measures included mean birthweight of newborns. Additionally, odds ratios with confidence intervals were calculated to investigate the risk for LBW in active and passive smoking groups of mothers. Lower birthweight (46 g - 307 g; p < 0.05) and a higher risk for LBW (OR = 1.35, 95% CI: 1.05-1.75; p < 0.05) were observed in all infants born to smoking mothers. A negative effect of ETS in pregnancy on the reduction of mean birthweight was also found. Additionally, we analyzed the cumulative effect of active and passive smoking on neonatal birthweight. A statistically significant reduction in neonatal weight at birth was found in a group of women who smoked actively and passively during pregnancy (130 g; p < 0.05). Smoking is associated with decreased birthweight and in a group of active smoking mothers increased risk for LBW. This effect is dose-dependent and is also present in a group of women who smoked before pregnancy. There is also a cumulative effect of active smoking and ETS causing decreased neonatal birthweight and increased risk for low birthweight.


Impaired physiological function and health-related QOL in patients before hematopoietic stem-cell transplantation.
Patients' physiological functions and health-related quality of life (QOL) are useful for planning physical therapy after allogeneic hematopoietic stem-cell transplantation (allo-HSCT), but have not been extensively examined prior to transplantation. We investigated whether physiological functions and health-related QOL were reduced in patients before undergoing allo-HSCT. All patients (n = 110) who underwent allo-HSCT between May 2007 and April 2010 at Hyogo College of Medicine Hospital were included in this study and evaluated for hand-grip and knee-extensor strength; 6-min walk test (6MWT) and health-related QOL (SF-36) were also used for evaluation. Grip strength, knee-extensor strength, 6MWT, and all eight SF-36 health-related QOL subscale scores significantly decreased in HSCT patients compared to population norms (all, P < 0.01). Health-related QOL is associated with various confounding factors such as fatigue and sex. Loss of physiological function is also associated with confounding factors; one such association was found between skeletal muscle strength and previous HSCT treatment. Health-related QOL and loss of physiological function have a variety confounding factors. Patients scheduled for HSCT may have physiological weaknesses prior to transplant, which need to be considered when planning an exercise regimen during and after transplantation.


Stigma and psychological distress among pediatric participants in the FD/MAS Alliance Patient Registry.
Stigma, both enacted and internalized, is part of the illness experience of many chronic conditions / diseases and has been found to increase psychological distress, lower self-esteem, and impact social engagement lowering quality of life (QOL). Stigma among pediatric patients is of particular concern due to its potential impact on identity formation. Using patient data from the online FD/MAS Alliance Patient Registry (FDMASAPR), this study seeks to 1) determine levels of enacted and self-stigma in a pediatric population of fibrous dysplasia (FD) / McCune Albright syndrome (MAS) patients and 2) to explore the relationship between stigma and anxiety and depression. This is a cross sectional analysis of deidentified self-report data from 18 pediatric patients. Key analytic variables include the Neuro-QOL stigma short form, the Hospital Anxiety and Depression Scale (HADS), diagnostic category and craniofacial involvement, and select demographics. Sample means and score distributions are examined. Bivariate relationships between stigma, anxiety and depression and patient's personal and medical characteristics are established through analysis of variance and correlation. Composite stigma levels for FD/MAS pediatric patients were comparable to those of children with multiple sclerosis, epilepsy, and muscular dystrophy. Self-stigma was more frequently reported than enacted/felt stigma, but few patients indicated complete freedom from either type of stigma. Diagnosis was significantly related to self-stigma. Significant bivariate relationships were found between depression and enacted/felt and self-stigma and between anxiety and self-stigma. This study establishes the illness experience of pediatric patients with FD / MAS is impacted by stigma and suggests they should be regularly screened for stigma and psychological distress. It supports the integration of clinical psychologists/ therapists in regular patient care, referral of families to advocacy organizations, and indicates that rare disease patient registries can be a useful tool in efforts to improve the QOL of patients.


DNA characterization by transverse electrical current in a nanochannel.
We review an approach for the characterization of single-stranded DNA based on the statistical identification of single bases via transverse electronic transport while DNA translocates in a nanopore or nanochannel. We describe the theoretical methods used to demonstrate this method for experimentally realizable systems and discuss the different physical processes involved. Recent experimental reports have shown the validity of this approach, although further work is necessary to make this a practical fast sequencing tool.


Comparison of three non-insulin-based insulin resistance indexes in predicting the presence and severity of coronary artery disease.
Insulin resistance (IR) has emerged as a risk factor for coronary heart disease (CAD), but there is currently insufficient data on the association of non-insulin-based IR indexes [triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio, triglyceride and glucose (TyG) index, and metabolic score for IR (METS-IR)] with the presence and severity of CAD. Thus, the present study aimed to examine the relationship between these three non-insulin-based IR indexes and CAD, as well as to further compare the predictive values of each index. In total, 802 consecutive patients who underwent coronary angiography for suspected CAD from January 2016 to April 2017 were included in this study and were divided into the control group (n = 149) and CAD group (n = 653) according to the angiography results. The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose index (TyG index), and METS-IR were calculated according to the corresponding formulas. The severity of CAD was evaluated using the Gensini score (GS). The relationship of the TG/HDL-C ratio, TyG index, and METS-IR with CAD was analyzed, and the predictive values of the indexes were compared. The TG/HDL-C ratio, TyG index, and METS-IR in the CAD group were significantly higher than those in the control group. The TG/HDL-C ratio and METS-IR in the high GS group were significantly higher than those in the non-high GS group. Multivariate logistic regression analysis showed that the TG/HDL-C ratio and METS-IR were independent predictors for the presence of CAD {adjusted odds ratio (OR) [95% confidence interval (CI)]: 1.32 (1.02-1.70) and 1.65 (1.32-2.05), respectively}, whereas only the METS-IR was an independent predictor of the severity of CAD [adjusted OR (95% CI): 1.22 (1.02-1.47)]. Further subgroup analysis indicated that statistical significance was observed only among men, younger patients (≤ 60), and patients with prediabetes mellitus (PDM). Receiver operator characteristic (ROC) analysis showed that the METS-IR had the highest predictive value for the prediction of both the presence and severity of CAD. The TG/HDL-C ratio, TyG index, and METS-IR are valuable predictors of the presence and severity of CAD, and the METS-IR has the highest predictive value among the three non-insulin-based IR indexes.


Copper-Sulfur Complexes Supported by N-Donor Ligands: Towards Models of the Cu(Z) Site in Nitrous Oxide Reductase.
The distinctive structure of the [(his)(7)Cu(4)(μ-S)](n+) cluster in the "Cu(Z)" active site of nitrous oxide reductase and the intriguing mechanistic hypotheses for its catalytic reactivity provide inspiration for synthetic model studies aimed at characterizing relevant copper-sulfur compounds and obtaining fundamental insights into structure and bonding. In this brief review, we summarize such studies that have focused on the synthesis and characterization of a range of copper-sulfur complexes supported by N-donor ligands. Compounds with variable nuclearities and sulfur redox levels have been isolated, with the nature of the species obtained being dependent on the supporting ligand, sulfur source, and the reaction conditions. Spectroscopic data and theoretical calculations, often performed with a view toward drawing comparisons to oxygen analogs, have provided insight into the nature of the copper-sulfur bonding interactions in the complexes.


[Pulmonary hypertension in interstitial lung diseases: diagnostic and therapeutic approach in 2011?].
Pulmonary hypertension is frequent in late-stage idiopathic pulmonary fibrosis, and is associated with a shorter survival. It should be suspected in case of dyspnea or hypoxemia disproportionate with the degree of parenchymal lung disease. It is particularly frequent in patients with the syndrome of combined pulmonary fibrosis and emphysema, and associated with a short survival (median survival less than 1 year). Pulmonary hypertension associated with chronic infiltrative lung diseases can be detected by echocardiography and must be confirmed by right-sided heart catheterization, especially to rule out post-capillary pulmonary hypertension frequent in this context. Management is mainly palliative and based on supplemental nasal oxygen. Therapy specific for pulmonary arterial hypertension, poorly evaluated in pulmonary hypertension associated with infiltrative lung diseases, is occasionally proposed to patients with disproportionate pulmonary hypertension (mean PAP > 35 mmHg), with often limited efficacy, and requiring careful follow-up (risk of increased hypoxemia) and invasive evaluation. Pulmonary transplantation should be considered in the absence of contra-indication.


Estimation of overdiagnosis in colorectal cancer screening with sigmoidoscopy and faecal occult blood testing: comparison of simulation models.
To estimate overdiagnosis of colorectal cancer (CRC) for screening with sigmoidoscopy and faecal occult blood testing (FOBT). Simulation study using data from randomised trials. Primary screening, UK, Norway PARTICIPANTS: 152 850 individuals from the Nottingham trial and 98 678 individuals from the Norwegian Colorectal Cancer Prevention (NORCCAP) trial. CRC screening. We estimated overdiagnosis using long-term data from two randomised trials: the Nottingham trial comparing FOBT screening every other year to no-screening, and the NORCCAP trial comparing once-only sigmoidoscopy screening to no-screening. To estimate the natural growth of adenomas to CRC, we used the following microsimulation models: (i) the Microsimulation Screening Analysis; (ii) the CRC Simulated Population model for Incidence and Natural history; (iii) the Simulation Model of Colorectal Cancer; (iv) a model derived by the German Cancer Research Center. We defined overdiagnosed cancers as the difference between the observed number of CRCs in the no-screening arm and the expected number of cancers in screening arm (sum of observed and prevented by adenoma removal). The amount of overdiagnosis is defined as the number of overdiagnosed cancers over the number of cancers observed in the no-screening arm. Overdiagnosis estimates were highly dependent on model assumptions. For FOBT screening with 2354 cancers observed in control arm, four out of five models predicted overdiagnosis, range 2.0% (2400 cancers expected in screening) to 7.6% (2533 cancers expected in screening). For sigmoidoscopy screening with 452 cancers observed in control arm, all models predicted overdiagnosis, range 25.2% (566 cancers expected in screening) to 128.1% (1031 cancers expected in screening). The amount of overdiagnosis estimated based on the microsimulation models varied substantially. Microsimulation models may not give reliable estimates of the preventive effect of adenoma removal, and should be used with caution to inform guidelines.


Aluminum dust exposure and risk of neurodegenerative diseases in a cohort of male miners in Ontario, Canada.
We estimated associations between respirable aluminum exposure through McIntyre Powder (MP), a fine-sized aluminum and aluminum compound powder, and neurological disease in a retrospective cohort of mining workers from Ontario, Canada. Outcomes included Alzheimer's disease, Alzheimer's with other dementias, Parkinson's disease, parkinsonism, and motor neuron disease. The cohort was created by linking a database of mining workers' work history to healthcare records. This analysis included 36 826 male miners potentially exposed to MP between 1943 and 1979, followed up for disease diagnosis between 1992 and 2018. Exposure was assessed using two approaches, self-reported and historical records. Neurological diseases were ascertained using physician billing and hospital discharge records. Poisson regression models were used to estimate associations between MP exposure and neurological outcomes using incidence rate ratios (RR) and 95% confidence intervals (95% CI). Exposure to self-reported MP was associated with an elevated incidence rate of Parkinson's disease (RR 1.34, 95% CI 1.14-1.57). The rate of Parkinson's disease appeared to increase with the duration of exposure assessed by historical records. Having ever been exposed to MP was positively associated with an elevated rate of Alzheimer's with other dementias (RR 1.12, 95% CI 1.06-1.19) but not Alzheimer's disease alone. This study found that miners who were exposed to MP (respirable aluminum) had elevated rates of Parkinson's disease. The rate of Parkinson's disease appeared to increase with the duration of exposure assessed by historical records.


Long-term treatment of bipolar disorder type I: A systematic and critical review of clinical guidelines with derived practice algorithms.
This systematic review aimed at providing a critical, comprehensive synthesis of international guidelines' recommendations on the long-term treatment of bipolar disorder type I (BD-I). MEDLINE/PubMed and EMBASE databases were searched from inception to January 15th, 2019 following PRISMA and PICAR rules. International guidelines providing recommendations for the long-term treatment of BD-I were included. A methodological quality assessment was conducted with the Appraisal of Guidelines for Research and Evaluation-AGREE II. The final selection yielded five international guidelines, with overall good quality. The evaluation of applicability was the weakest aspect across the guidelines. Differences in their updating strategies and the rating of the evidence, particularly for meta-analyses, randomized clinical trials (RCTs) and observational studies, could be responsible of some level of heterogeneity among recommendations. Nonetheless, the guidelines recommended lithium as the 'gold standard' in the long-term treatment of BD-I. Quetiapine was another possible first-line option as well as aripiprazole (for the prevention of mania). Long-term treatment should contemplate monotherapy, at least initially. Clinicians should check regularly for efficacy and side effects and if necessary, switch to first-line alternatives (i.e. Valproate), combine first-line compounds with different mechanisms of action or switch to second-line options or combinations. The possibility to monitor improvements in long-term outcomes, namely relapse prevention and inter-episode subthreshold depressive symptoms, based on the application of their recommendations is an unmet need of clinical guidelines. In terms of evidence of clinical guidelines, there is a need for more efficacious treatment strategies for the prevention of bipolar depression.


Effect of fluid and food intake on the body composition evaluation of elderly persons.
Several studies have shown that liquid and food intake interfere with the evaluation of body composition in adults. However, since there are no reports about this interference in the elderly population, the need to fast for this evaluation may be dispensable. The objective of the present study was to assess the influence of liquid and solid food on the measurement of body composition by bioelectrical impedance analysis (BIA) and by dual energy X-ray absorptiometry (DXA). Forty-one male volunteers aged 62 to 87 years participated in the study. The subjects were submitted to evaluation of body composition by DXA and BIA under fasting conditions and 1 hour after the ingestion of breakfast (500 ml of orange juice and one 50 g bread roll with butter). There was no significant difference in the variables fat-free mass (FFM) or fat mass (FM) between the fasting condition and the evaluation performed 1 hour after the meal as measured by BIA or DXA. There was also no significant difference when the same variables were compared between methods. In the present study, the ingestion of 500 ml orange juice and of one bread roll with butter by elderly subjects did not affect the results of the parameters of body composition determined by BIA or DXA. Thus, these exams could be performed without the rigor of fasting, often poorly tolerated by the elderly.


Effectiveness of soil conditioners to enhance salt extraction ability of Salicornia ramosissima in saline-sodic soil for different soil moisture contents.
Soil salinity is considered one of the main types of soil degradation in semiarid environments around the globe. This work aims to evaluate the effectiveness of soil conditioners to enhance the growth and salt extraction ability of Salicornia ramosíssima for different soil moisture contents. Salicornia plants were cultivated in pots in which the soils were treated with the following conditioners: control; gypsum + organic matter; elemental sulfur + organic matter; and gypsum + elemental sulfur + organic matter. Salicornia plants were subjected to two soil moisture rates - at 35 and 85% field capacity. Soil conditioners associated with higher contents of soil moisture promoted significant increases, compared to control, in fresh (6.20 - 11.13 g) and dry matter (1.20 - 2.07 g), relative biomass (100 - 179%) as well as significantly increased the concentrations of Na+ (56.09 - 65.64 mg kg-1) and Cl- (110.83 - 150.0 mg kg-1) in plant tissues. Soil conditioners significantly increased salt extraction ability under the two moisture levels, mainly by promoting higher values for both transfer factor and phytoremediation potential. The best performance of Salicornia in terms of plant yield and salt extraction, regardless of the moisture level, was the gypsum + organic matter.Novelty statementThere are no studies in the literature relating the use of conditioners as a strategy to enhance Salicornia's ability to extract salts.This work contributes to the management of salinized areas around the globe in two main aspects. The first is that many of these salt-degraded areas are desertified and through this study, it is possible to revegetate and recover them. The second one is that, since Salicornia is a plant with economic value, this can serve as an incentive for farmers to grow Salicornia in saline areas.


High S100A2 expression in keratinocytes in patients with drug eruption.
Telaprevir used as a protease inhibitor against hepatitis C virus is frequently associated with cutaneous adverse reactions. To explore a histological biomarker of cutaneous adverse events induced by telaprevir, we systematically searched for genes that were dysregulated by telaprevir in normal human epidermal keratinocytes (NHEKs). Microarray analysis and real-time polymerase chain reaction (PCR) revealed the significant increase in the expression of S100 calcium-binding protein A2 (S100A2) gene following treatment of NHEKs with telaprevir. Immunohistochemical analysis demonstrated that the expression of S100A2 was dominant in the spinous layer of the epidermis in patients with telaprevir-mediated severe-type drug eruptions and limited to the basal layer of the epidermis in healthy subjects. Furthermore, S100A2 expression increased after treatment with trichloroethylene and other medications, and the degree of S100A2 expression correlated with the severity of cutaneous adverse events. S100A2 expression also significantly increased in the skin of patients with atopic dermatitis and psoriasis. Taken together, S100A2 is highly expressed in the epidermis under inflammatory conditions and drug eruptions and may serve as a marker for keratinocyte damage in response to any inflammatory or toxic condition.


Morphology and measurements of the cervical spinal cord in computer-assisted myelography.
Thirty-six control subjects had computer assisted myelography (CAM) using the EMI CT 5005 scanner. The normal cervical cord is elliptical, more circular at the upper and lower ends and flatter in the mid-segments. Asymptomatic cord deformities, usually mild, were present in nine subjects (25%). Four measurements, namely, sagittal diameter (APD), transverse diameter (TD), area (a) and circumference (c) were made and two more parameters calculated i.e. APD/TD ratio and circularity (= 4 pi a/c2). These control values form the basis of qualitative and quantitative assessment of cord deformity. When cord measurements are to be used, control values should be obtained for each scanner and procedures should be standardized.


Cellular ubiquitination and proteasomal functions positively modulate mammalian nucleotide excision repair.
The ubiquitin-proteasome pathway is fundamental to synchronized continuation of many cellular processes, for example, cell-cycle progression, stress response, and cell differentiation. Recent studies have shown that the ubiquitin-proteasome pathway functions in the regulation of nucleotide excision repair (NER) in yeast. In order to investigate the role of the ubiquitin-proteasome pathway in the NER of mammalian cells, global genomic repair (GGR), and transcription-coupled repair (TCR) were examined in a mouse ts20 cell line that harbors a temperature-sensitive ubiquitin-activating enzyme (E1). We found that E1 inactivation-induced ubiquitination deficiency decreased both GGR and TCR, indicating that the ubiquitination system is involved in the optimization of entire NER machinery in mammalian cells. We specifically inhibited the function of 19S proteasome subunit by overexpressing 19S regulatory complex hSug1 or its mutant protein hSug1mk in repair competent human fibroblast, OSU-2, cells and compared their capacity for NER. The results showed that 19S regulatory complex positively modulates NER in cells. In addition, we treated OSU-2 cells with the inhibitors of 20S subunit function, MG132 and lactacystin, and demonstrated that the catalytic activity of 20S subunit is also required for efficient NER. Moreover, the UV-induced recruitment of repair factor xeroderma pigmentosum protein C (XPC) to damage sites was negatively affected by treatment of repair competent cells with MG132. Taken together, we conclude that the ubiquitin-proteasome pathway has a positive regulatory role for optimal NER capacity in mammalian cells and appears to act through facilitating the recruitment of repair factors to DNA damage sites.


Postoperative voiding function in patients undergoing tension-free vaginal mesh procedure for pelvic organ prolapse.
We compared pre- and postoperative voiding function in patients with POP and assessed the efficacy of urodynamic studies in these cases. Forty-six patients treated with the tension-free vaginal mesh (TVM) procedure between January 2009 and February 2010 underwent pressure flow study pre- and postoperatively. Pre- and postoperative voiding functions were assessed according to Schäfer nomograms. The mean postoperative detrusor pressure at maximal flow was decreased significantly compared with that preoperatively. The mean maximum flow rate was also improved significantly and the proportion of normal contractility was increased significantly after the operation, as was the proportion of non-obstructive patients. The TVM procedure for pelvic organ prolapse improved both detrusor contractility and urethral obstruction.


Normalization of wound healing and stem cell marker patterns in organ-cultured human diabetic corneas by gene therapy of limbal cells.
Overexpression of c-met and suppression of matrix metalloproteinase-10 (MMP-10) and cathepsin F genes was previously shown to normalize wound healing, epithelial and stem cell marker patterns in organ-cultured human diabetic corneas. We now examined if gene therapy of limbal cells only would produce similar effects. Eight pairs of organ-cultured autopsy human diabetic corneas were used. One cornea of each pair was treated for 48 h with adenoviruses (Ad) harboring full-length c-met mRNA or a mixture (combo) of Ad with c-met and shRNA to MMP-10 and cathepsin F genes. Medium was kept at the limbal level to avoid transduction of central corneal epithelium. Fellow corneas received control Ad with EGFP gene. After additional 5 (c-met) or 10 days (combo) incubation, central corneal epithelial debridement with n-heptanol was performed, and wound healing times were determined microscopically. Corneal cryostat sections were immunostained for diabetic and putative limbal stem cell markers, α3β1 integrin, nidogen-1, fibronectin, laminin γ3 chain, ΔNp63α, keratins 14, 15, and 17, as well as for activated signaling intermediates, phosphorylated EGFR, Akt, and p38. Limbal c-met overexpression significantly accelerated healing of 8.5-mm epithelial wounds over EGFP controls (6.3 days vs. 9.5 days, p < 0.02). Combo treatment produced a similar result (6.75 days vs. 13.5 days, p < 0.03). Increased immunostaining vs. EGFP controls for most markers and signaling intermediates accompanied c-met gene or combo transduction. Gene therapy of limbal epithelial stem cell compartment has a beneficial effect on the diabetic corneal wound healing and on diabetic and stem cell marker expression, and shows potential for alleviating symptoms of diabetic keratopathy.


Myelin-phagocytosing macrophages modulate autoreactive T cell proliferation.
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) in which macrophages play a central role. Initially, macrophages where thought to be merely detrimental in MS, however, recent evidence suggests that their functional phenotype is altered following myelin phagocytosis. Macrophages that have phagocytosed myelin may be less inflammatory and may exert beneficial effects. The presence of myelin-containing macrophages in CNS-draining lymph nodes and perivascular spaces of MS patients suggests that these cells are ideally positioned to exert an immune regulatory role. Therefore we evaluated in this study the effect of myelin-phagocytosing macrophages on lymphocyte reactivity. Thioglycolate-elicited rat peritoneal macrophages were loaded with myelin and cocultured with myelin-basic protein (MBP) or ovalbumin (OVA) reactive lymphocytes. Lymphocyte proliferation was determined by CFSE-labeling. The role of nitric oxide in regulating lymphocyte proliferation was assessed by addition of an inhibitor of inducible nitric oxide synthase to the coculture. In vivo immune regulation was investigated by treating MBP- and OVA-immunized animals subcutaneously with myelin. Cognate antigen specific lymphocyte proliferation and nitric oxide production were determined 9 d post-immunization. In this study we demonstrate that myelin-phagocytosing macrophages inhibit TCR-triggered lymphocyte proliferation in an antigen-independent manner. The observed immune suppression is mediated by an increase in NO production by myelin-phagocytosing macrophages upon contact with lymphocytes. Additionally, myelin delivery to primarily CD169+ macrophages in popliteal lymph nodes of OVA-immunized animals results in a reduced cognate antigen specific proliferation. In contrast to OVA-immunized animals, lymphocytes from MBP-immunized animals displayed an increased proliferation after stimulation with their cognate antigen, indicating that myelin-phagocytosing macrophages have dual effects depending on the specificity of surrounding lymphocytes. Collectively our data show that myelin phagocytosis leads to an altered macrophage function that inhibits lymphocyte proliferation. Additionally, results from this study indicate that myelin-phagocytosing macrophages fulfill a dual role in vivo. On one hand they aggravate autoimmunity by activating myelin-reactive lymphocytes and on the other hand they suppress lymphocyte reactivity by producing NO.


Cardiac isoform of alpha-2 macroglobulin--a new biomarker for myocardial infarcted diabetic patients.
Cardiac isoform of alpha-2 macroglobulin [cardiac alpha2M] has been shown to be an early marker in cardiac hypertrophy and left ventricular mass in humans. We, here, for the first time report its presence in myocardial infarcted humans and tried to explore the possibility of using this protein as a novel diagnostic marker for myocardial infarcted diabetic patients. A total of 260 samples were analyzed in this study for the presence of cardiac alpha2M. These include 55 patients of diabetic with post myocardial infarction [PMI], 45 diabetic patients without PMI, 60 patients of PMI alone and 100 controls without any ailments. Levels of cardiac alpha2M present in the sera of diabetic patients with PMI are significantly higher than that of normal human sera and diabetic patients without PMI but not with PMI alone group, suggesting this protein as a marker for PMI itself. However, our results reveal that cardiac alpha2M could be a valuable marker for the diagnosis of myocardial infarcted diabetic patients and differentiating them from diabetic patients without myocardial infarction by sandwich ELISA.


Dendritic Cell-Specific Role for Pellino2 as a Mediator of TLR9 Signaling Pathway.
Ubiquitination regulates immune signaling, and multiple E3 ubiquitin ligases have been studied in the context of their role in immunity. Despite this progress, the physiological roles of the Pellino E3 ubiquitin ligases, especially Pellino2, in immune regulation remain largely unknown. Accordingly, this study aimed to elucidate the role of Pellino2 in murine dendritic cells (DCs). In this study, we reveal a critical role of Pellino2 in regulation of the proinflammatory response following TLR9 stimulation. Pellino2-deficient murine DCs show impaired secretion of IL-6 and IL-12. Loss of Pellino2 does not affect TLR9-induced activation of NF-κB or MAPKs, pathways that drive expression of IL-6 and IL-12. Furthermore, DCs from Pellino2-deficient mice show impaired production of type I IFN following endosomal TLR9 activation, and it partly mediates a feed-forward loop of IFN-β that promotes IL-12 production in DCs. We also observe that Pellino2 in murine DCs is downregulated following TLR9 stimulation, and its overexpression induces upregulation of both IFN-β and IL-12, demonstrating the sufficiency of Pellino2 in driving these responses. This suggests that Pellino2 is critical for executing TLR9 signaling, with its expression being tightly regulated to prevent excessive inflammatory response. Overall, this study highlights a (to our knowledge) novel role for Pellino2 in regulating DC functions and further supports important roles for Pellino proteins in mediating and controlling immunity.


Immunosuppressant Tacrolimus Treatment Delays Acute Seizure Occurrence, Reduces Elevated Oxidative Stress, and Reverses PGF2α Burst in the Brain of PTZ-Treated Rats.
It is still an urgent need to find alternative and effective therapies to combat epileptic seizures. Tacrolimus as a potent immunosuppressant and calcineurin inhibitor is emerging as promising drug to suppress seizures. However, there are few reports applying tacrolimus to epilepsy and providing data for its antiseizure properties. In this study, we investigated the antiseizure effects of 5 and 10 mg/kg doses of tacrolimus treatment priorly to pentylenetetrazol (PTZ) induction of seizures in rats. As an experimental design, we establish two independent rat groups where we observe convulsive seizures following 70 mg/kg PTZ and sub-convulsive seizures detected by electroencephalography (EEG) following 35 mg/kg PTZ. Thereafter, we proceed with biochemical analyses of the brain including assessment of malondialdehyde level as an indicator of lipid peroxidation and detection of superoxide dismutase (SOD) enzyme activity and PGF2α. Tacrolimus pre-treatment dose-dependently resulted in lesser seizure severity according to Racine's scale, delayed start-up latency of the first myoclonic jerk and attenuated the spike percentages detected by EEG in seizure-induced rats. However, only the higher dose of tacrolimus was effective to restore lipid peroxidation. An increase in SOD activity was observed in the PTZ group, mediated by seizure activity per se, however, it was greater in the groups that received treatment with 5 and 10 mg/kg of Tacrolimus. PGF2α bursts following PTZ induction of seizures were reversed by tacrolimus pre-treatment in a dose-dependent manner as well. We report that the well-known immunosuppressant tacrolimus is a promising agent to suppress seizures. Comparative studies are necessary to determine the possible utilization of tacrolimus in clinical cases.


Mercury in blood and eggs of the sea turtle Lepidochelys olivacea from a nesting colony in Oaxaca, Mexico.
Mercury concentrations were assessed in the sea turtle Lepidochelys olivacea from a nesting colony of Oaxaca, Mexico; 25 female turtles were sampled, a total of 250 eggs were collected during the season 2005-2006. Higher concentrations were found in yolk fraction, while in blood and albumen mean levels were below of 0.0010μg g(-1) dry wt. On the basis of one nesting season, the maternal transfer of Hg via eggs-laying was estimated in 2.0±1.1%. According to international norms, the health of this population and its habitats is acceptable for Hg and corresponds to baseline levels of a nearly pristine environment.


In vitro and in vivo hypoglycemic effects of cyanidin 3-caffeoyl-p-hydroxybenzoylsophoroside-5-glucoside, an anthocyanin isolated from purple-fleshed sweet potato.
Anthocyanins are major components of purple sweet potatoes (PSP) with antioxidant, anti-obesity, and antidiabetic activity. In this study, we evaluated the hypoglycemic effects of 12 individual anthocyanins purified from PSP (Korean variety Shinzami). We separated the anthocyanins using liquid chromatography with diode array detection and electrospray ionization/mass spectrometry (LC-DAD-ESI/MS). Three anthocyanins were selected through a radical scavenging activity test. We examined whether individual anthocyanins inhibited glucose secretion in HepG2 cells (hepatic gluconeogenesis). Additionally, we determined the effect of each anthocyanin on fasting blood glucose levels in 6-week-old male C57BL/6J mice fed a 60% high-fat diet for 14 weeks. Mice were evaluated at 0, 1, 2, and 4 h after oral administration of anthocyanins (80 mg/kg), an anthocyanin-rich-fraction (80 mg/kg), positive control (metformin, 80 mg/kg), and distilled water (control). Cyanidin 3-caffeoyl-p-hydroxybenzoylsophoroside-5-glucoside (PEAK9) was the main PSP anthocyanin that inhibited hepatic glucose secretion and reduced blood glucose.


Chemotherapy: Current drugs still have potential in advanced ovarian cancer.
Dose-dense administration of paclitaxel as well as intraperitoneal administration of platinum and paclitaxel as first-line treatments provide similar advantages compared with standard treatment in advanced ovarian cancer. Both approaches, however, need to be confirmed by additional studies. a low dose of pegylated liposomal doxorubicin combined with carboplatin is superior to standard paclitaxel and carboplatin in relapsed platinum-sensitive ovarian cancer.


Neural Stem Cell Transplantation Promotes Functional Recovery from Traumatic Brain Injury via Brain Derived Neurotrophic Factor-Mediated Neuroplasticity.
Traumatic brain injury (TBI) induces cognitive impairments, motor and behavioral deficits. Previous evidences have suggested that neural stem cell (NSC) transplantation could facilitate functional recovery from brain insults, but their underlying mechanisms remains to be elucidated. Here, we established TBI model by an electromagnetic-controlled cortical impact device in the rats. Then, 5 μl NSCs (5.0 × 105/μl), derived from green fluorescent protein (GFP) transgenic mouse, was transplanted into the traumatic brain regions of rats at 24 h after injury. After differentiation of the NSCs was determined using immunohistochemistry, neurological severity scores (NSS) and rotarod test were conducted to detect the neurological behavior. Western blot and RT-PCR as well as ELASA were used to evaluate the expression of synaptophysin and brain-derived neurotrophic factor (BDNF). In order to elucidate the role of BDNF on the neural recovery after NSC transplantation, BDNF knockdown in NSC was performed and transplanted into the rats with TBI, and potential mechanism for BDNF knockdown in the NSC was analyzed using microassay analysis. Meanwhile, BDNF antibody blockade was conducted to further confirm the effect of BDNF on neural activity. As a result, an increasing neurological function improvement was seen in NSC transplanted rats, which was associated with the upregulation of synaptophysin and BDNF expression. Moreover, transplantation of BDNF knockdown NSCs and BDNF antibody block reduced not only the level of synaptophysin but also exacerbated neurological function deficits. Microassay analysis showed that 14 genes such as Wnt and Gsk3-β were downregulated after BDNF knockdown. The present data therefore showed that BDNF-mediated neuroplasticity underlie the mechanism of NSC transplantation for the treatment of TBI in adult rats.


Diet as a Source of Acrolein: Molecular Basis of Aldehyde Biological Activity in Diabetes and Digestive System Diseases.
Acrolein, a highly reactive α,β-unsaturated aldehyde, is a compound involved in the pathogenesis of many diseases, including neurodegenerative diseases, cardiovascular and respiratory diseases, diabetes mellitus, and the development of cancers of various origins. In addition to environmental pollution (e.g., from car exhaust fumes) and tobacco smoke, a serious source of acrolein is our daily diet and improper thermal processing of animal and vegetable fats, carbohydrates, and amino acids. Dietary intake is one of the main routes of human exposure to acrolein, which is a major public health concern. This review focuses on the molecular mechanisms of acrolein activity in the context of its involvement in the pathogenesis of diseases related to the digestive system, including diabetes, alcoholic liver disease, and intestinal cancer.


Scientific productivity in neurology: impact of the socio-economic status.
Scientific productivity is relevant to support clinical activity, improve therapeutic strategies, and understand the pathophysiological mechanisms of neurological disorders. We performed an updated bibliometric research to assess the country-specific relationship between neurological scientific production and socio-economic variables of dedicated resources. Neurological scientific productivity of 168 countries, from 1996 to 2019, was obtained using the SCImago online website. Data on gross domestic product (GDP), percentage of GDP spent in research and development, and number of researchers per million people were obtained using the World Bank Group website. The USA was the first country in terms of documents produced (260,030), followed by Germany (69,841), Japan (65,200), the UK (60,914), and Italy (50,017). Except for Japan, all the most productive countries had an increase in scientific productivity in the last 12 years. In 2019, the USA still ranked first in the number of neurological papers published, followed by Germany, the UK, Italy, and Japan. Among the most productive countries, Canada and Japan did not increase the percentage of GDP spent in research over time. Except for Canada and Japan, all the most productive countries increased the number of researchers in the last years. Our analysis provided novel evidence of the adequacy of the scientific return on country-specific investment of local dedicated resources.


Improved estimators for the rate parameter of gamma model using asymptotic properties.
In this paper we proposed three estimators namely linear shrinkage, preliminary test and shrinkage preliminary test for the rate parameter of univariate gamma. The salient feature of the proposed estimators is the admissibility property that is defined on belief of the uncertain prior information. Expressions for bias and relative efficiency under method of moment have been derived using asymptotic theory. A Monte Carlo simulation study shows that the proposed estimators are more efficient and minimally biased when prior information is close to the neighbourhood of the rate parameter.


Phase I study of conformal radiotherapy and concurrent full-dose gemcitabine with erlotinib for unresected pancreatic cancer.
To determine the recommended dose of radiotherapy when combined with full-dose gemcitabine and erlotinib for unresected pancreas cancer. Patients with unresected pancreatic cancer (Zubrod performance status 0-2) were eligible for the present study. Gemcitabine was given weekly for 7 weeks (1,000 mg/m(2)) with erlotinib daily for 8 weeks (100 mg). A final toxicity assessment was performed in Week 9. Radiotherapy (starting at 30 Gy in 2-Gy fractions, 5 d/wk) was given to the gross tumor plus a 1-cm margin starting with the first dose of gemcitabine. A standard 3 plus 3 dose escalation (an additional 4 Gy within 2 days for each dose level) was used, except for the starting dose level, which was scheduled to contain 6 patients. In general, Grade 3 or greater gastrointestinal toxicity was considered a dose-limiting toxicity, except for Grade 3 anorexia or Grade 3 fatigue alone. A total of 20 patients were treated (10 men and 10 women). Nausea, vomiting, and infection were significantly associated with the radiation dose (p = .01, p = .03, and p = .03, respectively). Of the 20 patients, 5 did not complete treatment and were not evaluable for dose-escalation purposes (3 who developed progressive disease during treatment and 2 who electively discontinued it). Dose-limiting toxicity occurred in none of 6 patients at 30 Gy, 2 of 6 at 34 Gy, and 1 of 3 patients at 38 Gy. The results of the present study have indicated that the recommended Phase II dose is 30 Gy in 15 fractions.


Characterization and fine mapping of the glabrous leaf and hull mutants (gl1) in rice (Oryza sativa L.).
The glabrous leaf and hull (gl1) mutants were isolated from M(2) generation of indica cultivar 93-11. These mutants produced smooth leaves and hairless glumes under normal growth conditions. By analyzing through scanning electron microscope, it was revealed that the leaf trichomes, including macro and micro hairs, were deficient in these mutants. Genetic analysis indicated that the mutation was controlled by a single recessive gene. Using nine SSR markers and one InDel marker, the gl1 gene was mapped between RM1200 and RM2010 at the short arm of chromosome 5, which was consistent with the mapping of gl1 in previous studies. To facilitate the map-based cloning of the gl1 gene, 12 new InDel markers were developed. A high-resolution genetic and physical map was constructed by using 1,396 mutant individuals of F(2) mapping population. Finally, the gl1 was fine mapped in 54-kb region containing 10 annotated genes. Cloning and sequencing of the target region from four gl1 mutants (gl1-1, gl1-2, gl1-3 and gl1-4) and four glabrous rice varieties (Jackson, Jefferson, Katy and Lemont) all showed that the same single point mutation (A-->T) occurred in the 5'-untranslated region (UTR) of the locus Os05g0118900 (corresponding to the 3'-UTR of STAR2). RT-PCR analysis of the locus Os05g0118900 revealed that its mRNA expression level was normal in gl1 mutant. RNA secondary structure prediction showed that the single point mutation resulted in a striking RNA conformational change. These results suggest that the single point mutation is most likely responsible for the glabrous leaf and hull phenotypes in rice.


Sinus inflammation associated with contralateral inverted papilloma.
To assess with computerized tomography (CT) the association of unilateral inverted papilloma (IP) and contralateral sinus inflammation. Retrospective analysis of CTfindings in a sample of patients with unilateral IP, a sample with other unilateral sinonasal tumors, and normal controls. Sixteen patients with unilateral IP comprised the study population. Nine patients with other unilateral sinonasal tumors (five with squamous papilloma, two with squamous cell carcinoma, and one each with adenocarcinoma and large cell carcinoma) were used as a comparison population. Patients undergoing maxillofacial CTfor nontraumatic orbital conditions comprised the control sample (n = 12 sides). Each patient's preoperative CT scan was evaluated with a modified Lund-Mackay scoring system. The scores for the sides opposite the IPs were compared with the sides contralateral to other sinonasal tumors as well as to normal controls. Analysis of all three samples' contralateral sides simultaneously using analysis of variance revealed a difference (p = 0.010). The contralateral sinus scores in IPs tended to be higher than the sides opposite the other sinonasal tumors (mean, 2.66 +/- 1.07 versus 1.18 +/- 0.76; p = 0.06). These in turn were higher than the normal controls (mean, 0.75 +/- 0.48; p < 0.02). Unilateral IPs are associated with contralateral inflammation as detected by CT. This degree of contralateral inflammation is greater than that seen in other sinonasal tumors. The etiology of this association is unclear. A recent histological review suggested IP is an inflammatory polyp and not a true papilloma. Our data further suggest inflammation may be involved in the pathogenesis of IP. Further work is needed to better understand the pathophysiology and behavior of IP and to define its relationship to sinus inflammation.


Separation of cathepsin D-like proteinase and acid thiol proteinase of squid mantle muscle.
When the proteinases of the squid mantle muscle were extracted in the presence of dithiothreitol (DTT), the acid proteinase activity increased, indicating that the squid mantle muscle contains a considerable amount of the acid thiol proteinase. The crude extract hydrolyzed neither alpha-N-benzoyl-D,L-arginine-p-nitroanilide (BAPA) nor azocasein, thus refuting the presence of cathepsins B and L in the mantle muscle. The cathepsin D-like proteinase and the acid thiol proteinase were separated by Sephadex A-50 column chromatography. Each of the above partially purified proteinases was able to degrade carp actomyosin at pH 2.5 and 5.0, respectively.


Social determinants do not affect access to specialized epilepsy care in veterans.
It is well established that sociodemographic and neighborhood determinants impact access to healthcare. Veterans with epilepsy (VWE) face unique challenges that may limit access to specialized epilepsy care, though institutional initiatives have aimed to minimize disparities. We assessed the extent to which surrogate markers of access to quality care in VWE were impacted by sociodemographic and neighborhood determinants. The sample included 180 VWE. Surrogate markers included time between initial diagnosis and admission to epilepsy monitoring unit (EMU) (time to referral, TTR), and the number of CT, MRI, and EEGs conducted prior to initial EMU evaluation. Sociodemographic and neighborhood determinants included age, sex, race, education, neighborhood advantage, rural status, distance from home to the nearest VAMC, and number of service connection (SC) conditions. Significant correlations across variables of interest were entered into a linear regression. Group differences between social factors were assessed for early and late TTR groups (based on 1st and 4th quartiles). The mean TTR was 12 years (SD ± 13.18). Longer TTR was correlated to older age (p < 0.001) and fewer SC conditions (p = 0.03). None of the other factors were significantly correlated to TTR. Older age significantly predicted longer TTR on regression. The earlier TTR group was younger, had more SC conditions, lived closer to a VAMC, and was more likely to be female. Greater geographic distance was correlated with fewer CT scans (p = 0.01). A greater number of MRIs was correlated with older age (p = 0.04). Younger age (p < 0.01) and greater education (p = 0.01) were correlated with more SC. Access to epilepsy care among VWE was largely unimpacted by social determinants, with the exception of older age leading to longer TTR. The TTR in VWE was considerably shorter than has been reported in the literature for civilian patients. The Veterans Health Administration model of care may harbor certain advantages in epilepsy treatment.


Cerebral blood flow velocity and oxygenation correlate predominantly with right ventricular function in cooled neonates with moderate-severe hypoxic-ischemic encephalopathy.
The relationship between right ventricular (RV) function and cerebral blood flow (CBF) velocity and cerebral oxygenation was assessed in neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH). Echocardiographic, transcranial Doppler, and hemodynamic data from 37 neonates with moderate-severe HIE + TH were reviewed. Twenty healthy newborns served as controls. Cardiac dysfunction in HIE + TH was characterized by a predominant RV dysfunction, with concomitantly reduced CBF velocity. A significant correlation was found between CBF velocity and tricuspid annular plane systolic excursion (TAPSE), RV output (RVO), and stroke volume (SVRV), as well as with left ventricular output and stroke volume. Brain oxygenation (rSO2) correlated significantly with RVO, SVRV, TAPSE, ejection fraction, and fractional shortening, whereas cerebral fractional tissue oxygen extraction (FTOEc) correlated with RVO, SVRV, RV myocardial performance index, and superior vena cava flow. CBF velocity and cerebral NIRS correlations were stronger with parameters of right ventricular performance.Conclusion: CBF velocity and brain oxygenation correlate predominantly with RV function in HIE + TH. This suggests a preferential contribution of RV performance to cerebral hemodynamics in this context. What is Known: • Neonates with hypoxic ischemic encephalopathy frequently exhibit alterations of cardiac function and cerebral blood flow. • These are considered organ-specific consequences of perinatal asphyxia. What is New: • We show that cerebral blood flow velocity and brain oxygenation are correlated predominantly with right ventricular function during therapeutic hypothermia. • This suggests a potential direct contribution of right ventricular performance to cerebral hemodynamics in this context.


Mesangial cells in the pathogenesis of progressive glomerular disease in animal models.
Increasing evidence supports a role for glomerular mesangial cell proliferation and over-production of extracellular matrix by mesangial cells in the development of focal or diffuse glomerulosclerosis. Experimental data obtained mainly in the chronic progressive remnant kidney model and in the acute mesangioproliferative anti-Thy 1.1 glomerulonephritis in rats have shed some insights into the factors governing mesangial cell proliferation and matrix synthesis in vivo. In these experimental models, mesangial cell activation can be demonstrated early in the course of disease as exemplified by the de novo expression by the mesangial cell of a smooth muscle "specific" actin isotype (i.e., alpha-smooth muscle actin). Following mesangial cell activation, cellular proliferation ensues both in the acute anti-Thy 1.1 model and, to a lesser degree, in the chronic remnant kidney model. While a multitude of mitogens for mesangial cells has been proposed on the basis of in vitro experiments, the factors involved in the regulation of mesangial cell proliferation in vivo remain largely undefined. Three growth factors which may have important roles in the in vivo mesangioproliferative response are platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and transforming growth factor-beta (TGF-beta). All three cytokine growth factors are present in various inflammatory cells as well as in mesangial cells themselves, thereby allowing these factors to mediate cell proliferation by either paracrine and/or autocrine pathways. In vivo studies show that PDGF, bFGF, and TGF-beta participate in the mesangial cell proliferation and/or the mesangial matrix expansion that follows mesangial cell injury with anti-Thy 1.1 antibody.(ABSTRACT TRUNCATED AT 250 WORDS)


Characterization of Self-Assembled Monolayers on a Ruthenium Surface.
We have modified and stabilized the ruthenium surface by depositing a self-assembled monolayer (SAM) of 1-hexadecanethiol on a polycrystalline ruthenium thin film. The growth mechanism, dynamics, and stability of these monolayers were studied. SAMs, deposited under ambient conditions, on piranha-cleaned and piranha + H2SO4 cleaned substrates were compared to monolayers formed on H-radical-cleaned Ru surfaces. We found that alkanethiols on H-radical-cleaned Ru formed densely packed monolayers that remained stable when kept in a nitrogen atmosphere. X-ray photoelectron spectroscopy (XPS) shows a distinct sulfur peak (BE = 162.3 eV), corresponding to metal-sulfur bonding. When exposed to ambient conditions, the SAM decayed over a period of hours.


Evaluation of fibrinolytic capacity in plasma during thrombolytic therapy with single (scu-PA) or two-chain urokinase type plasminogen activator (tcu-PA) by a combined assay system for urokinase type plasminogen activator antigen and function.
A combined assay for urokinase type plasminogen activator (u-PA) activity and antigen determination in plasma samples is described. This assay is based on binding of u-PA to an antibody immobilized on a microtiter plate followed by determination of the enzymatic activity of the bound u-PA. Thereafter bound u-PA antigen can be quantified by means of a specific peroxidase labelled monoclonal antibody against u-PA. By use of this assay system u-PA activity and antigen can be determined with lower detection limits of 0.08 IU/ml and 1.0 ng/ml, respectively, and intraassay as well as interassay coefficients of variation of 10% and 12% for activity and 5% and 7% for antigen determinations, respectively. Normal plasma levels of u-PA antigen could be determined to be 1.88 ng/ml +/- 0.61. Furthermore, this assay system allows specific quantification of u-PA antigen and activity during thrombolytic therapy.


Clinical outcomes of doubled-suture Nice knot augmented plate fixation in the treatment of comminuted midshaft clavicle fracture.
Free bone fragments were difficult to be fixed in many comminuted midshaft clavicle fractures, and the absence of cortical alignment in comminuted fractures had direct influence on the stability of fixation. This survey was performed to assess the efficacy of doubled-suture Nice knot augmented plate fixation in the treatment of comminuted midshaft clavicle fractures. Between 2013 and 2018, all patients with comminuted midshaft clavicle fractures treated with doubled-suture Nice knot augmented plate fixation were retrospectively reviewed and included in this research. Demographic data of the patients, characteristics of the fractures, intraoperative parameters and follow-up data of the patients were evaluated and summarized. A total of 56 patients were included in this study. The mean follow-up time was 25.6 months (range, 12-60 months). The number of male patients was 38 (67.9 %) and of the female patients was 18 (32.1 %). The average age of all patients was 47.89 ± 16.5 years. The mean time of surgery was 85.6 ± 24.0 min. The average length of incision was 9.2 ± 1.9 cm. The number of doubled-suture Nice knot applied ranged from 1 to 5 knots. All the patients reached bone union after the treatment. There was no implant failure or neurovascular injury observed. And most of the patients showed good functional outcome. The doubled-suture Nice knot could provide reliable fixation for small bone fragments in comminuted clavicle fractures. Combination of the doubled-suture Nice knot and plate screws fixation was a safe and effective method in comminuted midshaft clavicle fractures treatment.


Association of UDP-glucuronosyltransferase 1A9 polymorphisms with adverse reactions to catechol-O-methyltransferase inhibitors in Parkinson's disease patients.
To investigate the association between adverse reactions to catechol-O-methyltransferase (COMT) inhibitors and the UDP-glucuronosyltransferase 1A9 genotypes UGT1A9*1b and UGT1A9*3a, which were previously identified in individual cases of COMT inhibitor-induced toxicity. The study included 52 Parkinson's disease (PD) patients on COMT inhibitors without evidence of adverse reactions and 11 PD patients who had been withdrawn from COMT inhibitors due to adverse reactions. UGT1A9*1b was identified by direct sequencing of the PCR amplification of the gene and UGT1A9*3a was assayed by real-time PCR. The frequency of the *3a/*3a and *1/*3a genotype variants was 45.5 % in subjects with adverse reactions and 21.1 % in subjects without adverse reactions [overall UGT1A9*3a allele frequency 27.3 vs. 11.5 %, P = 0.087; odds ratio (OR) 2.87, 95 % confidence interval (CI) 0.94-8.77]. The frequency of genotype combinations leading to low glucuronosyltransferase activity (*3a/*3a irrespective of *1b or *1/*3a and *1/*1b) was 5.8 % in subjects without adverse reactions and 36.4 % in subjects with adverse reactions (P = 0.014; OR 9.33, 95 % CI 1.71-50.78). In PD patients UDP-glucuronosyltransferase 1A9 genotypes are associated with adverse reactions to COMT inhibitors, leading to treatment withdrawal. UDP-glucuronosyltransferase 1A9 genotyping may be a screening and/or diagnostic test to assist individualized treatments with COMT inhibitors.


Music in the operating theatre: opinions of staff and patients of a Nigerian teaching hospital.
The role of music during surgery has been studied, including its effect on theatre staff, users and patients. However, little attention has been paid to its application especially in our environment. It was a prospective study, involving theatre staff, users, and patients. Their opinions on acceptability and the role of music in operating theatre were determined. Information was obtained by questionnaire. There were 162 respondents; age range 25 to 76 years (median age 39). There were 109 (67.2%) males and 53 (32.7%) female. One hundred and forty five (89.5%) respondents agree that music should be played in the operating theatre. One fifty eight, (97.5%) considered low tone of music to be most appropriate in the theatre while 3(1.9%), and 1(0.6%) considered moderate and high tone respectively to be most appropriate. One hundred and sixteen, (71.6%) preferred jazz music while 19(11.7%) reggae, 11(6.8%) African music, 13 (8.0%) others (not specify), 2 (1.2%) classical, and 1(0.6%) Irish folk. The majority of the respondents were aware of the role of music in terms of its anxiolytic effect, reduction of stress and enhancement of performance when familiar music is played. Music in the operating theatre has immeasurable effects. It can prevent distraction, minimize annoyance, reduce stress and diminish the anxiety of patients, staff and users.


Systolic blood pressure and mortality in patients on hemodialysis.
Hypertension is extremely common in patients with end-stage renal disease who are receiving hemodialysis, and cardiovascular disease remains the leading cause of death in these patients. However, optimal blood pressure management strategies in this high-risk population are still controversial. This review first discusses the complex association of systolic blood pressure with clinical outcomes in patients on hemodialysis, with a focus on several recent studies. Next, it updates the reader on issues related to optimal timing and methods of blood pressure measurement, appropriate blood pressure targets, and pharmacologic and nonpharmacologic hypertension treatment strategies for patients on hemodialysis.


Implementing diagnostic criteria and estimating frequency of mild cognitive impairment in an urban community.
Reported rates of mild cognitive impairment (MCI) range widely depending on methodologic differences, including specific sample characteristics, cognitive measures used, normative samples used for neuropsychological tests, and diagnostic criteria. To operationalize diagnostic criteria for MCI and examine the frequency of MCI in ethnically and linguistically diverse elders (individuals older than 65 years). Prospective, community-based longitudinal cohort study. Northern Manhattan, New York, NY. A cohort of 1315 nondemented elderly participants. A diagnosis of MCI was assigned retrospectively on the basis of comprehensive neuropsychological, functional, and neurologic assessments. Amnestic MCI, as well as forms of mild impairment with other cognitive characteristics, were classified. The frequency of amnestic MCI was 5.0% (95% confidence interval, 3.8-6.2). Other subtypes of MCI ranged in frequency from 2.1% to 6.2%. Mild cognitive impairment was more common among those older than 75 years compared with those aged 65 to 75 years. Individuals with fewer than 9 years of schooling were more likely to meet MCI criteria. Apolipoprotein (APOE) E4 allele was more frequent among those with amnestic MCI. When proper normative values are used, only age and education, and not race or ethnicity, are associated with higher frequency of MCI. The proportion of nondemented elders with isolated memory deficits is smaller than the proportion with deficits in multiple cognitive domains. The strong association of the APOE E4 allele with only amnestic MCI suggests that there are likely to be multiple causes of cognitive impairment and differential rates of conversion to Alzheimer disease within the cognitive subtypes of MCI.


Economic impact of an electronic alert system to prevent venous thromboembolism in hospitalised patients.
The prevention of venous thromboembolism (VTE) is a priority for improved safety in hospitalised patients. Worldwide, there is growing concern over the undersuse of appropriate thromboprophylaxis. Computerised decision support improves the implementation of thromboprophylaxis and reduces inpatient VTE. However, an economic assessment of this approach has not yet been performed. To evaluate the economic impact of an electronic alert (e-alert) system to prevent VTE in hospitalised patients over a 4year period. All hospitalised patients at a single institution during the first semesters of 2005-2009 (n=32280) were included. All cases of VTE developed during hospitalisation were followed and direct costs of diagnosis and management collected. E-alerts achieved a sustained reduction of the incidence of in-hospital VTE, OR 0.50 (95% CI, 0.29-0.84), the impact being especially significant in medical patients, OR 0.44 (95% CI, 0.22-0.86). No increase in prophylaxis-related bleeding was observed. In our setting, the mean direct cost (during hospitalisation and after discharge) of an in-hospital VTE episode is €7058. Direct costs per single hospitalised patient were reduced after e-alerts from €21.6 to €11.8, while the increased use of thromboprophylaxis and the development of e-alerts meant €3 and €0.35 per patient, respectively. Thus, the implementation of e-alerts led to a net cost saving of €6.5 per hospitalised patient. Should all hospitalised patients in Spain be considered, total yearly savings would approach €30million. E-alerts are useful and cost-effective tools for thromboprophylaxis strategy in hospitalised patients. Fewer thromboembolic complications and lower costs are achieved by its implementation.


Pyruvate dehydrogenase deficiency disease detected by the enzyme activity of peripheral leukocytes.
Pyruvate dehydrogenase complex (PDHC) deficiency is a common neurodegenerative disease associated with abnormal mitochondrial energy metabolism. The diagnosis of PDHC is difficult because of the lack of a rapid, accurate, and cost-effective clinical diagnostic method. A 4-year-old boy was preliminarily diagnosed with putative Leigh syndrome based on the clinical presentation. PDHC activity in peripheral blood leukocytes and a corresponding gene analysis were subsequently undertaken. Sodium pyruvate 1-13 C was used for the analysis of PDHC activity in peripheral leukocytes. The genes encoding PDHC were then scanned for mutations. The results showed that the corresponding PDHC activity was dramatically decreased to 10.5 nmol/h/mg protein as compared with that of healthy controls (124.6 ± 7.1 nmol/h/mg). The ratio of PDHC to citrate synthase was 2.1% (control: 425.3 ± 27.1). The mutation analysis led to the identification of a missense mutation, NM_000284.4:g214C>T, in exon 3 of PDHC. The peripheral blood leukocyte PDHC activity assay may provide a practical enzymatic diagnostic method for PDHC-related mitochondrial diseases.


The value of the sinusoidal tcPO2 pattern in the evaluation and management of cyanotic congenital heart disease with ductus dependent lesions.
A characteristic sinusoidal tcPO2 pattern was observed in 17(27%) of 62 patients with congenital heart disease manifested by cyanosis or heart failure during the neonatal period. All of these 17 patients were definitively diagnosed by cardiac catheterization, as having 8 PPA; 3 ToF; 2 TGA + VSD + PA; 2 asplenia with PA; 1 TGA + VSD + PS; and 1 TA (no TGA type). The transcutaneous oxygen pressure pattern of these patients showed a sinusoidal change with a cycle length of 6-20 min with the maximum pressure not exceeding 50 torr and the minimum pressure occasionally close to 0 torr. This sinusoidal tcPO2 pattern was associated with various types of ductus-dependent congenital heart diseases and hence may be of diagnostic value. Transcutaneous oxygen pressure monitoring is also useful in evaluating the ductal response to PG. Other possible mechanisms underlying this phenomenon including biological oscillation should be considered.


The contribution of NMDA receptor activation to spinal c-Fos expression in a model of inflammatory pain.
1. Intraplantar carrageenin (6 mg 150 microliters-1) evoked a high level of spinal c-Fos expression in the dorsal horn, of segments L4-L5 of the spinal cord, and an extensive peripheral oedema; both parameters were assessed 3 h after carrageenin. 2. Two series of experiments were performed, with the mean total number of Fos like-immunoreactive neurones (Fos-LI), after carrageenin, not being significantly different for the two series of experiments (266 +/- 17 and 332 +/- 31 Fos-LI neurones). For both series of experiments Fos-LI neurones were predominantly located in the superficial and deep laminae, only 10% of the total number of Fos-LI neurones were located in the nucleus proprius and 10% were located in the ventral horn. 3. Pre-administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-HA966 (0.5 mg kg-1 and 2.5 mg kg-1, s.c.), 30 min before carrageenin, did not significantly influence the total number of Fos-LI neurones, as compared to control carrageenin expression. 4. Pre-administration of the highest dose of (+)-HA966 (10 mg kg-1) significantly reduced the number of deep laminae Fos-LI neurones (28 +/- 3% reduction of control number of Fos-LI neurones after carrageenin, P < or = 0.05), without influencing the number of superficial Fos-LI neurones. There was a tendency towards a reduction of the number of Fos-LI neurones in the nucleus proprius by the highest concentration of pre-administered (+)-HA966, (31 +/- 8% reduction), but this effect did not reach significance. 5. Pre-plus post-administered (+)-HA966 (0.5 mg kg-1), 30 min before and again 45 min afterintraplantar carrageenin, did not significantly influence the total number of Fos-LI neurones, as compared to control carrageenin expression.6. Pre- plus post-administration of 2.5 mg kg-1 (+)-HA966 significantly reduced the total number of Fos-LI neurones, as compared to control carrageenin expression. This effect was reflected by a significant reduction in the number of Fos-LI neurones in the nucleus proprius (36+/-7% reduction of control carrageenin c-Fos expression respectively, P<0.05).7. Pre-plus post-administration of 10 mg kg-1 of (+)-HA966 significantly reduced the number of Fos-LI neurones in the superficial laminae, nucleus proprius, deep laminae and ventral horn (33 +/-0.5%,55+/-6%, 40+/-4% and 51+/-4% reduction of control carrageenin c-Fos expression, respectively, P<0.05,for all areas).8. A single post-administration of (+)-HA966 (10 mg kg-1), 45 min after intraplantar carrageenin, did not significantly influence the number of Fos-LI neurones in the superficial, deep laminae or ventral horn, but significantly reduced the number of Fos-LI neurones in the nucleus proprius, as compared tocontrol carrageenin expression (39+-/8% reduction of control carrageenin c-Fos expression, P <0.05).9 None of the concentrations of (+)-HA966 studied, irrespective of the timing of administration,influenced the peripheral carrageenin oedema. Our results illustrate a contribution of central NMDA receptor activation to carrageenin-evoked spinal c-Fos expression. These results extend previous studies demonstrating the contribution of the NMDA receptor to central hyperalgesia and the expression of c-Fos.


Dose-Dense Chemotherapy Regimen for Breast Cancer Associated with Significant Decline in Ovarian Reserve.
Purpose: To determine the impact of dose-dense chemotherapy administration on ovarian reserve in women undergoing treatment for breast cancer. Patients and Methods: We conducted a retrospective cohort study of reproductive age women who underwent dose-dense chemotherapy regimens with doxorubicin hydrochloride and cyclophosphamide with or without paclitaxel for a new diagnosis of breast cancer. We compared pre- and post-treatment serum antimullerian hormone (AMH) levels and assessed changes in AMH over time. Results: Fifty-seven patients met inclusion criteria. Median pre-treatment AMH was 2.9 ng/mL, whereas post-treatment AMH was 0.1 ng/mL, demonstrating a dramatic reduction in AMH levels after treatment with a dose-dense regimen. This change was independent of age and was sustained over 12 months from treatment completion. Conclusions: Dose-dense chemotherapy regimens for breast cancer lead to marked and sustained decreases in AMH irrespective of patient age.


Stepwise tailoring and test-retest of reproducibility of an ethnic-specific FFQ to estimate nutrient intakes for South Asians in New Zealand.
To develop and test-retest the reproducibility of an ethnic-specific FFQ to estimate nutrient intakes for South Asians (SA) in New Zealand (NZ). Using culturally appropriate methods, the NZFFQ, a validated dietary assessment tool for NZ adults, was modified to include SA food items by analysing foods consumed by SA participants of the Adult Nutrition Survey, in-person audit of ethnic food stores and a web scan of ethnic food store websites in NZ. This was further refined via three focus group discussions, and the resulting New Zealand South Asian Food Frequency Questionnaire (NZSAFFQ) was tested for reproducibility. Auckland and Dunedin, NZ. Twenty-nine and 110 males and females aged 25-59 years of SA ethnicity participated in the focus group discussions and the test-retest, respectively. The development phase resulted in a SA-specific FFQ comprising of 11 food groups and 180 food items. Test-retest of the NZSAFFQ showed good reproducibility between the two FFQ administrations, 6 months apart. Most reproducibility coefficients were within or higher than the acceptable range of 0·5-0·7. The lowest intraclass correlation coefficients (ICC) were observed for β-carotene (0·47), vitamin B12 (0·50), fructose (0·55), vitamin C (0·57) and selenium (0·58), and the highest ICC were observed for alcohol (0·81), iodine (0·79) and folate (0·77). The ICC for fat ranged from 0·70 for saturated fats to 0·77 for polyunsaturated fats. The ICC for protein and energy were 0·68 and 0·72, respectively. The developed FFQ showed good reproducibility to estimate nutrient intakes and warrants the need for validation of the instrument.


Outcomes associated with antidepressant treatment according to the number of prescriptions and treatment changes: 5-year follow-up of a nation-wide cohort study.
Naturalistic studies regarding clinical outcomes associated with antidepressant treatment duration have yielded conflicting results, possibly because they did not consider the occurrence of treatment changes. This nation-wide population-based study examined the association between the number of filled prescriptions and treatment changes and long-term psychiatric outcomes after antidepressant treatment initiation. Based on the French national health insurance database, 842,175 adults who initiated an antidepressant treatment in 2011 were included. Cox proportional-hazard multi-adjusted regression models examined the association between the number of filled prescriptions and the occurrence of treatment changes 12 months after initiation and four outcomes during a 5-year follow-up: psychiatric hospitalizations, suicide attempts, sick leaves for a psychiatric diagnosis, new episodes of antidepressant treatment. During a mean follow-up of 4.5 years, the incidence rates of the four above-mentioned outcomes were 13.49, 2.47, 4.57, and 92.76 per 1,000 person-years, respectively. The number of filled prescriptions was associated with each outcome (adjusted HRs [95% CI] for one additional prescription ranging from 1.01 [1.00-1.02] to 1.10 [1.09-1.11]), as was the occurrence of at least one treatment change vs. none (adjusted HRs [95% CI] ranging from 1.18 [1.16-1.21] to 1.57 [1.79-1.65]). Furthermore, the adjusted HRs [95% CI] of the number of filled prescriptions were greater in patients with (vs. without) a treatment change for psychiatric hospitalizations (1.12 [1.11-1.14] vs. 1.09 [1.08-1.10], p for interaction = 0.002) and suicide attempts (1.12 [1.09-1.15] vs. 1.06 [1.04-1.08], p for interaction = 0.006). Lack of clinical data about the disorders warranting the prescriptions or their severity. Considering treatment changes is critical when using administrative claims database to examine the long-term psychiatric outcomes of antidepressant treatments in real-life settings.


Social factors predicting improvement of frailty in community-dwelling older adults: Korean Frailty and Aging Cohort Study.
The study aimed to identify social factors predicting improvement of frailty in community-dwelling older adults after 2 years using a population-based cohort study. We analyzed data from the 2016 and 2018 Korean Frailty and Aging Cohort Study. The participants of this study were 1428 community-dwelling older adults aged 70-84 years who were recruited from 10 medical centers across different regions. Frailty was measured using the five-item FRAIL scale, which evaluates fatigue, resistance, ambulation, illness and weight loss. Multilevel logistic regression analysis was used to examine baseline social factors that predict frailty improvement after 2 years by frailty status. In frail older adults, higher participation in social activities (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.02-1.34) was significantly associated with frailty improvement. In pre-frail older adults, there were no significant social factors predicting the improvement of frailty status; however, other modifiable factors such as high and moderate levels of physical activity (OR 1.17, 95% CI 1.07-1.28, OR 1.13, 95% CI 1.03-1.25, respectively) and low depressive symptoms (OR 0.88, 95% CI 0.84-0.91) were associated with pre-frail improvements. High levels of physical activity (OR 1.16, 95% CI 1.02-1.33) were also associated with improvements of frailty. Different strategies depending on the level of frailty are necessary to improve frailty status. Timely and appropriate interventions can promote frailty improvement and prevent negative health outcomes in community-dwelling older adults. Geriatr Gerontol Int 2021; 21: 465-471.


The community-function landscape of microbial consortia.
Quantitatively linking the composition and function of microbial communities is a major aspiration of microbial ecology. Microbial community functions emerge from a complex web of molecular interactions between cells, which give rise to population-level interactions among strains and species. Incorporating this complexity into predictive models is highly challenging. Inspired by a similar problem in genetics of predicting quantitative phenotypes from genotypes, an ecological community-function (or structure-function) landscape could be defined that maps community composition and function. In this piece, we present an overview of our current understanding of these community landscapes, their uses, limitations, and open questions. We argue that exploiting the parallels between both landscapes could bring powerful predictive methodologies from evolution and genetics into ecology, providing a boost to our ability to engineer and optimize microbial consortia.


IL-18 contributes to host resistance against infection with Pseudomonas aeruginosa through induction of IFN-gamma production.
Pseudomonas aeruginosa keratitis destroys the cornea in susceptible (B6), but not resistant (BALB/c) mice. To determine mechanisms mediating resistance, the role of IFN-gamma, IL-12, and IL-18 was tested in BALB/c mice. RT-PCR analysis detected IFN-gamma mRNA expression levels in cornea that were significantly increased at 1-7 days postinfection. IL-18 mRNA was detected constitutively in cornea and, at 1-7 days postinfection, levels were elevated significantly, while no IL-12 mRNA was similarly detected. To test whether IL-18 contributed to IFN-gamma production, mice were treated with anti-IL-18 mAb. Treatment decreased corneal IFN-gamma mRNA levels, and bacterial load and disease increased/worsened, compared with IgG-treated mice. To stringently examine the role of IFN-gamma in bacterial killing, knockout (-/-) vs wild-type (wt) mice also were tested. All corneas perforated, and bacterial load was increased significantly in -/- vs wt mice. Because disease severity was increased in IFN-gamma(-/-) vs IL-18-neutralized mice, and since IL-18 also induces production of TNF, we tested for TNF-alpha in both groups. ELISA analysis demonstrated significantly elevated corneal TNF-alpha protein levels in IFN-gamma(-/-) vs wt mice after infection. In contrast, RT-PCR analysis of IL-18-neutralized vs IgG-treated infected mice revealed decreased corneal TNF-alpha mRNA expression. Next, to resolve whether TNF was required for bacterial killing, TNF-alpha was neutralized in BALB/c mice. No difference in corneal bacterial load was detected in neutralized vs IgG-treated mice. These data provide evidence that IL-18 contributes to the resistance response by induction of IFN-gamma and that IFN-gamma is required for bacterial killing.


Selective restoration of the selenoprotein population in a mouse hepatocyte selenoproteinless background with different mutant selenocysteine tRNAs lacking Um34.
Novel mouse models were developed in which the hepatic selenoprotein population was targeted for removal by disrupting the selenocysteine (Sec) tRNA([Ser]Sec) gene (trsp), and selenoprotein expression was then restored by introducing wild type or mutant trsp transgenes. The selenoprotein population was partially replaced in liver with mutant transgenes encoding mutations at either position 34 (34T-->A) or 37 (37A-->G) in tRNA([Ser]Sec). The A34 transgene product lacked the highly modified 5-methoxycarbonylmethyl-2'-O-methyluridine, and its mutant base A was converted to I34. The G37 transgene product lacked the highly modified N(6)-isopentenyladenosine. Both mutant tRNAs lacked the 2'-methylribose at position 34 (Um34), and both supported expression of housekeeping selenoproteins (e.g. thioredoxin reductase 1) in liver but not stress-related proteins (e.g. glutathione peroxidase 1). Thus, Um34 is responsible for synthesis of a select group of selenoproteins rather than the entire selenoprotein population. The ICA anticodon in the A34 mutant tRNA decoded Cys codons, UGU and UGC, as well as the Sec codon, UGA. However, metabolic labeling of A34 transgenic mice with (75)Se revealed that selenoproteins incorporated the label from the A34 mutant tRNA, whereas other proteins did not. These results suggest that the A34 mutant tRNA did not randomly insert Sec in place of Cys, but specifically targeted selected selenoproteins. High copy numbers of A34 transgene, but not G37 transgene, were not tolerated in the absence of wild type trsp, further suggesting insertion of Sec in place of Cys in selenoproteins.


[Stimulating effect of partial cystectomy on regeneration of rat bladder urothelium and its significance for carcinogenesis (author's transl)].
Cell proliferation kinetics of the urinary bladder urothelium have been analyzed in a total of 218 female Wistar rats after partial cystectomy. After one-third resection of the bladder DNA synthesis started 15 h postoperatively in the bladder stump and reached its maximum at 25 h with a mean 3H-TdR index of 10.1%. In the area of resection the proliferative activity increased after 20 h and the highest 3H-TdR index was found to be 24.7% after 45 h. In the case of hemicystectomy the labeling index in the stump increased 15 h postoperatively and the highest 3H-T-dR index was determined at 20 h with 16.6%. The urothelial cells in the area of resection began to proliferate synchronously with those in the stump and the maximum of DNA synthesis was measured 35 h postoperatively with an 3H-TdR index of 24.2%. After 2 weeks the proliferative activity within the stump and operative region corresponded to that of the control urothelium. The basal cells showed absolutely the highest proliferative activity, the suprabasal cells exhibited on the other side the highest regenerative potential compared with the control urothelium. Partial cystectomy might possibly serve as an experimental model for testing low potential carcinogens, in the case where carcinogenic effects would be initiated, potentiated and accelerated via stimulation of the DNA synthesis.


Inhibiting biosynthesis and/or metabolism of progestins in the ventral tegmental area attenuates lordosis of rats in behavioural oestrus.
In the ventral tegmental area (VTA), lordosis of rats is facilitated by 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP). Central 3alpha,5alpha-THP results from metabolism of peripheral progesterone, from the ovaries and/or adrenals, by sequential enzymatic activity of 5alpha-reductase and 3alpha-hydroxysteroid oxidoreductase (3alpha-HSOR). In addition, in glial cells, cholesterol is converted into pregnenolone by the P450 side-chain cleavage enzyme (P450scc), which is then metabolized to progesterone by 3beta-hydroxysteroid dehydrogenase, and subsequently reduced to 3alpha,5alpha-THP. We hypothesize that, in the VTA, formation of 3alpha,5alpha-THP by both metabolism and biosynthesis is necessary for facilitation of lordosis of female rats. In Experiment 1, naturally-receptive rats received bilateral VTA infusions of a P450scc inhibitor, digitoxin (1 microg/side); a 5alpha-reductase inhibitor, finasteride (10 microg/side); digitoxin (1 microg/side)+finasteride (10 microg/side); or vehicle and were tested 3 h later for lordosis. In Experiment 2, the effects of VTA infusions of digitoxin, finasteride, digitoxin+finasteride, or vehicle on lordosis and midbrain and plasma 3alpha,5alpha-THP levels were examined. In Experiment 3, we investigated whether infusions of 3alpha,5alpha-THP to the VTA reinstated lordosis and midbrain 3alpha,5alpha-THP levels following administration of inhibitors. VTA infusions of digitoxin, finasteride, or digitoxin+finasteride, significantly and similarly reduced lordosis and midbrain, but not plasma 3alpha,5alpha-THP levels, compared to vehicle. Following receipt of inhibitor infusions, 3alpha,5alpha-THP to the VTA restored lordosis and midbrain 3alpha,5alpha-THP levels. These data suggest that, in the VTA, both central biosynthesis of progesterone and metabolism of progesterone (from central and/or peripheral sources) to 3alpha,5alpha-THP are important for mediating lordosis of rats.


Gene expression profiling of in vitro radiation resistance in cervical carcinoma: a feasibility study.
To determine the feasibility of integrating an in vitro chemo-radiation response assay (IVRRA) with a gene microarray system to investigate the molecular patterns of expression that contribute to radiation resistance in cervical cancer. Viable primary untreated cervical cancer specimens were obtained and exposed to gamma irradiation at a dose of 3 Gy in the IVRRA to determine in vitro radiation sensitivity. RNA was purified for microarray analysis with the Affymetrix Human Genome U95A Array carrying more than 12,000 gene probes. Gene expression analysis was performed, and specimen transcript patterns were correlated with radiation response using an iteration analysis model and Pearson's correlation coefficient. A feasibility set of eight tumor specimens was studied. Tumors were classified into 4 extreme (ERR), 2 intermediate (IRR) and 2 low radiation resistance (LRR) categories. An intrinsic radiation response gene set of 54 genes transcripts with 100% accuracy for the classification of each tumor's radiation response category was identified. Gene sets associated with in vitro radiation response profiles in cervical cancer can be generated using the IVRRA and microarray technology. This has direct applications to the study of the biological pathways contributing to radiation resistance and may lead to the development of alternative treatment modalities. The potential of these technologies for cancers in which radiotherapy is employed warrants further investigation.


Resilience in Web-Based Mental Health Communities: Building a Resilience Dictionary With Semiautomatic Text Analysis.
Resilience is an accepted strengths-based concept that responds to change, adversity, and crises. This concept underpins both personal and community-based preventive approaches to mental health issues and shapes digital interventions. Online mental health peer-support forums have played a prominent role in enhancing resilience by providing accessible places for sharing lived experiences of mental issues and finding support. However, little research has been conducted on whether and how resilience is realized, hindering service providers' ability to optimize resilience outcomes. This study aimed to create a resilience dictionary that reflects the characteristics and realization of resilience within online mental health peer-support forums. The findings can be used to guide further analysis and improve resilience outcomes in mental health forums through targeted moderation and management. A semiautomatic approach to creating a resilience dictionary was proposed using topic modeling and qualitative content analysis. We present a systematic 4-phase analysis pipeline that preprocesses raw forum posts, discovers core themes, conceptualizes resilience indicators, and generates a resilience dictionary. Our approach was applied to a mental health forum run by SANE (Schizophrenia: A National Emergency) Australia, with 70,179 forum posts between 2018 and 2020 by 2357 users being analyzed. The resilience dictionary and taxonomy developed in this study, reveal how resilience indicators (ie, "social capital," "belonging," "learning," "adaptive capacity," and "self-efficacy") are characterized by themes commonly discussed in the forums; each theme's top 10 most relevant descriptive terms and their synonyms; and the relatedness of resilience, reflecting a taxonomy of indicators that are more comprehensive (or compound) and more likely to facilitate the realization of others. The study showed that the resilience indicators "learning," "belonging," and "social capital" were more commonly realized, and "belonging" and "learning" served as foundations for "social capital" and "adaptive capacity" across the 2-year study period. This study presents a resilience dictionary that improves our understanding of how aspects of resilience are realized in web-based mental health forums. The dictionary provides novel guidance on how to improve training to support and enhance automated systems for moderating mental health forum discussions.


Merogony in in vitro cultures of Theileria parva.
In vitro studies were focussed on the duration and cessation of merogony in Theileria parva infected blood lymphocyte cell cultures. The cultures were infected using purified tick stabilates as an alternative to in vitro infections, using sporozoites obtained by labour intensive dissections of salivary glands from infected ticks. After establishment of infection in peripheral blood lymphocytes (PBL), merozoites were temporarily produced for about 2 months after which lymphoblasts only contained schizonts.


Photo-induced enhancement of lattice fluctuations in metal-halide perovskites.
The optoelectronic properties of metal-halide perovskites (MHPs) are affected by lattice fluctuations. Using ultrafast pump-probe spectroscopy, we demonstrate that in state-of-the-art mixed-cation MHPs ultrafast photo-induced bandgap narrowing occurs with a linear to super-linear dependence on the excited carrier density ranging from 1017 cm-3 to above 1018 cm-3. Time-domain terahertz spectroscopy reveals carrier localization increases with carrier density. Both observations, the anomalous dependence of the bandgap narrowing and the increased carrier localization can be rationalized by photo-induced lattice fluctuations. The magnitude of the photo-induced lattice fluctuations depends on the intrinsic instability of the MHP lattice. Our findings provide insight into ultrafast processes in MHPs following photoexcitation and thus help to develop a concise picture of the ultrafast photophysics of this important class of emerging semiconductors.


The Lisu people's traditional natural philosophy and its potential impact on conservation planning in the Laojun Mountain region, Yunnan Province, China.
In this study, we explored a conservation process from an ethnoprimatological perspective for the management of national parks and nature reserves. We accumulated attitude and knowledge data on the traditional culture, religion, and current attitudes to conservation of rural and urban groups of ethnic Lisu people, who live in the village of Liju or have migrated to urban areas, respectively. The data clearly indicated that most of the interviewees had similar feelings and attitudes toward the conservation of Yunnan snub-nosed monkeys (Rhinopithecus bieti) and Laojun Mountain National Park (LMNP), irrespective of whether they live in or have moved away from their home village, or if their educational background differs. Both the rural (96.6%) and urban (100%) interviewees expressed their deep affection for Yunnan snub-nosed monkeys and supported (90.3% and 89.0%, respectively) the seasonal closure of mountainous areas for conservation purposes. The Lisu peoples culture, history, and traditions were evaluated with regards to the developing trend for environmentalism, and their advanced attitudes toward environmental protection and resource utilization exceeded our expectations. The results of this study show huge potential for the optimal mitigation of human-animal conflict in the context of conservation planning not only for LMNP but also for other national parks and nature reserves.


Leukocyte activation induces surface redistribution of P-selectin glycoprotein ligand-1.
Binding of P-selectin on activated endothelium to P-selectin glycoprotein ligand-1 (PSGL-1) on neutrophils mediates the initial tethering and rolling of neutrophils on the vessel wall at inflammatory sites. Upon activation of rolling cells by locally expressed signaling molecules, integrin-dependent adhesion mechanisms are engaged and transendothelial migration proceeds. P-selectin binding sites are uniformly distributed on the surface of quiescent neutrophils, but are redistributed to the uropod of activated neutrophils. It is unclear whether this activation-induced change in the surface topography of P-selectin binding sites is due to surface redistribution of PSGL-1, shedding of PSGL-1 from the lamellapod, and/or movement of PSGL-1 from an intracellular compartment to the uropod of the polarized cell. With the use of immunogold electron microscopy we previously demonstrated that PSGL-1 was localized to the tips of microvilli on neutrophils. Here we document a similar localization for PSGL-1 on eosinophils, basophils, monocytes, and lymphocytes. On quiescent neutrophils, approximately 80% of the PSGL-1 label was on tips of microvilli, which are randomly distributed around the cell circumference. On activated, polarized neutrophils, the PSGL-1 label was restricted to a segment of approximately 42% of the cell circumference even though total labeling decreased by only approximately 26%. Latex microbeads coated with anti-PSGL-1 mAb bound preferentially to the uropod of activated neutrophils. Subcellular fractionation and immunogold analysis of frozen thin sections of neutrophils failed to detect PSGL-1 in any intracellular compartment. Taken together, these data indicate that the activation-induced change in the surface topography of PSGL-1 is due to surface redistribution of PSGL-1. This process may facilitate transendothelial migration by disrupting bonds between P-selectin and PSGL-1 at the leading edge of migrating cells.


A review of hyperfibrinolysis in cats and dogs.
The fibrinolytic system is activated concurrently with coagulation; it regulates haemostasis and prevents thrombosis by restricting clot formation to the area of vascular injury and dismantling the clot as healing occurs. Dysregulation of the fibrinolytic system, which results in hyperfibrinolysis, may manifest as clinically important haemorrhage. Hyperfibrinolysis occurs in cats and dogs secondary to a variety of congenital and acquired disorders. Acquired disorders associated with hyperfibrinolysis, such as trauma, cavitary effusions, liver disease and Angiostrongylus vasorum infection, are commonly encountered in primary care practice. In addition, delayed haemorrhage reported in greyhounds following trauma and routine surgical procedures has been attributed to a hyperfibrinolytic disorder, although this has yet to be characterised. The diagnosis of hyperfibrinolysis is challenging and, until recently, has relied on techniques that are not readily available outside referral hospitals. With the recent development of point-of-care viscoelastic techniques, assessment of fibrinolysis is now possible in referral practice. This will provide the opportunity to target haemorrhage due to hyperfibrinolysis with antifibrinolytic drugs and thereby reduce associated morbidity and mortality. The fibrinolytic system and the conditions associated with increased fibrinolytic activity in cats and dogs are the focus of this review article. In addition, laboratory and point-of-care techniques for assessing hyperfibrinolysis and antifibrinolytic treatment for patients with haemorrhage are reviewed.


[The use of photon absorptiometry in renal osteodystrophy (author's transl)].
In 58 patients with end-stage renal failure before commencement of regular hemodialyses treatment (RTD) and 58 patients under RTD bone mineral content (BMC) was determined by the use of the photon absorptiometry. Further the effect of a treatment with bitamin D3 and 5,6-trans-25-OH-vitamin D3 on BMC was studied. There existed a negative correlation between the duration of chronic renal failure or of RDT as well as of the serum parathyroid hormone level to BMC. No correlation was found between BMC and serum calcium level. During a 14 months-course treatment with vitamin D3 or 5,6-trans-25-OH-vitamin D3 BMC increased. The method of photon absorptiometry presented itself as an easy and well reproducible technique for routine examinations.