Miracle-dz/UniFAR-FTUs huggingface dataset:
Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination.

BACKGROUND The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive. METHODS We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model. RESULTS Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis. CONCLUSIONS The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.).
Pedobarographic Findings in Patients with Knee Osteoarthritis

Kul-Panza E, Berker N: Pedobarographic findings in patients with knee osteoarthritis. Am J Phys Med Rehabil 2006;85:228–233. Objective:The aim of this study was to evaluate pedobarographic findings and balance in knee osteoarthritis. Design:A total of 48 patients with knee osteoarthritis and 30 controls were included in this study. Pedobarographic measures were obtained from all patients and controls. Pain intensity of patients was measured using the Visual Analog Scale. The percentage of pressure on forefoot and hindfoot was measured using static pedobarography, and the peak pressures at forefoot, midfoot, and hindfoot were measured using dynamic pedobarography. The center-of-pressure sway length and width were measured for evaluation of balance. Results:The percentage of right hindfoot pressure (P < 0.05) and peak pressure of the right forefoot during walking were lower in the osteoarthritic group than in the controls (P < 0.05). The sway width in the patient group was higher than in the control group (P < 0.05). The Visual Analog Scale score at rest was negatively correlated with peak pressures of both right and left hindfeet in the osteoarthritic group (P < 0.05). The grade of osteoarthritis was positively correlated with sway length and sway width (P < 0.05). Conclusion:Pedobarography may become a useful technique to determine foot pressures that change because of disturbed weightbearing and balance problems in knee osteoarthritis.
Two novel cell specific receptor proteins, CRLR and CD 117 in human glial tumors.

OBJECTIVE CRLR (calcitonin receptor-like receptor) and CD 117, the gene product of c-kit have been shown to be expressed in cells of glial tumors, especially in those with higher malignancy. Here we report the distribution of these peptides in various cellular compartments within those tumors. MATERIAL Both receptor proteins have been investigated in 95 glial tumor biopsies of different grades. METHODS Both proteins were visualized by immunohistochemistry with antibodies either commercially available or raised for this purpose. RESULTS Both receptor peptides can be identified in or around tumor blood vessels. CRLR occurs in some endothelial cells, especially in the microvascular proliferations of glioblastoma multiforme, whereas CD 117 preferentially occurs in cells of the thickened vascular wall within cells of pericyte or fibroblast morphology. Both antigens are found in addition in few neoplastic cells of overt astrocyte morphology. CONCLUSIONS The occurrence of identical antigens in glial tumor blood vessels and in neighboring tumor cells underlines the common origin of "mesenchymal" and "neuroepithelial" components of such (malignant) glial neoplasms.
Understanding Drug Addiction: A Neuropsychological Perspective

The purpose of the present review is to describe the neuropsychological correlates of long-term substance abuse and to discuss the findings within the context of premorbid vulnerabilities, comorbidity and adolescent neurodevelopment. The authors critically review key findings from the neuropsychological literature related to the long-term sequelae of alcohol, cannabis, inhalant, opiates, psychostimulants and ecstasy use. Leading electronic databases such as PubMed were searched to identify relevant studies published in the past 20 years. References identified from bibliographies of pertinent articles and books in the field were also collected and selectively reviewed. Across substances, individuals with long-term abuse consistently demonstrate neuropsychological impairments of executive (inhibitory) control, working memory and decision making, together with neurobiological abnormalities involving frontotemporal and basal ganglia circuits. In some instances these deficits are dose dependent, implying that they are a direct consequence of prolonged drug exposure. However, comorbid behavioural, personality and mental health problems are common among drug-using populations and are associated with similar neuropsychological deficits. Presented herein is a neuropsychological model of addictive behaviour that highlights the complex interplay between cognition, brain maturation, psychopathology and drug exposure.
Dose‐finding study of amorolfine cream (0·125%, 0·25% and 0·5%) in the treatment of dermatomycoses

A total of 725 patients with mycosis of the skin folds, large areas of the body or feet were entered into this double‐blind, dose‐finding study. Treatment with 0·125, 0·25 or 0·5% amorolfine cream was randomly allocated to patients. The cream was applied once daily for 4 weeks on average. At screening, in 527 patients evaluated for efficacy, a total of 533 pathogens were isolated: T. rubrum (322), T. mentagrophytes (84), E. floccosum (45), M. canis (42), other dermatophytes (14), C. albicans (24) and other yeasts (2). One week after the end of treatment, the culture was negative in 80·5, 81·3 and 84·8% of patients treated with 0·125, 0·25 or 0·5% amorolfine cream, respectively. The differences were not statistically significant. Forty‐four out of 714 patients evaluated for safety had local adverse events: 14 (5·8%), 13 (5·5%) and 17 (7·1%) in the amorolfine cream 0·125%, 0·25 and 0·5% groups, respectively. Due to local adverse events, six patients (2·5%) in the 0·125 group, six patients (2·6%) in the 0·25% group and seven patients (2·9%) in the 0·5% group discontinued the trial treatment. The most common adverse events were burning, itching, erythema and scaling. No systemic adverse events were reported.
Spouses of Stroke Survivors Report Reduced Health-Related Quality of Life Even in Long-Term Follow-Up: Results From Sahlgrenska Academy Study on Ischemic Stroke

Background and Purpose— The consequences for the family of stroke survivor are generally studied in a short-term perspective. The aim of this study was to assess long-term aspects of health-related quality of life among spouses of stroke survivors. Methods— Data on stroke survivors, controls, and spouses were collected from the 7-year follow-up of the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The health-related quality of life of spouses was assessed by the Short Form-36, and the characteristics of stroke survivors were assessed using the National Institutes of Health Stroke Scale, the Mini-Mental State Examination, the Hospital Anxiety and Depression Scale, the Barthel Index, and the modified Rankin Scale. Results— Dyads of 248 stroke survivors aged <70 at stroke onset and 245 dyads of matched controls were included. Spouses of stroke survivors and spouses of controls had a median age of 64 and 65, respectively; proportion of men was 35% and 34%, respectively. The spouses of stroke survivors reported lower scores in all the mental domains (P=0.045; P<0.001), as well as in the domains of general health (P=0.013) and physical role (P=0.006), compared with the spouses of controls. Predictors of poor physical health of the spouses were their own age and the level of global disability of the stroke survivor. Predictors of poor mental health of the spouses were depressive symptoms, cognitive impairment, and global disability among the stroke survivors. Conclusions— The health-related quality of life of spouses of stroke survivors is reduced not only during the first years but also in the long-term perspective.
Phlebotomies or erythropoietin injections allow mobilization of iron stores in a mouse model mimicking intensive care anemia

Objective:Anemia in critically ill patients is frequent and consists of chronic disease associated with blood losses. These two mechanisms have opposite effects on iron homeostasis, especially on the expression of the iron regulatory hormone hepcidin. We developed a mouse model mimicking the intensive care anemia to explore iron homeostasis. Design:Experimental study. Setting:University-based research laboratory. Subjects:C57BL/6 mice. Interventions:Mice received either a single intraperitoneal injection of lipopolysaccharide followed 1 week later by zymosan, or were subjected to repeated phlebotomies by retro-orbital punctures, or both. Several subsets of mice were analyzed over a 14-day period to describe the mouse model of intensive care anemia. Additional mice received erythropoietin injections with or without the zymosan treatment and were killed at day 5, to perform a more detailed analysis. Measurements and Main Results:We observed anemia as soon as 5 days after zymosan injection, together with increased messenger RNA (mRNA) levels for interleukin-6 and hepcidin. Phlebotomies alone fully suppressed hepcidin mRNA expression. Interestingly, in mice treated with zymosan and phlebotomies, hepcidin expression was suppressed, despite the persistent increase in interleukin-6. Stimulation of erythropoiesis by erythropoietin injections also led to a decrease in hepcidin mRNA in zymosan-treated mice. In these situations combining inflammation and erythropoiesis stimulation, there was no change in ferroportin, the membrane iron exporter, at the mRNA level, whereas ferroportin protein increased. Macrophage iron stores (assessed by histology using diaminobenzidine staining, or by quantification of nonheme iron and ferritin concentrations) were depleted in the spleen. Conclusions:These results suggest that the erythroid factor dominates over inflammation for hepcidin regulation, and that iron could be mobilized in these situations combining inflammation and erythropoiesis stimulation.
If Not Now, When? The Timing of Childbirth and Labour Market Outcomes

We study the effect of childbirth and its timing on female labour market outcomes in Italy. The impact on yearly labour earnings and participation is traced up to 21 years since school completion by estimating a factor analytic model with dynamic selection into treatments. We find that childbearing, especially the first delivery, negatively affects female labour supply. Women having their first child soon after school completion are able to catch up with childless women only after 12–15 years. The timing matters, with minimal negative consequences observed if the first child is delayed up to 7–9 years after exiting formal education.
Phase I of The National Beef Quality Audit-2011: quantifying willingness-to-pay, best-worst scaling, and current status of quality characteristics in different beef industry marketing sectors.

The National Beef Quality Audit (NBQA)-2011 benchmarked the current status of and assessed progress being made toward quality and consistency of U.S. cattle, carcasses, and beef products after the completion of the first NBQA in 1991. Unlike previous NBQA, objectives of the 2011 Phase I study were to determine how each beef market sector defined 7 quality categories, estimate willingness-to-pay (WTP) for the same quality categories by market sector, and establish a best-worst (B/W) scaling for the quality categories. Structured face-to-face interviews were conducted and responses were recorded using dynamic routing software over an 11-mo period (February to December 2011) with decision makers in each of the following beef market sectors: Feeders (n = 59), Packers (n = 26), Food Service, Distribution, and Further Processors (n = 48), Retailers (n = 30), and Government and Allied Industries (n = 47). All respondents participated in a structured interview consisting of WTP and B/W questions that were tied to 7 quality categories and then were asked to "define" each of the 7 categories in terms of what the category meant to them, resulting in completely unbiased results. The 7 quality categories were a) how and where the cattle were raised, b) lean, fat, and bone, c) weight and size, d) cattle genetics, e) visual characteristics, f) food safety, and g) eating satisfaction. Overall, "food safety" and "eating satisfaction" were the categories of greatest and second most importance, respectively, to all beef market sectors except for Feeders. Feeders ranked "how and where the cattle were raised" and "weight and size" as the most important and second most important, respectively. Overall, "how and where the cattle were raised" had the greatest odds of being considered a nonnegotiable requirement before the raw material for each sector would be considered for purchase and was statistically more important (P < 0.05) as a requirement for purchase than all other categories except "food safety. " When all market sectors were considered, "eating satisfaction" was shown to generate the greatest average WTP percentage premium (11.1%), but that WTP premium value only differed statistically (P < 0.05) from "weight and size" (8.8%). Most notably, when a sector said that "food safety" was a nonnegotiable requirement, no sector was willing to purchase the product at a discounted price if the "food safety" of the product could not be assured.
Biochemistry of B-type natriuretic peptide – where are we now?

Abstract Background: The discovery of the cardiac endocrine function more than 25 years ago was a breakthrough for the implementation of a routine laboratory marker of heart failure. The heart secretes two different natriuretic peptides with similar biological effects. B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) emerged as the superior diagnostic markers compared to circulating A-type natriuretic peptide (ANP) and proANP derived peptide forms. However, the biochemistry with the processing and metabolism of proBNP, NT-proBNP and BNP with their impact on BNP quantification are still incompletely understood. Methods: Published data and own results were used. Results: This review shows that the present understanding of the biochemistry of BNP and its circulating forms is far from complete. The regulation of BNP secretion occurs mainly at the level of gene transcription with only minor stores of proBNP and processed BNP 1–32 within cardiomyocytes. proBNP is believed to be split into BNP 1–32 and NT-proBNP 1–76 mainly upon secretion, although limited amounts of processed BNP have also been described in the secretory granules of atrial cardiomyocytes. proBNP can be also detected in the circulation and exists as a monomer. There is no evidence for relevant processing of proBNP into BNP 1–32 and NT-proBNP in the circulation. Only small amounts of the intact hormone BNP 1–32 appear to circulate in plasma, there are no known BNP binding proteins. The major circulating BNP forms appear to be split products of BNP 1–32, but are still not sufficiently characterized. Dipeptidyl-peptidase IV degrades BNP 1–32 to BNP 3–32 at its N-terminal end. NT-proBNP appears to be rapidly truncated at both ends as well. proBNP and NT-proBNP are glycosylated to a variable degree. BNP and NT-proBNP are extracted by the kidneys to a comparable extent. In contrast to BNP, the biological half-life of NT-proBNP in humans is still not known. The current commercial BNP assays do not significantly cross-react with NT-proBNP and vice versa. However, BNP as well as NT-proBNP assays cross-react with proBNP to a varying extent. Conclusions: The better characterization of circulating proBNP, BNP, and NT-proBNP forms is necessary to define the relevant standard for assay standardization. Until then, assays should be designed to detect the total amount of the circulating analyte to achieve optimal sensitivity. The identification of possible disease effects on proBNP, BNP, and NT-proBNP metabolism could pave the way for the development of more disease specific assays in the clinical setting. Clin Chem Lab Med 2008;46:1507–14.
Elevated serum interleukin-6 (IL-6) in solid-organ transplant recipients is positively associated with tissue destruction and IL-6 gene expression in the periodontium.

BACKGROUND The number of transplanted solid organs and life expectancy after transplantation are steadily rising worldwide. Inflammation is widely recognized as playing a pivotal role in transplant rejection, and several studies have shown that serum interleukin-6 (IL-6) levels can identify individuals who are at greater risk for rejection. Given the known association between IL-6 and chronic periodontitis, the aim of our study was to assess the periodontal status of solid-organ transplant subjects compared to systemically healthy controls, to quantify the IL-6 levels in the serum and periodontal tissues, and to explore their association. METHODS Forty-seven heart and kidney transplant and 18 systemically healthy age-matched individuals were recruited. Subjects received a complete periodontal examination, and blood and periodontal tissue samples were collected for quantification of IL-6 protein and mRNA levels, respectively. RESULTS Transplant subjects had significantly higher serum IL-6 levels and slightly but statistically significantly increased mean probing depths than healthy controls. Multivariable linear regression analysis adjusting for gender, diabetes, smoking, and immunosuppressant dose showed that the mean probing depth, number of missing teeth, and mean percentage of sites with > or =4 mm attachment loss were independent predictors for elevated serum IL-6 levels. Transplant subjects with chronic periodontitis had higher mean serum IL-6 levels than those without chronic periodontitis, and there was a positive correlation between periodontal IL-6 gene expression levels and serum IL-6 protein levels. CONCLUSIONS Periodontal tissue destruction and local IL-6 synthesis are associated with elevated serum IL-6 levels in transplant recipients. This may have serious implications in solid-organ transplant deterioration and chronic rejection.
Intraductal Tubular Adenoma of the Pancreas, Pyloric Gland Type: A Clinicopathologic and Immunohistochemical Study of 6 Cases

Abstract:The intraductal tubular adenoma (ITA), pyloric gland type, of the pancreas is an uncommon benign tumor, akin to the pyloric gland type adenoma of the gallbladder. We report 6 cases of ITA of the pancreas: 3 male and 3 female aged 50 to 79 years (mean, 63.5 years; median, 65 years); all were examined clinicopathologically. Four patients showed no symptoms, but appetite loss and/or general fatigue presented in two. Grossly, all tumors formed a localized polypoid mass protruding into the lumen of the dilated pancreatic duct. Five of the six tumors were found within the main duct, and the other arose within the branch duct of the pancreas. Microscopically, the tumors were composed of closely packed tubular glands resembling pyloric type glands. They were lined by columnar or cuboidal epithelial cells with foci of mild to moderate dysplastic change. In 2 cases, the adjacent pancreas showed foci of intraductal papillary-mucinous adenoma. Histochemically, the tumors largely showed neutral mucin with a lesser amount of acidic mucin made up mainly of sialomucin. Endocrine cells were found in five tumors. Immunohistochemically, all tumors were labeled with M-GGMC-1 and MUC6, whereas MUC1 and MUC2 stains were negative. Pepsinogen II was positive in 5 tumors; thus, the results displayed a pattern of differentiation similar to those of ordinary gastric pyloric or metaplastic pyloric glands. DPC4 expression was maintained in all tumors and p53-positive nuclei were hardly encountered. All patients are alive with no evidence of disease 3 to 10.5 years after surgical resection.
Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes

Background: The healthy vascular endothelium, which forms the barrier between blood and the surrounding tissues, is known to efficiently respond to stress signals like hypoxia and inflammation by adaptation of cellular physiology and the secretion of (soluble) growth factors and cytokines. Exosomes are potent mediators of intercellular communication. Their content consists of RNA and proteins from the cell of origin, and thus depends on the condition of these cells at the time of exosome biogenesis. It has been suggested that exosomes protect their target cells from cellular stress through the transfer of RNA and proteins. We hypothesized that endothelium-derived exosomes are involved in the endothelial response to cellular stress, and that exosome RNA and protein content reflect the effects of cellular stress induced by hypoxia, inflammation or hyperglycemia. Methods: We exposed cultured endothelial cells to different types of cellular stress (hypoxia, TNF-α-induced activation, high glucose and mannose concentrations) and compared mRNA and protein content of exosomes produced by these cells by microarray analysis and a quantitative proteomics approach. Results: We identified 1,354 proteins and 1,992 mRNAs in endothelial cell-derived exosomes. Several proteins and mRNAs showed altered abundances after exposure of their producing cells to cellular stress, which were confirmed by immunoblot or qPCR analysis. Conclusion: Our data show that hypoxia and endothelial activation are reflected in RNA and protein exosome composition, and that exposure to high sugar concentrations alters exosome protein composition only to a minor extend, and does not affect exosome RNA composition. To access the supplementary material to this article: Tables SI-SIV and Figures S1-2, please see Supplementary files under Article Tools online.