Miracle-dz/UniFAR-FTUs huggingface dataset:
Total globozoospermia associated with increased frequency of immature spermatozoa with chromatin defects and aneuploidy: a case report

Globozoospermia, characterised by the presence of round spermatozoa lacking acrosomes in an ejaculate, is a known cause of male infertility. Semen analysis, including sperm chromatin structure assay, toluidine blue, chromomycin A3 and aniline blue staining and fluorescence in situ hybridisation, was performed in an infertile globozoospermic patient to establish to which extent these genetic factors contributed to his infertility. No spermatozoa capable of hyaluronan (HA) binding were detected in the HA binding assay. Increased rates of immature spermatozoa with defective replacement of histones by protamines, DNA breaks and disturbed chromatin integrity and sperm aneuploid for the sex chromosomes were observed. Intracytoplasmic sperm injection (ICSI) was used in three in vitro fertilisation (IVF) cycles, and enough morphologically well‐developing embryos were obtained in each cycle. However, no pregnancy was achieved. The infertility of our couple, resistant to IVF/ICSI treatment, was most probably caused by a combination of male and female factors.
Assessment of Alcohol Withdrawal in Native American Patients Utilizing the Clinical Institute Withdrawal Assessment of Alcohol Revised Scale

Background:The Clinical Institute Withdrawal Assessment of Alcohol Revised (CIWA-Ar) is a commonly used scale for assessing the severity of alcohol withdrawal syndrome in the acute setting. Despite validation of this scale in the general population, the effect of ethnicity on CIWA-Ar scoring does not appear in the literature. The purpose of our study was to investigate the validity of the CIWA-Ar scale among Native American patients evaluated for acute alcohol detoxification. Methods:A case series of all patients seen for alcohol withdrawal at an Acute Drug and Alcohol Detoxification facility was conducted from June 1, 2011, until April 1, 2012. The CIWA-Ar scores were recorded by trained nursing staff on presentation to Triage Department and every 2 hours thereafter. At our institution, a score of 10 or greater indicates the need for inpatient hospital admission and treatment. Ethnicity was self-reported. Age, sex, blood alcohol concentration, blood pressure, and pulse were recorded on presentation and vital signs repeated every 2 hours. Patients were excluded from the study if other drug use was noted by history or initial urine drug screen. A multivariate logistic regression model was utilized to identify statistically significant variables associated with admission to the inpatient unit and treatment. The relationship of CIWA-Ar scores and ethnicity was compared using analysis of variance. Results:A total of 115 whites, 45 Hispanics, and 47 Native Americans were included in the analysis. Native Americans had consistently lower CIWA-Ar scores at 0, 2, 4, and 6 hours than the other 2 ethnic groups (P = 0.002). In addition, Native Americans were admitted to the hospital less often than the other 2 groups for withdrawal (P < 0.001). Conclusions:The CIWA-Ar scale may underestimate the severity of alcohol withdrawal syndrome in certain ethnic group such as Native Americans. Further prospective studies should be undertaken to determine the validity of the CIWA-Ar scale in assessing alcohol withdrawal across different ethnic populations.
Methotrexate resistance in vitro is achieved by a dynamic selectionprocess of tumor cell variants emerging during treatment

Genetic instability leads to tumor heterogeneity, which in turn provides a source of cell variants responsible for drug resistance. However, the source of resistant cells during the process of acquired resistance is poorly understood. Our aim has been to characterize the mechanism by which acquired resistance to methotrexate emerges during the course of cancer cell treatment in vitro. We recently demonstrated that, in vitro, HT‐29 colon cancer cells become transiently sensitive to methotrexate by depleting the extracellular milieu of survival factors; on the other hand, the cell population under treatment can reversibly adapt to grow below a critical cell density in the presence of the drug. Here, we show that this adapted cell population gives rise to permanent resistant populations through repeated cycles of cell death and growth. This increased cell turnover, but not merely cell proliferation, is required for the appearance of increasing degrees of stable resistance that are progressively selected by drug pressure. Such a process, taking place in multiple steps, is here designated “dynamic selection. ” The analysis of sensitive and resistant HT‐29 cell populations revealed that methotrexate induces genomic instability—characterized by centrosome amplification and aberrant chromosome recombination—leading to a low‐level amplification of the 5q chromosome arm as one of the earliest genetic events selected during treatment. Therefore, this model provides a mechanism by which a tumor cell population lacking resistant subpopulations before treatment is able to acquire the genetic changes required for stable drug resistance. © 2006 Wiley‐Liss, Inc.
An investigation into the influence of binary drug solutions upon diffusion and partition processes in model membranes

Few studies have assessed the impact of binary systems on the fundamental mathematical models that describe drug permeation. The aim of this work was to determine the influence of varying the proportions of prilocaine and lidocaine in a binary saturated solution on mass transfer across synthetic membranes. Infinite‐dose permeation studies were performed using Franz diffusion cells with either regenerated cellulose or silicone membranes, and partition coefficients were determined by drug loss over 24 h. There was a linear relationship between the flux of prilocaine and lidocaine through regenerated cellulose membrane (R2 ≥ 0.985, n = 5) and their normalised ratio in solution. This linear model was also applicable for the permeation of prilocaine through silicone membrane (R2 = 0.991, n = 5), as its partition coefficient was independent of the drug ratio (15.84 ± 1.41). However, the partition coefficient of lidocaine increased from 27.22 ± 1.68 to 47.03 ± 3.32 as the ratio of prilocaine increased and this resulted in a non‐linear relationship between permeation and drug ratio. Irrespective of the membrane used, the permeation of one drug from a binary system was hindered by the presence of the second, which could be attributed to a reduction in available membrane diffusion volume.
Carboplatin and Gemcitabine Combination in Metastatic Triple-Negative Anthracycline- and Taxane-Pretreated Breast Cancer Patients: A Phase II Study

Abstract Triple-negative breast cancer (TNBC) is characterized by lack of hormone receptors and HER-2 and shares many features with BRCA1-associated cancer. Preclinical data indicate cisplatin sensitivity, suggesting that these tumors may have defects in the BRCA1 pathway. The carboplatin and gemcitabine (CG) combination is active in unselected anthracycline/taxane pretreated metastatic breast cancer patients, so we carried out a phase II study to evaluate the activity of the CG combination in pretreated metastatic TNbC patients. From 10/2004 to 3/2009 we enrolled 31 patients. Median age was 57 years and 29 patients out of 31 had visceral involvement. The overall response rate (ORR) was 32% (1 complete response /9 partial responses), in addition 5 patients obtained stable disease for ≥12 weeks. After a median follow-up of 34 months, all patients progressed with a median time to progression of 5.5 months and median overall survival of 11 months. Dose reductions, delays and omissions occurred in 75 (60%), 36 (29%) and 22 (18%) cycles. Grade 3/4 neutropenia occurred in 17 and febrile neutropenia in 4 patients. Ten patients had Grade 3/4 thrombocytopenia. Non hematological toxicities were manageable. The CG combination is a reasonable option for the treatment of metastatic pre-treated TNBC patients.
Effect of hens fed dietary flaxseed with and without a fatty liver supplement on hepatic, plasma and production characteristics relevant to fatty liver haemorrhagic syndrome in laying hens

1. Two long-term experiments were conducted with Single Comb White Leghorn (SCWL) hens (line UCD-003) predisposed to fatty liver haemorrhagic syndrome (FLHS). The first investigated the effect of adding a fatty liver supplement to the diet of laying hens prior to the onset of lay, and continuing either until peak production or throughout 39 weeks into lay. The second experiment, lasting 9 months into lay, investigated the effect of adding a fatty liver supplement, with or without 100 g/kg dietary ground flaxseed, to the diet. Body weight, feed intake, plasma triglycerides (in experiment 2) and egg production were measured throughout the experiment. Liver weight, liver fat content, liver malondialdehyde (MDA) content and liver haemorrhage score and fatty acid content of liver fat (in experiment 2) were measured at the end of each experiment. 2. In experiment 1, hens given diets containing the fatty liver supplement had higher egg production and eggshell strength, but there was no difference in liver parameters including MDA content or haemorrhage score compared with controls. 3. At the end of experiment 2, hens on 100 g/kg flaxseed diets had lower body weight, liver weight, liver dry matter and fat content, and plasma triglyceride concentrations than hens given the control diets. 4. Liver haemorrhage score was positively correlated with liver weight, but not with liver fat content, plasma triglyceride concentration or liver MDA content. This suggests that reducing the liver lipid content or feeding fatty liver supplements may not be as effective in controlling FLHS as controlling the size of the liver.
Endogenous glucagon-like peptide-1 slows gastric emptying in healthy subjects, attenuating postprandial glycemia.

INTRODUCTION The role of glucagon-like peptide-1 (GLP-1) in the regulation of gastric emptying is uncertain. The aim of this study was to determine the effects of endogenous GLP-1 on gastric emptying, glucose absorption, and glycemia in health. METHODS Ten healthy fasted subjects (eight males, two females; 48 +/- 7 yr) received the specific GLP-1 antagonist, exendin(9-39) amide [ex(9-39)NH(2)] (300 pmol/kg x min iv), or placebo, between -30 and 180 min in a randomized, double-blind, crossover fashion. At 0 min, a mashed potato meal ( approximately 2600 kJ) containing 3 g 3-ortho-methyl-D-glucose (3-OMG) and labeled with 20 MBq (99m)Technetium-sulphur colloid was eaten. Gastric emptying, including the time taken for 50% of the meal to empty from the stomach (T50), blood glucose, plasma 3-OMG, and plasma insulin were measured. RESULTS Ex(9-39)NH(2) accelerated gastric emptying [T50 ex(9-39)NH(2), 68 +/- 8 min, vs. placebo, 83 +/- 7 min; P < 0.001] and increased the overall glycemic response to the meal [area under the curve (0-180 min) ex(9-39)NH(2), 1540 +/- 106 mmol/liter x min, vs. placebo, 1388 +/- 90 mmol/liter x min; P < 0.02]. At 60 min, ex(9-39)NH(2) increased the rise in glycemia [ex(9-39)NH(2), 9.9 +/- 0.5 mmol/liter, vs. placebo, 8.4 +/- 0.5 mmol/liter; P < 0.01], plasma 3-OMG [ex(9-39)NH(2), 0.25 +/- 0.01 mmol/liter, vs. placebo, 0.21 +/- 0.01 mmol/liter; P < 0.05], and plasma insulin [ex(9-39)NH(2), 82 +/- 13 mU/liter, vs. placebo, 59 +/- 9 mU/liter; P < 0.05] concentrations. There was a close within-subject correlation between glycemia and gastric emptying [e.g. at 60 min, the increment in blood glucose and gastric emptying (T50); r = -0.89; P < 0.001]. CONCLUSION GLP-1 plays a physiological role to slow gastric emptying in health, which impacts on glucose absorption and, hence, postprandial glycemia.
Doxorubicin‐induced platelet cytotoxicity: a new contributory factor for doxorubicin‐mediated thrombocytopenia

Summary. Background: Doxorubicin (DOX) is a widely used anticancer drug for solid tumors and hematologic malignancy, but its active use is hampered by serious adverse effects, including thrombocytopenia. Although bone marrow toxicity of DOX has been suggested to be the sole mechanism underlying the reduced platelet counts, the direct effects of DOX on platelets have never been examined. Objective: Here, we investigated the DOX‐induced platelet cytotoxicity and its underlying mechanism in an effort to elucidate the contribution of platelet cytotoxicity to DOX‐induced thrombocytopenia. Results: In freshly isolated human platelets, DOX induced platelet cytotoxicity in a time‐dependent and concentration‐dependent manner. Reactive oxygen species (ROS) generation, decreased glutathione levels and subsequent protein thiol depletion were shown to underlie the DOX‐induced platelet cytotoxicity. Conspicuously, DOX‐treated platelets displayed apoptotic features such as caspase‐3 activation, reduced mitochondrial transmembrane potential, and phosphatidylserine exposure. Decreased glutathiolation of procaspase‐3 was shown to be a link between protein thiol depletion and caspase‐3 activation. It is of note that DOX‐mediated platelet cytotoxicity was significantly enhanced by shear stress, a common complicating factor in cancer patients. These in vitro results were further confirmed by an in vivo animal model, where administration of DOX induced a platelet count decrease, ROS generation, caspase‐3 activation, protein thiol depletion, and damaged platelet integrity. Conclusion: We demonstrated that DOX can directly induce platelet cytotoxicity through ROS generation, decreased glutathione levels, and protein thiol depletion. We believe that this study provides important evidence for the role of DOX‐induced platelet cytotoxicity in the development of thrombocytopenia in DOX‐treated patients.
A pilot study exploring the contribution of working memory to “jumping to conclusions” in people with first episode psychosis

Introduction. People with delusional beliefs “jump to conclusions” (JTC). This finding is well replicated. However, there is only limited exploration of the factors that might lead a person to JTC. The aim of the present study was to explore the contribution of working memory processes (WM) and IQ to hasty decision making and to investigate the stability of this bias over time. Methods. A single group cross-sectional design was utilised. The study was conducted in 2 phases: (1) an initial screening phase and (2) an experimental phase whereby we explored and tested hypotheses regarding the cognitive origins of the JTC bias. In Study 1, participants completed the beads task as well as measures of mood and symptoms. In Study 2, the same participants repeated the beads task, and completed a battery of neuropsychological tests designed to assess different facets of WM and IQ. Results. In most cases, “jumpers” were indistinguishable from “nonjumpers” in terms of their neuropsychological profiles. The only exception to this pattern was for visual working memory, in which “jumpers” performed better than “nonjumpers”. In terms of the temporal stability of the JTC bias, 8 individuals (out of the 29) effectively switched from being “jumpers” at T1 to “nonjumpers” at T2. Conclusions. This study casts doubt on reduced global WM as an explanation of JTC. Rather it may be that the differences in reasoning are related to the manipulation of visual material and do not extend to other areas of neuropsychological functioning. However, as our sample is small it may be underpowered to detect important differences. Future work is therefore needed to replicate these findings.
Effect of alcohol consumption on CpG methylation in the differentially methylated regions of H19 and IG-DMR in male gametes: implications for fetal alcohol spectrum disorders.

BACKGROUND Exposure to alcohol in utero is the main attributable cause of fetal alcohol spectrum disorders (FASD) which in its most severe form is characterized by irreversible behavioral and cognitive disability. Paternal preconception drinking is not considered to be a significant risk factor, even though animal studies have demonstrated that chronic paternal alcohol consumption has a detrimental effect on the physical and mental development of offspring even in the absence of in utero alcohol exposure. It has been documented that alcohol can reduce the levels and activity of DNA methyltransferases resulting in DNA hypomethylation and that reduced methyltransferase activity can cause activation of normally silenced genes. The aim of this study was to establish a link between alcohol use in men and hypomethylation of paternally imprinted loci in sperm DNA in genomic regions critical for embryonic development, thus providing a mechanism for paternal effects in the aetiology of FASD. METHODS Sperm DNA from male volunteers was bisulfite treated and the methylation patterns of 2 differentially methylated regions (DMRs), H19 and IG-DMR, analyzed following sequencing of individual clones. The methylation patterns were correlated with the alcohol consumption levels of the volunteer males. RESULTS There was a pattern of increased demethylation with alcohol consumption at the 2 imprinted loci with a significant difference observed at the IG-DMR between the nondrinking and heavy alcohol consuming groups. Greater inter-individual variation in average methylation was observed at the H19 DMR and individual clones were more extensively demethylated than those of the IG-DMR. CpG site #4 in the IG-DMR was preferentially demethylated among all individuals and along with the H19 DMR CpG site #7 located within the CTCF binding site 6 showed significant demethylation in the alcohol consuming groups compared with the control group. CONCLUSION This study demonstrates a correlation between chronic alcohol use and demethylation of normally hypermethylated imprinted regions in sperm DNA. We hypothesize that, should these epigenetic changes in imprinted genes be transmitted through fertilization, they would alter the critical gene expression dosages required for normal prenatal development resulting in offspring with features of FASD.
The Rat Genome Database, update 2007—Easing the path from disease to data and back again

The Rat Genome Database (RGD, ) is one of the core resources for rat genomics and recent developments have focused on providing support for disease-based research using the rat model. Recognizing the importance of the rat as a disease model we have employed targeted curation strategies to curate genes, QTL and strain data for neurological and cardiovascular disease areas. This work has centered on rat but also includes data for mouse and human to create ‘disease portals’ that provide a unified view of the genes, QTL and strain models for these diseases across the three species. The disease curation efforts combined with normal curation activities have served to greatly increase the content of the database, particularly for biological information, including gene ontology, disease, pathway and phenotype ontology annotations. In addition to improving the features and database content, community outreach has been expanded to demonstrate how investigators can leverage the resources at RGD to facilitate their research and to elicit suggestions and needs for future developments. We have published a number of papers that provide additional information on the ontology annotations and the tools at RGD for data mining and analysis to better enable researchers to fully utilize the database.
Repetitive DNA methylome analysis by small‐scale and single‐cell shotgun bisulfite sequencing

Whole‐genome shotgun bisulfite sequencing (WG‐SBS) is currently the most powerful tool available for understanding genomewide cytosine methylation with single‐base resolution; however, the high sequencing cost limits its widespread application, particularly for mammalian genomes. We mapped high‐ to low‐coverage SBS short reads of mouse and human female developing germ cells to consensus sequences of repetitive elements that were multiplied in the respective host genome. This mapping strategy effectively identified active and evolutionarily young retrotransposon subfamilies and centromeric satellite repeats that were resistant to DNA demethylation during the investigated progressive stages of germ cell development. Notably, quantities of only tens of thousands of uniquely mapped reads provided sufficient sensitivity to allow for methylation analyses of multiple retrotransposons and satellite repeats in mice. Furthermore, we produced SBS results from single female murine germ cells by an improved multiplexing and amplification‐free SBS method (scPBAT). The scPBAT results quantitatively provided ≥5× sequencing coverage for at least 30 repeats, and the individual methylation patterns detected were similar to the bulk cell‐based results. Our single‐cell methylome sequencing technique will allow researchers to investigate intergenic methylation characteristics from limited amounts of mammalian cells as well as cells from other organisms with genomic annotations.
Circulating Adipocytokines in Obese Nondiabetic Patients in Relationship with Cardiovascular Risk Factors, Anthropometry and Resting-Energy Expenditure

Background: Obesity and insulin resistance are associated with cardiovascular risk factors, including altered levels of inflammatory markers and adipocytokines. The aim of the present study was to examine the relationship between circulating adipocytokines and cardiovascular risk factors. Subjects: A population of 95 obese, nondiabetic outpatients was analyzed prospectively. A complete nutritional evaluation was performed. Results: In the multivariate analysis, with leptin as a dependent variable, only fat mass remained in the model (F = 66.6; p < 0.05), with an increase of 2.24 (95% CI 1.68–2.8) ng/ml of leptin with each 1 kg of fat mass. In a new model, with adiponectin as a dependent variable, the HDL cholesterol levels remained in the model (F = 8.46; p < 0.05), with an increase of 5.38 (95% CI 1.7–9.1) ng/ml of adiponectin with each 1 mg/dl of HDL cholesterol. In a third model, with interleukin 6 (IL-6) as a dependent variable, the resistin and C-reactive protein (CRP) levels remained in the model (F = 16.8; p < 0.01), with an increase of 0.48 (95% CI 0.27–0.85) pg/ml of IL-6 with each 1 ng/ml of resistin and an increase of 0.12 (95% CI 0.029–0.214) pg/ml with each 1 mg/dl of CRP. Conclusion: Circulating adipocytokine concentrations are associated with different cardiovascular risk factors in nondiabetic obese patients.
Issues Related to Using a Short-Form of the Center for Epidemiological Studies–Depression Scale

The study examined the reliability and validity, including the factor structure, of a 10-item abbreviated version of the Center for Epidemiological Studies–Depression (CES—Depression) scale when administered as part of a mail questionnaire. It also examined patterns of nonresponse to items and the effects of imputation of data for missing items on the factor structure of the inventory. A problem of missing data has been reported even with interview administration of the CES–Depression. Researchers have varied considerably in the amount of imputation used to replace missing datapoints. In this study, factor structures varied when items were imputed. In addition, those subjects with complete data were compared with those with up to two imputed datapoints. Those subjects with imputed data were more likely to be female, have lower functional status scores, lower self-reported health status, more advanced age, and a greater number of depressive symptoms than those with no missing data. While the estimate of coefficient alpha of . 78 indicated the inventory was reliable, the effects of missing data on construct validity were problematic.