Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of ospemifene and raloxifene on hormonal status, lipids, genital tract, and tolerability in postmenopausal women

Objective: To compare ospemifene and raloxifene regarding their effects on hormones, lipids, genital tract, and tolerability in postmenopausal women. Design: A randomized, double-blind study in which 118 healthy postmenopausal women received 30 (n = 29), 60 (n = 30), or 90 mg (n = 30) of ospemifene or 60 mg (n = 29) of raloxifene for 3 months. Results: There were no significant differences in the baseline characteristics between study groups. In comparison with raloxifene, follicle-stimulating hormone levels decreased significantly more in the 90-mg ospemifene group and sex hormone-binding globulin levels increased more in all ospemifene groups. Total cholesterol and low-density lipoprotein cholesterol levels decreased more in raloxifene than in ospemifene groups, although the difference in low-density lipoprotein cholesterol between 90-mg ospemifene and raloxifene was not significant. Endometrial thickness did not change in any study group and endometrial biopsies showed atrophy in the majority of subjects at 3 months. All ospemifene groups demonstrated a clear estrogenic effect on the vaginal epithelium, as seen in Pap smears. This was in sharp contrast to the raloxifene group, which had no effect on the vaginal epithelium. Kupperman index decreased in all study groups during treatment. The adverse events were mild, mainly single cases, and no clustering of events was observed. There were no clinically significant abnormal findings in laboratory safety parameters. Conclusions: Ospemifene, at the dose of 90 mg/day, was more estrogenic than raloxifene, as shown by changes in serum follicle-stimulating hormone and sex hormone-binding globulin levels. Neither agent stimulated endometrium, but in contrast to raloxifene, ospemifene had a clear estrogenic effect in the vagina. Further studies with ospemifene are needed in subjects with vaginal atrophy.
Changes in urinary dinor dihydro F2-isoprostane metabolite concentrations, a marker of oxidative stress, during and following asthma exacerbations

To investigate changes in oxidant stress during and following acute asthma exacerbations, this stidy measured 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M), the major urinary metabolite of 15-F2t-IsoP, in eight asthmatic adults, during and following an asthma hospitalization. F2-IsoP-M concentrations at admission and follow-up were significantly higher than discharge (admission median: 4.12 ng/Cr mg, range 1.89–7.8; follow-up: 2.47 ng/Cr mg (1.56–6.86); discharge: 1.42 ng/Cr mg (0.7–4.44); both p<0.01), but not significantly different between admission and follow-up. F2-IsoP-M concentrations at follow-up were higher than a control group with stable asthma (0.68 ng/Cr mg (0.31–1.5), p=0.0008). In conclusion, asthma exacerbations requiring hospitalization are associated with 6-fold higher urinary F2-IsoP-M concentrations compared to stable asthmatics. F2-IsoP-M concentrations decreased significantly during hospitalization, but significant elevations 3 months following hospitalization suggest ongoing oxidative stress despite clinical improvement. Urinary F2-IsoP-M may be a clinically useful, simple non-invasive systemic measure of oxidative stress in asthmatics, providing information not captured by spirometry or symptoms.
Two‐dose basiliximab compared with two‐dose daclizumab in renal transplantation: a clinical study

Abstract: Background: Addition of the interleukin‐2 receptor (IL‐2R) antagonists basiliximab or daclizumab to a calcineurin inhibitor‐based regimen significantly reduces risk of acute rejection with a tolerability profile similar to a placebo. Use of a truncated two‐dose regimen of daclizumab has been reported, but till date, there has been no controlled study of two‐dose daclizumab vs. two‐dose basiliximab.
Glucose Stimulates the Activity of the Guanine Nucleotide-exchange Factor eIF-2B in Isolated Rat Islets of Langerhans (*)

Over short time periods glucose controls insulin biosynthesis predominantly through effects on preexisting mRNA. However, the mechanisms underlying the translational control of insulin synthesis are unknown. The present study was carried out to determine the effect of glucose on the activity and/or phosphorylation status of eukaryotic initiation and elongation factors in islets. Glucose was found to increase the activity of the guanine nucleotide-exchange factor eIF-2B over a rapid time course (within 15 min) and over the same range of glucose concentrations as those that stimulate insulin synthesis (3-20 mM). A nonmetabolizable analogue of glucose (mannoheptulose), which does not stimulate insulin synthesis, failed to activate eIF-2B. The best characterized mechanism for modulating eIF-2B activity involves changes in the phosphorylation of the α-subunit of its substrate eIF-2. However, in islets, no change in eIF-2α phosphorylation was seen under conditions where eIF-2B activity was increased, implying that glucose regulates eIF-2B via an alternative pathway. Glucose also did not affect the phosphorylation states of three other regulatory translation factors. These are the cap-binding factor eIF-4E, 4E-binding protein-1, and elongation factor eEF-2, which do not therefore seem likely to be involved in modulating the translation of the preproinsulin mRNA under these conditions.
Switch of ESA therapy from darbepoetin-alpha to epoetin-beta in hemodialysis patients: a single-center experience.

AIMS No study has previously investigated a switch from darbepoetin-alpha to epoetin-beta in unselected dialysis patients. Our study determined the intravenous epoetin-beta dose necessary to maintain or to achieve hemoglobin targets after switching from darbepoetin-alpha. METHODS In our dialysis center, all eligible dialysis patients (n = 90) were switched from darbepoetin-alpha i.v. to epoetin-beta i.v. in 2005. The epoetin-beta dose was calculated according to the recommended European equimolar conversion factor (1 : 200 microg darbepoetin-alpha corresponds to 200 IU epoetin-beta. The intraindividual evaluation compared 12 weeks before with 16 weeks after the switch. The dose of the erythropoiesis-stimulating agents (ESA) and the hemoglobin levels were analyzed for the whole period and for the last 4 weeks of both treatment periods. RESULTS During treatment with darbepoetin-alpha, 71% of a total of 90 patients achieved a hemoglobin level > or = 11.0 g/dl. After switching to epoetin-beta, the mean hemoglobin level decreased significantly from 11.4 A+/- 1.0 g/dl to 11.1 A+/- 0.9 g/dl (p = 0.0016) and the percentage of patients with hemoglobin levels > or = 11.0 g/dl fell to 50% (p = 0.00138). Furthermore, the mean required ESA dose increased by 13% from 4,335 A+/- 3,217 IU/week darbepoetin-alpha to 4,885 A+/- 3,077 IU/week epoetin-beta (p = 0.0001). Comparing the last 4 weeks, the ESA dose increased by 17% from 4,583 A+/- 3,391 IU/week darbepoetin-alpha to 5,372 A+/- 3,672 IU/week epoetin-beta (p = 0.0003). CONCLUSIONS After switching from darbepoetin-alpha i.v. to epoetin-beta i.v. , the equimolar epoetin-beta dose was not sufficient to maintain hemoglobin levels with the same efficacy above 11.0 g/dl. Significantly less patients achieved hemoglobin target values as suggested by the EBPG guidelines.
Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation*

Tuberculosis, caused by Mycobacterium tuberculosis, still remains a major global health problem. The main obstacle in eradicating this disease is the ability of this pathogen to remain dormant in macrophages, and then reactivate later under immuno-compromised conditions. The physiology of hypoxic nonreplicating M. tuberculosis is well-studied using many in vitro dormancy models. However, the physiological changes that take place during the shift from dormancy to aerobic growth (reactivation) have rarely been subjected to a detailed investigation. In this study, we developed an in vitro reactivation system by re-aerating the virulent laboratory strain of M. tuberculosis that was made dormant employing Wayne's dormancy model, and compared the proteome profiles of dormant and reactivated bacteria using label-free one-dimensional LC/MS/MS analysis. The proteome of dormant bacteria was analyzed at nonreplicating persistent stage 1 (NRP1) and stage 2 (NRP2), whereas that of reactivated bacteria was analyzed at 6 and 24 h post re-aeration. Proteome of normoxially grown bacteria served as the reference. In total, 1871 proteins comprising 47% of the M. tuberculosis proteome were identified, and many of them were observed to be expressed differentially or uniquely during dormancy and reactivation. The number of proteins detected at different stages of dormancy (764 at NRP1, 691 at NRP2) and reactivation (768 at R6 and 983 at R24) was very low compared with that of the control (1663). The number of unique proteins identified during normoxia, NRP1, NRP2, R6, and R24 were 597, 66, 56, 73, and 94, respectively. We analyzed various biological functions during these conditions. Fluctuation in the relative quantities of proteins involved in energy metabolism during dormancy and reactivation was the most significant observation we made in this study. Proteins that are up-regulated or uniquely expressed during reactivation from dormancy offer to be attractive targets for therapeutic intervention to prevent reactivation of latent tuberculosis.
Genomic alterations in mucins across cancers

The significance of mucins in cancers has led to the development of novel biomarkers and therapeutic agents against cancers. Despite significant advances in the understanding of mucins, systemic investigations into the role of mucins in cancer biology focusing particularly on the histological subtypes and stages, along with other variables, are yet to be carried out to discover potential novel functions and cancer-specific roles. Here, we investigated 11 mucin expressing cancers for DNA mutations, mRNA expression, copy number, methylation, and the impacts these genomic features may have on patient survival by utilizing The Cancer Genome Atlas dataset. We demonstrate that mucin DNA mutations have a significant rate, pattern, and impact on cancer patient survival depending on the tissue of origin. This includes a frequent T112P mutation in MUC1 that is seen in half of the pancreatic MUC1 mutations, as well as being present in other cancers. We also observed a very frequent MUC4 mutation at H4205, which correlated with survival outcomes in patients. Furthermore, we observed significant alterations in mucin mRNA expression in multiple tumor types. Our results demonstrate de novo expression of certain mucins in cancer tissues, including MUC21 in colorectal cancers. We observed a general decrease in promoter methylation for mucins, which correlated with decreased expression of many genes, such as MUC15 in kidney cancers. Lastly, several mucin gene loci demonstrated copy number increase in multiple histological subtypes. Thus, our study presents a comprehensive analysis of genomic alterations in mucins and their corresponding roles in cancer progression.
Treatment of bipolar affective disorder in clinical practice

A case note survey of 100 outpatients with a clinical diagnosis of bipolar affective disorder in a UK inner city teaching hospital revealed monotherapy with a mood stabilizer in only 23% of patients, mostly lithium (15%). Overall, 51% of patients were prescribed lithium, 19% carbamazepine and 5% valproate with only 8% receiving a combination of two mood stabilizers. Treatment appeared to be inadequate in 13/51 of patients on lithium, 9/19 of those on carbamazepine and 1/5 of those on valproate. Antipsychotics were used as monotherapy in 20% of patients and combined with a mood stabilizer in 43% of patients. Only 6% of patients were on atypical antipsychotics. These findings suggest that the treatment for many patients does not match recommendations. Clearer evidence on the place of combination mood stabilizers and adjunctive antipsychotics, particularly atypicals is needed in the treatment of bipolar affective disorder.
Safety profiles of first-line therapies for metastatic non-squamous non-small-cell lung cancer

ABSTRACT Introduction: Lung cancer still represents the leading cause of death for cancer. About the 70% of diagnosis are in advanced-stage. Non-small-cell lung cancer (NSCLC) represents the 85% of all diagnosed lung cancers and non-squamous histology represents the 40% of all NSCLC. First-line therapies increase survival, control symptoms and improve quality of life, compared with best supportive care. It is crucial to choose a treatment with a low impact on patient’s life considering the related toxicities. Areas covered: Adverse events (AEs) of first-line therapies for non-squamous NSCLC are here reviewed and discussed, from evidences in clinical trials conducting to drugs approval. Expert opinion: For advanced disease, palliation and preserving patients QoL are still the primary goal of treatment. Therefore, differing toxicity profiles are often a deciding factor in first-line and also maintenance setting for non-squamous NSCLC. Special attention is necessary to renal function and drugs’ nephrotoxicity. Moreover, it is to consider the specific AEs of drugs classes: hypertension, bleeding, and proteinuria, for anti-VEGF therapy; skin toxicity, diarrhea, interstitial lung disease for TKIs; vision disorders, and hepatotoxicity for ALK-inhibitor. It is important to select patients for a treatment on the basis of their comorbidities and the presence of risk factors.
Construction and Transplantation of an Engineered Hepatic Tissue Using a Polyaminourethane-Coated Nonwoven Polytetrafluoroethylene Fabric

Background. Acute liver failure (ALF) is a serious condition that has a high mortality rate. Construction of an efficient culture and transplantation engineering system of hepatic tissue is an important approach to treat patients suffering from ALF to provide short-term hepatic support until the damaged liver spontaneously recovers or a donor liver becomes available for transplantation. Here, we evaluate the construction and transplantation of an engineered hepatic tissue (EHT) using primary isolated hepatocytes cultured onto polyaminourethane (PAU)-coated, nonwoven polytetrafluoroethylene (PTFE) fabric. Methods. The isolated hepatocytes cultured onto PAU-coated PTFE fabric were able to adhere and spread over the individual fibers of the net and formed hepatic clusters after 3 days, such clusters revealed Gap junctions and well-developed bile canaliculi. Results. When PAU-coated PTFE was utilized, ammonia-, and diazepam- metabolizing capacities and albumin production ability were significantly increased compared with collagen control. To test the function of this hepatic tissue in vivo, we transplanted a nonwoven PAU-coated PTFE fabric inoculated with one million hepatocytes on the surface of the spleen of Balb/c mice suffering from ALF induced by 90% hepatectomy, and found that this EHT prolonged the survival of liver failure-induced mice without adverse effects. Ultrastructure analyses showed good attachment of the cells on the surface of PTFE fabric and strong albumin expression seven days after the newly formed hepatic tissue was transplanted. Conclusion. We have here demonstrated the efficient construction and transplantation of hepatic tissue using primary hepatocytes and PAU-coated PTFE fabric.
IgA anti-tissue transglutaminase antibodies, first line in the diagnosis of celiac disease.

BACKGROUND According to the 2008 celiac disease working group run by Dr. A. Fassano under the auspices of the Federation of International Societies of Pediatric Gastroenterology, Hepatology and Nutrition, celiac disease is a chronic immune-mediated enteropathy characterized by gluten sensitivity, which can affect any organ or system, having a wide range of clinical manifestations of variable severity. The serological diagnosis of celiac disease is based on high sensitivity and specificity tests. The measurement of IgA anti-tissue transglutaminase antibodies by ELISA is universally accepted in the screening of celiac disease. METHODS Using the gold standard represented by IgA anti-endomysium antibodies in a group of 890 children investigated during 2008-2009, we aimed to evaluate IgA anti-tissue transglutaminase antibodies (tTG IgA), as well as to establish their prevalence in associated diseases. RESULTS Following the measurement of tTG IgA in the entire group, we obtained: sensitivity 773%, positive predictive value 55.2%, specificity 93.1%, negative predictive value 973%, p = 0.000, and in tTG IgA associations we obtained the value 0.51 for the ROC curve area. We found associations of tTG IgA with type 1 diabetes mellitus (235% prevalence), protein-calorie malnutrition (0.89% prevalence), and intestinal malabsorption (0.56% prevalence). CONCLUSIONS Our results have a high specificity and sensitivity in the screening of celiac disease, while requiring a second method of confirmation.
Faecal steroids and colorectal cancer: the effect of lactulose on faecal bacterial metabolism in a continuous culture model of the large intestine.

The effect of lactulose on intestinal bacterial metabolism in two identical single-stage chemostats has been studied. The study was designed as a single stage crossover. Both cultures were inoculated and treated in an identical manner except that whilst one fermenter was subject to pH control the other was not and vice versa. Complex bacterial populations were maintained for 23 days and many of the metabolic functions carried out by the micro-organisms in vivo were demonstrated in vitro. The predominant organisms belonged to the genera Bacteroides, Bifidobacterium and Clostridium with abundant levels of anaerobic Gram-positive rods. The redox potential in each fermenter showed considerable variation with maximum values of below -300 eV being attained. An indication of the stability of the bacterial communities was the production of short-chain volatile fatty acids; during steady-state conditions the mean ratio of the major acids acetic, propionic and butyric being 3.90:0.69:1.00 and 3.65:0.76:1.00 in each fermenter, respectively. During steady-state conditions, 7 alpha-dehydroxylation of the primary bile acid chenodeoxycholic acid was maintained at a constant rate with lithocholic acid representing over 85% of total steroid. Addition of the soluble fibre lactulose to the cultures had a profound effect on many of the parameters tested. Without pH control the culture pH dropped to below 5.0 and this coincided with a substantial decrease in total anaerobes, especially Bacteroides spp. , an increase in Lactobacillus spp. (concomitant with an increase in lactic acid), a decrease in the concentration of short-chain volatile fatty acids and a substantial decrease in 7 alpha-dehydroxylation of chenodeoxycholic acid. These results show that it is possible to maintain viable intestinal bacteria in vitro using a continuous culture chemostat and that the cultures respond to changing conditions as evinced by the inhibition of 7 alpha-dehydroxylation of chenodeoxycholic acid on addition of lactulose. This indicates that the model may be of further use in studying the modulation of secondary bile acid formation, a possible risk factor in colorectal carcinogenesis.
Type III hereditary angio‐oedema: clinical and biological features in a French cohort

To cite this article: Vitrat‐Hincky V, Gompel A, Dumestre‐Perard C, Boccon‐Gibod I, Drouet C, Cesbron JY, Lunardi J, Massot C, Bouillet L. Type III hereditary angio‐oedema: clinical and biological features in a French cohort. Allergy 2010; 65: 1331–1336.
Population genetic structure of the endangered tropical tree species Caryocar brasiliense, based on variability at microsatellite loci

We report the population genetic structure of the endangered tropical tree species Caryocar brasiliense, based on variability at 10 microsatellite loci. Additionally, we compare heterozygosity and inbreeding estimates for continuous and fragmented populations and discuss the consequences for conservation. For a total of 314 individuals over 10 populations, the number of alleles per locus ranged from 20 to 27 and expected and observed heterozygosity varied from 0.129 to 0.924 and 0.067 to 1.000, respectively. Significant values of θ and RST showed important genetic differentiation among populations. θ was much lower than RST, suggesting that identity by state and identity by descent have diverged in these populations. Although a significant amount of inbreeding was found under the identity by descent model (f = 0.11), an estimate of inbreeding for microsatellite markers based on a more adequate stepwise mutation model showed no evidence of nonrandom mating (RIS = 0.04). Differentiation (pairwise FST) was positively correlated with geographical distance, as expected under the isolation by distance model. No effect of fragmentation on heterozygosity or inbreeding could be detected. This is most likely due to the fact that Cerrado fragmentation is a relatively recent event (~60 years) compared to the species life cycle. Also, the populations surveyed from both fragmented and disturbed areas were composed mainly of adult individuals, already present prior to ecosystem fragmentation. Adequate hypothesis testing of the effect of habitat fragmentation will require the recurrent analysis of juveniles across generations in both fragmented and nonfragmented areas.
Cross‐species studies of cognition relevant to drug discovery: a translational approach

This review advances the case that bidirectional, cross‐species translation of findings from experimental animals to and from humans is an important strategy for drug discovery. Animal models of mental disorders require appropriate behavioural or cognitive outcome variables that can be generalized cross‐species. One example is the treatment of impulsive behaviour in attention deficit hyperactivity disorder (ADHD) with stimulant drugs. Performance on the stop signal reaction task as an index of impulsivity is improved both in healthy human volunteers and in patients with adult ADHD by stimulant drugs and also by the selective noradrenaline reuptake blocker atomoxetine. Functional neuroimaging evidence suggests a modulation of circuitry including the inferior prefrontal cortex by this drug. Parallel work in rats had shown that atomoxetine improves stop signal performance by affecting possibly homologous regions of the rodent prefrontal cortex. This parallel effect of atomoxetine in rodents and humans could potentially be exploited in other disorders in which impulsivity plays a role, such as stimulant abuse and Parkinson's disease. A contrasting relative lack of involvement of 5‐HT mechanisms in the stop signal reaction time task will also be described. Research in humans and experimental animals that demonstrate effects of serotoninergic agents such as the selective serotonin (5‐HT) reuptake inhibitor citalopram on probabilistic learning and reversal (upon which atomoxetine has little effect) will also be reviewed, possibly relevant to the treatment of clinical depression, Finally, other promising examples of parallel studies of behavioural effects of CNS‐active drugs in animals and humans will also be described.