Miracle-dz/UniFAR-FTUs huggingface dataset:
Dipeptidyl peptidase-4 inhibitors in progressive kidney disease

Purpose of reviewDipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs approved for the treatment of type 2 diabetes. The main action of DPP-4 inhibitors is to increase the level of incretin hormones such as glucagon-like peptide-1 (GLP-1), thereby stimulating insulin secretion from pancreatic &bgr; cells. Recently emerging evidence suggests the pleiotropic extrapancreatic function of GLP-1 or DPP-4 inhibitors, including kidney and cardiovascular protection. Here, we review the effects of DPP-4 inhibitors on progressive kidney disease such as diabetic nephropathy from a therapeutic point of view. Recent findingsA growing number of studies in animal models and human diseases have shown that DPP-4 inhibition ameliorates kidney disease by a process independent of glucose lowering. Possible mechanisms underlying such protective properties include the facilitation of natriuresis and reduction of blood pressure, and also local effects of the reduction of oxidative stress, inflammation and improvement of endothelial function in the kidney. DPP-4 inhibitors may also restore other DPP-4 substrates which have proven renal effects. SummaryTreatment of diabetes with DPP-4 inhibitors is likely to involve a variety of extrapancreatic effects including renal protection. Such pleiotropic action of DPP-4 inhibitors might occur by both incretin-dependent and incretin-independent mechanisms. Conclusive evidence is needed to translate the favorable results from animal models to humans.
ENHANCED EXPRESSION OF CARDIAC NERVE GROWTH FACTOR AND NERVE SPROUTING MARKERS IN RATS FOLLOWING GASTRIC PERFORATION: THE ASSOCIATION WITH CARDIAC SYMPATHOVAGAL BALANCE

Endotoxemia and/or systemic inflammation may lead to disturbances in the cardiac autonomic nervous system and consequent arrhythmia. The underlying mechanism remains unclear. Therefore, we investigated the expression of nerve growth factor (NGF) and its association with cardiac sympathovagal balance in a rodent model of self-limited peritonitis. Male Wistar rats were randomized into the following groups: normal control, sham, gastric perforation (GP), and GP treated with methylprednisolone. Cardiac expression of NGF, growth-associated protein 43 (GAP43), along with other nerve markers were evaluated at several time points (6 h to 2 weeks) after GP. An autoregressive process was performed on each detrended electrocardiogram to calculate the heart rate power spectrum. Compared with the normal control and sham groups, expression of NGF was significantly elevated for 1 week after GP. We also found the up-regulated GAP43 and tyrosine hydroxylase protein levels in the GP group, which persisted after recovery from peritonitis. Gastric perforation caused a biphasic change in the ratio of low-frequency to high-frequency power (an index of sympathovagal balance), with an initial decrease followed by recovery at 24 h. Increased NGF and cardiac sympathetic marker expression were temporally associated with the restoration of the cardiac sympathovagal balance. Methylprednisolone abrogated the NGF up-regulation induced by GP and delayed the resumption of sympathovagal balance. We conclude that GP resulted in up-regulation of cardiac NGF, GAP43, and tyrosine hydroxylase expression that coincided with recovery of cardiac sympathovagal balance. Moreover, methylprednisolone can effectively block GP-induced NGF up-regulation.
Pharmacokinetics of a Once-Daily Regimen of Lopinavir/Ritonavir in HIV-1-Infected Children

Introduction Lopinavir is an HIV protease inhibitor that is co-formulated with ritonavir. The approved paediatric dose is 230/57.5 mg/m2 twice daily. Once-daily dosing may offer an advantage to adherence. We studied the pharmacokinetics of lopinavir/ritonavir in a once-daily regimen in HIV-1-infected children. Methods HIV-1-infected children on stable antiretroviral therapy with a viral load <50 copies/ml for at least 6 months received lopinavir/ritonavir 460/115 mg/m2 once daily with zidovudine and lamivudine. Blood samples were collected at 0, 2, 4, 6, 8, 12, 18 and 24 h after observed intake during steady state. Target level for lopinavir Cmin was 1.0 mg/l, based on in vitro IC50 data. Results Nineteen HIV-1-infected children with a median (range) age of 4.5 (1.4–12.9) years were enrolled. The median (interquartile range) dose of lopinavir was 456 (444–477) mg/m2. The mean (standard deviation) AUC0–24, Cmax and Cmin of lopinavir were 149.8 ±58.8 h*mg/l, 10.77 ±2.90 mg/l and 2.88 ±3.74 mg/l respectively. These values are comparable to data observed in adults using lopinavir/ritonavir 800/200 mg once daily. In 10/19 (53%) children Cmin was considered to be too low (<1.0 mg/l). Younger children more often experienced subtherapeutic trough levels. Conclusion Our findings indicate that 460/115 mg/m2 lopinavir/ritonavir once daily leads to mean pharmacokinetic parameters comparable to data of 800/200 mg lopinavir/ritonavir once daily in adults, although the variability observed in the trough levels is much higher in children. Further research, especially in young children, is necessary to determine whether a higher dosage of lopinavir/ritonavir once daily must be given to reach the target level for Cmin.
Pilot study of vincristine, oral irinotecan, and temozolomide (VOIT regimen) combined with bevacizumab in pediatric patients with recurrent solid tumors or brain tumors

The combination of vincristine, oral irinotecan, and temozolomide (VOIT regimen) has shown antitumor activity in a pediatric Phase I trial. To further potentiate synergy, we assessed the safety and feasibility of adding bevacizumab to VOIT for children and young adults with recurrent tumors.
Analysis of secondary metabolite fate during anaerobic‐aerobic azo dye biodegradation in a sequential batch reactor

Abstract A great number of the reported examples of azo dye biodegradation comprise two main steps, the reductive cleavage of the azo bond under anaerobic conditions and the subsequent aerobic mineralization of the produced aromatic amines. Based on this possible metabolism a Sequencing Batch Reactor was chosen to study biological color removal from simulated cotton textile effluents containing a reactive azo dye. In previous studies high color removal levels of the azo dye Remazol Brilliant Violet 5R were achieved (up to 90% with an initial dye concentration of 100 mg l−1 ) during the anaerobic phase of Sequencing Batch Reactor operation. However, HPLC analyses revealed that the aromatic amines formed in the anaerobic phase were not mineralized during the subsequent aerobic phase. In an attempt to promote the aerobic biodegradation of these aromatic amines three different approaches were tested, the increase of the relative duration of the aerobic phase, the increase of the hydraulic retention time through the decrease of the daily fill flow and finally the increase of the dye/carbon source concentration ratio through the decrease of the fed volumetric organic load. The two aromatic amines directly resulting from azo bond reduction were detected by HPLC analysis. However, a third metabolite with significant peak area was also detected with a time profile suggesting an equilibrium with one of the aromatic amines. In spite of the conversions occurring between metabolites during the cycles of the tested approaches, no effective biodegradation of these metabolites was observed during the experimental period of over 810 days.
Measurement error correction in nutritional epidemiology based on individual foods, with application to the relation of diet to breast cancer.

Nutrient intake is often measured with error by commonly used dietary instruments such as the food frequency questionnaire (FFQ) or 24-hour recall. More accurate assessments of true intake are obtained by using weighed diet records, in which subjects record what they eat on a real-time basis, but these records are expensive to administer. Validation studies are often performed to relate "gold standard" intake to intake according to surrogate instruments and to correct relative risk estimates obtained in the main study for measurement error. Most measurement error correction methods use validation study data at the nutrient level. However, subjects almost always report intake at the food rather than the nutrient level. In addition, the validity of measurement of different foods can vary considerably; it is relatively high for some foods (e.g., beverages) but relatively low for others (e.g., meats, vegetables). This differential validity could be incorporated into measurement error methods and potentially improve on nutrient-based measurement error methods. In this paper, the authors discuss correction methods for food-based measurement error and apply them to study the relation between FFQ intake in 1980 and incident breast cancer in 1980-1994 among approximately 89,000 women in the Nurses' Health Study, in whom approximately 3,000 incident breast cancers were observed.
A new case of Ambras syndrome associated with a paracentric inversion (8) (q12; q22)

Ambras syndrome (AS) is a special form of congenital universal hypertrichosis described for the first time by Baumeister et al. (1). This form differs from other forms of congenital hypertrichosis in the pattern of hair distribution and its associated anomalies. The molecular‐genetic cause of AS is unknown; the association of AS with a pericentric inversion (8) (p11.2; q22) described in the case of Baumeister so far has been unique in the literature. This report is the tenth with clinical signs of AS so far described in the literature and the second with an inversion in chromosome 8 and the first with evaluation of peripheral androgens. The new‐born girl presented with abundant and dark hair on the face and ears, on the shoulders and on the arms; the other parts of the body were covered with fine, lightly pigmented hair. The face showed many dysmorphic features. Chromosome analysis showed a paracentric inversion of one chromosome 8. The breakpoints were localised at q12 and q22. The parental karyotypes were normal. Laboratory investigation showed normal plasma levels of testosterone, androstenedione (A), 17‐hydroxyprogesterone, dehydroepiandrosterone‐sulphate (DHA‐S), free testosterone (FT), dihydrotestosterone (DHT) and 3α‐androstanediol‐glucuronide (3AG). Here we report a chromosomal inversion similar to that found previously not associated with alterations in androgen plasma levels.
U.S. EPA regulatory perspectives on the use of QSAR for new and existing chemical evaluations.

As testing is not required, ecotoxicity or fate data are available for approximately 5% of the approximately 2,300 new chemicals/year (26,000 + total) submitted to the US-EPA. The EPA's Office of Pollution Prevention and Toxics (OPPT) regulatory program was forced to develop and rely upon QSARs to estimate the ecotoxicity and fate of most of the new chemicals evaluated for hazard and risk assessment. QSAR methods routinely result in ecotoxicity estimations of acute and chronic toxicity to fish, aquatic invertebrates, and algae, and in fate estimations of physical/chemical properties, degradation, and bioconcentration. The EPA's Toxic Substances Control Act (TSCA) Inventory of existing chemicals currently lists over 72,000 chemicals. Most existing chemicals also appear to have little or no ecotoxicity or fate data available and the OPPT new chemical QSAR methods now provide predictions and cross-checks of test data for the regulation of existing chemicals. Examples include the Toxics Release Inventory (TRI), the Design for the Environment (DfE), and the OECD/SIDS/HPV Programs. QSAR screening of the TSCA Inventory has prioritized thousands of existing chemicals for possible regulatory testing of: 1) persistent bioaccumulative chemicals, and 2) the high ecotoxicity of specific discrete organic chemicals.
Hypoalbuminemia and risk of death in pediatric patients with end-stage renal disease.

BACKGROUND Although serum albumin is a marker for malnutrition and associated with a higher mortality in adult patients with end-stage renal disease (ESRD), the risk of death associated with serum albumin is unknown in pediatric patients with ESRD. We evaluated the association between serum albumin and death among pediatric patients initiating dialysis. METHODS Data from the United States Renal Data System (USRDS) were used to identify all patients under the age of 18 who initiated dialysis between January 1, 1995 and December 31, 1998. Using the Cox proportional hazards models, the association between serum albumin obtained 45 days prior to dialysis initiation and death was estimated, controlling for demographic factors, dialysis modality, and anthropometric measures. RESULTS Of 1723 patients included in the analysis, there were 93 deaths over 2953 patient-years of observation. The multivariate analysis demonstrated that each -1 g/dL difference in serum albumin between patients was associated with a 54% higher risk of death [adjusted relative risk (aRR), 1.54; 95% confidence interval (CI), 1.15 to 1.85; P=0.002]. This was independent of glomerular causes for their ESRD and other potential confounding variables. CONCLUSIONS Pediatric patients initiating dialysis with hypoalbuminemia are at a higher risk for death. This finding persists after adjusting for glomerular causes for ESRD and other potential confounding variables. Low serum albumin at dialysis initiation is an important marker of mortality risk in pediatric ESRD patients.
White blood cell count at diagnosis and immunoglobulin variable region gene mutations are independent predictors of treatment-free survival in young patients with stage A chronic lymphocytic leukemia

A comprehensive panel of clinical-biological parameters was prospectively evaluated at presentation in 112 patients with chronic lymphocytic leukemia (<65 years), to predict the risk of progression in early stage disease. Eighty-one percent were in Binet stage A, 19% in stages B/C. Treatment-free survival was evaluated as the time from diagnosis to first treatment, death or last follow up. In univariate analysis, advanced stage, hemoglobin, platelets, white blood cell, leukemic lymphocyte count, raised beta 2-microglobulin and LDH, unmutated immunoglobulin variable region genes, CD38, del(17p), del(11q) and +12, were significantly associated with a short treatment-free survival; the T/leukemic lymphocyte ratio was associated with a better outcome. Multivariate analysis of treatment-free survival in stage A patients selected a high white blood cell count and unmutated immunoglobulin variable region genes as unfavorable prognostic factors and a high T/leukemic lymphocyte ratio as a favorable one. At diagnosis, these parameters independently predict the risk of progression in stage A chronic lymphocytic leukemia patients.
Comparison of objective methods to classify the pattern of respiratory sinus arrhythmia during mechanical ventilation and paced spontaneous breathing

Respiratory sinus arrhythmia (RSA) is a fluctuation of heart period that occurs during a respiratory cycle. It has been suggested that inspiratory heart period acceleration and expiratory deceleration during spontaneous ventilation (henceforth named positive RSA) improve the efficiency of gas exchange compared to the absence or the inversion of such a pattern (negative RSA). During mechanical ventilation (MV), for which maximizing the efficiency of gas exchange is of critical importance, the pattern of RSA is still the object of debate. In order to gain a better insight into this matter, we compared five different methods of RSA classification using the data of five mechanically ventilated piglets. The comparison was repeated using the data of 15 volunteers undergoing a protocol of paced spontaneous breathing, which is expected to result in a positive RSA pattern. The results showed that the agreement between the employed methods is limited, suggesting that the lack of a consensus about the RSA pattern during MV is, at least in part, of methodological origin. However, independently of the method used, the pattern of RSA within the respiratory cycle was not consistent among the subjects and conditions of MV considered. Also, the outcomes showed that even during paced spontaneous breathing a negative RSA pattern might be present, when a low respiratory frequency is imposed.
The Orbitofrontal Cortex, Real‐World Decision Making, and Normal Aging

Abstract: The present series of three studies aims at investigating the hypothesis that some seemingly normal older persons have deficits in reasoning and decision making due to dysfunction in a neural system which includes the ventromedial prefrontal cortices. This hypothesis is relevant to the comprehensive study of aging, and also addresses the question of why so many older adults fall prey to fraud. To our knowledge, this work represents the first of its kind to begin to identify, from an individual‐differences perspective, the behavioral, psychophysiological, and consumer correlates of defective decision making among healthy older adults. Our findings, in a cross‐sectional sample of community‐dwelling participants, demonstrate that a sizeable subset of older adults (approximately 35–40%) perform disadvantageously on a laboratory measure of decision making that closely mimics everyday life, by the manner in which it factors in reward, punishment, risk, and ambiguity. These same poor decision makers display defective autonomic responses (or somatic markers), reminiscent of that previously established in patients with acquired prefrontal lesions. Finally, we present data demonstrating that poor decision makers are more likely to fall prey to deceptive advertising, suggesting compromise of real‐world judgment and decision‐making abilities.
A prospective study of HIV disease progression in female and male drug users.

OBJECTIVE To compare HIV disease progression and mortality in a cohort of female and male drug users. DESIGN A prospective cohort study of 222 HIV-seropositive women and 302 HIV-seropositive men who attended a hospital-affiliated methadone maintenance program with on-site primary care. METHODS Regression slopes of CD4+ cell decline were compared using the two sample t-test, and the distribution of AIDS-defining illnesses evaluated by Mantel-Haenszel chi2 test. Time to AIDS-defining clinical conditions and death were compared using the Kaplan-Meier log-rank test. Multivariate estimates of progression to clinical AIDS or death, for all participants, stratified by sex, were derived from Cox proportional hazards models. RESULTS Ninety-five persons (43 women and 52 men) developed AIDS-defining conditions. Analyses of the rates of CD4+ cell decline, the distribution of first AIDS-defining illnesses, and the time to clinical AIDS did not differ by sex. In the multivariate model, sex was not associated with an AIDS outcome, whereas crack-cocaine use [hazards ratio (HR), 1.815; 95% confidence interval (CI), 1.151-2.863], CD4+ cell count (100 x 10(6)/l; HR, 0.589; 95% CI, 0.511-0.679), and two or more HIV-related symptoms (HR, 1.702; 95% CI, 1.125-2.576) were associated. Mortality rates (8.71 per 100 person-years in women and 9.85 per 100 person-years in men) were similar, using univariate or multivariate methods. CONCLUSIONS There was little difference in clinical outcomes or mortality between HIV-seropositive female and male drug users with access to primary care. However, crack-cocaine use was independently associated with progression to clinical AIDS.
Clinical neurophysiology in GJA12-related hypomyelination vs Pelizaeus-Merzbacher disease

Background: Among the hypomyelinating leukoencephalopathies with onset in childhood, Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD) constitute a large subgroup with almost indistinguishable clinical and neuroradiologic features. Whereas PMD is due to X-linked PLP1 mutations, PMLD is genetically heterogeneous, with about 8% of patients carrying autosomal recessive GJA12/GJC2 mutations. The aim of this study was to evaluate whether neurophysiologic testing may separate PMD from GJA12/GJC2-associated PMLD. Methods: Retrospective data collection study with reevaluation of evoked potentials (EP) and nerve conduction studies (NCS) in 10 patients from 7 families with PMLD due to various GJA12/GJC2 mutations and 8 boys from 7 families with classic PMD caused by a PLP1 duplication or missense mutation. Results: In brainstem auditory EP, waves III–V were absent in all patients with PMD, but clearly recordable in 11 of 13 investigations in 8 patients with PMLD. Visual evoked potentials and somatosensory evoked potentials revealed conduction delay in both PMD and PMLD, without significant difference. NCS were normal in all patients with PMD and indicated mild peripheral neuropathy in only 2 of 10 patients with PMLD. Conclusion: In a patient with clinical and neuroradiologic features of Pelizaeus-Merzbacher disease/Pelizaeus-Merzbacher-like disease and a pedigree consistent with both conditions, brainstem auditory evoked potentials provide good selectivity between these disorders and point in the right direction for identifying the primary genetic defect.
Effect of dispersant on the composition of the water‐accommodated fraction of crude oil and its toxicity to larval marine fish

Newly hatched mummichog (Fundulus heteroclitus) were exposed in a 96‐h static renewal assay to water‐accommodated fractions of dispersed crude oil (DWAF) or crude oil (WAF) to evaluate if the dispersant‐induced changes in aqueous concentrations of polycyclic aromatic hydrocarbons (PAH) affected larval survival, body length, or ethoxyresorufin‐O‐deethylase (EROD) activity. Weathered Mesa light crude oil (0.05–1 g/L) and filtered seawater with or without the addition of Corexit 9500® were used to prepare DWAF and WAF. At 0.2 g/L, the addition of dispersant caused a two‐ and fivefold increase in the concentrations of total PAH (ΣPAH) and high‐molecular‐weight PAH (HMWPAH) with three or more benzene rings. Highest mortality rates (89%) were observed in larvae exposed to DWAF (0.5 g/L; ΣPAH, 479 ng/ml). A reduction in body length was correlated with increased levels of ΣPAH (r2 = 0.65, p = 0.02) and not with HMWPAH. The EROD activity increased linearly with HMWPAH (r2 = 0.99, p = 0.001) and not with ΣPAH. Thus, chemical dispersion increased both the ΣPAH concentrations and the proportion of HMWPAH in WAF. Dispersed HMWPAH were bioavailable, as indicated by a significantly increased EROD activity in exposed mummichog larvae, and this may represent a significant hazard for larval fish.
Body mass index mediates inflammatory response to acute dietary challenges.

SCOPE Acute metabolic challenges provide an opportunity to identify mechanisms of metabolic and nutritional health. In this study, we assessed the transcriptomic response to oral glucose and lipid challenges in a cohort of individuals ranging in age and BMI. The main goal is to identify whether BMI can mediate the metabolic and transcriptional response to dietary challenges, and the differences between lipid and glucose tests. METHODS AND RESULTS Two hundred fourteen healthy adults were assigned to the challenges and twenty-three individuals were selected for further transcriptomic proofing, using microarray analysis of peripheral blood mononuclear cells. Through linear-mixed models and network analysis, different sets of transcripts and pathways were identified that responded to the challenges depending on BMI. Different transcripts that responded to the lipid and glucose tests, independently of BMI, were also identified. In the network analysis, inflammatory and adhesion processes were strongly represented for both challenges. CONCLUSION Our results indicate that BMI is strongly linked to the transcriptomic and metabolic response to acute challenges. The emerging biological processes are mainly inflammation-related pathways, highlighting an interconnection between obesity, inflammation/adhesion, and response to nutritional challenge. The comparison between lipid and glucose challenges shows how these trigger a substantially different molecular response.