Genetic and Neurophysiological Correlates of the Age of Onset of Alcohol Use Disorders in Adolescents and Young Adults

Discrete time survival analysis was used to assess the age-specific association of event-related oscillations (EROs) and CHRM2 gene variants on the onset of regular alcohol use and alcohol dependence. The subjects were 2,938 adolescents and young adults ages 12–25. Results showed that the CHRM2 gene variants and ERO risk factors had hazards which varied considerably with age. The bulk of the significant age-specific associations occurred in those whose age of onset was under 16. These associations were concentrated in those subjects who at some time took an illicit drug. These results are consistent with studies which associate greater rates of alcohol dependence among those who begin drinking at an early age. The age specificity of the genetic and neurophysiological factors is consistent with recent studies of adolescent brain development, which locate an interval of heightened vulnerability to substance use disorders in the early to mid teens.     

The effects of thrombin and cytokines upon the biomechanics and remodeling of isolated amnion membrane, in vitro

Abruption-induced thrombin generation and inflammation/infection induced cytokine production have both been associated with fetal membrane (FM) weakening and preterm premature rupture of the fetal membranes (PPROM). Using our in vitro model system we have demonstrated that thrombin, and separately the cytokines, tumor necrosis factor-alpha (TNFα) and interleukin-1-beta (IL-1β), remodel and weaken full thickness FM. Additionally, we have reported that the anti-oxidant and NFκB inhibitor, alpha-lipoic acid (LA), blocks these thrombin and cytokine induced effects. The purpose of these studies was to determine whether thrombin and cytokines directly weaken the amnion membrane (AM), the major load-bearing component of FM. Isolated AM or full thickness FM fragments from unlabored Cesarean deliveries were incubated with thrombin, TNFα, or IL-1β, for 48 h. Rupture strength (breaking force) of each fragment was thereafter determined using our published methodology. Biochemical evidence of remodeling and apoptosis; immunoreactive Matrix Metalloproteinase 9 (MMP9), Tissue Inhibitor of Matrix Metalloproteinase 3 (TIMP3) and cleaved poly (ADP-ribose) polymerase (C-PARP) levels in tissue extracts, were determined by western blot and densitometry. Thrombin induced a dose-dependent weakening of isolated AM (P < 0.001) coupled with dose dependent increases in PARP cleavage, and reciprocal increases and decreases, respectively, in MMP9 and TIMP3 protein (all P < 0.01). Thrombin receptor activating peptide-6 (TRAP) also weakened isolated AM. Neither TNFα nor IL-1β weakened isolated AM. However, both cytokines weakened AM when it was incubated together with the choriodecidua as part of full thickness FM (P < 0.001). Cytokine-conditioned choriodecidua medium also weakened isolated AM (P < 0.001). Under conditions in which cytokines weakened the AM, the changes in MMP9, TIMP3 and PARP cleavage were consistent with those seen after thrombin incubation. LA blocked the FM weakening and remodeling effects. In summary, thrombin weakens AM directly whereas cytokines weaken AM indirectly by causing the release of soluble intermediates from the choriodecidua.     

Anti-Complement Factor H Autoantibody-Associated Atypical Hemolytic Uremic Syndrome

Indian Journal of Pediatrics -     

Simultaneous Quantification of Baricitinib and Methotrexate in Rat Plasma by LC-MS/MS: Application to a Pharmacokinetic Study

Efficacy assessments using a combination of baricitinib and methotrexate necessitate the development of an analytical method for the determination of both drugs in plasma with precision. A high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of baricitinib and methotrexate in rat plasma. Extraction of baricitinib, methotrexate, and tolbutamide (internal standard; IS) from 50 µL of rat plasma was carried out by protein precipitation with methanol. Chromatographic separation of the analytes was performed on the YMC pack ODS AM (150 mm × 4.6 mm, 5 µm) column under gradient conditions with methanol: 2.0 mM ammonium acetate buffer as the mobile phases at a flow rate of 1 mL/min. The precursor ion and product ion transition for both analytes and IS were monitored on a triple quadrupole mass spectrometer, operated with selective reaction monitoring in positive ionization mode. The method was validated over a concentration range of 0.5–250.00 ng/mL for baricitinib and methotrexate. Mean extraction recoveries for baricitinib, methotrexate, and IS of 86.8%, 89.4%, and 91.8% were consistent across low, medium, and high QC levels, respectively. Precision and accuracy at low, medium, and high quality control levels were less than 15% across the analytes. Benchtop, wet, freeze-thaw, and long-term stability were evaluated for both of the analytes. The analytical method was applied to support the pharmacokinetic study of simultaneous estimation of baricitinib and methotrexate in Wistar rats. Assay reproducibility was demonstrated by reanalysis of 18 incurred samples     

Heritability of Bipolar EEG Spectra in a Large Sib-pair Population

The additive genetic heritability of both monopolar and bipolar EEG spectral power in a sample of 305 non-twin sibships comprising 690 individuals (age range 7–65) was estimated in order to investigate their regional variation. The heritabilities of the bipolar EEG spectral power ranged from 0.10 to 0.63 in 38 electrode-pairs, and those of monopolar power ranged from 0.23 to 0.68 in 19 electrodes in six frequency bands from theta to high beta. The bipolar data shows significantly greater topographic variation compared to that of the monopolar data. The mean of bivariate genetic correlations were consistently lower for the bipolar data and the coefficients of variation consistently higher when compared to those of the monopolar data for each of the frequency bands. The results from the bipolar derivations are in greater accord with genetic findings in brain anatomy and show the possibility of multiple genetic sources for the phenotypic variability of EEG activity. Edited by Danielle Posthuma This work was supported by NIAAA Investigator-Initiated Interactive Research Project Grant (IRPG): AA 12560 at SUNY Downstate Medical Center, AA 12555 at Indiana University School of Medicine, grant AA 12557 at Washington University School of Medicine, and AA 12553 at Howard University. We would like to dedicate this paper to the memory of Henri Begleiter, who initiated its writing, and whose death during its preparation only inspired us to continue to follow the high scientific standards which his work exemplified.     

Angiotensin-converting enzyme inhibitor use in elderly patients hospitalized with heart failure and left ventricular systolic dysfunction

PURPOSE: Although angiotensin-converting enzyme (ACE) inhibitors are recommended for all patients with systolic heart failure, prior studies suggest that elderly cohorts are less likely to receive such therapy. The purpose of this study was to determine the age dependence of adherence to guideline-based medical care in hospitalized heart failure patients. METHODS: We performed a multicenter observational cohort study including 613 patients admitted to participating hospitals with a primary diagnosis of heart failure with ejection fraction < or =40%. This cohort was divided into four age groups (group 1: <60, group 2: 60-69, group 3: 70-79, and group 4: 80 years) and adherence to guideline-based medical care was measured. RESULTS: ACE inhibitors were administered to 83% of ideal heart failure patients, and this rate was similar for all age groups. Elderly patients received significantly lower ACE inhibitor dosages compared to their younger counterparts (168, 148, 125 and 117 mg captopril in groups 1, 2, 3, and 4, respectively, p=0.001). Lower creatinine clearance (p<0.001), prior residence in a long-term care facility (p=0.037), intolerance to ACE inhibitors (p=0.006), lower blood pressure (p=0.005), absence of a history of hypertension (p=0.005), and no prior heart failure hospitalizations within the past year (p=0.001) were found to be independent predictors of low ACE inhibitor dosing. CONCLUSIONS: In this heart failure benchmarking project, elderly patients received guideline-based ACE inhibitor therapy at similar rates, but at lower doses, compared to their younger counterparts.     

Genome‐wide association study of theta band event‐related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence

Event‐related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome‐wide association study (GWAS) of an ERO endophenotype—frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty‐two SNPs of the Illumina HumanHap 1 M microarray were selected from the theta ERO GWAS for replication in family‐based samples (N = 1,095), with four markers revealing nominally significant association. The most significant marker from the two‐stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher's combined P = 3.68 × 10^?6). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P = 1.53 × 10^?4), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM‐IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case–controls (P = 0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case–control and family‐based samples (P = 0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders. © 2010 Wiley‐Liss, Inc.     

Macrofollicular encapsulated papillary thyroid carcinoma--a case report

Macrofollicular encapsulated papillary thyroid carcinoma (MEPC) is a rare variant of papillary carcinoma of thyroid with a favourable clinical course. It could be mistaken for a follicular neoplasm or a hyperplastic nodule. We report cytological and histopathological features of this rare variant of papillary carcinoma in a 22 year old female with brief review of literature.