Consistent copy number changes and recurrent PRKAR1A mutations distinguish Melanotic Schwannomas from Melanomas: SNP‐array and next generation sequencing analysis

Melanotic Schwannomas (MS) are rare tumors that share histological features with melanocytic tumors and schwannomas. However, their genetics are poorly understood. To elucidate the genetic characteristics of MS, we performed genome‐wide studies in a series of cases. Twelve MS cases were available for the study. Genomic DNAs extracted from formalin‐fixed paraffin embedded tumor tissues were subjected to copy number (CN) and allelic imbalance (AI) analysis by Single Nucleotide Polymorphism (SNP)‐array and screened for mutations in coding exons of 341 key cancer‐associated genes using a hybrid capture‐based next‐generation sequencing (NGS) assay. Sanger sequencing was used to further verify recurrent mutations detected by NGS study. SNP‐array analysis revealed remarkably stereotypic chromosomal abnormalities in MS. Hypodiploidy was common, typically involving monosomies of chromosomes 1, 2, and 17. All 12 samples showed mutations in PRKAR1A gene, including 2 cases with 2 mutations each. The 14 mutations were scattered across PRKAR1A, and most were inactivating mutations. AI on 17q, presenting as loss of heterozygosity with or without CN losses, combined with a PRKAR1A mutation was observed in 9/12 MS cases. The remaining 3 cases included the two samples harboring two mutations in PRKAR1A. MS exhibits a stereotypic pattern of chromosomal losses. In contrast, melanomas are typically characterized by the presence of multiple CN aberrations, without demonstrable differences in the frequency of losses and gains. Inactivation of both alleles of PRKAR1A by “two hits” observed in almost all cases underscores the central role of PRKAR1A in the pathogenesis of this neoplasm. © 2015 Wiley Periodicals, Inc.     

Bromocriptine for Cocaine Dependence

On the basis of the dopamine depletion theory, bromocriptine has been tested to treat cocaine withdrawal and dependence. The authors conducted a 6-week study with 1 week of pretreatment observation and 5 weeks of a randomized, double-blind, placebo-controlled clinical trial of bromocriptine for DSM-III-R-defined cocaine dependence in methadone-maintained male patients. The bromocriptine group (n = 24) did not differ from the placebo group (n = 26) in self-reported cocaine use, proportion of positive urine toxicology samples, craving for cocaine, resistance to cocaine use, or mood symptoms between the pretreatment baseline and the last week of the clinical trial. Both groups showed significant reduction in self-reported frequency of cocaine use, resistance to craving, and mood symptoms during participation in the protocol. The results of this study are consistent with recent clinical and laboratory findings in primary cocaine users. Despite initially promising pilot studies, recent evidence does not support the efficacy of bromocriptine to reduce cocaine use or craving.     

Regional myocardial function in idiopathic hypertrophic subaortic stenosis. An echocardiographic study.

To assess regional contractility in idiopathic hypertrophic subaortic stenosis (IHSS), a primary myopathic disorder with documented hyperdynamic ventricular contractions, systolic wall thickening and velocity of contraction of the septum and left ventricular posterior wall were measured in echocardiograms from 16 patients with IHSS and 16 normal subjects. The average thickening of the normal septum and posterior wall was 75.9+/-8.8% and 84.8+/-6.3%, respectively. The posterior wall in IHSS thickened by 75.1+/-6.8%. None of these values differed significantly. However, the increase in thickness of the IHSS septum averaged 22.5+/-2.4%, significantly less than that of either the IHSS posterior wall or the normal septum. Velocity measurements confirmed the impression of diminished septal function. The mean velocity of normal septal contraction averaged 37.0+/-2.3 mm/sec, normal posterior wall 42.3+/-2.0 mm/sec and IHSS posterior wall 55.7+/-3.5 mm/sec, whereas the septum in IHSS contracted at the rate of 26.0+/-2.5 mm/sec. Thus, the IHSS septum contracted significantly more slowly than the normal septum or IHSS posterior wall. However, the posterior wall velocity in IHSS was significantly more rapid than that measured in normal ventricles--perhaps to compensate for the septum. Normalization of all velocities for left ventricular end-diastolic internal diameter did not alter the sifnificance of the results. Consideration of IHSS as an asymmetric myopathy based on prior observations of predominantly septal hypertrophy and distorted septal cellular architecture is now supported by the above evidence of functional left ventricular asymmetry. Although the total left ventricular function in IHSS may be hyperdynamic, regional function is not uniform. The septum appears to be hypodynamic, while the contractile capacity of the posterior wall is increased.     

Evidence for the involvement of endogenous opioids in the regulation of gonadotropin secretion in male goldfish, Carassius auratus

The in vivo effects of the opioid receptor antagonist naloxone (NAL) alone, and in combination with des-Gly10[D-Ala6]LHRH ethylamide (LHRH-A) and the dopamine receptor antagonist domperidone (DOM) on serum gonadotropic hormone (GtH) levels in male goldfish, Carassius auratus, were investigated. NAL caused a significant decrease in serum GtH 1 hr following treatment, with a return to control levels by 2 hr. NAL treatment attenuated the stimulation of GtH levels in response to DOM; NAL treatment 2 hr prior to or 2 hr following DOM resulted in a significantly reduced response to DOM. During late recrudescence, NAL pretreatment significantly blocked the stimulatory effects of LHRH-A on serum GtH. During early recrudescence, when LHRH-A alone did not significantly elevate GtH levels, NAL treatment simultaneously with or 1 hr following LHRH-A significantly elevated serum GtH. In DOM-pretreated fish, combined LHRH-A and NAL treatment resulted in a nine-fold increase in serum GtH compared to DOM alone. These data indicate the ability of NAL to both suppress and increase GtH levels in male goldfish. Interactions between NAL, DOM, and LHRH-A suggest that opioids modulate both dopamine and GnRH secretion, and possibly the pituitary sensitivity to GnRH and dopamine, thus affecting GtH levels.     

Studying the dynamics of autonomic activity during emotional experience

Recent theories emphasize the dynamic aspects of emotions. However, the physiological measures and the methodological approaches that can capture the dynamics of emotions are underdeveloped. In the current study, we investigated whether moment‐to‐moment changes in autonomic nervous system (ANS) activity are reliably associated with the unfolding of emotional experience. We obtained cardiovascular and electrodermal signals from participants while they viewed emotional movies. We found that the ANS signals were temporally aligned across individuals, indicating a reliable stimulus‐driven response. The degree of response reliability was associated with the emotional time line of the movie. Finally, individual differences in ANS response reliability were strongly correlated with the subjective emotional responses. The current research offers a methodological approach for studying physiological responses during dynamic emotional situations.     

Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma,and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity

Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies.     

Which women develop urgency or urgency urinary incontinence following midurethral slings?

Introduction and hypothesis

De novo urgency has a negative impact on women after midurethral sling (MUS). We aimed to identify risk factors for de novo urgency (dU) and urgency urinary incontinence (dUUI) following MUS, using multivariate analysis.

Methods

We investigated 358 consecutive women with only stress urinary incontinence (SUI) [or urodynamic stress incontinence (USI)] and 598 women with both SUI (or USI) and urgency (but not UUI) who underwent MUS with a mean follow-up of 50 months. Women who developed dU or dUUI at long-term follow-up were compared to those who did not.

Results

dU occurred in 27.7 % (99/358) and dUUI occurred in 13.7 % (82/598) of women at long-term follow-up after midurethral sling. Intrinsic sphincter deficiency {odds ratio (OR) dU 3.94 [95 % confidence interval (CI) 1.50–10.38]; OR dUUI 2.5 (1.31–4.80)}, previous stress incontinence surgery [sling: OR dU 3.69 (1.45–9.37); colposuspension: OR dUUI 2.5 (1.23–5.07)], previous prolapse surgery [OR dU 2.45 (1.18–5.10)], preexisting detrusor overactivity [OR dU 1.99 (1.15–3.48); OR dUUI 1.85 (1.31–2.60)] increased the risk, whereas performing concomitant apical prolapse surgery [OR dU 0.5 (0.41–0.81); OR dUUI 0.29 (0.087–0.97)] significantly decreased the risk. Women are more likely to not recommend surgery when they experienced dU (18.2 vs 0.8 %, p?<?0.0001) or dUUI (20.7 vs 2.1 %, p?<?0.0001).

Conclusions

Urodynamic parameters, history of prior incontinence or prolapse surgery and concomitant apical prolapse operation were important predictors of dU or dUUI following MUS.