Paternal age and sporadic schizophrenia: evidence for de novo mutations

Schizophrenia is an etiologically heterogeneous syndrome. It has a strong genetic component and exists in clinically indistinguishable familial and nonfamilial (sporadic) forms. A significant role for de novo genetic mutations in genetic schizophrenia vulnerability is suggested by a strong monotonic increase in schizophrenia risk with advancing paternal age. However, an alternative explanation for the paternal age effect in schizophrenia is that childbearing is delayed in fathers who themselves have genetic schizophrenia vulnerability. In this study, we compared paternal birth ages between patient groups with familial (n = 35) and sporadic (n = 68) patients with DSM-IV schizophrenia from an inpatient schizophrenia research unit. If later age of fathering children is related to having some genetic schizophrenia vulnerability, then paternal birth age should be later in familial schizophrenia cases than in sporadic cases, and any association of father's age and schizophrenia risk in offspring would be a spurious finding, unrelated to etiology. However, if de novo mutations cause sporadic schizophrenia, then patients without a family history of schizophrenia would have older fathers than familial patients. We found that patients without a family history of schizophrenia had significantly older fathers (4.7 years) than familial patients; so later childbirth was not attributable to parental psychiatric illness. These findings support the hypothesis that de novo mutations contribute to the risk for sporadic schizophrenia.     

An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line

Metastasis is the major cause of prostate cancer deaths and there is a need for clinically relevant in vivo models allowing elucidation of molecular and cellular mechanisms underlying metastatic behavior. Here we describe the development of a new in vivo model system for metastatic prostate cancer. Pieces of prostate cancer tissue from a patient were grafted in testosterone-supplemented male NOD-SCID mice at the subrenal capsule graft site permitting high tumor take rates. After five serial transplantations, the tumor tissues were grafted into mouse prostates. Resulting tumors and suspected metastatic lesions were subjected to histopathological and immunohistochemical analysis. Samples of metastatic tissue were regrafted in mouse anterior prostates and their growth and spread examined, leading to isolation from lymph nodes of a metastatic subline, PCa1-met. Orthotopic grafting of PCa1-met tissue in 47 hosts led in all cases to metastases to multiple organs (lymph nodes, lung, liver, kidney, spleen and, notably, bone). Histopathological analysis showed strong similarity between orthotopic grafts and their metastases. The latter were of human origin as indicated by immunostaining using antibodies against human mitochondria, androgen receptor, prostate-specific antigen and Ki-67. Spectral karyotyping showed few chromosomal alterations in the PCa1-met subline. This study indicates that transplantable subrenal capsule xenografts of human prostate cancer tissue in NOD-SCID mice can, as distinct from primary cancer tissue, be successfully grown in the orthotopic site. Orthotopic xenografts of the transplantable tumor lines and metastatic sublines can be used for studying various aspects of metastatic prostate cancer, including metastasis to bone.     

Genetic testing for inherited eye conditions in over 6,000 individuals through the eyeGENE network

Genetic testing in a multisite clinical trial network for inherited eye conditions is described in this retrospective review of data collected through eyeGENE®, the National Ophthalmic Disease Genotyping and Phenotyping Network. Participants in eyeGENE were enrolled through a network of clinical providers throughout the United States and Canada. Blood samples and clinical data were collected to establish a phenotype:genotype database, biorepository, and patient registry. Data and samples are available for research use, and participants are provided results of clinical genetic testing. eyeGENE utilized a unique, distributed clinical trial design to enroll 6,403 participants from 5,385 families diagnosed with over 30 different inherited eye conditions. The most common diagnoses given for participants were retinitis pigmentosa (RP), Stargardt disease, and choroideremia. Pathogenic variants were most frequently reported in ABCA4 (37%), USH2A (7%), RPGR (6%), CHM (5%), and PRPH2 (3%). Among the 5,552 participants with genetic testing, at least one pathogenic or likely pathogenic variant was observed in 3,448 participants (62.1%), and variants of uncertain significance in 1,712 participants (30.8%). Ten genes represent 68% of all pathogenic and likely pathogenic variants in eyeGENE. Cross‐referencing current gene therapy clinical trials, over a thousand participants may be eligible, based on pathogenic variants in genes targeted by those therapies. This article is the first summary of genetic testing from thousands of participants tested through eyeGENE, including reports from 5,552 individuals. eyeGENE provides a launching point for inherited eye research, connects researchers with potential future study participants, and provides a valuable resource to the vision community.     

Admission levels of soluble CD137 are increased in patients with acute pancreatitis and are associated with subsequent complications

The progression of acute pancreatitis to necrotizing pancreatitis which often results in high morbidity and mortality is difficult to predict. Here we report that serum concentrations of sCD137 are increased in patients with acute pancreatitis. Admission levels and 10-day median sCD137 levels positively correlate with markers of biliary pancreatitis and the 10-day sCD137 median is significantly higher in metabolic than in alcoholic pancreatitis. Serum concentrations of sCD137 at time of admission and the 10-day median of sCD137 correlate with the Ranson and APACHE II disease scores but not with the radiological Balthazar and Schroeder scores that reflect pancreatic and peripancreatic necrosis. Further, sCD137 levels correlate with the probability of complications and lethality. The association of sCD137, a product of activated T cells, with the severity of acute pancreatitis suggests that T cells contribute to the pathogenesis of acute pancreatitis.     

Blunted reward responsiveness in remitted depression

Major depressive disorder has been associated with blunted responsiveness to rewards, but inconsistencies exist whether such abnormalities persist after complete remission. To address this issue, across two independent studies, 47 adults with remitted major depressive disorder (rMDD) and 37 healthy controls completed a Probabilistic Reward Task, which used a differential reinforcement schedule of social or monetary feedback to examine reward responsiveness (i.e., ability to modulate behavior as a function of reinforcement history). Relative to controls, adults with rMDD showed blunted reward responsiveness. Importantly, a history of depression predicted reduced reward learning above and beyond residual depressive (including anhedonic) symptoms and perceived stress. Findings indicate that blunted reward responsiveness endures even when adults are in remission and might be a trait-related abnormality in MDD. More research is warranted to investigate if blunted reward responsiveness may predict future depressive episodes and whether targeting reward-related deficits may prevent the re-occurrence of the disorder.     

Dissociations among daytime sleepiness,nighttime sleep,and cognitive status in Parkinson's disease

BackgroundDaytime and nighttime sleep disturbances and cognitive impairment occur frequently in Parkinson's disease (PD), but little is known about the interdependence of these non-motor complications. Thus, we examined the relationships among excessive daytime sleepiness, nighttime sleep quality and cognitive impairment in PD, including severity and specific cognitive deficits.MethodsNinety-three PD patients underwent clinical and neuropsychological evaluations including the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). Patients were classified as having normal cognition (PD-NC), mild cognitive impairment (PD-MCI), or dementia (PDD) using recently proposed Movement Disorder Society PD-MCI and PDD criteria. Relationships between the sleep and cognitive measures and PD cognitive groups were examined.ResultsThe PD cohort included PD-NC (n = 28), PD-MCI (n = 40), and PDD (n = 25) patients. ESS scores, as a measure of daytime sleepiness, were significantly worse (p = 0.005) in cognitively impaired PD patients, particularly PDD patients. ESS scores correlated significantly with Mini-Mental State Examination scores and also with cognitive domain scores for attention/working memory, executive function, memory, and visuospatial function. In contrast, PSQI scores, as a measure of nighttime sleep quality, neither differed among cognitive groups nor correlated with any cognitive measures.ConclusionsDaytime sleepiness in PD, but not nighttime sleep problems, is associated with cognitive impairment in PD, especially in the setting of dementia, and attention/working memory, executive function, memory, and visuospatial deficits. The presence of nighttime sleep problems is pervasive across the PD cognitive spectrum, from normal cognition to dementia, and is not independently associated with cognitive impairment or deficits in cognitive domains.     

Intratumoral injection of cyanoacrylate glue in head and neck paragangliomas

BACKGROUND AND PURPOSE: Substantial intraoperative bleeding during surgical removal of head and neck paragangliomas may be a major problem in the management of these highly vascularized tumors. Traditional preoperative embolization via a transarterial approach has proved beneficial but is often limited by complex vascular anatomy and unfavorable locations. We report our experience with the preoperative devascularization of head and neck paragangliomas by using direct puncture and an intralesional injection of cyanoacrylate. METHODS: We retrospectively analyzed nine consecutive patients with head and neck paragangliomas who were referred for preoperative devascularization. Three patients were treated for carotid-body tumors; two for vagal lesions; and four, for jugular paragangliomas. Direct puncture of the lesion was performed by using roadmap fluoroscopic guidance. Acrylic glue was injected by using continuous biplane fluoroscopy. All patients underwent postembolization control angiography and immediate postoperative CT scanning. RESULTS: Angiograms showed that complete devascularization was achieved in all cervical glomus tumors, whereas subtotal devascularization was achieved in jugular paragangliomas. In this latter location, the injection of acrylic glue was limited by the potential risk of reflux into normal brain territory via feeders from the internal carotid or vertebral artery. The tumors were surgically removed and histologically examined. No technical or clinical complications related to the embolization procedure occurred. CONCLUSION: Percutaneous puncture of paragangliomas in the head and neck region and their preoperative devascularization by intralesional injection of acrylic glue is a feasible, safe, and effective technique.