Molecular Basis of Autosomal Recessive Chronic Granulomatous Disease in Iran

Introduction  

Chronic granulomatous disease (CGD) is a rare inherited condition resulting from mutations in the genes that encode the proteins of the NADPH oxidase enzyme in phagocytes, rendering these cells incapable of killing invading pathogens.     

Large‐scale brain network abnormalities in Huntington's disease revealed by structural covariance

Huntington's disease (HD) is a progressive neurodegenerative disorder that can be diagnosed with certainty decades before symptom onset. Studies using structural MRI have identified grey matter (GM) loss predominantly in the striatum, but also involving various cortical areas. So far, voxel‐based morphometric studies have examined each brain region in isolation and are thus unable to assess the changes in the interrelation of brain regions. Here, we examined the structural covariance in GM volumes in pre‐specified motor, working memory, cognitive flexibility, and social‐affective networks in 99 patients with manifest HD (mHD), 106 presymptomatic gene mutation carriers (pre‐HD), and 108 healthy controls (HC). After correction for global differences in brain volume, we found that increased GM volume in one region was associated with increased GM volume in another. When statistically comparing the groups, no differences between HC and pre‐HD were observed, but increased positive correlations were evident for mHD, relative to pre‐HD and HC. These findings could be explained by a HD‐related neuronal loss heterogeneously affecting the examined network at the pre‐HD stage, which starts to dominate structural covariance globally at the manifest stage. Follow‐up analyses identified structural connections between frontoparietal motor regions to be linearly modified by disease burden score (DBS). Moderator effects of disease load burden became significant at a DBS level typically associated with the onset of unequivocal HD motor signs. Together with existing findings from functional connectivity analyses, our data indicates a critical role of these frontoparietal regions for the onset of HD motor signs. Hum Brain Mapp 37:67–80, 2016. © 2015 Wiley Periodicals, Inc.     

Review of prospective longitudinal studies of children with ADHD: Mental health, educational, and social outcomes

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood, resulting in impairments in academic, mental health, and functional domains. Whereas the short-term effects of ADHD are well documented, much less is understood about the adolescent and adult outcomes of children diagnosed with ADHD. This article attempts to increase understanding of these outcomes by providing an integrated summary of prospective longitudinal cohort studies investigating the outcomes of children with ADHD. Particular focus is paid to mental health, educational, and social outcomes, in addition to ADHD persistence. Overall, the data show that children with ADHD experience serious functional deficits across domains in adolescence and early-adulthood. Furthermore, the impairing symptoms of ADHD do not disappear in adulthood, as was once thought. We hope that through improved understanding of risk and protective factors in ADHD, clinicians, families, and schools can better help children with ADHD reach their full potential.     

Decreased redox state in red blood cells from patients with sarcoidosis

BACKGROUND AND AIM OF THE WORK: The glutathione system has a key role in the defence against oxidative stress. To function properly, this system needs NADPH to maintain glutathione (GSH) in its reduced form. We hypothesized that the clinical problems associated with sarcoidosis might be related to a decreased anti-oxidant defence and we therefore measured the activity of the NADPH-generating enzyme glucose-6-phosphate dehydrogenase (G6PD), the GSH-regenerating enzyme glutathione reductase (GR) and indirectly the level of NADPH in red blood cells from patients with sarcoidosis. METHODS: In a population of sarcoidosis (n = 88) patients, G6PD, GR and GR activity after incubation with chromate (GR-Cr) were measured in erythrocytes. A decreased concentration of NADPH was revealed by an increased GR-Cr (> 0.6 IU/g Hb). To exclude a mutation in the G6PD gene, sequencing was performed in cases with an abnormal GR-Cr. Sarcoidosis pulmonary disease severity was evaluated by means of laboratory data, radiographic staging, HRCT scoring, pulmonary function and exercise capacity testing. RESULTS: Fourteen (29.2%) females and one (2.5%) male demonstrated an increased GR-Cr test, indicative of a decreased NADPH level. Patients with an abnormal test result demonstrated also significantly increased ACE and GR values (p < 0.05). Only one female case (of 6 tested) appeared to have a mutation in the G6PD gene. CONCLUSION: In a considerable percentage of female patients with sarcoidosis, a decreased level of NADPH in the erythrocytes was found.     

Differences in survival by histologic type of pancreatic cancer.

OBJECTIVE: Although pancreatic cancer has an extremely high case fatality rate, little is known about differences in mortality by histologic types. We examined median survival and risk of mortality for endocrine pancreatic tumors and two types of exocrine tumors, adenocarcinomas, and mucinous tumors. METHOD: This analysis included 35,276 pancreatic cancer cases reported to the nine population-based cancer registries participating in the Surveillance, Epidemiology, and End Results program from 1973 to 2000. Survival among cases with pancreatic adenocarcinomas, mucinous tumors, and endocrine tumors were compared using Kaplan-Meier plots. Comparative risks of mortality were evaluated using multivariate adjusted Cox regression models. RESULTS: Endocrine pancreatic cancer cases had a median survival of 27 months compared with a median survival of 4 months for adenocarcinoma and mucinous tumor cases. Compared with adenocarcinoma cases, endocrine tumor cases had a 0.28-fold lower risk of mortality [95% confidence interval (95% CI), 0.26-0.30], and mucinous tumor cases had a 0.88-fold lower risk (95% CI, 0.84-0.91). These results were similar for men and women. Within histologic types, advanced tumor stage, older diagnosis age, surgery, and Black race were associated with increased risks of mortality, whereas female sex and more recent year of diagnosis were associated with decreased risks. CONCLUSION: This study confirms the clinical observation that patients with endocrine pancreatic cancer survive longer than patients with exocrine tumors. A better understanding of these differences could contribute to identifying the underlying causes of pancreatic cancer and to improving survival rates across all histologic types.     

Rehabilitation after anterior cruciate ligament reconstruction: a prospective, randomized, double-blind comparison of programs administered over 2 different time intervals

BACKGROUND: There are adverse effects associated with immobilization of the knee after anterior cruciate ligament reconstruction, yet very little is known about how much activity will promote adequate rehabilitation without permanently elongating the graft, producing graft failure, or creating damage to articular cartilage. HYPOTHESIS: Rehabilitation with either an accelerated or nonaccelerated program produces no difference in anterior-posterior knee laxity, clinical assessment, patient satisfaction, functional performance, and the synovial fluid biomarkers of articular cartilage metabolism. STUDY DESIGN: Randomized controlled clinical trial; Level of evidence, 1. METHODS: Twenty-five patients who tore their anterior cruciate ligament were enrolled and underwent anterior cruciate ligament reconstruction. Patients were randomized to accelerated rehabilitation or nonaccelerated rehabilitation. At the time of surgery and 3, 6, 12, and 24 months later, measurements of anterior-posterior knee laxity, clinical assessment, patient satisfaction, functional performance, and cartilage metabolism were completed. RESULTS: At the 2-year follow-up, there was no difference in the increase of anterior knee laxity relative to the baseline values that were obtained immediately after surgery between the 2 groups (2.2-mm vs 1.8-mm increase relative to the normal knee). The groups were similar in terms of clinical assessment, patient satisfaction, activity level, function, and response of the bio-markers. After 1 year of healing, synthesis of collagen and turnover of aggrecan remained elevated in both groups. CONCLUSION: Anterior cruciate ligament reconstruction with a bone-patellar tendon-bone graft followed by either accelerated or nonaccelerated rehabilitation produces the same increase of anterior knee laxity. Both programs had the same effect in terms of clinical assessment, patient satisfaction, functional performance, and the biomarkers of articular cartilage metabolism. There is concern that the cartilage biomarkers remained elevated for an extended period.     

High‐throughput genotyping of mannose‐binding lectin variants using high‐resolution DNA‐melting analysis

High Resolution Melting Analysis (HRMA) is a rapid and sensitive method for single nucleotide polymorphism (SNP) analysis. In the present study we present a novel HRMA assay to detect three SNPs in close proximity of each other in the first exon of the gene encoding mannose‐binding lectin (MBL), a key molecule of innate immunity. These SNPs have been selected for their known biological and clinical relevance. The three SNPs in MBL2 were simultaneously determined in sixty‐nine human DNA samples using HRMA and a single non‐fluorescent melting probe, without any post‐PCR processing of samples. Combining analyses from amplicon melting and probe melting, we have been able to discriminate ten exon 1 MBL2 genotypes with HRMA, making it a suitable tool for MBL genotyping. A second HRMA assay is presented to detect a relevant polymorphism (Y/X SNP) in the MBL2 promoter region. In conclusion, HRMA is a closed tube assay that is easy to setup and lends itself perfectly for high throughput genotyping of MBL2 variants. The present study thereby facilitates further clinical studies into the role of MBL in inflammatory and infectious disease. © 2010 Wiley‐Liss, Inc.