Does the adenosine deaminase (ADA) gene confer risk of sleepwalking?

Sleepwalking is a common non-rapid eye movement (NREM) parasomnia and a significant cause of sleep-related injuries. While evidence suggest that the occurrence of this condition is partly determined by genetic factors, its pattern of inheritance remains unclear, and few molecular studies have been conducted. One promising candidate is the adenosine deaminase (ADA) gene. Adenosine and the ADA enzyme play an important role in the homeostatic regulation of NREM sleep. In a single sleepwalking family, genome-wide analysis identified a locus on chromosome 20, where ADA lies. In this study, we examined if variants in the ADA gene were associated with sleepwalking. In total, 251 sleepwalking patients were clinically assessed, and DNA samples were compared to those from 94 unaffected controls. Next-generation sequencing of the whole ADA gene was performed. Bio-informatic analysis enabled the identification of variants and assessed variants enrichment in our cohort compared to controls. We detected 25 different coding and non-coding variants, of which 22 were found among sleepwalkers. None were enriched in the sleepwalking population. However, many missense variants were predicted as likely pathogenic by at least two in silico prediction algorithms. This study involves the largest sleepwalking cohort in which the role of a susceptibility gene was investigated. Our results did not reveal an association between ADA gene and sleepwalking, thus ruling out the possibility of ADA as a major genetic factor for this condition. Future work is needed to identify susceptibility genes.

Association between pre-operative magnetic resonance imaging and reparability of large and massive rotator cuff tears.

PURPOSE: It is recognized that a percentage of large and massive rotator cuff tears (RCTs) cannot be anatomically repaired. We hypothesized that factors identified on pre-operative MRI would be associated with rotator cuff reparability. METHODS: A single-surgeon retrospective study was performed on patients who had undergone either an anatomical or partial repair of a large or massive RCT. Pre-operative MRI images were evaluated by a fellowship-trained shoulder surgeon, blinded to the surgical outcome. Stump location, tear dimension in the coronal and sagittal plane, fatty infiltration, muscle atrophy (occupation ratio, tangent sign), and superior migration of the humeral head (acromion-humeral distance, inferior glenohumeral distance, and best-fit humeral circle technique) were assessed as the predictors of repair. Logistic regression and chi-square analyses were used. RESULTS: A total of sixty patients with median age 63 (range 40-83) were included. On MRI, reparability was associated with increased medial-lateral (ML) tear size (p = 0.003), but not increased AP tear size (n.s.). An association was seen between partial repair and tendon retraction to or beyond the glenoid (p = 0.0005), positive tangent sign (p = 0.04), advanced supraspinatus fatty infiltration in isolation (p = 0.046), combined advanced supraspinatus and infraspinatus fatty infiltration (p = 0.04), and superior migration of the humeral head as measured by the inferior glenohumeral distance only (p = 0.004). Multivariable analysis identified increased ML tear size as the most significant factor associated with partial repair. CONCLUSION: This study demonstrates that MRI findings of tendon retraction to or beyond the glenoid, increased inferior glenohumeral distance, and a positive tangent sign are associated with irreparability of large and massive RCTs.

The LORIS MyeliNeuroGene rare disease database for natural history studies and clinical trial readiness.

BACKGROUND: Rare diseases are estimated to affect 150-350 million people worldwide. With advances in next generation sequencing, the number of known disease-causing genes has increased significantly, opening the door for therapy development. Rare disease research has therefore pivoted from gene discovery to the exploration of potential therapies. With impending clinical trials on the horizon, researchers are in urgent need of natural history studies to help them identify surrogate markers, validate outcome measures, define historical control patients, and design therapeutic trials. RESULTS: We customized a browser-accessible multi-modal (e.g. genetics, imaging, behavioral, patient-determined outcomes) database to increase cohort sizes, identify surrogate markers, and foster international collaborations. Ninety data entry forms were developed including family, perinatal, developmental history, clinical examinations, diagnostic investigations, neurological evaluations (i.e. spasticity, dystonia, ataxia, etc.), disability measures, parental stress, and quality of life. A customizable clinical letter generator was created to assist in continuity of patient care. CONCLUSIONS: Small cohorts and underpowered studies are a major challenge for rare disease research. This online, rare disease database will be accessible from all over the world, making it easier to share and disseminate data. We have outlined the methodology to become Title 21 Code of Federal Regulations Part 11 Compliant, which is a requirement to use electronic records as historical controls in clinical trials in the United States. Food and Drug Administration compliant databases will be life-changing for patients and families when historical control data is used for emerging clinical trials. Future work will leverage these tools to delineate the natural history of several rare diseases and we are confident that this database will be used on a larger scale to improve care for patients affected with rare diseases.

Antipsychotics' effects on blood levels of cytokines in schizophrenia: a meta-analysis.

OBJECTIVES: Evidence-based medicine suggests that schizophrenia is associated with an inflammatory syndrome, but the extent to which this syndrome is normalized by antipsychotic treatment has yet to be determined. METHODS: A systematic quantitative review of the effects of antipsychotics on peripheral cytokine levels in schizophrenia was performed, using follow-up studies providing in vivo cytokine assessments before and after treatment. RESULTS: We retrieved 23 studies (total of 762 subjects) which showed that antipsychotic treatment significantly increases plasma levels of soluble interleukin-2 receptor and reduces the plasma levels of interleukin-1ß and interferon-γ. CONCLUSIONS: These results show that antipsychotics produce anti-inflammatory effects in schizophrenia.

Mild hyperthermia promotes and accelerates development and maturation of erythroid cells.

Hyperthermia treatment has at times been associated with increased platelet levels in humans. The heat shock protein HSP70, which can be induced by hyperthermia in megakaryocytes and erythrocytes, was recently shown to protect GATA-1 from degradation and to be required for erythroid differentiation. Based on these findings, we hypothesize that mild hyperthermia (MH), such as fever (39°C), could impact the differentiation of hematopoietic progenitors into erythrocytes and their subsequent maturation. Cell growth and erythroid differentiation increased dramatically in cord blood CD34(+) cell cultures incubated under MH. Erythroid maturation was also strongly promoted, which resulted in an increased proportion of hemoglobinized and enucleated erythroids. The rise in erythroid development was traced to a strong synergistic activity between MH and erythropoietin (EPO). The molecular basis for this potent synergy appears to originate from the capacity of MH to increase the basal activation of several signaling molecules downstream of the EPO receptor and the transcriptional activity of GATA-1. Moreover, the potent impact of MH on erythroid development was found be dependent on increased intracellular levels of reactive oxygen species. Thus, fever-like temperatures can promote the differentiation of progenitors along the erythroid lineage and accelerate their maturation through normal regulatory circuitry.

Employment related productivity loss associated with herpes zoster and postherpetic neuralgia: a 6-month prospective study.

We conducted a prospective multi-center study to assess productivity loss associated with herpes zoster (HZ) and postherpetic neuralgia (PHN). From 10/2005 to 07/2006, we recruited immunocompetent subjects aged ≥50 years with HZ within 14 days of rash onset across Canada. Of the 249 patients recruited, 88 were employed. Data on employment status, absences from work, reasons for absence and effectiveness at work were documented at recruitment, 7-14-21-30-60-90-120-150 and 180 days later. The majority (64%) of employed subjects missed work because of HZ and 76% reported decreased effectiveness at work (i.e. presenteeism) because of HZ/PHN. Mean hours of absenteeism and presenteeism per working individual were 27 and 34 h, respectively. Pain severity and duration were associated with greater productivity loss. These results provide new information about the burden of HZ and PHN, which is useful for public health planning and cost-effectiveness analyses of HZ vaccination among individuals of working age.