On-Going Frontal Alpha Rhythms Are Dominant in Passive State and Desynchronize in Active State in Adult Gray Mouse Lemurs

The gray mouse lemur (Microcebus murinus) is considered a useful primate model for translational research. In the framework of IMI PharmaCog project (Grant Agreement n°115009, www.pharmacog.org), we tested the hypothesis that spectral electroencephalographic (EEG) markers of motor and locomotor activity in gray mouse lemurs reflect typical movement-related desynchronization of alpha rhythms (about 8–12 Hz) in humans. To this aim, EEG (bipolar electrodes in frontal cortex) and electromyographic (EMG; bipolar electrodes sutured in neck muscles) data were recorded in 13 male adult (about 3 years) lemurs. Artifact-free EEG segments during active state (gross movements, exploratory movements or locomotor activity) and awake passive state (no sleep) were selected on the basis of instrumental measures of animal behavior, and were used as an input for EEG power density analysis. Results showed a clear peak of EEG power density at alpha range (7–9 Hz) during passive state. During active state, there was a reduction in alpha power density (8–12 Hz) and an increase of power density at slow frequencies (1–4 Hz). Relative EMG activity was related to EEG power density at 2–4 Hz (positive correlation) and at 8–12 Hz (negative correlation). These results suggest for the first time that the primate gray mouse lemurs and humans may share basic neurophysiologic mechanisms of synchronization of frontal alpha rhythms in awake passive state and their desynchronization during motor and locomotor activity. These EEG markers may be an ideal experimental model for translational basic (motor science) and applied (pharmacological and non-pharmacological interventions) research in Neurophysiology.     

Cost-Effectiveness of HBV and HCV Screening Strategies – A Systematic Review of Existing Modelling Techniques

Introduction

Studies evaluating the cost-effectiveness of screening for Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are generally heterogeneous in terms of risk groups, settings, screening intervention, outcomes and the economic modelling framework. It is therefore difficult to compare cost-effectiveness results between studies. This systematic review aims to summarise and critically assess existing economic models for HBV and HCV in order to identify the main methodological differences in modelling approaches.

Methods

A structured search strategy was developed and a systematic review carried out. A critical assessment of the decision-analytic models was carried out according to the guidelines and framework developed for assessment of decision-analytic models in Health Technology Assessment of health care interventions.

Results

The overall approach to analysing the cost-effectiveness of screening strategies was found to be broadly consistent for HBV and HCV. However, modelling parameters and related structure differed between models, producing different results. More recent publications performed better against a performance matrix, evaluating model components and methodology.

Conclusion

When assessing screening strategies for HBV and HCV infection, the focus should be on more recent studies, which applied the latest treatment regimes, test methods and had better and more complete data on which to base their models. In addition to parameter selection and associated assumptions, careful consideration of dynamic versus static modelling is recommended. Future research may want to focus on these methodological issues. In addition, the ability to evaluate screening strategies for multiple infectious diseases, (HCV and HIV at the same time) might prove important for decision makers.     

Ultrasound-Assisted Thoracic Paravertebral Block Reduces Intraoperative Opioid Requirement and Improves Analgesia after Breast Cancer Surgery: A Randomized,Controlled, Single-Center Trial

Objectives

The contribution of ultrasound-assisted thoracic paravertebral block to postoperative analgesia remains unclear. We compared the effect of a combination of ultrasound assisted-thoracic paravertebral block and propofol general anesthesia with opioid and sevoflurane general anesthesia on volatile anesthetic, propofol and opioid consumption, and postoperative pain in patients having breast cancer surgery.

Methods

Patients undergoing breast cancer surgery were randomly assigned to ultrasound-assisted paravertebral block with propofol general anesthesia (PPA group, n = 121) or fentanyl with sevoflurane general anesthesia (GA group, n = 126). Volatile anesthetic, propofol and opioid consumption, and postoperative pain intensity were compared between the groups using noninferiority and superiority tests.

Results

Patients in the PPA group required less sevoflurane than those in the GA group (median [interquartile range] of 0 [0, 0] vs. 0.4 [0.3, 0.6] minimum alveolar concentration [MAC]-hours), less intraoperative fentanyl requirements (100 [50, 100] vs. 250 [200, 300]μg,), less intense postoperative pain (median visual analog scale score 2 [1, 3.5] vs. 3 [2, 4.5]), but more propofol (median 529 [424, 672] vs. 100 [100, 130] mg). Noninferiority was detected for all four outcomes; one-tailed superiority tests for each outcome were highly significant at P<0.001 in the expected directions.

Conclusions

The combination of propofol anesthesia with ultrasound-assisted paravertebral block reduces intraoperative volatile anesthetic and opioid requirements, and results in less post operative pain in patients undergoing breast cancer surgery.

Trial Registration

ClinicalTrial.gov NCT00418457     

FORGE Canada Consortium: Outcomes of a 2-Year National Rare-Disease Gene-Discovery Project

Inherited monogenic disease has an enormous impact on the well-being of children and their families. Over half of the children living with one of these conditions are without a molecular diagnosis because of the rarity of the disease, the marked clinical heterogeneity, and the reality that there are thousands of rare diseases for which causative mutations have yet to be identified. It is in this context that in 2010 a Canadian consortium was formed to rapidly identify mutations causing a wide spectrum of pediatric-onset rare diseases by using whole-exome sequencing. The FORGE (Finding of Rare Disease Genes) Canada Consortium brought together clinicians and scientists from 21 genetics centers and three science and technology innovation centers from across Canada. From nation-wide requests for proposals, 264 disorders were selected for study from the 371 submitted; disease-causing variants (including in 67 genes not previously associated with human disease; 41 of these have been genetically or functionally validated, and 26 are currently under study) were identified for 146 disorders over a 2-year period. Here, we present our experience with four strategies employed for gene discovery and discuss FORGE’s impact in a number of realms, from clinical diagnostics to the broadening of the phenotypic spectrum of many diseases to the biological insight gained into both disease states and normal human development. Lastly, on the basis of this experience, we discuss the way forward for rare-disease genetic discovery both in Canada and internationally.     

De Novo Loss-of-Function Mutations in SETD5, Encoding a Methyltransferase in a 3p25 Microdeletion Syndrome Critical Region,Cause Intellectual Disability

To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations—four nonsense (c.1195A>T [p.Lys399^∗], c.1333C>T [p.Arg445^∗], c.1866C>G [p.Tyr622^∗], and c.3001C>T [p.Arg1001^∗]) and three frameshift (c.2177_2178del [p.Thr726Asnfs^∗39], c.3771dup [p.Ser1258Glufs^∗65], and c.3856del [p.Ser1286Leufs^∗84])—were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID.     

Genetic diversity in Puerto Rico and its implications for the peopling of the Island and the West Indies

Puerto Rico and the surrounding islands rest on the eastern fringe of the Caribbean's Greater Antilles, located less than 100 miles northwest of the Lesser Antilles. Puerto Ricans are genetic descendants of pre‐Columbian peoples, as well as peoples of European and African descent through 500 years of migration to the island. To infer these patterns of pre‐Columbian and historic peopling of the Caribbean, we characterized genetic diversity in 326 individuals from the southeastern region of Puerto Rico and the island municipality of Vieques. We sequenced the mitochondrial DNA (mtDNA) control region of all of the samples and the complete mitogenomes of 12 of them to infer their putative place of origin. In addition, we genotyped 121 male samples for 25 Y‐chromosome single nucleotide polymorphism and 17 STR loci. Approximately 60% of the participants had indigenous mtDNA haplotypes (mostly from haplogroups A2 and C1), while 25% had African and 15% European haplotypes. Three A2 sublineages were unique to the Greater Antilles, one of which was similar to Mesoamerican types, while C1b haplogroups showed links to South America, suggesting that people reached the island from the two distinct continental source areas. However, none of the male participants had indigenous Y‐chromosomes, with 85% of them instead being European/Mediterranean and 15% sub‐Saharan African in origin. West Eurasian Y‐chromosome short tandem repeat haplotypes were quite diverse and showed similarities to those observed in southern Europe, North Africa and the Middle East. These results attest to the distinct, yet equally complex, pasts for the male and female ancestors of modern day Puerto Ricans. Am J Phys Anthropol 155:352–368, 2014. © 2014 Wiley Periodicals, Inc.     

Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia

Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.     

Genome scan for Tourette disorder in affected-sibling-pair and multigenerational families

Tourette disorder (TD) is a neuropsychiatric disorder with a complex mode of inheritance and is characterized by multiple waxing and waning motor and phonic tics. This article reports the results of the largest genetic linkage study yet undertaken for TD. The sample analyzed includes 238 nuclear families yielding 304 "independent" sibling pairs and 18 separate multigenerational families, for a total of 2,040 individuals. A whole-genome screen with the use of 390 microsatellite markers was completed. Analyses were completed using two diagnostic classifications: (1) only individuals with TD were included as affected and (2) individuals with either TD or chronic-tic (CT) disorder were included as affected. Strong evidence of linkage was observed for a region on chromosome 2p (-log P = 4.42, P = 3.8 x 10(-5) in the analyses that included individuals with TD or CT disorder as affected. Results in several other regions also provide moderate evidence (-log P >2.0) of additional susceptibility loci for TD.     

Genetic diversity and subdivision of 57 European and Middle-Eastern sheep breeds

The population structure and genetic diversity of 57 European and Middle Eastern marginal and cosmopolitan sheep breeds from 15 countries were analysed by typing 31 microsatellite markers. Mean unbiased expected heterozygosities ranged from 0.63 in British Exmoor Horn to 0.77 in Albanian Ruda. South-eastern European and Middle-Eastern sheep breeds were significantly more variable than northwestern and western European breeds. An overall heterozygote deficiency (f) across all loci was observed (P < 0.001), while genetic differentiation (theta) was 5.7%. Principal component analysis and Bayesian model-based clustering indicate a south-east to north-west cline, but also revealed distinct groups of Middle-Eastern fat-tailed sheep, south-eastern European sheep and north-western/western European sheep. Within the last group, two less-distinct clusters comprised the Merino-type and Alpine breeds respectively. The incomplete demarcations of most clusters probably reflects cross-breeding and/or upgrading.