Test of the half-center model for locomotor activity in adult lamprey spinal cord [abstract]

Abstract only availableRhythmic motor behaviors, such as locomotion, chewing, scratching, copulation, and communication, are critical for survival. In all animals, rhythmic motor activity is produced by central patterns generators (CPGs) which consist of neuronal modules that are coupled by a coordinating system. For example, in a cat separate spinal modules control the movements of each limb, and the coordinating system can couple the modules in different ways to produce different gaits (walk, trot, gallop). Each module can be divided into oscillators that usually are connected by reciprocal inhibition (i.e. "half-center" model) to produce alternating motor patterns (e.g. flexion « extension). These oscillators generally are assumed to be autonomous and able to function without the reciprocal connections. In the lamprey, locomotion (swimming) is produced by pairs of oscillators that are distributed along the spinal cord and connected by left-right reciprocal inhibition (Hagevik and McClellan, 1994). In adult lamprey, we tested the half-center model by investigating whether the phasing of left-right burst activity could be correctly maintained in the absence of left-right reciprocal coupling. Adult lamprey received a longitudinal midline lesion in the rostral spinal cord (10% à 35% body length). After the midline lesion, the animals were able to swim, and the appropriate phasing of left and right muscle burst activity was present in both caudal and rostral parts of the body. After a spinal transection was made at 35% body length to isolated the rostral left and right halves of the spinal cord from intact cord, locomotor-like burst activity was no longer present in the rostral spinal cord. We obtained similar results in larval lamprey (Jackson et al., 2005). Thus, in lamprey, the data do not support the "half-center" model because left and right spinal cord oscillators are not autonomous but appear to require left-right reciprocal coupling to function properly

Recovery of locomotor function following spinal cord hemi-transections in larval lamprey [abstract]

Abstract only availableIn vertebrates, reticulospinal (RS) neurons in the brain activate spinal motor networks to initiate locomotor behavior. Following spinal cord injury (SCI), RS neurons no longer communicate with the spinal cord, and animals are paralyzed below the lesion. In higher vertebrates, such as birds and mammals, the axons of RS neurons do not regenerate, and paralysis usually is permanent. In contrast, spinal cord transected lower vertebrates such as the lamprey display robust axonal regeneration and recovery of function within a few weeks. In our previous studies we showed that following spinal cord hemi-transections (HTs) in larval lamprey, injured RS neurons undergo a number of substantial changes in electrical properties and expression of ion channels which recover within several weeks. The purpose of the present study is to determine the rate of behavioral recovery following HTs and ultimately to correlate axonal regeneration of injured RS neurons with recovery of normal properties of these neurons. In the present study, animals received HTs on the right side of the rostral spinal cord and recovered for 1d - 6 wks. At early recovery times (1 day), animals swam with a spiraling movement and turned toward the intact side of the spinal cord, but the pattern of muscle activity was relatively normal. Swimming movements began to recover within the first week, and by the fourth week animals swam normally with little or no spiraling. In the future, anatomical experiments will be conducted to determine if recovery of swimming following HTs is due to regeneration of injured axons through the HT or to functional compensation of intact pathways on the opposite side of the spinal cord. This information will be important in determining what factors alter the properties of RS neurons following SCI and if these altered properties are important for successful axonal regeneration

Provider Perceptions of Treatment Options for Immature Permanent Teeth

The purpose of this study was to survey endodontists and pediatric dentists on the use of apexification and regenerative endodontics for the treatment of immature permanent teeth. We surveyed pediatric dentists (n=1941) and endodontists (n=1615) in four geographically and demographically diverse states- North Carolina, New York, Texas and California. The surveys were created using qualtrics and teleform and distributed using the Salant and Dillman method. Data was analyzed using chi square, linear and multinominal regression. 574 Endodontists (32.9% success rate) and 526 pediatric dentists (27.1% response rate) responded to the surveys. Both endodontists and pediatric dentists reported that they occasionally to rarely diagnose and treat patients with pulpal necrosis. Of the 43.3% of pediatric dentists who do not refer, 24% indicated that they perform only apexification. Predictability of outcome (p<.01), continued root development (p=0.01) and apical closure (p=0.01) significantly influence the decision to choose one treatment option for both specialties.Master of Scienc

Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer

Purpose: Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials. Methods: Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years. Results: Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9 %) and 31 (1.2 %) in the denosumab and ZA groups, respectively. In total, 32 (6.9 %) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1 %, in patients continuing and switching to denosumab, respectively. Conclusion: These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals

IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals

Retiree Health Benefit Coverage and Retirement

Employer-provided health benefits for workers who retire before age 65 has fallen over the last decade. We examine a cohort of male workers from the Health and Retirement Survey to explore the dynamics of retiree health benefits and the relationship between retiree health benefits and retirement behavior. A better understanding of this relationship is important to the policy debate over the best way to increase health coverage for older Americans without reducing work incentives. Concerning the dynamics at work, we find that, between 1992 and 1996, 24 percent of full-time workers who had retiree health benefits lost their coverage, while 15 percent of full-time workers who lacked coverage gained it. Also, of the full-time employed men who were covered by retiree health benefits in 1992 and had retired by 1996, 3 percent were uninsured, and 15 percent were covered by health insurance other than employer-provided insurance. On the relationship between retiree health benefits and retirement, we find that workers with retiree benefits were 29 to 55 percent more likely to retire than those without. We also find that workers who are eligible for retiree health benefits tend to take advantage of them when they are relatively young

ADEPT - Abnormal Doppler Enteral Prescription Trial

<p>Abstract</p> <p>Background</p> <p>Pregnancies complicated by abnormal umbilical artery Doppler blood flow patterns often result in the baby being born both preterm and growth-restricted. These babies are at high risk of milk intolerance and necrotising enterocolitis, as well as post-natal growth failure, and there is no clinical consensus about how best to feed them. Policies of both early milk feeding and late milk feeding are widely used. This randomised controlled trial aims to determine whether a policy of early initiation of milk feeds is beneficial compared with late initiation. Optimising neonatal feeding for this group of babies may have long-term health implications and if either of these policies is shown to be beneficial it can be immediately adopted into clinical practice.</p> <p>Methods and Design</p> <p>Babies with gestational age below 35 weeks, and with birth weight below 10th centile for gestational age, will be randomly allocated to an "early" or "late" enteral feeding regimen, commencing milk feeds on day 2 and day 6 after birth, respectively. Feeds will be gradually increased over 9-13 days (depending on gestational age) using a schedule derived from those used in hospitals in the Eastern and South Western Regions of England, based on surveys of feeding practice. Primary outcome measures are time to establish full enteral feeding and necrotising enterocolitis; secondary outcomes include sepsis and growth. The target sample size is 400 babies. This sample size is large enough to detect a clinically meaningful difference of 3 days in time to establish full enteral feeds between the two feeding policies, with 90% power and a 5% 2-sided significance level. Initial recruitment period was 24 months, subsequently extended to 38 months.</p> <p>Discussion</p> <p>There is limited evidence from randomised controlled trials on which to base decisions regarding feeding policy in high risk preterm infants. This multicentre trial will help to guide clinical practice and may also provide pointers for future research.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN: 87351483</p

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms