Sex-Specific Trends in Incidence and Mortality for Urban and Rural Ambulatory Patients with Heart Failure in Eastern Ontario from 1994 to 2013

Background

Differences in outcomes have previously been reported between urban and rural settings across a multitude of chronic diseases. Whether these discrepancies have changed over time, and how sex may influence these findings is unknown for patients with ambulatory heart failure (HF). We examined the temporal incidence and mortality trends by geography in these patients.

Dominant or recessive mutations in the RYR1 gene causing central core myopathy in Brazilian patients

Central Core Disease (CCD) is an inherited neuromuscular disorder characterized by the presence of cores in muscle biopsy. CCD is caused by mutations in the RYR1 gene. This gene encodes the ryanodine receptor 1, which is an intracellular calcium release channel from the sarcoplasmic reticulum to the cytosol in response to depolarization of the plasma membrane. Mutations in this gene are also associated with susceptibility to Malignant Hyperthermia (MHS).In this study, we evaluated 20 families with clinical and histological characteristics of CCD to identify primary mutations in patients, for diagnosis and genetic counseling of the families.We identified variants in the RYR1 gene in 19/20 families. The molecular pathogenicity was confirmed in 16 of them. Most of these variants (22/23) are missense and unique in the families. Two variants were recurrent in two different families. We identified six families with biallelic mutations, five compound heterozygotes with no consanguinity, and one homozygous, with consanguineous parents, resulting in 30% of cases with possible autosomal recessive inheritance. We identified seven novel variants, four of them classified as pathogenic. In one family, we identified two mutations in exon 102, segregating in cis, suggesting an additive effect of two mutations in the same allele.This work highlights the importance of using Next-Generation Sequencing technology for the molecular diagnosis of genetic diseases when a very large gene is involved, associated to a broad distribution of the mutations along it. These data also influence the prevention through adequate genetic counseling for the families and cautions against malignant hyperthermia susceptibility.Key words: central core disease, RYR1, Next Generation Sequencing     

Mineral density changes in bovine carious dentin after treatment with bioactive dental cements: a comparative micro-CT study

Objectives

To evaluate the potential of conventional glass ionomer cement (GIC), Biodentine™, MTA, and Portland cement to induce mineral density changes in carious dentin compared to zinc oxide eugenol control cement (ZOE).

Materials and methods

Fifty blocks of bovine root dentin were prepared and a biofilm model using ATCC strains of S.mutans, S.sobrinus, and L.casei was used to promote artificial dentin lesions. After demineralization, the blocks were randomly divided into the five cement groups. Half of the surface of each specimen received the tested material and the other half was covered with wax (control). Samples were stored in phosphate buffered saline solution for 30 days and after that were scanned in a micro-CT with standardized parameters. Dentin mineral density changes were calculated using differences in plot profiles of the exposed and control carious dentin. Friedman’s test, followed by Wilcoxon signed-rank test was used with 5% significance.

Results

Mean ΔZ values for the cements were 48.63 ± 19.09 for the control (ZOE), 63.31 ± 32.59 for Biodentine™, 114.63 ± 72.92 for GIC, 109.56 ± 66.28 for MTA, and 106.88 ± 66.02 for Portland cement. All cements showed a statistically significant increase in ΔZ values compared to the control, but Biodentine™ values were statistically significantly lower compared to GIC and the other calcium silicate cements.

Conclusions

Tested materials present potential to induce mineral density changes in carious bovine dentin. MTA, Portland, and GIC showed higher bioactivity potential than Biodentine™.

Clinical relevance

Based on minimally invasive concept, materials with remineralization potential can be used to preserve diseased but still repairable dental tissue.

     

Managing Novel Oral Anticoagulants in Patients With Atrial Fibrillation Undergoing Device Surgery: Canadian Survey

Background

Approximately 10% of patients who undergo surgical procedures require chronic oral anticoagulation. Physicians must balance the thromboembolic and bleeding risks to make informed decisions on whether to continue anticoagulant medication. Evidence is lacking regarding the perioperative management of novel oral anticoagulant (NOAC) agents. This survey aims to describe the management of perioperative NOAC use during device implantation by Canadian centres.

Methods

A Web-based tool was used to survey all Canadian adult pacemaker/defibrillator implant centres. The survey collected data regarding the perioperative management of NOACs in atrial fibrillation patients at high risk for thromboembolism who undergo device implantation.

Results

Twenty-two centres performed approximately 14,971 device implants; 1150 (8%) of these implants were in patients who were prescribed a NOAC. In 82% of centres, the NOAC is discontinued in anticipation of device implantation; 73% of these centres do not bridge with heparin. In patients with normal renal function at high risk of thromboembolic events (Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack; CHADS₂ ≥ 2), 72% of the centres restart the NOAC within 48 hours of the procedure. For patients with abnormal renal function (glomerular filtration rate < 80 mL/min), the timing of NOAC discontinuation is variable. Hematoma rates vary from 0 to 30%.

Conclusions

Most Canadian centres perform device implantation with NOAC interruption without the use of bridging. The timing of stopping and restarting anticoagulation and incidence of bleeding complications is variable. These findings emphasize the need for randomized controlled studies to guide the optimal approach to management of NOACs during device implantation.     

The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase

Complex hereditary spastic paraplegia (HSP) is a genetic disorder that causes lower limb spasticity and weakness and intellectual disability. Deleterious mutations in the poorly characterized serine hydrolase DDHD2 are a causative basis for recessive complex HSP. DDHD2 exhibits phospholipase activity in vitro, but its endogenous substrates and biochemical functions remain unknown. Here, we report the development of DDHD2^−/− mice and a selective, in vivo-active DDHD2 inhibitor and their use in combination with mass spectrometry-based lipidomics to discover that DDHD2 regulates brain triglycerides (triacylglycerols, or TAGs). DDHD2^−/− mice show age-dependent TAG elevations in the central nervous system, but not in several peripheral tissues. Large lipid droplets accumulated in DDHD2^−/− brains and were localized primarily to the intracellular compartments of neurons. These metabolic changes were accompanied by impairments in motor and cognitive function. Recombinant DDHD2 displays TAG hydrolase activity, and TAGs accumulated in the brains of wild-type mice treated subchronically with a selective DDHD2 inhibitor. These findings, taken together, indicate that the central nervous system possesses a specialized pathway for metabolizing TAGs, disruption of which leads to massive lipid accumulation in neurons and complex HSP syndrome.Determining the genetic basis for rare hereditary human diseases has benefited from advances in DNA sequencing technologies (1). As a greater number of disease-causing mutations are mapped, however, it is also becoming apparent that many of the affected genes code for poorly characterized proteins. Assigning biochemical and cellular functions to these proteins is critical to achieve a deeper mechanistic understanding of human genetic disorders and for identifying potential treatment strategies.Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurologic syndrome marked by spasticity and lower extremity weakness (2). Many genetic types of HSP have been identified and are numbered according to their order of discovery [spastic paraplegia (SPG) 1-72] (2, 3). Of these genetic variants, more than 40 have been mapped to causative mutations in protein-coding genes. HSP genes code for a wide range of proteins that do not conform to a single sequence- or function-related class. A subset of HSP genes, including PNPLA6 (or neuropathy-target esterase) (SPG39) (4), DDHD1 (SPG28) (5), and DDHD2 (SPG54) (3, 6–8), code for serine hydrolases. These enzymes have been designated as (lyso)phospholipases based on in vitro substrate assays (9–11), but their endogenous substrates and physiological functions remain poorly understood. The mutational landscape that affects these lipid hydrolases to cause recessive HSP is complex but collectively represents a mix of null and putatively null and/or functional mutations. Moreover, the type of HSP appears to differ in each case, with DDHD1 mutations causing uncomplicated HSP, whereas PNPLA6 and DDHD2 mutations lead to complex forms of the disease that exhibit additional phenotypes including, in the case of DDHD2, intellectual disability. Human subjects with DDHD2 mutations also displayed evidence of brain lipid accumulation as detected by cerebral magnetic resonance spectroscopy (6). Both rodent and human DDHD2 enzymes are highly expressed in the brain compared with most peripheral tissues (6, 9); however, the specific lipids regulated by DDHD2 in the central nervous system (CNS) have not yet been identified.Determining the metabolic function of DDHD2 in the brain is an important step toward understanding how mutations in this enzyme promote complex HSP and for identifying possible therapeutic strategies for the disease. Toward this end, we report herein the generation and characterization of DDHD2^−/− mice and a selective DDHD2 inhibitor. DDHD2^−/− mice exhibit defects in movement and cognitive function. Mass spectrometry (MS)-based lipidomics (12, 13) revealed a striking and selective elevation in triglycerides (triacylglycerols, or TAGs) throughout the CNS, but not in peripheral tissues, of DDHD2^−/− mice. This metabolic change correlated with pervasive lipid droplet (LD) accumulation in neuronal cell bodies of DDHD2^−/− mice. Biochemical assays confirmed that DDHD2 possesses TAG hydrolase activity. Finally, wild-type mice treated subchronically with a DDHD2 inhibitor also exhibited significant elevations in CNS TAGs. These data, taken together, indicate that DDHD2 is a principal TAG hydrolase of the mammalian brain and point to deregulation of this pathway as a major contributory factor to complex HSP.     

Imputation of confidential data sets with spatial locations using disease mapping models

Data that include fine geographic information, such as census tract or street block identifiers, can be difficult to release as public use files. Fine geography provides information that ill‐intentioned data users can use to identify individuals. We propose to release data with simulated geographies, so as to enable spatial analyses while reducing disclosure risks. We fit disease mapping models that predict areal‐level counts from attributes in the file and sample new locations based on the estimated models. We illustrate this approach using data on causes of death in North Carolina, including evaluations of the disclosure risks and analytic validity that can result from releasing synthetic geographies. Copyright © 2014 John Wiley & Sons, Ltd.     

Micromorphology of the Dental Pulp Is Highly Preserved in Cancer Patients Who Underwent Head and Neck Radiotherapy

Introduction

Teeth are often included in the radiation field during head and neck radiotherapy, and recent clinical evidence suggests that dental pulp is negatively affected by the direct effects of radiation, leading to impaired sensitivity of the dental pulp. Therefore, this study aimed to investigate the direct effects of radiation on the microvasculature, innervation, and extracellular matrix of the dental pulp of patients who have undergone head and neck radiotherapy.

Methods

Twenty-three samples of dental pulp from patients who finished head and neck radiotherapy were analyzed. Samples were histologically processed and stained with hematoxylin-eosin for morphologic evaluation of the microvasculature, innervation, and extracellular matrix. Subsequently, immunohistochemical analysis of proteins related to vascularization (CD34 and smooth muscle actin), innervation (S-100, NCAM/CD56, and neurofilament), and extracellular matrix (vimentin) of the dental pulp was performed.

Results

The morphologic study identified preservation of the microvasculature, nerve bundles, and components of the extracellular matrix in all studied samples. The immunohistochemical analysis confirmed the morphologic findings and showed a normal pattern of expression for the studied proteins in all samples.

Conclusions

Direct effects of radiotherapy are not able to generate morphologic changes in the microvasculature, innervation, and extracellular matrix components of the dental pulp in head and neck cancer patients.