An updated interactive database for 1692 genetic variants in coagulation factor IX provides detailed insights into hemophilia B.

Background: Genetic variants in coagulation factor IX (FIX) are associated with hemophilia B, a rare bleeding disease. F9 variants are widespread across the gene and were summarized in our FIX variant database introduced in 2013.

Objectives: We aimed to rationalize the molecular basis for 598 new F9 variants and 1645 new clinical cases, totaling 1692 F9 variants and 5358 related patient cases.

Analysis of 180 Genetic Variants in a New Interactive FX Variant Database Reveals Novel Insights into FX Deficiency.

Coagulation factor X (FX), often termed as Stuart-Prower factor, is a plasma glycoprotein composed of the γ-carboxyglutamic acid (GLA) domain, two epidermal growth factor domains (EGF-1 and EGF-2), and the serine protease (SP) domain. FX plays a pivotal role in the coagulation cascade, activating thrombin to promote platelet plug formation and prevent excess blood loss. Genetic variants in FX disrupt coagulation and lead to FX or Stuart-Prower factor deficiency.

Analysis of 272 Genetic Variants in the Upgraded Interactive FXI Web Database Reveals New Insights into FXI Deficiency.

Coagulation Factor XI (FXI) is a plasma glycoprotein composed of four apple (Ap) domains and a serine protease (SP) domain. FXI circulates as a dimer and activates Factor IX (FIX), promoting thrombin production and preventing excess blood loss. Genetic variants that degrade FXI structure and function often lead to bleeding diatheses, commonly termed FXI deficiency.

Autophagy in neonatal hypoxia ischemic brain is associated with oxidative stress.

Autophagy is activated when the neonatal brain exposed to hypoxia ischemia (HI), but the mechanisms underlying its activation and its role in the neuronal cell death associated with HI is unclear. We have previously shown that reactive oxygen species (ROS) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase play an important role in HI-mediated neuronal cell death. Thus, the aim of this study was to determine if ROS is involved in the activation of autophagy in HI-mediated neonatal brain injury and to determine if this is a protective or deleterious pathway.

Nitric oxide induces hypoxia ischemic injury in the neonatal brain via the disruption of neuronal iron metabolism.

We have recently shown that increased hydrogen peroxide (H2O2) generation is involved in hypoxia-ischemia (HI)-mediated neonatal brain injury. H2O2 can react with free iron to form the hydroxyl radical, through Fenton Chemistry. Thus, the objective of this study was to determine if there was a role for the hydroxyl radical in neonatal HI brain injury and to elucidate the underlying mechanisms.

Consensus Guidelines and Contouring Atlas for Pelvic Node Delineation in Prostate and Pelvic Node Intensity Modulated Radiation Therapy.

Purpose: The purpose of this study was to establish reproducible guidelines for delineating the clinical target volume (CTV) of the pelvic lymph nodes (LN) by combining the freehand Royal Marsden Hospital (RMH) and Radiation Therapy Oncology Group (RTOG) vascular expansion techniques.

Methods And Materials: Seven patients with prostate cancer underwent standard planning computed tomography scanning. Four different CTVs (RMH, RTOG, modified RTOG, and Prostate and pelvIs Versus prOsTate Alone treatment for Locally advanced prostate cancer [PIVOTAL] trial) were created for each patient, and 6 different bowel expansion margins (BEM) were created to assess bowel avoidance by the CTV.

Proposed genitalia contouring guidelines in anal cancer intensity-modulated radiotherapy.

Objective: Intensity-modulated radiotherapy (IMRT) for anal canal carcinoma (ACC) is associated with favourable toxicity outcomes. Side effects include sexual dysfunction, skin desquamation, pain and fibrosis to perineum and genitalia region. The genitalia are situated anterior to the primary ACC between two inguinal regions providing a challenging structure to avoid.

Ca²⁺/calmodulin-dependent protein kinase II contributes to hypoxic ischemic cell death in neonatal hippocampal slice cultures.

We have recently shown that p38MAP kinase (p38MAPK) stimulates ROS generation via the activation of NADPH oxidase during neonatal hypoxia-ischemia (HI) brain injury. However, how p38MAPK is activated during HI remains unresolved and was the focus of this study. Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) plays a key role in brain synapse development, neural transduction and synaptic plasticity.

Increased NADPH oxidase-derived superoxide is involved in the neuronal cell death induced by hypoxia-ischemia in neonatal hippocampal slice cultures.

Neonatal brain hypoxia-ischemia (HI) results in neuronal cell death. Previous studies indicate that reactive oxygen species, such as superoxide, play a key role in this process. However, the cellular sources have not been established.

Pediatric injuries attributable to falls from windows in the United States in 1990-2008.

Objective: To examine the epidemiological features of pediatric injuries related to falls from windows.

Methods: By using the National Electronic Injury Surveillance System, emergency department (ED) data for pediatric injury cases associated with window falls in 1990-2008 were reviewed.

Results: An estimated 98 415 children (95% confidence interval [CI]: 82 416-114 419) were treated in US hospital EDs for window fall-related injuries during the 19-year study period (average: 5180 patients per year [95% CI: 4828-5531]).

Treatment with transducible phosphopeptide analogues of the small heat shock-related protein, HSP20, after experimental subarachnoid hemorrhage: prevention and reversal of delayed decreases in cerebral perfusion.

Object: Delayed vasospasm is a significant cause of morbidity and mortality after subarachnoid hemorrhage (SAH). Proteomic therapeutics offers a new modality in which biologically active proteins or peptides are transduced into cells via covalent linkage to cell permeant peptides (CPPs). The hypothesis of this study was that either intrathecal or intravenous delivery of a phosphopeptide mimetic of the small heat shock-related protein, HSP20, linked to a CPP, would inhibit delayed decreases in cerebral perfusion after experimental SAH in a rat model.

Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade.

We compare the clinical course of 74 boys 10-18 years of age with Duchenne muscular dystrophy (DMD) treated (40) and not treated (34) with deflazacort. Treated boys were able to rise from supine to standing, climb stairs and walk 10 m without aids, 3-5 years longer than boys not treated. After 10 years of age, treated boys had significantly better pulmonary function than boys not treated and after 15 years of age, 8 of 17 boys not treated required nocturnal ventilation compared with none of the 40 treated boys.

Alendronate in the treatment of low bone mass in steroid-treated boys with Duchennes muscular dystrophy.

Objective: To examine alendronates side-effect profile and effect on bone mineral density (BMD) in deflazacort-treated boys with Duchennes muscular dystrophy (DMD) and low BMD.

Design: Before-after trial.

Setting: Neuromuscular clinic at a children's hospital in Canada between 1999 and 2000.

Deflazacort in Duchenne muscular dystrophy: a comparison of two different protocols.

We compare the long-term benefits and side effects of deflazacort using two treatment protocols from Naples (N) and Toronto (T). Boys with Duchenne muscular dystrophy between the ages of 8 and 15 years and who had four or more years of deflazacort treatment were reviewed. Diagnostic criteria included males with proximal muscle weakness evident before 5 years, increased serum creatine kinase and genetic testing and/or a muscle biopsy consistent with Duchenne muscular dystrophy.

Heat shock protein expression in cerebral vessels after subarachnoid hemorrhage.

Objective: The mechanisms of cerebral vasospasm after subarachnoid hemorrhage (SAH) remain controversial. Recent data have implicated two small heat shock proteins (HSPs), namely HSP20 and HSP27, in the regulation of vascular tone. Increases in the phosphorylation of HSP20 are associated with vasorelaxation, and increases in the phosphorylation of HSP27 are associated with impaired vasorelaxation.

Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity.

Recent studies of human immunodeficiency virus type 1 (HIV-1) infection in humans and of simian immunodeficiency virus (SIV) in rhesus monkeys have shown that resolution of the acute viral infection and control of the subsequent persistent infection are mediated by the antiviral cellular immune response. We comparatively assessed several vaccine vector delivery systems-three formulations of a plasmid DNA vector, the modified vaccinia Ankara (MVA) virus, and a replication incompetent adenovirus type 5 (Ad5) vector-expressing the SIV gag protein for their ability to elicit such immune responses in monkeys. The vaccines were tested either as a single modality or in combined modality regimens.

Preconditioning with cortical spreading depression does not upregulate Cu/Zn-SOD or Mn-SOD in the cerebral cortex of rats.

Previous studies have demonstrated that preconditioning the brain with cortical spreading depression (CSD) induces tolerance to a subsequent episode of ischemia. In other models of preconditioning, induction of ischemic tolerance has been associated with increased expression of the antioxidant enzyme, superoxide dismutase (SOD). The objective of the present study was to determine whether CSD upregulates Cu/Zn-SOD or Mn-SOD.

Dose-dependent induction of mRNAs encoding brain-derived neurotrophic factor and heat-shock protein-72 after cortical spreading depression in the rat.

Previous studies have demonstrated that cortical spreading depression (CSD) increases the expression of putative neuroprotective proteins. The objective of the present study was to elucidate the relationship between the number of episodes of CSD and steady-state levels of mRNAs encoding brain-derived neurotrophic factor (BDNF), heat-shock protein-72 (hsp72) and c-fos. Wistar rats were administered one, five, or twenty-five episodes of CSD evoked by application of 2 M KCl to the frontal cortex of one hemisphere.

In vivo protein expression from mRNA delivered into adult rat brain.

The expression of proteins after local mRNA delivery has a great potential for analysis of protein function in vivo. To explore the feasibility of such a technique within the central nervous system (CNS), we delivered luciferase-encoding mRNA into the rat brain. The tissue distribution and stability of injected mRNA were analyzed using in situ detection and Northern hybridization, while luciferase expression was measured by enzymatic assay.

Deflazacort treatment of Duchenne muscular dystrophy.

Objective: We report the long-term effects on muscle strength and side effects with deflazacort in Duchenne muscular dystrophy (DMD).

Study Design: Boys with DMD between the ages of 7 and 15 years were reviewed retrospectively; 30 had been treated with deflazacort, and 24 had not. Muscle function, pulmonary function, and side effects were compared.

Effect of cortical spreading depression on the levels of mRNA coding for putative neuroprotective proteins in rat brain.

Previous studies have demonstrated that cortical spreading depression (CSD) induces neuronal tolerance to a subsequent episode of ischemia. The objective of the present investigation was to determine whether CSD alters levels of mRNA coding for putative neuroprotective proteins. Unilateral CSD was evoked in male Wistar rats by applying 2 mol/L KCl over the frontal cortex for 2 hours.

Quantifying Targets for Rehabilitating Degraded Areas of the Great Lakes.

/ One attempt to quantify targets for rehabilitating degraded aquatic ecosystems has been through a United States-Canada program to develop and implement comprehensive remedial action plans (RAPs) to restore beneficial uses in 42 Great Lakes Areas of Concern. The International Joint Commission has facilitated agreement on listing/delisting guidelines for determining when use impairments exist in areas of concern and when uses have been restored, while federal/state/provincial governments and local stakeholders have provided leadership in establishing quantitative targets for restoring uses and in determining how to achieve them. The listing/delisting guidelines have been instrumental in helping reach agreement on problem definition (lack of agreement on problem definition has historically been used as a reason to delay action) and reaching agreement on quantitative targets for restoring uses.

Correlation of diffusion MRI and heat shock protein in a rat embolic stroke model.

The expression of 70 kDa heat shock protein (HSP-70) in focal ischemia occurs in regions that sustain sub-lethal ischemic injury, and may therefore be considered as a biological marker of the ischemic penumbra. In a rat embolic stroke model, using fibrin-rich emboli, we correlated the expression of HSP-70 mRNA with diffusion magnetic resonance imaging (MRI) to determine if HSP-70 mRNA expression was associated with alterations in the apparent diffusion coefficient (ADC) of brain tissue water, a putative early marker of cytotoxic injury that is readily measured in vivo. Serial ADC measurements were made for 120 min following embolic infarction in the right carotid artery territory.

Spreading depression induces tolerance of cortical neurons to ischemia in rat brain.

Cortical spreading depression (CSD) was induced in male Wistar rats by applying 2 M KCl to the frontal cortex of one hemisphere for 2 h. Saline was applied to the contralateral cortex in the same manner. Following recovery for 24 h, bilateral forebrain ischemia was induced for 6 min, and the animals were permitted to survive for 6 days for assessment of histopathology.