ABSTRACT
Genetic insights into the pathophysiology of amyotrophic lateral sclerosis (ALS) are untangling the clinical heterogeneity that may contribute to poor clinical trial outcomes and thus to a ...lack of effective treatments. Mutations in a large number of genes, including SOD1, C9ORF72, TARDBP, FUS, VAPB, VCP, UBQLN2, ALS2, SETX, OPTN, ANG, and SPG11, are thought to cause ALS, whereas others, including ATAXN2, GRN, HFE, NEFH, UNC13A, and VEGF, appear to be disease‐modifying genes. Epigenetic influences may also play important roles. An improved understanding of ALS genetics should lead to better trial designs, insights into common molecular pathways, and better characterization of preclinical models. New genetic sequencing techniques, which use high‐throughput methods to assess variants across the genome or exome, may facilitate rational patient stratification for clinical trials and permit more individualized prognostic information and treatment decisions in clinical care. Muscle Nerve 49: 786–803, 2014
HMG-CoA reductase inhibitors (statins) and H63D HFE polymorphism may modify amyotrophic lateral sclerosis (ALS). We hypothesized that statins worsen phenotype in ALS mice, dependent on HFE genotype.
...Mice harboring SOD1(G93A) heterozygous for H67D Hfe (homologous to human H63D HFE) were administered simvastatin and/or coenzyme Q10, and were allowed to reach end stage. Disease progression was measured by grip strength. A separate group of animals was administered simvastatin and euthanized at the symptomatic 120-day time-point. Mitochondria from gastrocnemius muscle and lumbar spine were analyzed.
Simvastatin and H67D Hfe accelerated disease progression. Simvastatin decreased survival. Coenzyme Q10 did not rescue statin-induced effects. Statins did not alter mitochondrial protein levels.
Statins and Hfe genotype alter disease course in the ALS mouse model. Because the H63D HFE polymorphism is present in 30% of patients with ALS, studying disease progression in patients who receive statins, stratified for HFE genotype, may guide therapy. Muscle Nerve, 2016 Muscle Nerve 54: 284-291, 2016.
Improvements in peri‐ and postoperative surgical techniques have greatly improved outcomes for pediatric patients undergoing cardiopulmonary bypass (CPB) in the treatment of congenital heart defects ...(CHDs). With decreased mortality rates, the incidence of adverse neurological outcomes, comprising cognitive and speech impairments, motor deficits, and behavioral abnormalities, has increased in those patients surviving bypass. A number of mechanisms, including ischemia, reperfusion injury, hypothermia, inflammation, and hemodilution, contribute to brain insult, which is further confounded by unique challenges presented in the pediatric population. However, a number of brain monitoring and preventative techniques have been developed or are being currently evaluated in the practice of pediatric CPB. Monitoring techniques include electroencephalography, near‐infrared as well as visible light spectroscopy, transcranial Doppler ultrasound, and emboli detection and classification quantitation. Preventative measures include hypothermic perfusion techniques such as deep hypothermic circulatory arrest, low‐flow CPB, blood gas management, and pharmacologic prophylaxes, among others. The present review summarizes the principles of brain insult, neurodevelopmental abnormalities, monitoring techniques, methods of prevention, as well as preexisting morbidities and risk factors in pediatric CPB, with a focus on brain protection. Clinical and translational research is presented with the aim of determining methods that may optimize neurological outcomes post CPB and guiding further study.
Brain monitoring techniques near-infrared spectroscopy (NIRS) and transcranial Doppler (TCD) ultrasound were used in pediatric patients undergoing cardiopulmonary bypass for congenital heart defect ...(CHD) repair to analyze the effect of pulsatile or nonpulsatile flow on brain protection. Regional cerebral oxygen saturation (rSO2) and cerebrovascular pulsatility index (PI) were measured by NIRS and TCD, respectively, in 111 pediatric patients undergoing bypass for CHD repair randomized to pulsatile (n = 77) or nonpulsatile (n = 34) perfusion. No significant differences in demographic and intraoperative data, including surgical risk stratification, existed between groups. Patients undergoing pulsatile perfusion had numerically lower decreases in rSO2 from baseline for all time points analyzed compared with the nonpulsatile group, with significant ∼12% lower decreases at 40 and 60 min after crossclamp. Patients undergoing pulsatile perfusion had numerically lower decreases in PI from baseline for the majority of time points compared with the nonpulsatile group, with significant ∼30% lower decreases between 5 and 40 min after crossclamp. Pulsatile flow has advantages over nonpulsatile flow as measured by NIRS and TCD, especially at advanced time points, which may improve postoperative neurodevelopmental outcomes.
ABSTRACT
Introduction
HMG‐CoA reductase inhibitors (statins) and H63D HFE polymorphism may modify amyotrophic lateral sclerosis (ALS). We hypothesized that statins worsen phenotype in ALS mice, ...dependent on HFE genotype. Methods: Mice harboring SOD1G93A heterozygous for H67D Hfe (homologous to human H63D HFE) were administered simvastatin and/or coenzyme Q10, and were allowed to reach end stage. Disease progression was measured by grip strength. A separate group of animals was administered simvastatin and euthanized at the symptomatic 120‐day time‐point. Mitochondria from gastrocnemius muscle and lumbar spine were analyzed. Results: Simvastatin and H67D Hfe accelerated disease progression. Simvastatin decreased survival. Coenzyme Q10 did not rescue statin‐induced effects. Statins did not alter mitochondrial protein levels. Conclusions: Statins and Hfe genotype alter disease course in the ALS mouse model. Because the H63D HFE polymorphism is present in 30% of patients with ALS, studying disease progression in patients who receive statins, stratified for HFE genotype, may guide therapy. Muscle Nerve, 2016 Muscle Nerve 54: 284–291, 2016
Abstract
Our objective was to measure serum ferritin levels, which reflect iron metabolism, in ALS patients versus healthy and disease controls, and determine whether serum ferritin levels correlate ...with survival. We retrospectively analyzed data from 138 ALS patients, 152 healthy controls, and 82 disease controls. Gender, age, site of onset, and dates of symptom onset and death were recorded. Survival was defined as the time from symptom onset to death. Serum ferritin levels were measured using immunoassay. ANOVA and Pearson's correlation were used to compare ferritin levels between groups and test the association between ferritin levels and age and survival. Ferritin levels were categorized into high and low groups, and Kaplan-Meier analysis performed. Results showed that gender proportions differed between ALS patients versus healthy and disease controls, and gender affected serum ferritin levels. Ferritin comparisons were stratified for gender. In both males and females, ferritin levels were higher in ALS patients versus healthy and disease controls. However, ferritin levels were unrelated to survival in either gender, by tests of association or survival analysis. In conclusion, ALS patients have altered iron metabolism that is not simply due to the presence of neurological disease. Serum ferritin levels alone are not sufficient to predict survival.
ABSTRACT
Introduction
H63D HFE polymorphisms increase the risk of neurodegenerative disorders and, specifically, may increase amyotrophic lateral sclerosis (ALS) risk. Investigating the physiological ...alterations induced by H63D polymorphisms in ALS patients may elucidate mechanisms by which this genotype alters disease.
Methods
Clinical measures and muscle biopsies were available from patients previously diagnosed with ALS who underwent HFE genotyping. Clinical outcomes and SOD1 protein expression were analyzed using standard statistical analyses.
Results
ALS patients harboring H63D HFE (n = 16) had 28.1 months longer average disease duration and 39.3% lower muscle SOD1 protein than ALS patients with wild‐type HFE (n = 22).
Conclusions
Combined with previous reports suggesting the H63D polymorphism is associated with ALS, these results support a model wherein the H63D polymorphism is involved in ALS by means of pathways involving SOD1 but may limit cellular damage in individuals who develop disease. The association between HFE genotype and disease duration has important implications for clinical care and treatment trials. Muscle Nerve, 48: 242–246, 2013
Degradation of the vascular basement membrane stimulates angiogenesis and is tightly controlled by balancing the actions of metalloproteases and their inhibitors. Previous work demonstrated that ...electroconvulsive seizure (ECS) elevates angiogenic factors and endothelial proliferation in the hippocampus. The robust induction of tissue inhibitor of matrix metalloprotease 1 (TIMP-1) in the stratum lacunosum moleculare (SLM) corresponds to sites of increased vascular density. This led us to examine the spatial and cellular expression of TIMP-1 and its substrate, matrix metalloprotease 9 (MMP-9). Chronic ECS increased TIMP-1 by 12-fold and MMP-9 by 3-fold in discrete SLM cells. We then characterized the expression of TIMP-1 mRNA in relation to vasculature in the SLM and glial-limiting membrane (GLM). Employing laser microdissection we identified the cell types associated with SLM vasculature and also phenotyped the cells expressing TIMP-1 and MMP-9. We concluded that TIMP-1 is produced by perivascular cells positive for alpha smooth actin and that MMP-9 is expressed by GFAP-positive astrocytes. These studies suggest that ECS-induced remodelling occurs at the vascular basement membrane and facilitates neovascularization.
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