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Jeffrey Rosenfeld

Publications and source records attributed to Jeffrey Rosenfeld.

12 recordsLinked to original sources
PubMed2006

Species- and tissue-specific relationships between mitochondrial permeability transition and generation of ROS in brain and liver mitochondria of rats and mice.

In animal models of neurodegenerative diseases pathological changes vary with the type of organ and species of the animals. We studied differences in the mitochondrial permeability transition (mPT) and reactive oxygen species (ROS) generation in the liver (LM) and brain (BM) of Sprague-Dawley rats and C57Bl mice. In the presence of ADP mouse LM and rat LM required three times less Ca(2+) to initiate mPT than the corresponding BM. Mouse LM and BM sequestered 70% and 50% more Ca(2+) phosphate than the rat LM and BM. MBM generated 50% more ROS with glutamate than the RBM, but not with succinate. With the NAD substrates, generation of ROS do not depend on the energy state of the BM. Organization of the respiratory complexes into the respirasome is a possible mechanism to prevent ROS generation in the BM. With BM oxidizing succinate, 80% of ROS generation was energy dependent. Induction of mPT does not affect ROS generation with NAD substrates and inhibit with succinate as a substrate. The relative insensitivity of the liver to systemic insults is associated with its high regenerative capacity. Neuronal cells with low regenerative capacity and a long life span protect themselves by minimizing ROS generation and by the ability to withstand very large Ca(2+) insults. We suggest that additional factors, such as oxidative stress, are required to initiate neurodegeneration. Thus the observed differences in the Ca(2+)-induced mPT and ROS generation may underlie both the organ-specific and species-specific variability in the animal models of neurodegenerative diseases.

Animals↗
PubMed2006

Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology.

For the majority of Duchenne muscular dystrophy (DMD) mutations, antisense oligonucleotide (AON)-mediated exon skipping has the potential to restore a functional protein. Here we show that weekly intravenous injections of morpholino phosphorodiamidate (morpholino) AONs induce expression of functional levels of dystrophin in body-wide skeletal muscles of the dystrophic mdx mouse, with resulting improvement in muscle function. Although the level of dystrophin expression achieved varies considerably between muscles, antisense therapy may provide a realistic hope for the treatment of a majority of individuals with DMD.

Animals↗
PubMed2006

Cervical spine clearance in unconscious traumatic brain injury patients: dynamic flexion-extension fluoroscopy versus computed tomography with three-dimensional reconstruction.

BACKGROUND: An optimal protocol for clearing the cervical spine in unconscious patients with traumatic brain injury remains controversial. Protocols include plain radiographs and computed tomography (CT), and ligamentous injury may be identified with flexion-extension radiographs. We questioned whether cervical CT with three-dimensional (3D) reconstructions may obviate the need for flexion-extension radiology in the detection of occult ligamentous injury. METHODS: Between July 1999 and November 2001, 276 unconscious traumatic brain injured patients admitted to The Alfred Hospital received cervical spine plain radiographs, CT with 3D reconstructions, and dynamic flexion-extension X-ray studies with fluoroscopy as part of a routine protocol. These patients were identified from a prospective intensive care unit database and all radiology reports were reviewed. RESULTS: Dynamic flexion-extension X-ray studies with fluoroscopy identified no new fractures or instability; there were no instances of true-positive results. Dynamic flexion-extension was true-negative in 260 of 276 (94%) patients, falsely positive in six patients (2.2%) and falsely negative in one (0.4%) patient. In nine patients, dynamic flexion-extension was inadequate. CONCLUSION: Dynamic flexion-extension X-ray studies with fluoroscopy delayed cervical spine clearance and were almost always reported as normal. In a cervical spine clearance protocol for unconscious traumatic brain injury patients, dynamic flexion-extension X-ray studies with fluoroscopy did not identify any patients with cervical fracture or instability not already identified by plain radiographs and fine-cut CT (C0 to T2) with 3D reconstructions.

Algorithms↗
PubMed2005

Sertoli cells improve survival of motor neurons in SOD1 transgenic mice, a model of amyotrophic lateral sclerosis.

Cell replacement therapy has been widely suggested as a treatment for multiple diseases including motor neuron disease. A variety of donor cells have been tested for treatment including isolated preparations from bone marrow and embryonic spinal cord. Another cell source, Sertoli cells, have been successfully used in models of diabetes, Parkinson's disease and Huntington's disease. The ability of these cells to secrete cytoprotective proteins and their role as 'nurse cells' supporting the function of other cell types in the testes suggest their potential use as neuroprotective cells. The current study examines the ability of Sertoli cells injected into the parenchyma of the spinal cord to protect motor neurons in a mouse model for amyotrophic lateral sclerosis. Seventy transgenic mice expressing the mutant (G93A) human Cu-Zn superoxide dismutase (SOD1) received a unilateral spinal injection of Sertoli-enriched testicular cells into the L4-L5 ventral horn (1 x 10(5) cells total) prior to the onset of clinical symptoms. The animals were euthanized at the end stage of the disease. Histological and morphometric analyses of the transplant site were performed. A significant increase in the number of surviving ChAT positive motor neurons was found ipsilateral to the injection compared with contralateral and uninjected spinal cord. The ipsilateral increase in motor neuron density was dependent upon proximity to the injection site. Sections rostral or caudal to the injection site did not display a similar difference in motor neuron density. Implantation of a Sertoli-cell-enriched preparation has a significant neuroprotective benefit to vulnerable motor neurons in the SOD1 transgenic model. The therapeutic benefit may be the result of secreted neurotrophic factors present at a critical stage of motor neuron degeneration in this model.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Functional plasticity or vulnerability after early brain injury?

CONTEXT: Traumatic brain injury (TBI) is a common, acquired, childhood disability that may be used as a model to understand more completely the impact of early brain injury on both brain structure and day-to-day function. Contrary to previously held views of the "plasticity" of the young brain, recent research suggests that such early insults may have a profound impact on development. To date, these suggestions remain largely untested. OBJECTIVES: To plot changes in cognitive abilities after childhood TBI over the 30 months after injury and to examine the impact of age at injury on cognitive outcomes. DESIGN: Prospective longitudinal study. SETTING: Royal Children's Hospital, Victoria, Australia. MAIN OUTCOME MEASURES: Global intellectual ability, verbal and nonverbal skills, attention, and processing speed. PARTICIPANTS: A total of 122 children admitted to the hospital with a diagnosis of TBI were divided according to injury age, ie, young (age: 3-7 years) or old (age: 8-12 years), and injury severity (mild, moderate, or severe) and were evaluated acutely and at 12 and 30 months after injury. An additional sample of children injured before 3 years of age (n = 27) was compared with these groups with respect to global intellectual ability only. RESULTS: A clear relationship was documented between injury severity and cognitive performance. For children who sustained severe injury, younger age at injury was associated with minimal, if any, recovery after injury, but better outcomes were observed after severe TBI among older children. Age at injury was not predictive of outcomes for children with mild or moderate TBI, although infants (age: 0-2.11 years) with moderate TBI showed poorer outcomes than did older children with injury of similar severity. CONCLUSIONS: Findings support a "double-hazard" model for severe and early brain insults and add to the ongoing debate regarding cerebral plasticity, suggesting that, contrary to traditional views, young children who sustain severe TBI in early childhood or moderate or severe TBI in infancy may be particularly vulnerable to significant residual cognitive impairment. From a clinical perspective, results indicate that long-term follow-up monitoring and management should be targeted to this high-risk group.

Brain Injuries↗
PubMed2004

The Neurophysiological Index in ALS.

The Neurophysiological Index (NI) consists of a mathematical derivation of three standardised neurophysiological measurements. Since these measurements are part of routine practice in any clinical neurophysiology laboratory, calculation of the NI is within the capability of any laboratory. The NI is derived from the CMAP, the DML and the F-wave frequency (CMAP amplitude/DML) x F frequency %), representing aspects of the effects of denervation and reinnervation, of degeneration of the terminal part of the motor axons, and of the excitability of anterior horn cells. We have shown that this simple index is reproducible in consecutive studies of normal subjects and of patients with ALS (intra-rater reliability), and is sensitive to change. In ALS, the NI differentiates rapidly and slowly progressive disease at least as sensitively as other measures in common use, including the ALS-FRS. We propose that the NI could be used as a sensitive measure of change during the course of ALS and its treatment. In combination with relevant measures of clinical benefit, such as ALS-FRS and a QoL measure, this could simplify trial design and allow more rapid determination of the efficacy of putative new therapies in clinical trials.

Amyotrophic Lateral Sclerosis↗
PubMed2004

The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disorders.

Creatine is consumed in the diet and endogenously synthesised in the body. Over the past decade, the ergogenic benefits of synthetic creatine monohydrate have made it a popular dietary supplement, particularly among athletes. The anabolic properties of creatine also offer hope for the treatment of diseases characterised by weakness and muscle atrophy. Moreover, because of its cellular mechanisms of action, creatine offers potential benefits for diseases involving mitochondrial dysfunction. Recent data also support the hypothesis that creatine may have a neuroprotective effect. Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of motor neurons, resulting in weakening and atrophy of skeletal muscles. In patients with this condition, creatine offers potential benefits in terms of facilitating residual muscle contractility as well as improving neuronal function. It may also help stabilise mitochondrial dysfunction, which plays a key role in the pathogenesis of ALS. Indeed, the likely multifactorial aetiology of ALS means the combined pharmacodynamic properties of creatine offer promise for the treatment of this condition. Evidence from available animal models of ALS supports the utility of treatment with creatine in this setting. Limited data available in other neuromuscular and neurodegenerative diseases further support the potential benefit of creatine monohydrate in ALS. However, few randomised, controlled trials have been conducted. To date, two clinical trials of creatine monohydrate in ALS have been completed without demonstration of significant improvements in overall survival or a composite measure of muscle strength. These trials have also posed unanswered questions about the optimal dosage of creatine and its beneficial effects on muscle fatigue, a measure distinct from muscle strength. A large, multicentre, clinical trial is currently underway to further investigate the efficacy of creatine monohydrate in ALS and address these unresolved issues. Evidence to date shows that creatine supplementation has a good safety profile and is well tolerated by ALS patients. The purpose of this article is to provide a short, balanced review of the literature concerning creatine monohydrate in the treatment of ALS and related neurodegenerative diseases. The pharmacokinetics and rationale for the use of creatine are described along with available evidence from animal models and clinical trials for ALS and related neurodegenerative or neuromuscular diseases.

Amyotrophic Lateral Sclerosis↗
PubMed2003

Amyotrophic lateral sclerosis: a review of current concepts.

Amyotrophic lateral sclerosis (ALS), once thought to be a rare neurodegenerative disease, affects between 1.2 and 1.8/100,000 individuals. This age-dependent disorder, similar to other major neurological disorders of the aging population (Alzheimer's and Parkinson's disease) is increasing in incidence at a rate which cannot be accounted for by population aging alone. Multiple clinical variants of ALS are now recognized which are associated with a spectrum of clinical outcomes from aggressive to rather indolent. Three variants of ALS are generally accepted, including the western Pacific type (often associated with dementia), familial (the majority of which are autosomal dominant in their inheritance) and classic sporadic ALS. Considerable biological heterogeneity underlies the disease process of ALS. By the time ALS is clinically evident, derangements at the cellular level in ALS are extensive and include alterations in the cytoskeleton, mitochondrial function, microglial activation, and the metabolism of reactive oxygenating species and glutamate. Our understanding of the genetic aspects of the disease continues to expand. These observations have led to the suggestion that multiple distinct etiologies may be responsible. Recent advances have also included the observation that cognitive decline may be present in a population of patients not previously recognised. Significant advances in both symptomatic and adjunctive therapy have resulted in prolonged quality and duration of life.

Age Factors↗
PubMed2002

Nutritional issues and supplements in amyotrophic lateral sclerosis and other neurodegenerative disorders.

PURPOSE OF REVIEW: Aggressive nutritional intervention has become a cornerstone of treatment for many patients with neuromuscular diseases, in particular, motor neuron disease. Malnutrition is a common problem among patients with amyotrophic lateral sclerosis. Over the past decade, the recognition of nutrition as an independent, prognostic factor for survival and disease complications in amyotrophic lateral sclerosis has illustrated the importance of individualized nutritional management in symptomatic treatment. Paramount issues for nutritional management in amyotrophic lateral sclerosis include caloric supplementation, the diagnosis/treatment of dysphagia, and the timing/safety/efficacy of percutaneous endoscopic gastrostomy placement. RECENT FINDINGS: In addition, many amyotrophic lateral sclerosis patients self-medicate with a variety of vitamins, herbs, and other dietary supplements. Outcome-based research for the use of nutraceuticals and functional foods in the treatment and prevention of amyotrophic lateral sclerosis and other neuromuscular diseases is in its early stages. In the past year, however, several interesting papers have been published that lend support to the use of dietary supplements as primary treatments for amyotrophic lateral sclerosis and other motor neuron disorders. SUMMARY: Common or overlapping etiologies in disparate neurodegenerative diseases have led to the promise that optimal nutritional care and the appropriate use of dietary supplements in amyotrophic lateral sclerosis will have implications for the nutritional management of other degenerative conditions such as Parkinson's, Alzheimer's, and Huntington's disease. Furthermore, evidence supporting the efficacy of dietary supplements in amyotrophic lateral sclerosis may lend clues to the treatment of other neuromuscular disorders such as the muscular dystrophies.

Amyotrophic Lateral Sclerosis↗