Clinical neuroscience (New York, N.Y.)最新文献

Defects of the peripheral nervous system are common in patients with diabetes mellitus. At least 50% of diabetic patients will develop a form of diabetic neuropathy within 25 years after diagnosis. Currently the cornerstone of treatment lies with the maintenance of euglycaemia using insulin, which has inherent problems of its own. In addition, the signs and symptoms of diabetic neuropathy are often intractable. Therefore, the development of effective treatments for diabetic neuropathy is urgently needed. Thus, animal models have been developed to investigate the pathogenesis of diabetic neuropathy and evaluate potential therapeutic agents. However, no model is perfect and no one would suggest that diabetic rats can replicate the human condition fully. In this review the appropriateness of established animal models of diabetic neuropathy is discussed with reference to the pathology and pathophysiology of the human case with the hope of addresssing some of the questions surrounding this general issue.

Glucose is a main energy source to neurons in brain (with limited storage capability) and retina (where it is stored in glial Müller cells and supplied upon demand). Glucose availability and visual function are related. Human positron emission tomography studies indicate increased blood flow and glucose metabolic rate in primary visual cortex during stimulation, with retinotopic distribution. Retinal electrophysiology covaries with glucose concentration in in vitro models as well as in humans, at comparable concentrations in the physiological range. The interactions between retinal electrophysiology (notably the electroretinogram b-wave) and glucose metabolism appear more stringent than for cortical evoked responses. K-channels regulated by intracellular ATP are thought to link neuron excitability (and electrophysiological activity) on the metabolic state. High-affinity sulphonylurea binding sites for K-channels are widely distributed in brain. K-channels conceivably modulate neurotransmitter release and are inactivated by elevated glucose concentrations and sulfonylurea drugs used to treat diabetes.

Diabetes mellitus affects over 14 million people in the United States and the number of diabetics is increasing by 5% per year. Diabetic neuropathy (DN) is a common complication of diabetes and occurs in approximately 50% of diabetic patients over time. Clinical trials have proven that hyperglycemia almost certainly conditions the development of DN. Despite this fact, we still do not understand the mechanism(s) underlying DN. Several possible etiologies have been proposed including altered metabolism of polyol, lipids, or amino acids, vascular insufficiency, increased superoxide-induced free radical formation, impaired axonal transport or reduced neurotrophism. Accumulating evidence suggests that these defects are likely interrelated and that their interaction(s) within the diabetic milieu are responsible for the development and progression of DN. In this review we will discuss these theories, their interrelationships and how, collectively, these ideas may begin to explain the etiology of DN.

Little is known about the central visual function of patients with normal tension glaucoma (NTG). We estimated the contrast sensitivity of patients with NTG and normal subjects with the use of pattern visually evoked cortical potentials (PVECPs). PVECPs were recorded using checkerboard pattern reversal system display on television monitor of check size 15', 60' and frequency 3 reversals per second and contrast varied in 7 steps. Our results show that a significant delay of the P100 component for 60' check size in the NTG group was found at every contrast level (P < 0.05). Contrast threshold was determined as the value to obtain a criterion peak latency from a regression line calculated within a contrast range from 10% to 56%. The contrast threshold for both check sizes of the NTG group showed an increased threshold (P < 0.05). We conclude that contrast sensitivity decreased in NTG as determined by PVECP. The PVECP was a sensitive test for detecting the functional abnormalities of NTG.

Leber's hereditary optic neuropathy (LHON) is a bilateral subacute optic neuropathy caused by mutations in the mitochondrial genome. Primary mutations are located at nucleotide positions 3460, 11778, and 14484 in genes encoding subunits of Complex 1 of the respiratory chain. Molecular diagnosis has expanded the spectrum of the LHON phenotype and prompted investigation into optic neuropathies due to demyelinating disease, glaucoma, tobacco/alcohol amblyopia, and nutritional optic neuropathy. While mitochondrial mutations are required for LHON disease expression, other genetic or epigentic factors must play a role in disease penetrance and expression. Proposed determinants of disease include heteroplasmy, an X-linked vision loss susceptibility locus, environmental factors, and secondary mitochondrial mutations.

An enormous interest in cell death over the past several years has catapulted apoptosis to the forefront of scientific research. Apoptosis has been found to mediate cell deletion in tissue homeostasis, embryological development and immunologic function. It also occurs in pathological situations including cancer and AIDS, and is implicated in a variety of ocular diseases. This review presents a brief history of apoptosis and the proper evidence needed in order to claim that apoptosis is taking place. A summary and critique of important investigations concerning the genetic and biochemical regulation of apoptosis is presented, as well as a focus on other studies drawing a connection between apoptosis and cell death in physiological and pathological situations.

Brain activation studies using positron emission tomography (PET) to study language have produced a breakthrough in our understanding of the neural basis of language over the past decade. A neural basis for the visual lexicon and for auditory verbal short term memory components have been proposed. Wernicke's and Broca's areas are being recast in terms of localized components of phonological input and output. Some classical regions, such as the arcuate fasciculus, are having their "classical" roles questioned, while other regions, such as the basal temporal language zone, are growing progressively in terms of their recognized importance. Finally, other areas, such as the anterior cingulate and the left inferior prefrontal area, seem to be activated across a range of tasks, but their exact processing roles remain a matter of some debate.

Negative myoclonus (NM) is a motor phenomenon characterized by involuntary jerky movements due to a brief, sudden interruption of muscular activity. This motor disturbance can be observed in a variety of clinical conditions, that can range from physiological NM, occurring when falling asleep or after prolonged exercise, to asterixis, a form of NM observed in patients with toxic-metabolic encephalopathies or with focal brain lesions, or, as a paroxysmal phenomenon, labelled as epileptic negative myoclonus, in epileptic patients. Neurophysiological investigations are essential to diagnose NM and to distinguish it from other motor disorders, such as tremor or positive myoclonus. Furthermore, neurophysiological findings can provide useful information supporting a subcortical or cortical origin of NM. In cortical NM, recent data suggest a role of cortical active inhibitory areas in the generation of this motor phenomenon.

Recent advances in stem cell biology, molecular neurobiology, and gene transfer in combination with our understanding of neurotrophic actions in vivo have provided refined procedures for the gene transfer of bioactive molecules to the mammalian brain with the ability to interfere with neurodegenerative processes or stimulate repair. These new methodologies, when combined with behavioral in vivo studies to assess functional recovery, provide the framework for the development and characterization of gene transfer procedures that might be relevant for the design of future therapies to counteract degeneration in the mammalian brain. In this review we summarize recent evidence demonstrating the usefulness of immortalized neural stem cell lines for long-term and localized gene transfer to the brain, in particular in relation to the cellular and functional effects of gene transfer to trophic factors. Recent experimental evidence demonstrates that localized nerve growth factor supplements to discrete cholinergic nuclei can counteract age-associated cognitive impairments.

Friedreich ataxia is an autosomal recessive ataxia with onset usually before puberty whose characteristic clinical features include progressive ataxia of gait and limbs, dysarthria, loss of joint position and vibratory sense, absent knee and ankle jerks, and Babinski signs. Foot deformity, scoliosis, diabetes mellitus, and cardiac involvement are common and characteristic. Patients survive until about age 30 years although longer survivals occur. A later onset, more slowly progressive form seems to be an allelic variant. The basic process seems to be a dying-back of neuronal processes. Using linkage mapping techniques, the classical form of Friedreich ataxia has been localized to 9q13-q21, a region on the long arm of chromosome 9. Haplotype analysis, analysis of recombinants, and physical mapping techniques, including construction of a YAC contig, have narrowed the interval for the Friedreich ataxia gene, FRDA, to a few hundred thousand base pairs. Candidate genes in the region are being studied by techniques of mutation analysis. It is likely that the Freidreich ataxia gene will be cloned soon. A condition resembling Friedreich ataxia with decreased vitamin E levels has been localized to chromosome 8 and is discussed elsewhere.