Degenerative Disease Of Central Nervous System Research Articles

The Discovery of Endothelium-Derived Relaxing Factor and Its Importance in the Identification of Nitric Oxide

The discovery of endothelium-derived relaxing factor (EDRF) and its importance in the identification of nitric oxide (NO) originated with studies using rabbit aorta to examine drug-receptor interactions in vascular smooth muscle. Smooth muscle relaxation by acetylcholine and a number of other agonists was found to be dependent on the presence of endothelial cells, which, when stimulated by the agonist, released a diffusable, very labile, nonprostanoid substance, termed EDRF, that acted on vascular smooth muscle cells to activate relaxation. The characteristics of EDRF, when released from endothelial cells, were similar to the characteristics of NO. It is now established that EDRF, either as NO or some related nitrosyl substance, has a major role in a variety of important biological processes, including the regulation of vascular tone, local blood flow, and blood pressure, inhibition of platelet aggregation and adhesion, and involvement in postischemic reperfusion, memory function, and central nervous system degenerative diseases.

The 1996 Albert Lasker Medical Research Awards. The discovery of endothelium-derived relaxing factor and its importance in the identification of nitric oxide

The discovery of endothelium-derived relaxing factor (EDRF) and its importance in the identification of nitric oxide (NO) originated with studies using rabbit aorta to examine drug-receptor interactions in vascular smooth muscle. Smooth muscle relaxation by acetylcholine and a number of other agonists was found to be dependent on the presence of endothelial cells, which, when stimulated by the agonist, released a diffusable, very labile, nonprostanoid substance, termed EDRF, that acted on vascular smooth muscle cells to activate relaxation. The characteristics of EDRF, when released from endothelial cells, were similar to the characteristics of NO. It is now established that EDRF, either as NO or some related nitrosyl substance, has a major role in a variety of important biological processes, including the regulation of vascular tone, local blood flow, and blood pressure, inhibition of platelet aggregation and adhesion, and involvement in postischemic reperfusion, memory function, and central nervous system degenerative diseases.

Neurological disorder and excessive accumulation of calcium in brain of clinically vitamin A-deficient rats.

Three groups of rats were fed two types of synthetic diets for 52 d. The -A group was allowed free access to a vitamin A-deficient diet and showed classical signs of vitamin A deficiency. The brain was the only organ in our experiment where no significant weight difference was present among the three groups. In the brain, calcium concentration was significantly higher in the -A group when compared with the PF (Pair-fed; allowed restricted amount of control diet) and +A groups (allowed free access to control diet). In the tibia, calcium and magnesium concentrations were significantly lower in the -A group when compared with other two groups. Excessive accumulation of calcium in brain and apparently similar unbalance in bone mineral concentration were observed in central nervous system (CNS) degenerative diseases. Our results suggest that abnormal metabolism of calcium and magnesium in some tissues and excessive accumulation of calcium in brain may be responsible for the development of neurological disorders in vitamin A-deficient rats.

Divalproex sodium: migraine treatment and monitoring.

Divalproex sodium is an effective drug for the treatment of migraine. Most adverse drug events are transient and not of great clinical concern. Although rare, well-documented examples of liver toxicity have been reported in children under 2 years of age on polypharmacy. Additional cases occur in children under 10 who are receiving polypharmacy, particularly those who have intractable seizures and degenerative central nervous system disease. Clinicians who treat migraineurs with divalproex sodium do not need to be overly preoccupied with monitoring of drug levels and liver function tests. The most valuable test is clinical observation of the patient.

Capillary zone electrophoretic determination of 5-hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid from patients with neuropsychiatric disorders.

Capillary zone electrophoresis (CZE) was applied to the separation and determination of two major monoamine metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF) from patients with neuropsychiatric disorders. Ethyl acetate extracts of acidified CSF were analyzed by CZE with ultraviolet absorbance detection (UVD). The peaks of 5-HIAA and HVA were clearly detected on the electropherograms, and their levels in the CSF samples were determined on the basis of the peak-area ratios relative to p-methoxybenzoate spiked as an internal standard. The results showed that the CSF levels of 5-HIAA and HVA reduced in patients with some diseases, such as Parkinson's disease, Altzheimer's disease, depressive illness, etc., supporting the conclusions obtained earlier by high-performance liquid chromatography (HPLC). The present CZE-UVD system, which consumes only a far smaller amout of sample solutions to be injected than that required in HPLC-UVD, seems to be useful as an aid in the biochemical diagnosis of neuropsychiatric disorders, especially in distinguishing dementia associated with central nervous system-degenerative diseases (both of the 5-HIAA and HVA levels in CSF are reduced) from that with cerebrovascular diseases (neither the CSF 5-HIAA nor HVA levels are changed).

Consultation with the Specialist

Many general pediatricians feel that the assessment of an infant or child who has a developmental delay and possible neurologic impairment is one of their most difficult challenges. Frequently the parents or relatives, during the course of a well-child visit, first voice concerns about the failure to attain or master one or more expected developmental milestones. Other times the pediatrician is the first to note a problem with development in one or more areas. One of the most important tasks for the pediatrician is to be able to identify the subset of patients who may have a progressive rather than a static neurologic process and to refer them promptly for further evaluation of a possible neurodegenerative disorder. In the past, the diagnosis of a childhood neurodegenerative disease was associated with a sense of hopelessness; frequently, the need for a definitive diagnosis was questioned. Breakthroughs in our understanding of the genetic and biochemical basis of many of these disorders, together with advances in enzyme replacement and gene therapy, have made antenatal diagnosis, treatments, and even cures a reality. The numerous types of central nervous system (CNS) degenerative diseases encountered in children go beyond the scope of a few pages and are covered well in the standard texts (see the excellent chapter by Johnson and Rapin in Rudolph's Pediatrics, 19th ed, 1991).

Consultation withthe Specialist

Many general pediatricians feel that the assessment of an infant or child who has a developmental delay and possible neurologic impairment is one of their most difficult challenges. Frequently the parents or relatives, during the course of a well-child visit, first voice concerns about the failure to attain or master one or more expected developmental milestones. Other times the pediatrician is the first to note a problem with development in one or more areas. One of the most important tasks for the pediatrician is to be able to identify the subset of patients who may have a progressive rather than a static neurologic process and to refer them promptly for further evaluation of a possible neurodegenerative disorder. In the past, the diagnosis of a childhood neurodegenerative disease was associated with a sense of hopelessness; frequently, the need for a definitive diagnosis was questioned. Breakthroughs in our understanding of the genetic and biochemical basis of many of these disorders, together with advances in enzyme replacement and gene therapy, have made antenatal diagnosis, treatments, and even cures a reality. The numerous types of central nervous system (CNS) degenerative diseases encountered in children go beyond the scope of a few pages and are covered well in the standard texts (see the excellent chapter by Johnson and Rapin in Rudolph9s Pediatrics, 19th ed, 1991).

A competitive dual-label time-resolved immunofluorometric assay for simultaneous detection of carbonic anhydrase I and II in cerebrospinal fluid

Carbonic anhydrase (CA) is functionally an important enzyme in the central nervous system (CNS) where it is involved in the control of acid-base balance and regulation of the production of cerebrospinal fluid (CSF). Isoenzyme II (CAII) is the most widely distributed CA in the CNS being specifically present in CNS glial tissue and therefore it is expected to be leaked to CSF in degenerative CNS diseases. A competitive dual-labeled time-resolved immunofluorometric assay was developed for simultaneous quantification of human CAI (HCA I) and II (HCA II) in CSF. HCA I was measured to determine the blood contamination in the samples. This solid-phase immunoassay is based on competition between europium (Eu 3+)- or samarium (Sm 3+)-labeled antigen and the sample antigens for polyclonal rabbit antibodies which are attached to microtiter-plate wells precoated with sheep anti-rabbit IgG. The subsequent immunoassay, including the separation of free and bound HCA I and II, requires only one incubation step, after which an enhancement solution dissociates Sm 3+ and Eu 3+ ions from the labeled HCA I and II, respectively, into a solution where they form highly fluorescent chelates. Spectra of the fluorescent chelates in the microtitration strip wells were run on time-resolved fluorometers equipped with filters for Eu 3+ (613 nm) and Sm 3+ (643 nm), the fluorescence from each sample being inversely proportional to the concentration of antigens. The detection limit of the HCA II assay was 0.3 μg/l and that of the HCA I assay was 5.2 μg/l. The intra- and inter-assay imprecisions (C.V.s) were 8.0% for HCA I and 6.3% and 4.8% for HCA II, respectively. The analytical recovery ranged from 96 to 110% for HCA I and from 95 to 108% for HCA II. The concentration of HCA II derived from brain tissue present in the CSF of hydrocephalic children varied between 1.0 and 35.9 μg/1 ( n = 25).

Kohlschütter‐Tönz syndrome: Epilepsy, dementia, and amelogenesis imperfecta

Kohlschütter-Tönz syndrome is a central nervous system (CNS) degenerative disease with convulsions and mental regression in which the affected children present with yellow teeth due to defective enamel. We present a family in which 2 affected children (a boy and a girl) were born to consanguineous parents. This report confirms the autosomal recessive inheritance of the disorder. The combination of a CNS and an enamel defect may represent pleiotropy or a contiguous gene syndrome.

Familial aggregation of multiple myeloma and central nervous system diseases.

Degenerative central nervous system diseases such as Alzheimer's disease and lymphoreticular malignancies such as multiple myeloma occur with increased frequency with advancing age. Relatives of early-onset Alzheimer's disease patients may have an increased risk of lymphoreticular malignancies. This led us to evaluate the family history of central nervous system diseases in a case-control study of multiple myeloma. Thirteen of 439 multiple myeloma cases had one or more first-degree relatives with degenerative or demyelinating central nervous system disease. In comparison, there were nine "positive" family histories in 1,317 matched hospital controls (relative risk = 4.4, 95% confidence interval = 1.9-10.3). Relative risks for the component categories of Parkinson's disease, multiple sclerosis, and miscellaneous degenerative central nervous system diseases were 3.0, 4.0 and 11.9, respectively. Our findings suggest that the degenerative and demyelinating central nervous system diseases and the lymphoreticular malignancies may comprise an etiologically related group of "protean diseases." These diseases may have a shared genetic susceptibility, possibly an immunologic abnormality. The varied disease manifestation in family members suggests a second necessary etiologic step of a variable and possibly environmental nature.

Percutaneous gastrostomy and percutaneous gastrojejunostomy in children: antegrade approach.

Twenty-five percutaneous gastrostomies and nine percutaneous gastrojejunostomies were performed in 24 children aged 4 months to 22 years. Indications for percutaneous gastrostomy included severe injury to the central nervous system (nine patients), malignancy (seven patients), failure to thrive (four patients), degenerative central nervous system disease (one patient), and miscellaneous conditions (three patients). All procedures were performed under local anesthesia and sedation. An antegrade approach is described for percutaneous gastrostomy and percutaneous gastrojejunostomy placement. No major complication occurred, and only three skin infections have been encountered. The children were evaluated and followed up by a nutritional support team. Early experience with percutaneous gastrostomy and percutaneous gastrojejunostomy in the pediatric population suggests that the technique is safe and applicable to children of all ages and sizes. In particular, the antegrade approach appears to be an acceptable solution for enteric alimentation.

Treatment of subacute sclerosing panencephalitis: an overview.

Subacute sclerosing panencephalitis (SSPE) is a rare central nervous system degenerative disease that occurs primarily in children and adolescents. It is believed to be caused by a measles-like virus. Initial symptoms usually present as a variety of personality changes followed by myoclonus with progression of mental and motor deterioration, which leads to death within a few months to years. New experimental treatment with inosiplex has been shown to be helpful for patients stricken with this progressive neurological disease. A response to inosiplex therapy is best in patients with a slowly progressing form of the disease. Inosiplex treatment is safe with few adverse effects. The duration of treatment appears to be lifelong since many patients relapse when inosiplex therapy is discontinued. This article reviews the etiology, pathogenesis, and experimental treatment of SSPE.

The influence of inosiplex treatment on the neurological disability of patients with subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis is a central nervous system degenerative disease that rapidly progresses to death in most untreated cases. In this study we compare the level of neurological disability longitudinally in a group of SSPE patients receiving inosiplex (Isoprinosine) treatment (12) to a historical control group of untreated patients (15). The mean ND did not differ between the groups from onset of SSPE through 21 months. From two years through four and one-half years the inosiplex group had significantly lower ND compared to the nontreatment group. The subjects were then divided into four subgroups: Group 1, rapidly progressing SSPE, not treated; Group 2, slowly progressing SSPE, not treated; Group 3, rapidly progressing SSPE, inosiplex treated; and Group 4 slowly progressing SSPE, inosiplex treated. The rapidly developing groups did not differ in ND at any time. The slowly developing treated group had significantly lower ND than the slowly developing untreated group from two and one-half years to four and one-half years after onset of SSPE. These findings suggest that inosiplex is effective in the slowly developing or chronic form of SSPE.

Demonstration of cerebrospinal fluid oligoclonal banding in neurologic diseases by agarose gel electrophoresis and immunofixation.

Demonstration of an oligoclonal immunoglobulin pattern in cerebrospinal fluid by a commercial agarose gel electrophoresis system and immunofixation were evaluated in the service clinical laboratory of a university hospital. In 303 patients, 45 with clinically definite multiple sclerosis and 209 with other neurologic diseases, the sensitivity of oligoclonal banding for multiple sclerosis was 71%, and the specificity, 83%. Oligoclonal banding was frequent in inflammatory disease, tumor/pseudotumor or vascular diseases of the central nervous system (35%, 36% and 26%, respectively) and less frequent in degenerative central nervous system disease and peripheral neuropathy (5.2% and 15%). No patient with non-neurologic disease had oligoclonal banding. The addition of an immunochemical step (immunofixation) did not increase sensitivity and only minimally increased specificity. It did permit distinction in selected cases between immunoglobulin and other molecules with identical electrophoretic mobility.

Transplantation of the adult kidney into the very small child: Long-term outcome

Adult kidneys were transplanted into 12 children weighing between 5,400 and 8,800 gm. Ten received parental and two received cadaver grafts. Ten of the 12 children are alive 18 months to 9 years post transplant; eight have their original grafts and two required retransplantation-their original grafts were lost at 4 and 9 years because of chronic rejection. All but these two surviving children had normal or accelerated growth rates despite growth retardation prior to transplant. All children evidenced moderate to severe delay in psychomotor development prior to transplant. Seven of the ten survivors now have normal psychomotor function. Two are behind in school, and one with a degenerative central nervous system disease prior to transplant remains profoundly retarded. We conclude that because of donor availability, capacity for good donor-recipient matching, and minimization of time on dialysis, transplantation of adult kidneys into pediatric patients is preferable to awaiting the relatively uncommon pediatric cadaver donor. We further conclude that the procedure is warranted.

Progressive encephalopathy due to chronic hydantoin intoxication.

Ten patients receiving long-term hydantoin therapy had progressive neurological deterioration indistinguishable from a degenerative central nervous system disease. The deterioration abated in all cases and in six of the patients, restoration to pretherapy status subsequently occurred after discontinuation of the therapy. The patients exhibited not only the cerebellar signs of nystagmus and ataxia characteristic of hydantoin intoxication, but also variable manifestations of more diffuse encephalopathy, including impaired intellectual performance, bizarre behavior, increased seizure frequency, impaired speech, and electroencephalographic changes. This series extends the spectrum of hydantoin neurotoxicity to include neurologic and mental deterioration over many years and underscores the irreversibility and severe disability that may characterize this easily overlooked and entirely preventable disorder of therapy.

Some Inherited Disorders of Brain and Muscle: Proceedings of the Fifth Symposium of the Society for the Study of Inborn Errors of Metabolism.

This book is the result of the Proceedings of the Fifth Symposium of the Society for the Study of Inborn Errors of Metabolism held at Newcastle upon Tyne, England in 1967. The book consists of 14 papers on the genetics, biochemistry, and pathology of muscle diseases and central nervous system degenerative diseases. In general, the emphasis is on the review of recent developments in these fields, rather than the authors' presentation of their original material. The overall level of the symposium is very good. The chapters by D. N. Raine and H. Jatzkewitz on recent advances in the biochemistry of the sphingolipidoses are outstanding. Their discussion of the nomenclature and classification of the ganglioside diseases (Tay-Sachs) in terms of their biochemical abnormalities is very useful. Diagrams and explanations showing the biochemical interrelationships of such entities as the amaurotic idiocies, Krabbe's globoid leukodystrophy, metachromatic leukodystrophy, Fabry's disease, and Gaucher's disease

Progress in the Treatment of Parkinson’s Disease

Parkinson’s disease is a common central nervous system degenerative disease,its pathogenesis has not yet been clear.There are many difficulties in its treatment.At present the most effective way is to use levodopa replacement therapy,but still can not effectively prevent or slow the disease development.Therefore,inhibitors of monoamine oxidase B,dopamine receptor agonists and other drugs for adjuvant treatment also can be used in the clinical practice.In the middle and advanced stage,the appropriate surgery can be taken.Stem cell transplantation and gene therapy has broad prospects.