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Biomedical subjects

J D England

Publications and source records attributed to J D England.

At least 37 records · Page 2Linked to original sources
PubMed1998

Genetic galactocerebrosidase deficiency (globoid cell leukodystrophy, Krabbe disease) in rhesus monkeys (Macaca mulatta).

Globoid cell leukodystrophy, or Krabbe disease, is a severe disorder of the peripheral and central nervous system myelin caused by deficient galactocerebrosidase (GALC) activity. This autosomal recessive disease affects humans and animals including dogs, mice, and rhesus monkeys. Cloning of the human and animal GALC genes opened opportunities for therapeutic trials using animal models. We describe the clinical, pathologic, and biochemical features of the affected rhesus monkey. Affected monkeys had very low GALC activity and a two base pair deletion in both copies of the GALC gene. Clinical signs of tremors, hypertonia, and incoordination led to humane euthanasia by 5 months of age. At necropsy, peripheral nerves were enlarged. Microscopically, the cerebral, cerebellar, and spinal cord white matter was infiltrated with periodic acid-Schiff-positive multinucleated globoid cells, and there was a striking lack of myelin. Peripheral nerve fibers were decreased in number and separated by Alcian blue- and safranin O-positive material. Myelin sheaths were greatly diminished. Lipid analysis of brains of 12-day-old and 158-day-old affected monkeys revealed a great excess of psychosine in white matter. The rhesus monkey model will be especially useful for exploring treatment options, including prenatal bone marrow transplantation and various approaches to gene therapy.

Animals↗
PubMed1997

Mononeuropathy multiplex in rhesus monkeys with chronic Lyme disease.

Peripheral neuropathy is a recognized but poorly understood manifestation of Lyme disease. We performed serial electrophysiological studies on 8 rhesus monkeys chronically infected with the JD1 strain of Borrelia burgdorferi and compared the results with those of similar studies on 10 uninfected control monkeys. Four infected and 2 uninfected animals underwent sural nerve biopsy. Five of the infected and 1 of the uninfected animals also had postmortem neuropathological examinations. Altogether, 5 of the infected monkeys demonstrated primarily axonal-loss-variety multifocal neuropathies. Only one nerve lesion exhibited findings compatible with demyelination. Pathologically, peripheral nerve specimens showed multifocal axonal degeneration and regeneration and occasional perivascular inflammatory cellular infiltrates without vessel wall necrosis. Free spirochetal structures were not seen, but several macrophages exhibited positive immunostaining with a highly specific anti-B. burgdorferi, 7.5-kd lipoprotein monoclonal antibody. In the infected animals, serial analysis of serum antibodies to B. burgdorferi showed increasing numbers of IgG specificities and new IgM specificities, suggesting persistent infection. Thus, peripheral neuropathy in the form of a mononeuropathy multiplex develops frequently in rhesus monkeys chronically infected with B. burgdorferi. The pathogenesis of these nerve lesions is not yet known, but our studies suggest an immune-mediated process perhaps driven by persistent infection with B. burgdorferi.

Animals↗
PubMed1997

The outer surface protein A (OspA) vaccine against Lyme disease: efficacy in the rhesus monkey.

The efficacy of an outer surface protein A (OspA) vaccine in three different formulations was investigated in the rhesus monkey. The challenge infection was administered using Ixodes scapularis ticks that were infected with the B31 strain of Borrelia burgdorferi. Protection was assessed against both infection and disease, by a variety of procedures. Some of the animals were radically immune suppressed, as an attempt to reveal any putative low level infection in the vaccinated animals. The significant difference found between the spirochaetal infection rates of ticks that had fed on vaccinated vs. control monkeys, lack of seroconversion in the vaccinated animals, and the absence of spirochaetal DNA in the skin of vaccinated animals in the weeks following the challenge, indicate that vaccinated monkeys were protected against tick challenge. The post-mortem immunohistochemical and polymerase chain reaction analyses, however, suggest that these monkeys may have undergone a low-level infection that was transient.

Animals↗
PubMed1997

Lyme neuroborreliosis in the rhesus monkey.

Although there are several animal models of Lyme disease, only the rhesus monkey model exhibits all of the key manifestations of the disease. After infection with Borrelia burgdorferi, rhesus monkeys develop signs of early localized, early disseminated, and chronic Lyme disease. Specific features include erythema migrans, uveitis, myocarditis, arthritis, and disease of the peripheral and central nervous system. One of the unique features of the rhesus monkey model is the development of Lyme neuroborreliosis. Peripheral nervous system (PNS) involvement is usually in the form of a mononeuropathy multiplex with primarily axonal-loss features. Evidence of central nervous system (CNS) disease has included CSF pleocytosis, meningeal inflammation, spinal cord lesions, and polymerase chain reaction (PCR) data consistent with chronic CNS infection. The pathogenesis of Lyme neuroborreliosis is not well understood, but it is likely to involve complex interactions between B. burgdorferi and host immune mechanisms.

Animals↗
PubMed1996

Immunocytochemical investigations of sodium channels along nodal and internodal portions of demyelinated axons.

Voltage-gated sodium channels are largely localized to the nodes of Ranvier in myelinated axons, providing the physiological basis for saltatory conduction. Studies using antisodium channel antibodies have shown that along demyelinated axons sodium channels form new distributions. The nature of this changed distribution appears to vary with the time course and mechanism of demyelination. In chronic demyelination, sodium channels increase in number and redistribute along previously internodal axon segments. In chronic demyelination produced by doxorubicin, the increase in sodium channels appeared independently of Schwann cells, suggesting increased neuronal synthesis. In acute demyelination produced by lysolecithin new clusters of sodium channels developed but only in association with the edges of remyelinating Schwann cells, which appeared to control the distribution and mobility of the channels. These findings affirm the plasticity of sodium channels in demyelinated axons and are relevant to understanding how these axons recover conduction.

Animals↗
PubMed1996

Polymyositis, arthritis, and uveitis in a macaque experimentally infected with human T lymphotropic virus type I.

OBJECTIVE: To establish a simian model of human T lymphotropic virus type I (HTLV-I) infection and disease. METHODS: Irradiated HTLV-I-producing cells were used to infect two 2-year-old rhesus macaque monkeys (Macaca mulatta). One monkey was also simultaneously inoculated with a cell-free suspension of simian immunodeficiency virus (SIV). Evidence of infection was monitored by serial clinical examinations and by serologic, molecular, and virologic assays. RESULTS: Both HTLV-I-inoculated monkeys became persistently infected following inoculation. Clinical disease was observed in the singly inoculated monkey, which developed arthritis (with synovial fluid positive for HTLV-I by culture and polymerase chain reaction), anterior chamber uveitis, and steroid-responsive polymyositis confirmed by electrophysiologic studies. The dually inoculated animal remained clinically healthy, despite high levels of SIV and HTLV-I virus expression and loss of HTLV-I-specific antibodies. CONCLUSION: These results indicate the utility of a nonhuman primate model for studying HTLV-I disease pathogenesis and the dynamics of SIV-1/HTLV-I retroviral coinfection.

Animals↗
PubMed1996

Electrophysiological studies in the different genotypes of Charcot-Marie-Tooth disease.

Electrophysiological studies remain one of the cornerstones in the diagnosis of Charcot-Marie-Tooth syndrome and related genetic neuropathies. They are helpful in defining the subtypes of this heterogeneous group of hereditary neuropathies and in differentiating them from acquired neuropathies. Major advances in defining the molecular genetics of Charcot-Marie-Tooth disease are occurring. The increasingly refined diagnosis of these disorders is highlighted. It is possible by the combination of electrophysiological studies and genetic testing. These developments are especially important for practicing neurologists as they can result immediately in more specific diagnosis of patients with inherited neuropathies.

Charcot-Marie-Tooth Disease↗
PubMed1996

Sodium channel accumulation in humans with painful neuromas.

Painful neuromas from 16 patients were examined using site-specific antisodium channel antibodies employed in immunocytochemical and radioimmunoassay methods. Normal sural nerves from six of these patients served as controls. Immunocytochemistry showed abnormal segmental accumulation of sodium channels within many axons in the neuromas. Dens immunolocalization was especially apparent within the axonal tips. Radioimmunoassay confirmed a significantly greater density of sodium channels in the neuromas as compared with the sural nerves. Thus, sodium channel accumulate abnormally within the axons of neuromas in humans. This alteration of the sodium channels may underlie the generation of axonal hyperexcitability and the resulting abnormal sensory phenomena (pain and paresthesias), which frequently occur after peripheral nerve injury.

Amino Acid Sequence↗
PubMed1995

Progression of neuropathy in peripheral arterial disease.

Atherosclerotic peripheral arterial disease (PAD) can cause muscle denervation, but whether it is associated with more severe peripheral nerve disease is not clear. Equally unclear is the effect of exercise training on the neuromuscular aspects of this disease. We performed serial electrophysiologic studies (nerve conduction studies and quantitative electromyography) and muscle strength assessment on 16 patients with moderately severe PAD. Seven of the patients were assigned to a natural history (control) group and 9 to an exercise training group. Over study periods ranging from 3 to 23 months, 6 of 7 patients in the control group and 8 of 9 patients in the exercise training group showed progression of multifocal neuropathic disease in their ischemic legs. For equivalent lengths of time, the degree of neuropathic progression was not significantly different between the control and exercise training groups. There was a significant decline in muscle strength for the control group but not for the exercise training group. These results demonstrate that PAD can be associated with the development of a multifocal predominantly motor neuropathy, which is most likely ischemic in etiology. Furthermore, exercise training does not pose an additional risk for the development of neuropathy in patients with moderately severe PAD.

Aged↗
PubMed1995

Clinical variability in two pairs of identical twins with the Charcot-Marie-Tooth disease type 1A duplication.

We report two pairs of male homozygotic twins in two unrelated families with the Charcot-Marie-Tooth disease type 1A duplication. Homozygosity was supported by DNA analysis. There was remarkable congruity of conduction velocities between the left and right side of each twin and between twin brothers. The similarity and symmetry of the electrophysiologic deficit contrast with the variable and asymmetric clinical presentations. Variability of clinical expression in these patients with identical mutations suggests the action of stochastic factors or environmental modulation of disease severity.

Adult↗
PubMed1994

Postsurgical idiopathic brachial neuritis.

Idiopathic brachial neuritis (IBN) is a well-recognized clinical syndrome characterized by brachial pain followed by a patchy amyotrophy of muscles in the shoulder girdle and arm innervated by individual branches of the brachial plexus. Postsurgical IBN has not been widely recognized since Parsonage and Turner's original description in which 10% of patients had antecedent surgery. We present 6 patients who 1-13 days postoperatively developed signs and symptoms which met the clinical and electrophysiologic criteria for IBN. Postsurgical neuralgic amyotrophy is an under-recognized clinical entity which in most cases is ascribed to brachial plexus stretch injuries occurring during anesthesia. Early recognition of this condition may prevent unnecessary surgical exploration and allow for a more accurate prediction of functional recovery.

Adult↗
PubMed1994

Sodium channels accumulate at the tips of injured axons.

The axolemmal distribution of voltage-gated sodium channels largely determines the regions of axonal electrical excitability. Using a well-characterized anti-sodium channel antibody, we examined peripheral nerve fibers focally injured by exposure to the neurotoxic agent, potassium tellurite (K2TeO3). Immunocytochemical and radioimmunoassay data showed a focal accumulation of sodium channels within the tips of injured axons. The major increase in sodium channel concentration occurred between 7 and 11 days after toxin exposure; however, immunocytochemically, excess sodium channels persisted in several axonal endings for a much longer time. The accumulation of sodium channels at injured axonal tips may be responsible, in part, for ectopic axonal excitability and the resulting abnormal sensory phenomena (especially pain and paresthesias) which frequently complicate peripheral nerve injury in humans.

Animals↗
PubMed1994

Glycated haemoglobin predicts progression to diabetes mellitus in Pima Indians with impaired glucose tolerance.

Glycated haemoglobin could offer several practical advantages over the OGTT for assessing glucose metabolism. Initial cross-sectional studies (1983-1985) on 381 subjects (mostly Pima Indians) described the relationship between HbA1c (a specific glycated Hb) and the OGTT. We performed follow-up OGTTs and HbA1c measurements on 257 of these same subjects 1.6-6.1 years later. Subjects were again grouped according to both the result of the OGTT (normal, IGT or diabetes, by WHO criteria) and HbA1c result (normal or elevated based on mean +/- 1.96 SD of normal). Of 66 subjects with IGT at baseline, 47 (71%) had normal HbA1c and 19 (29%) had elevated HbA1c. Twenty-six (39%) of these subjects had diabetes at follow-up. Of these subjects with IGT, a significantly greater percentage of subjects with elevated HbA1c at baseline (68%) showed worsening to diabetes than those with a normal HbA1c (28%); (chi-square = 7.8, df = 1, p < 0.01). Thus, in subjects with IGT, glycated Hb may be a useful predictor of progression to diabetes.

Adolescent↗
PubMed1994

Distal accentuation of conduction slowing in polyneuropathy associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside.

In four patients with a chronic, demyelinating polyneuropathy associated with monoclonal IgM antibodies to myelin-associated glycoprotein (MAG) and sulphated glucuronyl paragloboside (SGPG), we have observed a marked prolongation of distal motor latencies disproportionate to proximal segment-conduction velocities, in nearly all nerves studied. Distal accentuation of conduction slowing distinguished these patients from those with Charcot-Marie-Tooth polyneuropathy type 1A, chronic inflammatory polyneuropathy, and from controls, as demonstrated by regression of distal motor latency on proximal conduction velocity. Sixteen of 21 nerves (76%) studied in the patients with anti-MAG/SGPG polyneuropathy had a terminal latency index of < or = 0.25 versus 11 of 195 nerves (6%) of Charcot-Marie-Tooth polyneuropathy type 1A patients, three of 49 nerves (6%) of patients with chronic inflammatory polyneuropathy and none of the controls (P = 0.0001). Recognition of this unique pattern of generalized, distally predominant conduction slowing in anti-MAG/SGPG polyneuropathy may be useful in clinically distinguishing this from other chronic demyelinating polyneuropathies, and in possibly providing insights into the pathophysiology of this disorder.

Aged↗
PubMed1994

Is glycohemoglobin testing useful in diabetes mellitus? Lessons from the diabetes control and complications trial.

To address the question, Do laboratory tests cost money or save money? we have used as a model for discussion a common chronic disease, diabetes mellitus, and a widely used laboratory test, that for glycohemoglobin, a measure of long-term glycemia used to manage diabetic patients. Diabetes mellitus is serious, highly prevalent, and costly. In 1992, $1 of every $7 spent on health in the US was for diabetes, predominantly for treatment of the chronic complications of the disease. The recently completed Diabetes Control and Complications Trial (DCCT) demonstrated that development and progression of the chronic complications of diabetes are related to the degree of altered glycemia as quantified by determinations of glycohemoglobin. Thus, use of glycohemoglobin testing for routine diabetes care provides an objective measure of a patient's risk for developing diabetic complications. Results of this test can alert patients and health providers to the need for change in the treatment plan. Optimal use of glycohemoglobin testing for diabetes care will require standardization of test results.

Clinical Trials as Topic↗
PubMed1993

Glycemic control and development of retinopathy in youth-onset insulin-dependent diabetes mellitus. Results of a 12-year longitudinal study.

BACKGROUND: In 1979, the authors began a prospective study of the natural history of retinopathy in youth-onset insulin-dependent diabetes mellitus (IDDM). Their major goal was to determine if there was an association between glycemic control and the development and progression of retinopathy. METHODS: The study consisted of 420 individuals with IDDM (onset younger than 20 years of age) and no retinopathy at baseline. Study subjects were enrolled between 1979 and 1988. Stereo color fundus photographs were obtained annually. Two eye endpoints were recorded: duration when retinopathy was first detected, and when proliferative retinopathy was detected. Glycemic control was assessed by quarterly determinations of glycohemoglobin (GHb). Life-table analyses were performed relating duration of diabetes, sex, GHb, and age of diabetes onset to development of retinopathy. RESULTS: Retinopathy did not develop before 2 years' duration or before puberty. The prevalence of retinopathy was 50% by 9 years' duration and 100% by 20 years' duration. Retinopathy developed in females approximately 2 years sooner than in males, but plotting duration as postpubertal years resulted in nearly identical rates. Retinopathy developed significantly earlier in subjects with prepubertal onset of diabetes than in subjects with postpubertal onset if duration was plotted as postpubertal years. When separated into three groups based on GHb levels (< 7.5%, 7.5%-9%, > 9%), retinopathy developed approximately 2 years later in subjects in the less than 7.5% GHb group than those in the higher GHb groups. Proliferative retinopathy developed in 11 subjects. Their mean GHb level was higher than the mean GHb for those without proliferative retinopathy (10.9 versus 8.6%; P < 0.01). The higher the level of GHb, the sooner proliferative changes were detected. CONCLUSION: Long-term glycemic control is significantly related to both development and progression of retinopathy. Prepubertal duration of diabetes is a significant risk factor for the development of retinopathy.

Adolescent↗
PubMed1993

The natural history of amyotrophic lateral sclerosis.

Using 42 strength and functional assessments recorded monthly, the natural history of amyotrophic lateral sclerosis (ALS) is described in 167 patients (98 men, 67 women) followed in five medical centers in the western United States. The mean age at onset was 57.4 years, and symptoms were present for 2.64 years before study entry. Although there was a highly variable rate of decline within the group of patients, there were no differences in rate of decline by age or gender. Older patients and women were weaker on entry. Forty-eight patients died during the study. The median survival was 4.0 years for the study cohort but 2.1 years for newly diagnosed cases. Decline in pulmonary function most closely correlated with death. Our results emphasize the importance of considering clinical variability in planning clinical trials. One possible strategy is to identify and stratify patients by rate of decline in pulmonary function since prospectively identifying homogeneous subgroups allows investigators to substantially reduce sample size in therapeutic trials.

Adult↗