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Biomedical subjects

J Griffin

Publications and source records attributed to J Griffin.

At least 145 records · Page 8Linked to original sources
PubMed1982

Insulin resistance and diabetes due to a genetic defect in insulin receptors.

A 14-yr-old woman presented with fasting hyperglycemia (269 mg/dl), fasting hyperinsulinemia (45 microU/ml), acanthosis nigricans, and insulin resistance. The patient's circulating insulin was normal by physical and biological criteria, and insulin receptor antibodies were not detected. Both the patient's in vivo dose-response curve for insulin-stimulated glucose transport in isolated adipocytes were shifted to the right and showed marked decreases in the maximal insulin response. Basal hepatic glucose output was significantly increased, and the in vivo dose-response curve for insulin-mediated suppression of basal hepatic glucose output was shifted to the right. Insulin binding to the patient's erythrocytes, monocytes, and adipocytes was markedly decreased. To confirm that the severe reduction in cellular insulin receptors was a primary rather than an acquired defect, similar studies were conducted using cultured fibroblasts. No detectable binding of insulin to these cells was observed. Further studies showed that the patient's mother and two sisters were hyperinsulinemic and insulin resistant, and had comparable, although less severe, changes in insulin binding. The patient was also demonstrated to have an insulin secretory defect both to both oral and iv glucose challenges. We thus conclude that this family demonstrates a genetic deficiency of insulin receptors, resulting in insulin resistance and, in this patient, severe diabetes mellitus.

Adipose Tissue↗
PubMed1982

In vivo deactivation of peripheral, hepatic, and pancreatic insulin action in man.

The in vivo deactivation of insulin action has been studied in 10 lean, nondiabetic subjects using a modification of the euglycemic glucose clamp technique. Following cessation of 40- and 120-mU/m2/min insulin infusions, the serum insulin levels fell to one-half their initial values (mean +/- SE) of 126 +/- 7 and 350 +/- 14 microunits/ml in 7 +/- 1 and 8 +/- 1 min, respectively. The mean incremental glucose disposal rates (IGDR) fell more slowly following discontinuation of the 40- and 120-mU/m2/min insulin infusions, so that the time required for the IGDRs to fall to one-half their initial values (D50 IGDR) were were 42 +/- 5 and 78 +/- 1 min, respectively. Mean hepatic glucose output was totally suppressed during the 40- and 120-mU/m2/min insulin infusions, remained completely suppressed following cessation of the infusions for 50 and 80 mi, and subsequently returned to basal levels. The times required for the HGOs to return to one-half their basal levels (R50 HGO) were 59 +/- 8 and 119 +/- 6 min, respectively. The times required for insulin action to decrease to one-half the initial values in the periphery (D50 IGDR) and in the liver (R50 HGO) were correlated with the preceding steady-state glucose disposal rates in individual subjects (r = 0.75, P less than 0.001 and r = 0.58, P less than 0.05, respectively). The suppression of endogenous insulin secretion by exogenous insulin infusions was also studied in 4 subjects during a total of 5 euglycemic glucose clamps; the mean basal serum C-peptide level was 0.67 +/- 0.24 pmol/ml before administration of the exogenous insulin, fell to 0.34 +/- 0.17 pmol/ml during the steady-state phase of the study, and remained suppressed throughout the duration of the deactivation phase of the glucose clamp. Residual pancreatic insulin secretory capacity was demonstrated by a rise in the serum C-peptide level to 1.77 +/- 0.50 pmol/ml at 120 min following a standardized meal given at the conclusion of the deactivation phase of the glucose clamp. These results demonstrate that the deactivation of insulin action in the periphery, liver, and pancreas lags behind the disappearance of insulin from the plasma. The mechanisms responsible for this lag in in vivo deactivation are not known for certain, but may include slower clearance of insulin form tissue compartments than form the plasma, the necessity for the target tissues to generate specific deactivation signals, or a slow rate of decay of saturable steps in the cellular activation process.

Adult↗
PubMed1982

Induction of differentiation of human myeloid leukemia cells by inhibitors of DNA synthesis.

The HL-60 human leukemic promyelocyte can be induced to mature into terminally differentiated cells using certain nucleosides and chemotherapeutic agents. The mechanisms responsible for this induction of differentiation, however, remain unclear. We have monitored the effects of two specific inhibitors of DNA synthesis to determine whether slowing of DNA polymerization can induce HL-60 differentiation. The results demonstrate that cytosine arabinoside (ara-C) induces nonspecific esterase activity in HL-60 cells and increases surface expression of the monocyte antigen MY-4. The results also demonstrate that aphidicolin, an inhibitor of DNA polymerase which is not incorporated in DNA, induces similar phenotypic changes. The induction of differentiation by both agents was accompanied by loss of clonogenic potential as monitored by colony formation in methylcellulose. These observations suggest that terminal differentiation of HL-60 cells can be induced by drugs known to inhibit DNA synthesis.

Aphidicolin↗
PubMed1982

Antibody and MHC genes.

The striking homology relationships, both in sequence and in general organizational features, among the genes encoding antibodies, transplantation antigens and beta 2-microglobulin suggest that these genes are members of a supergene family. It will be interesting to determine whether any of the regulatory strategies displayed by the antibody gene families will also be employed by the MHC gene families. Indeed, the recombinant DNA approach has given us profound insights into the organization and expression of antibody genes. These same techniques are now beginning to unravel the mysteries of the MHC complex. It is clear that the future will require a much closer collaboration between molecular biologists, cellular immunologists, and immunogeneticists to obtain the appropriate reagents and cell lines necessary to expand our understanding of the molecular biology and enzymology of gene expression in these fascinating systems.

Animals↗
PubMed1981

Acute effects of alcohol on evoked potentials in visual cortex and superior colliculus of the rat.

This study examined the effects of alcohol on visually evoked potentials recorded from the primary visual cortex (VC) and superior colliculus (SC) of chronically implanted rats. Animals were given intraperitoneal injections of saline, and of 0.15, 0.5, 1.0 and 1.5 g ethanol/kg body weight on separate days. Evoked potentials were recorded at 5, 20, 40, and 60 min following injection. There were differential effects of both alcohol and habituation on the early versus late VC components. The amplitudes of the late components decreased over time and were also depressed by both the 1.0 and 1.5g/kg doses of alcohol. Amplitudes of the early components increased over time and were unaffected by the 1.0g/kg alcohol dose. The 1.5g/kg dose depressed the early negative component but augmented the early positive component. In contrast to the amplitudes, the latencies of both early components were increased at both the l.0 and 1.5g/kg doses. However, the latency of the late positive component was increased at only the 1.5 g/kg dose, while the latency of the late negative component was unaffected by any alcohol dose. In the SC, the peak amplitude of the early positive complex was unaffected by either habituation or alcohol. However, both the amplitude and latency of a later negative component (latency of 52 msec) were affected by alcohol. The 1.0 and 1.5g/kg doses decreased peak amplitude, while the latency was increased at the highest dose. These effects of alcohol on the SC component were in directions opposite to those resulting from habituation.

Animals↗
PubMed1981

Changes in immune function in patients with rheumatoid arthritis following treatment with sodium aurothiomalate.

The mitogenic response of peripheral blood lymphocytes from 21 patients with rheumatoid arthritis to concanavalin-A (con--A), phytohaemagglutinin (PHA), and pokeweed mitogen (PWM) was significantly lower than in 30 normal subjects. After 15--24 weeks' treatment with sodium aurothiomalate (GST) the response to these mitogens rose to within the normal range. Improvement over pretreatment values was significant for con-A and PWM measured as area under the dose response curve but only for con--A if response at optimal mitogen concentration is the sole criterion. The improvement in PHA response was not significant with either method of measurement. There was an improvement in disease activity by 15--24 weeks as measured by a fall in serum C-reactive protein (CRP), IgM rheumatoid factor (RF), Clq binding activity (ClqBA), and Ritchie articular index. Con--A lymphocyte responsiveness was inversely related to serum CRP levels, but measurements of disease activity were otherwise unrelated to lymphocyte mitogen responsiveness. The observed improvement in peripheral blood lymphocyte responsiveness during gold treatment contrasts with the suppressive effect of gold in vitro. We suggest that the improvement in lymphocyte function is due to the lessening of rheumatoid disease activity during gold treatment, and that the low serum gold levels in our patients were insufficient to mask this effect. Sera from some of our patients were capable of suppressing the function of normal lymphocytes, and this was less apparent after treatment. The suppressive effect of sera correlated with ClqBA. Suppressive factors in serum, including possibly immune complexes, may be one factor leading to suppression of lymphocyte function during rheumatoid arthritis. Such an inverse relationship between humoral and cellular immune mechanisms might influence the clinical expression of rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed1981

Fall in immune complex levels during gold treatment of rheumatoid arthritis.

Prior to starting gold treatment 30 patients with rheumatoid arthritis had an elevated mean level of circulating immune complexes measured by Clq binding activity. Gold treatment led to an improvement in disease reflected by significant falls in erythrocyte sedimentation rate (p less than 0.001), C-reactive protein (p less than 0.01), Ritchie articular index (p less than 0.001), and duration of morning stiffness (p less than 0.05). Concurrently immune complex levels fell, and this change first reached significance after 3 months' treatment (p less than 0.05). Serum Clq binding activity was not related to clinical and laboratory measurements of joint inflammation. This suggested to us that there is no direct immunopathological relationship between circulating immune complexes and joint inflammation in rheumatoid arthritis. Serum Clq binding activity was strongly related to IgM-RF levels measured at latex titre (r - 0.7, p less than 0.001). Removal of immune complexes from serum with Sepharose 4B-staph A (staphylococcal protein A) led to a fall in IgM-RF from 2 mg/ml (2 g/l) to 0.4 mg/ml (0.4 g/l). This suggests that the reason for the relationship between Clq BA and IgM-RF is that, on average 80% of serum IgM-RF exists as part of immune complexes containing IgG.

Adult↗
PubMed1981

Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus.

We have assessed the mechanisms involved in the pathogenesis of the insulin resistance associated with impaired glucose tolerance and Type II diabetes mellitus by exploring, by means of the euglycemic glucose-clamp technique, the in vivo dose-response relationship between serum insulin and the overall rate of glucose disposal in 14 control subjects; 8 subjects with impaired glucose tolerance, and 23 subjects with Type II diabetes. Each subject had at least three studies performed on separate days at insulin infusion rates of 40, 120, 240, 1,200, or 1,800 mU/M2 per min. In the subjects with impaired glucose tolerance, the dose-response curve was shifted to the right (half-maximally effective insulin level 240 vs. 135 microunits/ml for controls), but the maximal rate of glucose disposal remained normal. In patients with Type II diabetes mellitus, the dose-response curve was also shifted to the right, but in addition, there was a posal. This pattern was seen both in the 13 nonobese and the 10 obese diabetic subjects. Among these patients, an inverse linear relationship exists (r = -0.72) so that the higher the fasting glucose level, the lower the maximal glucose disposal rate. Basal rates of hepatic glucose output were 74 +/- 4, 82 +/- 7, 139 +/- 24, and 125 +/- 16 mg/M2 per min for the control subjects, subjects with impaired glucose tolerance, nonobese Type II diabetic subjects, and obese Type II diabetic subjects, respectively. Higher serum insulin levels were required to suppress hepatic glucose output in the subjects with impaired glucose tolerance and Type II diabetics, compared with controls, but hepatic glucose output could be totally suppressed in each study group. We conclude that the mechanisms of insulin resistance in patients with impaired glucose tolerance and in patients with Type II noninsulin-dependent diabetes are complex, and result from heterogeneous causes. (a) In the patients with the mildest disorders of carbohydrate homeostasis (patients with impaired glucose tolerance) the insulin resistance can be accounted for solely on the basis of decreased insulin receptors. (b) In patients with fasting hyperglycemia, insulin resistance is due to both decreased insulin receptors and postreceptor defect in the glucose mechanisms. (c) As the hyperglycemia worsens, the postreceptor defect in peripheral glucose disposal emerges and progressively increases. And (d) no postreceptor defect was detected in any of the patient groups when insulin's ability to suppress hepatic glucose output was measured.

Adult↗
PubMed1980

HLA-DR antigens and toxic reaction to sodium aurothiomalate and D-penicillamine in patients with rheumatoid arthritis.

To investigate the possible relation between certain HLA antigens and toxicity during treatment with sodium aurothiomalate of D-penicillamine, we studied 91 patients with rheumatoid arthritis. Seventy-one had toxic reactions to either drug or both drugs; the remaining 20 took one of the drugs for at least six months, without toxicity. Nineteen of 24 patients in whom proteinuria developed were positive for HLA-B8 and HLA-DRW3 antigens; 14 of 15 episodes of aurothiomalate-induced proteinura and nine of 13 episodes of penicillamine-induced proteinura occurred in patients with these antigens. All 13 episodes of proteinuria in which urinary protein exceeded 2 g in 24 hours occurred in patients with DRw3. The relative risk of proteinuria during treatment with aurothiomalate is increased 32 times in patients who are HLA-DRw3 positive. No significant associations were found between any HLA antigen and development of skin rashes or hematologic complications. Toxicity during aurothiomalate or penicillamine treatment for rheumatoid arthritis may be under genetic control.

Adult↗
PubMed1980

Improvement in peripheral blood lymphocyte response to concanavalin A and pokeweed mitogen during gold treatment of rheumatoid arthritis.

Peripheral blood lymphocyte mitogen responsiveness was studied in 21 patients with rheumatoid arthritis being treated with sodium aurothiomalate. There was a significant increase in lymphocyte response to concanavalin A and pokeweed mitogen but not to phytohaemagglutinin. This observed increase in lymphocyte response contrasts with the suppressive effect of gold salts in vitro. We propose that this apparent contradiction may be explained by the relatively low serum gold levels measured in our patients, compared with expected levels in synovial membrane. Thus gold could suppress rheumatoid inflammation in the "target tissue" while having little suppressive action in the peripheral blood compartment, where a removal of suppressive influences due to active disease might then be seen as a net improvement in lymphocyte responsiveness.

Adult↗
PubMed1979

Cromolyn DSG effects in hyperkinetic and psychotic children with allergies.

Preliminary findings of an open trial of cromolyn in hyperkinetic and psychotic children indicates that the medication is useful, safe and well tolerated. Further controlled studies are suggested to determine the efficacy and indications of cromolyn in child psychiatry. Positive findings could clarify the biochemical mechanisms of hyperkinesis.

Adolescent↗