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Biomedical subjects

A Vinik

Publications and source records attributed to A Vinik.

At least 19 recordsLinked to original sources
PubMed2000

Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical Investigator Group.

CONTEXT: Nerve growth factor is a neurotrophic factor that promotes the survival of small fiber sensory neurons and sympathetic neurons in the peripheral nervous system. Recombinant human nerve growth factor (rhNGF) has demonstrated efficacy as treatment for peripheral neuropathy in experimental models and phase 2 clinical trials. OBJECTIVE: To evaluate the efficacy and safety of a 12-month regimen of rhNGF in patients with diabetic polyneuropathy. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial conducted from July 1997 through May 1999. SETTING: Eighty-four outpatient centers throughout the United States. PATIENTS: A total of 1019 men and women aged 18 to 74 years with either type 1 or type 2 diabetes and a sensory polyneuropathy attributable to diabetes. INTERVENTIONS: Patients were randomly assigned to receive either rhNGF, 0.1 microg/kg (n = 504), or placebo (n = 515) by subcutaneous injection 3 times per week for 48 weeks. Patients were assessed at baseline, 12 weeks, 24 weeks, and 48 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was a change in neuropathy between baseline and week 48, demonstrated by the Neuropathy Impairment Score for the Lower Limbs, compared between the 2 groups. Secondary outcome measures included quantitative sensory tests using the CASE IV System, the Neuropathy Symptom and Change questionnaire, the Patient Benefit Questionnaire (PBQ), and a global symptom assessment, as well as nerve conduction studies and occurrence of new plantar foot ulcers. Patients also were evaluated for presence of adverse events. RESULTS: Among patients who received rhNGF, 418 (83%) completed the regimen compared with 461 (90%) who received placebo. Administration of rhNGF was safe, with few adverse events attributed to treatment apart from injection site pain/hyperalgesia and other pain syndromes. However, neither the primary end point (P =.25) nor most of the secondary end points demonstrated a significant benefit of rhNGF. Exceptions were the global symptom assessment (P =.03) and 2 of 32 comparisons within the PBQ, which showed a modest but significant benefit of rhNGF (P =.05 for severity of pain in the legs and P =.003 for 6-month symptoms in the feet and legs). CONCLUSION: Unlike previous phase 2 trials, this phase 3 clinical trial failed to demonstrate a significant beneficial effect of rhNGF on diabetic polyneuropathy. JAMA. 2000;284:2215-2221.

Activities of Daily Living↗
PubMed2000

Possible relationship between changes in islet neogenesis and islet neogenesis-associated protein-positive cell mass induced by sucrose administration to normal hamsters.

The possible relationship between changes in islet cell mass and in islet neogenesis-associated protein (INGAP)-cell mass induced by sucrose administration to normal hamsters was investigated. Normal hamsters were given sucrose (10% in drinking water) for 5 (S8) or 21 (S24) weeks and compared with control (C) fed hamsters. Serum glucose and insulin levels were measured and quantitative immunocytochemistry of the endocrine pancreas was performed. Serum glucose levels were comparable among the groups, while insulin levels were higher in S hamsters. There was a significant increase in beta-cell mass (P<0.02) and in beta-cell 5-bromo-2'-deoxyuridine index (P<0.01), and a significant decrease in islet volume (P<0.01) only in S8 vs C8 hamsters. Cytokeratin (CK)-labelled cells were detected only in S8 hamsters. INGAP-positive cell mass was significantly larger only in S8 vs C8 hamsters. Endocrine INGAP-positive cells were located at the islet periphery ( approximately 96%), spread within the exocrine pancreas ( approximately 3%), and in ductal cells (<1%) in all groups. INGAP positivity and glucagon co-localization varied according to topographic location and type of treatment. In C8 hamsters, 49.1+/-6. 9% cells were INGAP- and glucagon-positive in the islets, while this percentage decreased by almost half in endocrine extra-insular and ductal cells. In S8 animals, co-expression increased in endocrine extra-insular cells to 36.3+/-9.5%, with similar figures in the islets, decreasing to 19.7+/-6.9% in ductal cells. INGAP-positive cells located at the islet periphery also co-expressed CK. In conclusion, a significant increase of INGAP-positive cell mass was only observed at 8 weeks when neogenesis was present, suggesting that this peptide might participate in the control of islet neogenesis. Thus, INGAP could be a potentially useful tool to treat conditions in which there is a decrease in beta-cell mass.

Animals↗
PubMed1993

Factors controlling pancreatic islet neogenesis.

We have established a model in which cellophane wrapping induces reiteration of the normal ontogeny of beta-cell differentiation from ductal tissue. The secretion of insulin is physiologic and coordinated to the needs of the animal. Streptozotocin-induced diabetes in hamsters can be 'cured' at least half the time. There appears to be activation of growth factor(s) within the pancreas acting in an autocrine, paracrine or juxtacrine manner to induce ductal cell proliferation and differentiation into functioning beta-cells. Given the results of our studies to date, it does not seem premature to envisage new approaches to the treatment of diabetes mellitus. Identification of the factor(s) which regulates islet cell proliferation and differentiation in our model may permit proto-undifferentiated cells and islets to be grown in culture. This concept could be extended to induce endocrine cell differentiation in vitro as well. Furthermore, islet cell growth factors could be used to provide 'trophic support' to islet transplants as a means of maintaining graft viability. There may also be greater scope for gene therapy when the growth factor(s) has been isolated, purified, sequenced and cloned.

Animals↗
PubMed1990

Treatment of panic-like attacks with a long-acting analogue of somatostatin.

Psychiatric evaluations were completed on four patients who were treated for "idiopathic flushing" with a long-acting analogue of somatostatin. All four patients had symptom profiles consistent with a diagnosis of panic disorder. All four experienced clinically significant relief from panic-like attacks while on the experimental medication. These findings suggest a possible role for somatostatin in the pathophysiology and treatment of panic disorder.

Adult↗
PubMed1989

Use of somatostatin analog in management of carcinoid syndrome.

Carcinoid tumors are the most frequent gut neuroendocrine tumors accounting for more than 50% of all tumors of the gastroenteropancreatic (GEP) axis. These tumors appear to derive from a stem cell line capable of differentiating into a variety of malignant cells that secrete many different peptides and amines. The symptoms of carcinoid tumors are often non-specific, vague abdominal pain that may precede the diagnosis by a median of 9 years. Carcinoid syndrome occurs in less than 10% of patients. We evaluated the effects of SMS 201-995 in 14 such patients, 12 with diarrhea, 8 with flushing, 3 with wheezing, one with tricuspid valve incompetence, 6 with facial telangiectasia, 3 with a pellagra type dermatosis and one with myopathy. Diarrhea was abolished or significantly reduced in 83%, flushing in 100%, wheezing in 100%, and myopathy improved in the one patient. Blood serotonin was resistant to change, urine 5HIAA fell in 75%, and most gut neuropeptide hormones apart from somatostatin were suppressed. Tumor growth appeared to be slowed in 2/3 of cases treated for up to 4 years. The analog of somatostatin appears to be a useful addition to the therapeutic armamentarium for carcinoid tumors and the symptom complex.

Aged↗
PubMed1989

The surgical treatment of gastrinoma in MEN I syndrome patients.

The pancreatic component of the multiple endocrine neoplasia type I (MEN I) syndrome is a difficult and controversial problem because the entire endocrine pancreas is diffusely involved with varying degrees of islet-cell hyperplasia, microadenomatosis, and nesidioblastosis. In addition, in patients with functional syndromes, islet-cell tumors usually develop, and these may or may not be malignant. Because of the presumed inability to alleviate or cure the Zollinger-Ellison syndrome (ZES) in MEN patients, total gastrectomy was the treatment of choice before the introduction of H2 antagonists and omeprazole. At present, many physicians and surgeons consider H2 antagonists the best treatment and advise pancreatic exploration only when a gross pancreatic tumor is demonstrated on imaging studies. During the past 10 years we have studied all MEN I patients with ZES without hepatic metastases or gross pancreatic tumors using percutaneous transhepatic selective venous gastrin samplings. Two patterns of gastrin secretion were identified: (1) diffuse from multiple pancreatic sites and (2) localized regional secretion. Four patients from the latter group were selected for attempted surgical "cure" without gastrectomy or total pancreatectomy. Two additional patients are included who had resection of gastrinomas and have maintained basal serum gastrin levels within the normal range for extended periods. The follow-up on these patients ranges from 5 months to 12 years. All six patients have normal basal gastrin values, and those with remaining stomachs require no drug therapy.

Adult↗
PubMed1988

Clinical aspects of diabetic neuropathies.

Diabetic neuropathy is a common complication of diabetes that may be associated both with considerable morbidity (painful polyneuropathy, neuropathic ulceration) and mortality (autonomic neuropathy). The epidemiology and natural history of diabetic neuropathy is clouded with uncertainty, largely due to confusion in the definition and measurement of this disorder. We have reviewed a variety of the clinical manifestations associated with somatic and autonomic neuropathy and discussed current views related to the management of the different abnormalities. Although unproven, the best evidence suggests that near normal control of blood glucose in the early years following onset of diabetes may help delay the development of clinically significant nerve impairment. Intensive therapy to achieve normalization of blood glucose may also lead to reversibility of early diabetic neuropathy, but again this is unproven. Our ability to manage successfully the many different manifestations of diabetic neuropathy depends ultimately on our success in uncovering the pathogenic processes underlying this disorder. The recent resurgence of interest in the vascular hypothesis, for example, has opened up new avenues of investigation for therapeutic intervention. Paralleling our increased understanding of the pathogenesis of diabetic neuropathy, there must be refinements in our ability to measure quantitatively the different types of defects that occur in this disorder. These tests must be validated and standardized to allow comparability between studies and more meaningful interpretation of study results.

Diabetes Mellitus, Type 1↗
PubMed1988

Mutant insulin syndromes.

Highly sensitive procedures for the characterization of molecular species of insulin in the circulation and for the isolation of the gene encoding human insulin have recently been developed. Nine subjects with abnormal forms of insulin or proinsulin have been reported. These include: [Leu B25], [Ser B24], [Leu A3] insulin as well as others that have not yet been identified. The clinical syndrome associated with the secretion of an abnormal insulin or proinsulin molecule presents with apparent endogenous insulin resistance with inappropriate high levels of insulin for the prevailing blood glucose concentration and a high insulin/C-peptide ratio due to the reduced catabolism of the abnormal insulin molecule. Diabetes occurs if there is concomitant insulin resistance or pancreatic beta cell failure. In addition, abnormal forms of insulin have been found in the insulin autoimmune syndrome presenting with recurrent, self-limiting hypoglycemia. Abnormal insulin in the autoimmune insulin syndrome suggests that abnormalities in endogenous antigens may be important in the formation of antibodies in other autoimmune states. However, although abnormalities in the insulin molecule may provoke the autoimmune response, it is also feasible that the presence of antibodies to normal insulin and proinsulin in some way alters their metabolism to yield abnormal products on high performance liquid chromatography (HPLC). Abnormal forms of insulin have also been found in subjects with reactive hypoglycemia and exogenous insulin-resistance and appear to be transmitted in an autosomal dominant manner. A protocol for the sequence of investigating subjects who potentially harbor a mutant or otherwise abnormal form of insulin using HPLC and recombinant DNA technology is presented.

Humans↗
PubMed1988

Hepatic extraction of somatostatin in conscious dogs.

Fractional hepatic extraction of endogenous somatostatin immunoreactivity was examined in conscious dogs with Doppler flow probes on the portal vein and hepatic artery and catheters in the portal and hepatic veins and carotid artery before and after induction of hypoglycemia by infusion of insulin. Insulin infusion (1 and 2 mU.kg-1.min-1) decreased arterial plasma glucose from 76 +/- 4 mg/dl to a nadir of 41 +/- 2 mg/dl. Basal portal vein somatostatin was 117 +/- 11 pg/ml, which was significantly greater than the 97 +/- 12 pg/ml in the hepatic vein (P less than 0.05) and 79 +/- 8 pg/ml in the carotid artery (P less than 0.05). Hypoglycemia significantly augmented portal vein somatostatin to 206 +/- 32 pg/ml with parallel increases in the hepatic vein and carotid artery. The mean basal fractional hepatic extraction of total somatostatin immunoreactivity was 9 +/- 6% and was unchanged during hypoglycemia (14 +/- 4%). Column chromatography of the portal vein somatostatin immunoreactivity in the basal period yielded three peaks with most of the material eluting with somatostatin-14 and the void volume. Very little somatostatin-28 was detected. There was very little hepatic extraction of the void volume material while approximately 50% of somatostatin-14 was removed by that organ. After insulin-induced hypoglycemia, there was the greatest percent increase in somatostatin-28 and a doubling of somatostatin-14 and the void volume material. Most of the somatostatins-14 and -28 were removed by the liver, while extraction of the void volume material was negligible.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Immunohistochemical localization of a specific ileal peptide in the pig.

The tissue distribution of a polypeptide purified from pig ileal mucosa tentatively called porcine ileal polypeptide (PIP) and known to have potent acid secretagogue activity has been studied with immunohistochemical methods together with extraction of different tissues followed by radioimmunoassay for PIP content. Histochemically the peptide is found in superficial epithelial cells in the mucosa of the distal 20% of the small intestine and to some extent in the mucosa of the urinary tract. There is no staining of goblet cells or crypt cells. The staining in the urinary tract mucosa is due to antigenic peptides with Mr identical to PIP. While the presence of PIP in the ileum is compatible with a function as an enterooxyntin, it is not possible at present to explain the physiologic role of PIP entirely as a hormone regulating acid secretion in light of the immunohistochemical distribution.

Animals↗
PubMed1986

Characterization of circulating insulin in insulin autoimmune syndrome.

We examined the forms of circulating insulin in three patients with the insulin autoimmune syndrome by a method combining gel filtration and reverse phase high performance liquid chromatography (RP-HPLC). Insulin bound to circulating antibody was dissociated by molecular sieve chromatography at acid pH. The free insulin peak eluted from a Sephadex G-50 column was subsequently chromatographed on a Bio-Gel P-30 column. In all three patients, insulin coeluted with normal human insulin. However, when the partially purified insulins, obtained by gel filtration, were applied to RP-HPLC, an abnormally migrating insulin was found in two of three patients. The insulins were more hydrophobic than normal human, porcine, or bovine insulin, but were different from each other. A third patient had only a single insulin peak on RP-HPLC which corresponded to normal insulin. In contrast, the insulin from insulin-treated diabetic patients with antibodies to exogenous insulin corresponded to either porcine or bovine and normal human insulin. The antibodies in the circulation of these patients with the autoimmune syndrome were of the immunoglobulin G type and contained kappa and lambda-chains in the same proportions as antibodies in insulin-treated patients. Autoantibodies could not be distinguished from those secondary to exogenous insulin treatment on the basis of displacement of binding by human, beef, or pork insulin. These results suggest that in certain patients with the insulin autoimmune syndrome, there may be a molecular abnormality of circulating insulin. Whether this comprises a cause for the syndrome or is a result of posttranslational processing of insulin remains to be determined.

Adult↗
PubMed1985

Hyperuricemia in glycogen storage disease type I. Contributions by hypoglycemia and hyperglucagonemia to increased urate production.

Studies were performed to determine whether hypoglycemia or the glucagon response to hypoglycemia increases uric acid production in glycogen storage disease type I (glucose-6-phosphatase deficiency). Three adults with this disease had hyperuricemia (serum urate, 11.3-12.4 mg/dl) and reduced renal clearance of urate (renal urate clearance, 1.1-3.1 ml/min). These abnormalities were improved in one patient by intravenous glucose infusion for 1 mo, suggesting a role for hypoglycemia and its attendant effects on urate metabolism and excretion. A pharmacologic dose of glucagon caused a rise in serum urate from 11.4 to 13.0 mg/dl, a ninefold increase in urinary excretion of oxypurines, a 65% increase in urinary radioactivity derived from radioactively labeled adenine nucleotides, and a 90% increase in urinary uric acid excretion. These changes indicate that intravenous glucagon increases ATP breakdown to its degradation products and thereby stimulates uric acid production. To observe whether physiologic changes in serum glucagon modulate ATP degradation, uric acid production was compared during saline and somatostatin infusions. Serum urate, urinary oxypurine, radioactivity, and uric acid excretion increased during saline infusion as patients became hypoglycemic. Infusion of somatostatin suppressed these increases despite hypoglycemia and decreased the elevated plasma glucagon levels from a mean of 81.3 to 52.2 pg/ml. These data suggest that hypoglycemia can stimulate uric acid synthesis in glucose-6-phosphatase deficiency. Glucagon contributes to this response by activating ATP degradation to uric acid.

Adenosine Triphosphate↗
PubMed1985

Identification of insulin variants in patients with hyperinsulinemia by reversed-phase, high-performance liquid chromatography.

We have characterized the molecular forms of circulating insulins in patients with hyperinsulinemia of diverse etiology. We have also compared the efficacy of various chromatographic conditions using reversed-phase (RP) HPLC. Using 0.2% trifluoroacetic acid (TFA) and triethylamine (TEA) with acetonitrile as the organic modifier, at an elution rate of 0.17%/min, porcine, bovine, and human insulins could be easily separated as well as abnormal insulins in the plasma of a patient (J.R.) with hyperinsulinemia of unknown etiology. When the reversed-phase C18 column was changed and a gradient of 0.33%/min was used, the abnormal insulin in patient J.R. could not be separated. By changing the solvent system to acetonitrile and isopropanol (vol:vol, 3:1) containing 0.1% TFA, omitting the TEA, and using a gentle gradient of 0.1%/min, various semisynthetic analogues of human insulin could be easily separated and the abnormal insulin could be identified in the plasma of the patient J.R. Abnormal insulin was also found in a patient with MEN-I, but in contrast, the insulins in eight patients with benign sporadic insulinomas appeared to be normal. These results suggest that certain hyperinsulinemic states may be associated with an abnormal insulin and that RP-HPLC is useful for identification of insulin variants in the circulation. However, the conditions of RP-HPLC may be critical if the abnormalities of the insulin are subtle.

C-Peptide↗
PubMed1983

Role of calcium and calmodulin in activation of the oxyntic cell by histamine and carbamylcholine in the guinea pig.

The role of calcium in stimulation of the oxyntic cell by histamine and carbamylcholine was studied using a sensitive quantitative cytochemical staining technique that measures oxyntic cell hydroxyl ion production (HIP) as an index of acid secretion. Histamine (10(-17)-10(-14) M), carbamylcholine (10(-12)-10(-9) M), and extracellular calcium (10(-7)-10(-3) M) caused a linear, dose-dependent stimulation of the oxyntic cell. EGTA (10(-6) M) inhibited carbamylcholine by 50% but not histamine-stimulated activity. Lanthanum chloride (10(-6) M) caused 100% inhibition of carbamylcholine-induced activity but did not affect histamine-stimulated activity. A maximally effective dose of calcium (10(-4) M) caused additive effects on HIP at low doses of carbamylcholine without alteration of the maximal effect of carbamylcholine. Calcium (10(-4) M) did not enhance the effects of histamine. The calmodulin antagonists, trifluoperazine (10(-5) M), pimozide (10(-5) M), and a naphthalenesulfonamide (W-7), inhibited the integrated response to histamine by 54, 56, and 53%, and that of carbamylcholine by 65, 64, and 99%, respectively. Thus, extracellular calcium per se, stimulates the oxyntic cell. The action of carbamylcholine is completely dependent upon calcium/calmodulin mediation, supporting the concept that cholinergic actions are mediated via calcium-calmodulin events. Although histamine does not require extracellular or membrane calcium events to stimulate the oxyntic cell, calmodulin appears to participate in histamine action.

Animals↗