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Biomedical subjects

K Perlman

Publications and source records attributed to K Perlman.

At least 37 records · Page 2Linked to original sources
PubMed1987

Induction of monocytic differentiation of HL-60 cells by 1,25-dihydroxyvitamin D analogs.

1,25-Dihydroxyvitamin D3, the hormonal form of vitamin D, induces differentiation of HL-60 human promyelocytes into monocyte-like cells in vitro. We assessed the relative activity of 30 analogs of 1,25-dihydroxyvitamin D3 in inducing development of monocytic markers in HL-60 cells. The three differentiation markers assayed were nonspecific acid esterase activity, nitro blue tetrazolium reducing activity, and phagocytic capacity. Of the known metabolites of vitamin D, 1,25-dihydroxyvitamin D3 is the most active; 50% of the cells exhibit the mature phenotype following a 4-day treatment with 10(-8) M 1,25-dihydroxyvitamin D3. Removal of either the C-1 or C-25-hydroxyl group reduces activity by 2 orders of magnitude, while epimerization of the 1 alpha- to 1 beta-hydroxyl group virtually abolishes activity. Elongation of the steroidal side chain of 1,25-dihydroxyvitamin D3 by addition of one carbon at C-24 or C-26 improves the potency by an order of magnitude. Truncation of the steroidal side chain leads to a 10-fold reduction in activity for each carbon removed. Elimination of the C-26 and C-27 methyl groups reduces activity 100-fold. Analogs with short aliphatic side chains as 1 alpha-hydroxyhomo- and bishomopregnacholecalciferol have surprisingly high activity, being only 20-fold less potent than the natural hormone. The activity of most analogs in the HL-60 system parallels their known relative affinities for the well characterized 1,25-dihydroxyvitamin D3 receptor in chick intestine, providing further evidence that this function of 1,25-dihydroxyvitamin D3 is receptor mediated.

Calcitriol↗
PubMed1987

A new tritium-release assay for 25-hydroxyvitamin D-1 alpha-hydroxylase.

A new, rapid assay for 1 alpha-hydroxylase has been developed using 25-hydroxy-[1 alpha-3H]vitamin D3 as the substrate. Using the solubilized and reconstituted chick 1 alpha-hydroxylase, conversion of this substrate to 1,25-dihydroxyvitamin D3 causes the release of tritium into the aqueous medium. This 3H2O can be easily separated from the labeled substrate by passing the reaction mixture through a reverse-phase silica cartridge. The release of tritium is stereospecific as evidenced by the lack of 3H2O formed when 25-hydroxy-[1 beta-3H]vitamin D3 is used as the substrate. In parallel reactions containing the 25-hydroxy-[26,27-3H]vitamin D3 substrate, production of labeled 1,25-dihydroxyvitamin D3 was assessed by extraction and high-performance liquid chromatography and found to agree very closely with the amount of 3H2O produced from 25-hydroxy-[1 alpha-3H]vitamin D3, validating the accuracy of the new assay. Finally, a major advantage of the tritium-release assay for 1 alpha-hydroxylase is that the results are not affected by further metabolism of the 1,25-dihydroxyvitamin D formed in the incubations.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1984

Chemical synthesis of (24R)-24,25-dihydroxy[26,27-3H]vitamin D3 of high specific activity.

Chemical synthesis of (24R)-24,25-dihydroxy-[26,27-3H]vitamin D3, and its 24-epimer has been devised that allows introduction of 3H at the terminal step of the synthesis. The epimeric mixture is derivatized as the tris(trimethylsilyl) ethers and resolved by high-performance liquid chromatography. The product has a specific activity of 178 Ci/mmol and is fully active in binding to the rat plasma vitamin D binding protein and in the elevation of serum calcium levels of vitamin D deficient rats. The synthesis begins with the readily available 3 beta-hydroxy-5-cholenic acid methyl ester and involves a Pummerer rearrangement, introduction of the delta 7, irradiation, and isolation of the 26,27-dinor-25-carboxylic acid methyl ester of vitamin D3. This compound is then treated with a Grignard reagent containing 3H (80 +/- 10 Ci/mmol).

24,25-Dihydroxyvitamin D 3↗
PubMed1984

Sustained normoglycemia in newly diagnosed type I diabetic subjects. Short-term effects and one-year follow-up.

The impact on remission of normalizing blood glucose levels immediately after diagnosis of type I diabetes was studied in 14 adolescents. Accordingly, in this randomized prospective primary intervention study, 7 of the subjects (i.v. group) received insulin by continuous intravenous (i.v.) infusion via a portable preprogrammed system for 28-62 days and 7 (s.c. group) received conventional subcutaneous (s.c.) therapy. Before therapy, the two groups did not differ significantly with respect to glycosylated hemoglobin, fasting plasma C-peptide, or 24-h urinary C-peptide excretion. During the infusion period, the overall mean fasting plasma glucose (FPG) concentration for the i.v. group was 84 mg/dl with a mean coefficient of variation of 18 +/- 4% (mean +/- SD). During the comparable period for the s.c. group, the mean FPG was 253 mg/dl with a coefficient of variation of 30 +/- 20%. Twenty-four-hour urinary glucose excretions for the two groups were 0.29 +/- 0.06 (mean +/- SEM) and 59 +/- 11 g/day, respectively. Daily insulin requirements in the i.v. group decreased from 1.47 +/- 0.19 U/kg body wt/day at the start to 0.47 +/- 0.10 U/kg/day at the end of the infusion period. Notably, 10-25 days after the infusion period, 5 of 7 subjects experienced a further decrease to a low of 0.27 +/- 0.01 U/kg/day. The mean peak and low requirements in the s.c. group were 0.71 +/- 0.15 and 0.33 +/- 0.13 U/kg/day, respectively, with the only peak requirements being significantly different (P less than 0.01). No patient was able to discontinue insulin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1984

Long term open loop intravenous insulin infusion in type I diabetes: feasibility, problems and promise.

The response of four Type I diabetic patients to long term (1,4,4, and 8 months) intravenous insulin infusion is reported. As compared to their usual subcutaneous depot insulin treatment, glycosylated hemoglobin (HbAl) decreased from 12.2 +/- 0.7 to 8.8 +/- 0.9 (p less than 0.05). However, only 49 to 76.5% of self blood glucose monitoring results were between 60-179 mg/dl range. Although 6.3 to 15.2% of capillary blood glucose levels were less than 60 mg/dl, severe hypoglycemia occurred only on one occasion. Plasma cholesterol, triglyceride and high density lipoprotein all decreased significantly (p less than 0.005). The major motivating factors for participation in this study were: (1) the hope of preventing diabetic complications; (2) the wish for more knowledge about diabetes; (3) a sense of special purpose and (4) a general interest in science and research. Catheter obstruction as a result of insulin aggregation terminated the study in two subjects. A third subject requested the study be stopped primarily because of imposed travel restrictions. In one subject, the study was stopped because of a disrupted personal life and developing depression. Diabetic ketoacidosis or sepsis from the centrally placed intravenous catheter did not occur. Although long term intravenous insulin infusion is feasible in a clinical research setting, insulin aggregation continues to be a major limiting factor. The widespread clinical use of implantable pumps will have to await the development of a suitable insulin formulation.

Adult↗
PubMed1983

Unanticipated amyloidosis in dogs infused with insulin.

Highly purified regular porcine insulin was given by portable insulin pumps through indwelling vena caval catheters to 17 (13 normal, and 4 pancreatectomized) dogs initially weighing 15 +/- 2 kg at rates ranging from 2 to 10 mU/min (total 17-250 mg) over time periods ranging from 37 to 252 days. During the course of the study, many of the animals lost weight and became anemic. Since these conditions persisted and weight loss progressed even after cessation of insulin infusion, as many of the dogs as possible (15 of 17) were autopsied for microscopic studies. Large amounts of amyloid were demonstrated in the liver, kidney, spleen, and/or pancreas in 55% (6/11) of normal, and in 75% (3/4) of pancreatectomized dogs. The amyloid deposits were Congo red positive, exhibited classical apple green fluorescence under polarized light, and possessed the characteristic ultrastructural features of amyloid. Massive deposits of amyloid were observed in animals receiving as little as 17 mg of insulin over a time span of 52 days. In those animals with hepatic amyloid, marked hepatomegaly was present (i.e., 1200 +/- 250, X +/- SD, versus 300 +/- 25 g for normal animals) and preterminal serum alkaline phosphatase levels were markedly elevated (434 +/- 285 versus 30 +/- 14 IU/L for animals without hepatic amyloid). The magnitude of the hepatic amyloid deposits precludes the possibility that they represent insulin aggregates or insulin-derived products per se. No evidence of amyloid was present in any of the tissue biopsy specimens obtained prior to insulin infusion. Moreover, the possibility that this represents an immune response to the injected porcine insulin has to be viewed in light of the fact that the amino acid sequences of dog and porcine insulins are identical. It is of particular interest that the affinity of the amyloid deposits for Congo red stain was totally abolished by prior permanganate treatment, suggesting that the amyloid was derived from serum amyloid A protein rather than from immunoglobulin light chains or insulin aggregates per se. Further evidence that the protein was of the AA-type came from the initial biochemical characterization. Gel filtration on Sephadex G100 in 6 M guanidine hydrochloride identified two small molecular weight peaks of about 13,000 and 25,000 daltons, both of which inhibited the radioimmunoassay for human AA protein.(ABSTRACT TRUNCATED AT 400 WORDS)

Amyloid↗
PubMed1982

Steroid diabetes in childhood.

Hyperglycemia and glycosuria are known to occur in some children receiving corticosteroids. In a retrospective study 24 such episodes were identified in 17 patients receiving steroids for a variety of primary diseases from 1968 to 1979. Detection based on symptoms averaged 26 days from initiation of steroid treatment, whereas detection based on the presence of glycosuria or hyperglycemia averaged 4.5 days. Acidosis, ketosis, and hyperglycemia (glucose level, greater than 500 mg/dL) occurred in 2, 4, and 8 patients, respectively. Insulin therapy was necessary in 15 episodes in 11 patients, but in three episodes the insulin dosage was reduced while the steroid dosage remained high. Permanent insulin dependence developed immediately in one patient and eventually in three others. Steroid-precipitated diabetes must be anticipated but should not interfere with the treatment of the primary disease.

Adolescent↗
PubMed1981

A physiological solvent for crystalline insulin.

Insulin is insoluble in water at physiological pH, but dissolves relatively rapidly in plasma. To quantify the ability of various solutions to dissolve crystalline insulin, a simple assay measuring dissolution time was developed. At pH 7.5 and room temperature, distilled water, 0.154 mol/l NaCl, Ringer's lactate solution, and 5% albumin in 0.154 mol/l NaCl did not dissolve insulin crystals within 30 min. Normal postprandial human plasma and a protein-free cell culture medium dissolved insulin crystals within 3 to 8 min. This ability was inhibited by acid titration of the fluids to a stable pH of 6.30, at which point bicarbonate depletion could be implied. Repletion of bicarbonate did restore the ability of these solutions to dissolve insulin crystals, but back-titration to the initial pH with NaOH did not. The effect of sodium bicarbonate alone was strongly concentration dependent above 23 mmol/l. We suggest that the ability of physiological fluids to dissolve insulin crystals at normal pH depends on their bicarbonate content. The ability to dissolve insulin with a physiological solvent which prevents its reaggregation promises to facilitate its use in portable pumping systems.

Adult↗
PubMed1980

Clinical and surgical aspects of hypothalamic hamartoma associated with precocious puberty in a 15-month-old boy.

A case is reviewed of precocious puberty associated with hypothalamic hamartoma in a 15-month-old boy. The authors believe this to be the first documented case in which significant reductions occurred in the level of serum testosterone and in the result of the luteinizing hormone-releasing hormone (LHRH) infusion test following surgical removal of the tumor. Such surgery appears to be safe when a planned microsurgical course is employed.

Follicle Stimulating Hormone↗
PubMed1980

Nonaggregating insulin solutions for long-term glucose control in experimental and human diabetes.

A physiologic additive for dissolving insulin crystals for parenteral application has been found. Insulin crystals are relatively insoluble in simple aqueous solutions. They will dissolve, however, in highly acidic solutions, but these are not suitable for parenteral use. Both neutral and acid pH insulin solutions have a tendency for the dissolved hormone to reaggregate. Notwithstanding possible changes in biologic activity, such formed aggregates must be prevented because they interfere with the flow in portable insulin delivery devices and result in the loss of glycemic control. The addition of 1.5% autologous serum to the aqueous diluent for insulin has eliminated these difficulties and increased by 37% the apparent biologic activity of insulin solutions prepared in this way. With this additive, continuous uninterrupted intravenous insulin infusion has provided near ideal blood glucose control in four pancreatectomized dogs for 5 mo and four patients with juvenile-onset diabetes for 18--23 days. Serum apparently contains factor(s) that promote the dissolution of insulin and prevent the formation of peptide aggregates in dilute solutions.

Adolescent↗
PubMed1978

Circulating alanine production and disposal in healthy subjects.

UNLABELLED: Circulating-alanine production and disposal rates were estimated in eight healthy postabsorptive subjects by means of U-14C alanine and U-14C glucose infusions. The mean circulating-alanine production rate was 368 +/- S.E.M. 28 mumol/min. -1.8(2). Approximately 50 percent of circulating-alanine carbon exchanged rapidly with that of circulating lactate. Approximately 30 per cent of circulating alanine exchanged with protein stores. Other disposal was 29 +/- 2 per cent to circulating glucose and 40 +/- 4 per cent to oxidation. CONCLUSIONS: (1) The carbon moieties of circulating alanine and lactate are freely exchangeable. (2) Assessment of the contribution of alanine to gluconeogenesis will depend on establishing the extent to which the precursor pyruvate carbon is derived from glycolysis or from proteolysis. (3) If the principal pyruvate precursor is glycolysis, then the principal specific function of the glucose-alanine cycle appears to be ammonia transport.

Aged↗
PubMedDate not supplied

Frequency and characteristics of lingual thyroid not detected by screening.

Four patients with lingual thyroid glands presenting beyond the neonatal period have been evaluated at the Hospital for Sick Children, Toronto since the advent of neonatal TSH screening. All were female, clinically euthyroid at diagnosis and presented with symptoms of a lingual mass. We estimate that 1.6% of lingual thyroids are missed by this TSH based thyroid screening program and approximately 1/600,000 live births present in childhood or adolescence with a lingual thyroid. Physicians should still include lingual thyroid in the differential diagnosis of a mass at the base of the tongue.

Child↗
PubMedDate not supplied

Controlled crossover study of subcutaneous and intravenous insulin infusion in type I diabetes.

Various routes of insulin infusion have been utilized to improve metabolic control in type I (insulin-dependent) diabetes. To determine the relative effectiveness of subcutaneous (SC) and intravenous (IV) systems of insulin-pump therapy, we studied five type I diabetic subjects aged 20-39 yr who were randomly assigned to a 3-mo period of either SC or IV insulin infusion and then crossed over to the alternate route for a similar period. After an initial 7- to 14-day period of in-hospital insulin-dose adjustment, all subjects were similarly followed as outpatients during both infusion periods, with a minimum of four daily preprandial self-measurements of blood glucose. Although the overall mean levels of blood glucose and HbA1c (116 +/- 6 vs. 114 +/- 5 mg/dl and 6.1 +/- 0.2 vs. 5.9 +/- 0.1% for the SC and IV systems, respectively) were similar, there was a greater incidence of low (less than 50 mg/dl) and high (greater than 180 mg/dl) preprandial blood glucose readings during SC- than during IV-pump therapy (P less than .05). Furthermore, the frequency of nocturnal and preprandial hypoglycemia was greater during SC-pump therapy (P less than .05 and P less than .02, respectively). Eight documented technical problems related to the pump and catheter occurred with the SC system, whereas 17 episodes occurred with the IV system. The number of episodes of ketosis (4 vs. 5 for SC and IV, respectively) was similar with both systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗