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Biomedical subjects

K Perlman

Publications and source records attributed to K Perlman.

At least 19 recordsLinked to original sources
PubMed1995

Savant characteristics in a child with developmental delay and deletion in the short arm of chromosome 20.

The development outcome of a four-year-old boy with a deletion of the short arm of chromosome 20 is described. Despite a number of early medical problems, including infantile hypoglycemic convulsions secondary to growth hormone deficiency and delayed motor and language development, he has been reading (self-taught) since 2.5 years and currently has computer proficiency, and exceptional memory for maps and spatial locations, an extremely rich and active fantasy life, good diction, and an extensive spoken vocabulary. Neuropsychological evaluation revealed low-average intelligence with normal language, memory and attention functions, and impaired visuomotor and graphomotor ability and motor skills. He showed extremely advanced decoding and reading comprehension skills while mathematics, spelling and general knowledge abilities were average.

Achievement↗
PubMed1991

Induction of calbindin-D 9k mRNA but not calcium transport in rat intestine by 1,25-dihydroxyvitamin D3 24-homologs.

The function and precise mechanism of regulation of calbindin-D 9k in intestine is largely unknown. It is suggested that this calcium binding protein is involved in active intestinal calcium transport and that its expression is mainly mediated by 1,25-dihydroxyvitamin D3. We examined the effect of two side chain modified analogs of 1,25-dihydroxyvitamin D3 as compared to 1,25-dihydroxyvitamin D3 itself on the regulation of the calbindin-D 9k at the mRNA level and on intestinal calcium transport in the rat. delta 22-24,24-dihomo-1,25-dihydroxyvitamin D3 at a single dose of 500, 1,000, and 2,000 pmol caused greater than 7.0-fold increase in calbindin-D 9k mRNA without stimulating intestinal calcium transport. A 10,000-pmol dose of delta 22-24,24,24-trihomo-1,25-dihydroxyvitamin D3 caused a 7.6-fold increase in calbindin-D 9k mRNA without significantly increasing intestinal absorption of calcium. In contrast, 1,25-dihydroxyvitamin D3 caused a parallel increase in calbindin-D 9k mRNA and intestinal absorption of calcium. Thus, calbindin 9k is not by itself responsible for 1,25-dihydroxyvitamin D3-mediated increase in intestinal absorption of calcium.

Animals↗
PubMed1990

24-homologated 1,25-dihydroxyvitamin D3 compounds: separation of calcium and cell differentiation activities.

A series of 24-homologated 1,25-dihydroxyvitamin D3 compounds have been chemically synthesized and studied with regard to their activity in inducing differentiation of human promyelocyte HL-60 cells to monocytes and in calcium mobilizing activity in vitamin D deficient rats. Homologation of 1,25-dihydroxyvitamin D3 or its delta 22 analogue by one or two carbons increases by 10-fold and three-carbon homologation reduces by half the activity in causing differentiation of HL-60. On the other hand, homologation causes a substantial decrease in in vivo calcium mobilization activity. The addition of each carbon at the 24-position decreases binding to the HL-60 receptor or rat intestinal receptor by 5-10-fold so that binding affinity of the trihomo compound for the receptors is 130 times less that of 1,25-dihydroxyvitamin D3. Thus, binding affinity for the receptor cannot account for the preferential activity of the 24-homologated compounds in inducing cell differentiation.

Animals↗
PubMed1990

24- and 26-homo-1,25-dihydroxyvitamin D3 analogs: potencies on in vitro bone resorption differ from those reported for cell differentiation.

It has been proposed that the stimulatory effects of 1,25-dihydroxyvitamin D on bone resorption may be mediated through actions on differentiation of marrow cells into monocytic osteoclast precursors. In human promyelocytic leukemia cells (HL-60), 24- and 26-homo-1,25-dihydroxyvitamin D3 and their delta 22 analogs and 24,24-dihomo-1,25-dihydroxyvitamin D3 are 10-fold more potent than 1,25-dihydroxyvitamin D3, and delta 22-24,24,24-trihomo-1,25-dihydroxyvitamin D3 is equipotent with 1,25-dihydroxyvitamin D3 in inducing differentiation into the monocytic phenotype. The effect of these 1,25-dihydroxyvitamin D3 analogous on resorption of fetal rat limb bones in vitro was determined in the present study. 1,25-Dihydroxyvitamin D3 was equipotent with 24-homo-1,25-dihydroxyvitamin D3, delta 22-24-homo-1,25-dihydroxyvitamin D3, 26-homo-1,25-dihydroxyvitamin D3, and delta 22-26-homo-1,25-dihydroxyvitamin D3 for in vitro bone resorption, whereas 24,24-dihomo-1,25-dihydroxyvitamin D3 and delta 22-24,24,24-trihomo-1,25-dihydroxyvitamin D3 were inactive. The failure of these analogs to show a higher bone-resorbing activity than 1,25-dihydroxyvitamin D3 were inactive. The failure of these analogs to show a higher bone-resorbing activity than 1,25-dihydroxyvitamin D3 provides evidence to suggest that the mechanism of 1,25-dihydroxyvitamin D3-induced bone resorption may not involve stimulation of monocytic cell differentiation.

Animals↗
PubMed1990

Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus.

It has been proposed that lowering glomerular pressure in children with insulin-dependent diabetes mellitus will reduce microalbuminuria and that this reduction may preserve renal function. We therefore conducted a double-blind, placebo-controlled, crossover trial to compare 3 months of treatment with the angiotensin converting enzyme inhibitor captopril (0.9 mg/kg/day), and 3 months of placebo administration to 12 normotensive adolescents with insulin-dependent diabetes mellitus, 11 with microalbuminuria (albumin excretion rate of 15 to 200 micrograms/min) and one with early overt nephropathy. Mean age (+/- SD) was 14.4 +/- 1.7 years, and disease duration was 5.1 +/- 2.5 years. Albumin excretion rate decreased significantly during captopril therapy (baseline 78 +/- 114 micrograms/min; mean of monthly measurements 38 +/- 55 micrograms/min vs placebo 78 +/- 140 micrograms/min; p less than 0.001). During captopril therapy, albumin excretion was reduced by 41 +/- 44% and decreased in 10 of 12 subjects, but was unchanged in two, one with a borderline albumin excretion rate (16.3 micrograms/min) and one with diabetes of short duration (2.9 years). Plasma renin activity rose significantly during captopril therapy, and mean arterial pressure decreased slightly (placebo 81 +/- 7 mm Hg; captopril 76 +/- 5 mm Hg; p = 0.004). After 3 months of captopril treatment, glomerular filtration rate and renal plasma flow did not change significantly. Hemoglobin Alc values remained stable during the study. The only side effect of captopril was diarrhea in one patient. We conclude that, in the short term, captopril is effective in decreasing albumin excretion rate in normotensive children with insulin-dependent diabetes mellitus and microalbuminuria, without significant side effects. Longer trials are indicated in an attempt to delay or prevent overt nephropathy.

Adolescent↗
PubMed1989

Severe hypoglycemia in children with insulin-dependent diabetes mellitus: frequency and predisposing factors.

We surveyed 311 children with insulin-dependent diabetes mellitus to evaluate the frequency and characteristics of those children experiencing severe hypoglycemia (defined by an episode of coma, convulsion, or both). The children and their parents completed a questionnaire, and we reviewed the hospital records to confirm reported episodes. Ninety-seven (31%) reported severe hypoglycemia, and a further 50 (16%) reported moderate hypoglycemia requiring the assistance of another person but not resulting in coma or convulsion. In 164 children (53%) there was no history of either moderate or severe hypoglycemia. Sixty-nine (22%) reported the occurrence of more than one severe hypoglycemic episode (range 2 to 20); 52 (16%) reported such an event in a single year. A total of 285 episodes were reported, 39% during sleep and 61% while awake. Children reporting such events tended to have diabetes of longer duration and be younger at the time of the first episode. Hemoglobin A1c concentration at the time closest to the severe episode was significantly lower than in children reporting no hypoglycemia. All families had been taught to use glucagon to reverse severe hypoglycemia at home, but it was available in only 80 of the 97 homes and used in only 30. These data suggest that severe hypoglycemia is common in children with insulin-dependent diabetes mellitus who are treated conventionally. Greater vigilance and education are required both to prevent and to treat severe hypoglycemia in children with insulin-dependent diabetes mellitus.

Adolescent↗
PubMed1988

Counterregulatory hormone responses preserved after long-term intravenous insulin infusion compared to continuous subcutaneous insulin infusion.

The counterregulatory hormone responses of cortisol, growth hormone, glucagon, epinephrine, norepinephrine, and dopamine to a fixed hypoglycemic stimulus (50 mg/dl for 1 h) were studied in five type I (insulin-dependent) diabetic subjects during conventional insulin therapy (CT), after 3 mo of continuous subcutaneous insulin infusion (SC), and after 3 mo of continuous intravenous insulin infusion (IV). During the two infusion periods, the overall mean levels of preprandial blood glucose (116 +/- 6 SC vs. 114 +/- 5 mg/dl IV) and glycosylated hemoglobin (6.1 +/- 2 SC vs. 5.9 +/- 2% IV) were virtually identical, but there were more hypoglycemic episodes and greater variability of preprandial blood glucose levels during SC than with IV. During the last 30 min of the hypoglycemic clamps, the mean levels of epinephrine and cortisol were significantly lower after 3 mo of SC (epinephrine, 268 +/- 80 pg/ml; cortisol, 14 +/- 1 microgram/dl) than with both CT (epinephrine 485 +/- 80 pg/ml; cortisol, 20 +/- 2 micrograms/dl) and IV (epinephrine, 443 +/- 62 pg/ml; cortisol, 19 +/- 2 micrograms/dl)(P less than .05). The mean growth hormone level was significantly (P less than .05) lower after SC (37 +/- 9 ng/ml) than after IV (79 +/- 12 ng/ml), but it did not reach statistical significance compared with CT (66 +/- 12 ng/ml). The mean glucagon, dopamine, and norepinephrine levels during the same period of hypoglycemia were not different when all treatment regimens were compared. We conclude that intensified insulin therapy with SC leads to significant blunting of the counterregulatory hormone response to hypoglycemia, whereas IV does not.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
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↗