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Biomedical subjects

B Glaser

Publications and source records attributed to B Glaser.

At least 37 records · Page 2Linked to original sources
PubMed2001

Recombinant thyroid-stimulating hormone in differentiated thyroid cancer.

Recombinant TSH is effective in providing exogenous TSH stimulation for patients with differentiated thyroid cancer on thyroid hormone-suppressive therapy. It allows for detection of thyroid remnant and metastases by radioiodine scan and by serum thyroglobulin determination. The sensitivity and image quality of the WBS are similar after rTSH and after THSH withdrawal in the majority of patients. The equivalent 100% sensitivity of rTSH- and withdrawal-stimulated serum thyroglobulin measurement alone in identifying patients with radioiodine uptake outside the thyroid bed [38] may eventually lead to more extensive use of serum thyroglobulin testing after rTSH, with more selective application of radioiodine WBS [39]. Currently, a phase IV trial is in progress to evaluate the efficacy of rTSH-stimulated thyroglobulin levels as the primary modality for long-term follow-up of low risk thyroid cancer patients. The use of rTSH prevents the morbidity, metabolic impairment and the risk of tumor progression associated with THST withdrawal, because of shorter exposure time to elevated TSH [38]. Furthermore, it decreases the radiation exposure of healthy tissues due to faster iodine clearance in euthyroidism. rTSH is well tolerated, with transient nausea in 10.5% and headache in 7.3% of patients. No antibodies specific to rTSH were documented, even after multiple courses of the drug. Currently, rTSH is suggested for patients who do not respond to hormone withdrawal or cannot tolerate hypothyroidism. For patients with low risk of tumor recurrence, rTSH-stimulated testing may be used at 6-12 months after postoperative I-131 ablation and with a repeat cycle of rTSH one year later, followed by testing every 3-5 years. In high risk patients, one set of negative I-131 scan and thyroglobulin test results after hormone withdrawal are recommended before using rTSH testing, because of a greater sensitivity of the withdrawal scan and because rTSH is not currently approved for subsequent I-131 therapy often indicated in these patients [24]. Subsequently, two cycles of rTSH testing are recommended at 6-12 month intervals, followed by testing every 1-3 years for at least the first decade after initial diagnosis. The cost of this commercially available form of rTSH has been considered a major impediment to its common use; however, this should be weighed against the loss of productivity of working hours related to withdrawal [40]. In the therapeutic setting, rTSH is the only acceptable option in a subgroup of patients with hypopituitarism, ischemic heart disease, a history of "myxedema madness," debilitation due to advanced disease, or inability to elicit TSH elevation due to continued production of thyroxine by thyroid remnant or metastatic tumor [33,38]. In conclusion, recombinant TSH facilitates the management of patients with differentiated thyroid carcinoma. It increases the sensitivity of thyroglobulin testing during thyroid hormone suppression therapy and enables radioiodine uptake for whole-body scan and occasionally for radioiodine therapy, without the need for prolonged THST withdrawal and its associated hypothyroidism, reduced quality of life and risk of tumor progression.

Animals↗
PubMed2000

A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene.

Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, vestibular hypofunction and childhood onset retinitis pigmentosa. It is an autosomal recessive condition and is subdivided on the basis of linkage analysis into types 1A through 1E. Usher type 1C maps to the region containing the genes ABCC8 and KCNJ11 (encoding components of ATP-sensitive K + (KATP) channels), which may be mutated in patients with hyperinsulinism. We identified three individuals from two consanguineous families with severe hyperinsulinism, profound congenital sensorineural deafness, enteropathy and renal tubular dysfunction. The molecular basis of the disorder is a homozygous 122-kb deletion of 11p14-15, which includes part of ABCC8 and overlaps with the locus for Usher syndrome type 1C and DFNB18. The centromeric boundary of this deletion includes part of a gene shown to be mutated in families with type 1C Usher syndrome, and is hence assigned the name USH1C. The pattern of expression of the USH1C protein is consistent with the clinical features exhibited by individuals with the contiguous gene deletion and with isolated Usher type 1C.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Hyperinsulinism of the newborn.

Neonatal hyperinsulinism (HI) is a clinical syndrome of pancreatic beta-cell dysfunction characterized by failure to suppress insulin secretion in the presence of hypoglycemia. Although rare, it is the most common cause for persistent hypoglycemia in the newborn period. Treatment can be extremely difficult, and partial pancreatectomy is frequently required to prevent recurrent hypoglycemia and irreversible brain damage. In the last 5 years much has been learned about the pathophysiology of this disease. In most patients, the disease is caused by recessive mutations in either of the 2 functional subunits of the beta-cell KATP channel (SUR1 or Kir6.2). Although in most families, the disease is transmitted as an autosomal recessive trait, a novel form of transmission, resulting in focal involvement of the pancreas has recently been described. Not all patients with HI have mutations in the KATP channel genes. An activating mutation in the "glucose sensor" glucokinase has recently been reported in one family with diazoxide-responsive autosomal dominant hyperinsulinemic hypoglycemia. Also, a new syndrome of hyperinsulinism associated with benign hyperammonemia was recently described and found to be caused by activating mutations in the glutamate dehydrogenase (GDH) gene (GLUD-1). Thus, the clinical syndrome of HI can be caused by mutations in 4 different genes and can be transmitted as either a recessive or a dominant trait. These findings aid in the therapeutic decision-making process and improve the accuracy and precision of genetic counseling. Despite these recent discoveries, however, the metabolic origin of the disease is still unknown in about 50% of cases.

Glucokinase↗
PubMed2000

Calcium-stimulated insulin secretion in diffuse and focal forms of congenital hyperinsulinism.

OBJECTIVES: To identify infants with hyperinsulinism caused by defects of the beta-cell adenosine triphosphate-dependent potassium channel complex and to distinguish focal and diffuse forms of hyperinsulinism caused by these mutations. STUDY DESIGN: The acute insulin response to intravenous calcium stimulation (CaAIR) was determined in 9 patients <20 years with diffuse hyperinsulinism caused by defective beta-cell sulfonylurea receptor (SUR1(-/-)), 3 patients with focal congenital hyperinsulinism (6 weeks to 18 months), a 10-year-old with insulinoma, 5 with hyperinsulinism/hyperammonemia syndrome caused by defective glutamate dehydrogenase (6 months to 28 years), 4 SUR1(+/-) heterozygotes with no symptoms, and 9 normal adults. Three infants with congenital focal disease, 1 with diffuse hyperinsulinism, and the child with insulinoma underwent selective pancreatic intra-arterial calcium stimulation with hepatic venous sampling. RESULTS: Children with diffuse SUR1(-/-) disease and infants with congenital focal hyperinsulinism responded to CaAIR, whereas the normal control group, patients with hyperinsulinism/hyperammonemia syndrome, and SUR1(+/-) carriers did not. Selective arterial calcium stimulation of the pancreas with hepatic venous sampling revealed selective, significant step-ups in insulin secretion that correlated anatomically with the location of solitary lesions confirmed surgically in 2 of 3 infants with congenital focal disease and in the child with insulinoma. Selective arterial calcium stimulation of the pancreas with hepatic venous sampling demonstrated markedly elevated baseline insulin levels throughout the pancreas of the infant with diffuse hyperinsulinism. CONCLUSIONS: The intravenous CaAIR is a safe and simple test for identifying infants with diffuse SUR1(-/-) hyperinsulinism or with focal congenital hyperinsulinism. Preoperative selective arterial calcium stimulation of the pancreas with hepatic venous sampling can localize focal lesions causing hyperinsulinism in children. The combination of these calcium stimulation tests may help distinguish focal lesions suitable for cure by local surgical resection.

ATP-Binding Cassette Transporters↗
PubMed2000

Genetics of neonatal hyperinsulinism.

Congenital hyperinsulinism (HI) is a clinically and genetically heterogeneous entity. The clinical heterogeneity is manifested by severity ranging from extremely severe, life threatening disease to very mild clinical symptoms, which may even be difficult to identify. Furthermore, clinical responsiveness to medical and surgical management is extremely variable. Recent discoveries have begun to clarify the molecular aetiology of this disease and thus the mechanisms responsible for this clinical heterogeneity are becoming more clear. Mutations in 4 different genes have been identified in patients with this clinical syndrome. Most cases are caused by mutations in either of the 2 subunits of the beta cell ATP sensitive K(+) channel (K(ATP)), whereas others are caused by mutations in the beta cell enzymes glucokinase and glutamate dehydrogenase. However, for as many as 50% of the cases, no genetic aetiology has yet been determined. The study of the genetics of this disease has provided important new information about beta cell physiology. Although the clinical ramifications of these findings are still limited, in some situations genetic studies might greatly aid in patient management.

B-Lymphocytes↗
PubMed2000

Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators.

Glutamate dehydrogenase (GDH) is allosterically activated by the amino acid leucine to mediate protein stimulation of insulin secretion. Children with the hyperinsulinism/hyperammonemia (HI/HA) syndrome have symptomatic hypoglycemia plus persistent elevations of plasma ammonium. We have reported that HI/HA may be caused by dominant mutations of GDH that lie in a unique allosteric domain that is encoded within GDH exons 11 and 12. To examine the frequency of mutations in this domain, we screened genomic DNA from 48 unrelated cases with the HI/HA syndrome for exon 11 and 12 mutations in GDH. Twenty-five (52%) had mutations in these exons; 74% of the mutations were sporadic. Clinical manifestations included normal birth weight, late onset of hypoglycemia, diazoxide responsiveness, and protein-sensitive hypoglycemia. Enzymatic studies of lymphoblast GDH in seven of the mutations showed that all had reduced sensitivity to inhibition with GTP, consistent with an increase in enzyme activity. Mutations had little or no effect on enzyme responses to positive allosteric effectors, such as ADP or leucine. Based on the three-dimensional structure of GDH, the mutations may function by impairing the binding of an inhibitory GTP to a domain responsible for the allosteric and cooperativity properties of GDH.

Adenosine Diphosphate↗
PubMed2000

Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy.

Hyperinsulinism of infancy (HI), also known as persistent hyperinsulinemic hypoglycemia of infancy, is a rare genetic disorder that occurs in approximately 1 of 50,000 live births. Histologically, pancreases from HI patients can be divided into 2 major groups. In the first, diffuse HI, beta-cell distribution is similar to that seen in normal neonatal pancreas, whereas in the second, focal HI, there is a discrete region of beta-cell adenomatous hyperplasia. In most patients, the clinical course of the disease suggests a slow progressive loss of beta-cell function. Using double immunostaining, we examined the proportion of beta-cells undergoing proliferation and apoptosis during the development of the normal human pancreas and in pancreases from diffuse and focal HI patients. In the control samples, our findings show a progressive decrease in beta-cell proliferation from 3.2 +/- 0.5% between 17 and 32 weeks of gestation to 0.13 +/- 0.08% after 6 months of age. In contrast, frequency of apoptosis is low (0.6 +/- 0.2%) in weeks 17-32 of gestation, elevated (1.3 +/- 0.3% ) during the perinatal period, and again low (0.08 +/- 0.3%) after 6 months of age. HI beta-cells showed an increased frequency of proliferation, with focal lesions showing particularly high levels. Similarly, the proportion of apoptotic cells was increased in HI, although this reached statistical significance only after 3 months of age. In conclusion, we demonstrated that islet remodeling normally seen in the neonatal period may be primarily due to a wave of beta-cell apoptosis that occurs at that time. In HI, our findings of persistently increased beta-cell proliferation and apoptosis provide a possible mechanism to explain the histologic picture seen in diffuse disease. The slow progressive decrease in insulin secretion seen clinically in these patients suggests that the net effect of these phenomena may be loss of beta-cell mass.

Age of Onset↗
PubMed1999

Intragenic single nucleotide polymorphism haplotype analysis of SUR1 mutations in familial hyperinsulinism.

Familial hyperinsulinism (HI; MIM# 256450) is an autosomal recessive disorder of pancreatic beta-cell function, characterized by inadequate suppression of insulin secretion despite severe recurrent fasting hypoglycemia. Subtotal pancreatectomy is frequently required to prevent permanent neurologic sequelae. The incidence of HI in the Caucasian population is estimated at 1:50,000, however an apparent increased incidence among Ashkenazi Jews and Saudi Arabian Arabs has been reported. A locus for HI was assigned by linkage analyses to human chromosome 11p15.1. The sulfonylurea receptor (MIM# 600509, SUR1) and the potassium channel, inwardly rectifying, subfamily J member 11 (MIM# 600937, KIR6.2) genes, 2 components of the beta-cell K(ATP) channel, are clustered in this chromosomal region, and mutations in these genes have been implicated in HI. We previously demonstrated that two mutations in the SUR1 gene are present on approximately 88% of HI-associated chromosomes in Ashkenazi Jewish patients. Haplotype analysis with microsatellite markers flanking the gene revealed that one mutation (delF1388), reported only in Ashkenazi probands, occurred on two related extended haplotypes. By contrast, the second, more common mutation (3992-9g-->a) was associated with nine different intergenic haplotypes and has been reported in non-Jewish HI patients as well. In this study, we evaluated disease-associated chromosomes from 41 Ashkenazi Jewish and 2 non-Jewish HI patients carrying the 3992-9g-->a mutation by assessing haplotypes defined by nine common single nucleotide polymorphisms (SNPs), six in the SUR1 gene, and three in the KIR6.2 gene. Our results indicate that all 54 chromosomes carrying the 3992-9g-->a mutation in the Jewish patients appear to have originated from one founder mutation, whereas the same mutation on chromosomes from non-Jewish patients originated independently. Furthermore, our findings have implications concerning the HI-associated chromosomes on which no mutation has been identified.

ATP-Binding Cassette Transporters↗
PubMed1999

Neonatal Hyperinsulinism.

Hypoglycemia as a result of hyperinsulinism in the newborn (HI) is a clinically heterogeneous entity that presents a diagnostic and therapeutic challenge to the treating physician. Recent discoveries have shown that mutations in four different beta-cell genes cause HI. However, for many HI patients, the molecular etiology is unknown, and other genes might be involved. The study of the molecular biology of HI has led to a better understanding of pancreatic beta-cell physiology. In the future, this might result in the development of novel drugs for the treatment of both hyperinsulinism and non-insulin-dependent diabetes.

Journal Article↗
PubMed1999

Somatostatin receptor scintigraphy for early detection of regional and distant metastases of medullary carcinoma of the thyroid.

Three patients are described who had regional and distant metastases of medullary thyroid cancer detected by somatostatin receptor scintigraphy but not by CT; two had minimal disease that was amenable to surgery. The first patient had been followed for 2 years before having a repeated scan and positive CT, with subsequent surgical removal of metastatic paratracheal nodes. The plasma calcitonin level, however, did not approach normal values after surgery, and a third scan showed persistence of focal uptake in the left paratracheal area of the lower neck, whereas CT was negative. At repeated exploration, a tumor mass of medullary carcinoma, embedded in lymphatic tissue, was removed. Nine months after the last surgical procedure, calcitonin and carcinoembryonic antigen levels were normal. The second patient underwent microdissection of the mediastinum and removal of two metastatic nodes that were demonstrable only by the scintigraphic technique. The plasma calcitonin level subsequently became normal. The third patient, with multiple endocrine neoplasia IIB and associated pheochromocytoma, had bony metastatic involvement of the left shoulder, demonstrable initially on somatostatin receptor scintigraphy and subsequently with radioiodinated metaiodobenzylguanidine but not on CT.

3-Iodobenzylguanidine↗
PubMed1999

Sulfate transport is not impaired in pendred syndrome thyrocytes.

Pendred syndrome is the most common form of syndromic deafness, characterized by dyshormonogenic goiter associated with sensory-neural deafness. The gene responsible for the disease (PDS) has been cloned, but its function is as yet unknown and the connection between thyroid goiter and sensory-neural deafness remains an enigma. PDS codes for a novel protein, pendrin, which is closely related to a number of sufate transporters. Mechanisms by which abnormal sulfate transport could deleteriously affect iodide organification have been proposed. We tested sulfate transport in thyrocytes obtained from Pendred syndrome patients and found that it was not defective. This suggests that pendrin in fact may not be a sulfate transporter, and emphasizes the importance of functional studies on this novel protein.

Biological Transport↗
PubMed1999

Hyperinsulinism caused by paternal-specific inheritance of a recessive mutation in the sulfonylurea-receptor gene.

Neonatal hyperinsulinism (HI) is a genetic disorder of pancreatic beta-cells characterized by failure to suppress insulin secretion in the presence of hypoglycemia, resulting in brain damage or death if not adequately treated. Germline mutations in four genes have been associated with HI. Some patients have focal regions of beta-cell proliferation (focal HI). Seventy HI probands in whom at least one SUR-1 mutation was identified were studied. Clinical data from patients with two SUR-1 mutant alleles were compared with those from patients with single paternally inherited mutations. Thirty-seven probands were homozygous or compound heterozygous for SUR-1 mutations. In 33 probands, only a single mutation was identified, and in 31, the parental origin of the proband could be determined; in 29, the mutation was on the paternal allele (P < 0.0002). For three of these, pancreatic tissue was available and showed focal beta-cell hyperplasia. DNA extracted from the focal lesion and adjacent normal pancreas revealed loss of the maternal chromosome 11p15, resulting in reduction to homozygosity for the SUR-1 mutation within the focal lesion only. Using the Tdt-mediated dUTP nick end labeling (TUNEL) reaction, apoptotic beta-cells were identified exclusively within the focal region. At diagnosis, disease severity was similar in patients with paternally inherited mutations and those with two mutations. For patients who did not undergo surgery, those with only paternal mutations entered clinical remission within 16 +/- 6.2 months, compared with 48 +/- 23 months for those with two SUR-1 mutations (P = 0.001). In conclusion, we identified a novel mechanism to explain the pathophysiology of focal HI and provide evidence to suggest that this entity may be self-limiting, since affected beta-cells undergo apoptosis.

ATP-Binding Cassette Transporters↗
PubMed1998

Mapping of the human insulin receptor substrate-2 gene, identification of a linked polymorphic marker and linkage analysis in families with Type II diabetes: no evidence for a major susceptibility role.

Insulin receptor substrate 2 (IRS-2) is a substrate of the insulin receptor and mediates the action of the insulin. Disruption of the IRS-2 gene in mice results in peripheral insulin resistance and relative insulin deficiency. It is therefore possible that defects in the IRS-2 gene contribute to Type II (non-insulin-dependent) diabetes mellitus. We have examined the gene for evidence of linkage to Type II diabetes in Ashkenazi Jewish families. Radiation hybrid panel mapping was used to refine the map position of the IRS-2 gene and, in the absence of polymorphic markers within the gene, to identify nearby markers. The IRS-2 gene was placed 23cR from the marker D13S1265 on chromosome 13q34. 200 affected sib-pairs were genotyped for three markers across the region. Nonparametric linkage analysis (GENEHUNTER) used with this data found no evidence of excess allele sharing in the IRS-2 gene region. We therefore concluded that variation in the IRS-2 gene is unlikely to contribute to Type II diabetes in this discrete Caucasian population.

Animals↗
PubMed1998

Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant.

We describe three families with hypoglycemia caused by familial hyperinsulinism (HI) in whom vertical transmission of the disorder occurred, suggesting autosomal dominant (AD) inheritance. We therefore examined the relationship between the apparent AD disorder and the more common autosomal recessive (AR) form of HI, which has recently been linked to the sulfonylurea receptor on chromosome 11p15.1. The clinical features of the 11 patients with AD HI were milder than those seen in 14 patients with AR HI. Hypoglycemia was readily controlled with either diet alone or with diazoxide in 10 of 11 patients with AD HI but in none of those with the AR form. In one large pedigree, analysis of genomic DNA with polymorphic simple sequence repeat markers excluded linkage of AD HI to the SUR locus in a dominant manner. The possibility of linkage to the SUR locus could not be absolutely excluded in the two smaller pedigrees. None of the published mutations of the SUR gene identified in patients with AR HI were detected in the patients with the AD form. We conclude that the AD form of hyperinsulinism is phenotypically different from the AR variant. The identification of more families with this form of HI may make it possible to locate the responsible gene by the use of linkage analysis.

Adolescent↗