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Biomedical subjects

R E Weiss

Publications and source records attributed to R E Weiss.

At least 19 recordsLinked to original sources
PubMed1996

Mineralocorticoid insufficiency due to suramin therapy.

BACKGROUND: During a Phase I trial of suramin, a novel antineoplastic agent with activity against hormone-refractory prostate carcinoma, the authors observed two patients with clinical mineralocorticoid insufficiency in spite of hydrocortisone replacement therapy. METHODS: The authors retrospectively assessed adrenal cortical function in 20 such patients via adrenocorticotropic stimulation testing, measuring both cortisol and aldosterone responses, either at the time or treatment of immediately after discontinuation of treatment. RESULTS: Two of 9 patients (22%) treated at relatively low dose levels (< or = 1200 mg/m2 on Day 1) demonstrated adrenal cortical insufficiency, as compared with 9 of 11 patients (32%) treated with relatively high doses (> 1200 mg/m2 on Day 1) (P = 0.03 by 1-tailed Fisher's exact test). There appeared to be a cumulative dose-response relationship to the development of glucocorticoid insufficiency, with no instances being observed at doses < 4.8 g/m2 and uniform toxicity occurring at doses > 7.6 g/m2. Long term glucocorticoid insufficiency was present in 1 of 5 patients (20%) tested at an interval of > 90 days after discontinuation of suramin treatment. All instances of glucocorticoid insufficiency were associated with mineralocorticoid insufficiency. Suramin did not affect the absorption or excretion of exogenously administered glucocorticoid in one patient. CONCLUSIONS: Suramin causes both primary mineralocorticoid and primary glucocorticoid insufficiency. This may occur in a dose-dependent manner. Long term glucocorticoid insufficiency appears to occur in a minority of patients treated with low doses of suramin. Patients receiving high doses of suramin for treatment of advanced carcinoma should receive at least physiologic replacement doses of both mineralocorticoid and glucocorticoid. Higher doses of glucocorticoid may be required in selected patients.

Addison Disease↗
PubMed1996

Penile replantation using the leech Hirudo medicinalis.

A 37-year-old chronic schizophrenic man underwent penile replantation after complete autoamputation using a kitchen knife. We report the first case of using medicinal leeches to salvage a penile replant after the development of postoperative venous congestion.

Adult↗
PubMed1996

Effect of thyroid hormone on growth. Lessons from the syndrome of resistance to thyroid hormone.

Thyroid hormone deprivation results in deleterious effects on bone growth. The delayed bone development is mediated by a direct effect of thyroid hormone on bone and an indirect effect of the hormone on GH release and IGF-1 action. Both TR alpha and TR beta are expressed in bone cells. To examine the role of TR beta on bone, we have reviewed the growth abnormalities in the human syndrome of RTH caused by mutations in the TR beta gene. The mutant TR beta reduces the tissue responsiveness to thyroid hormone, producing in some tissues variable degrees of thyroid hormone deprivation. With regard to bone, relative thyroid hormone deficiency caused by the mutant TR beta produces short stature and delayed bone growth but does not attenuate growth to the extent that absolute thyroid hormone deficiency does. These observations indicate that an intact TR beta is required for normal bone development and growth.

Bone and Bones↗
PubMed1996

Mutation in the thyroid hormone receptor (TR) beta gene (M313T) not previously reported in two unrelated families with resistance to thyroid hormone (RTH).

Two families expressing the RTH phenotype and harboring the same mutation in the TRbeta gene are described. Five and four affected members in each family were investigated as well as a total of 12 unaffected relatives. The mutation, a T to C transition of nucleotide 1223 in one allele of affected individuals, results in the replacement of the normal Met for a Thr. Haplotyping revealed that the same mutation developed in each family independently. Whereas attention deficit hyperactivity disorder was associated with RTH in 7 of the 9 affected individuals, it was also present in 2 family members without RTH.

Alleles↗
PubMed1996

Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor alpha or beta genes may be due to a defective cofactor.

Resistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to thyroid hormone. To date, all individuals expressing the RTH phenotype have been found to harbor mutations in the thyroid hormone receptor beta (TR beta) gene that impair T3-mediated function. We describe a unique family in which the dominantly inherited RTH is not associated with abnormalities in the TR beta or TR alpha genes, as determined by gene sequencing and linkage analysis. However, affected family members manifest a severe form of RTH, with reduced responses of thyrotrophs and peripheral tissues requiring 8- to 10-fold the normal replacement doses of L-T4 and L-T3. No other endocrine abnormalities were detected. The defect developed de novo in the proposita and was transmitted to her two children of unrelated fathers. As cultured fibroblasts from the proposita responded poorly to T3 despite a normal concentration of TR, other abnormalities in the mediation of T3 action were sought. Nucleotide sequences of the TSH beta promoter, containing thyroid hormone response elements, and TR-interacting protein 1 were normal. Nuclear extracts (NE) of cultured skin fibroblasts from affected individuals of this family were tested for their interaction with normal TR beta and thyroid hormone response elements by the electrophoretic mobility shift assay. NE from the proposita showed a strong additional band compared to NEs from normal individuals and patients with RTH caused by TR beta mutations or deletion. Far Western analysis of NE from the affected daughter hybridized with labeled TR beta demonstrated an additional band that was not seen in NEs from a normal control or patients with TR beta gene defects. It is concluded that the etiology of RTH is not confined to abnormalities in the TR beta gene. An abnormal cofactor with a specific function in the regulation of thyroid hormone action is probably involved in the expression of the RTH phenotype in this family.

Child, Preschool↗
PubMed1996

A new family with hyperthyroxinemia caused by transthyretin Val109 misdiagnosed as thyrotoxicosis and resistance to thyroid hormone--a clinical research center study.

Serum transthyretin (TTR) is a protein of liver origin that under normal conditions transports approximately 20% T4. Missense mutations of the TTR gene produce familial amyloidotic polyneuropathy and rarely, euthyroid hyperthyroxinemia (EHT). Of the 3 TTR variants so far identified with increased affinity for T4, Ser6, Thr109, and Met119, only TTR-Thr109 has high enough affinity for T4 to produce consistent hyperthyroxinemia in the heterozygous individuals. Because the mutation GCC-->ACC in codon 109 results in the loss of one Bso FI site in exon 4 of the TTR gene, the use of this enzyme was suggested to screen for TR-Thr109 in subjects with EHT. We investigated a family with dominantly inherited EHT, in which two of eight affected members received ablative thyroid treatment for presumed thyrotoxicosis, and one was misdiagnosed as having resistance to thyroid hormone. All affected individuals had serum reverse T3 concentrations above normal and average T4 50% above the mean of unaffected relatives. Total T3 and TSH levels were within the normal range. Although loss of the Bso FI site in one allele of the two TTR suggested the presence of Thr109, gene sequencing revealed a different mutation in the same codon (GCC-->GTC) producing TTR-Val109. T4-binding to TTR-Val109 was compared to that of the normal TTR-Ala109 and the formerly identified variant TTR-Thr109. Association constants were 1.3, 9.5, and 13.6 X 10(7) M-1 for TTR-Ala109, Val109, and Thr109, respectively. Thus, for equally expressed mutant and normal allele and 20% of serum T4 bound to TTR, the calculated mean serum T4 concentration of heterozygotes for TTR-Val109 should be 50% above the normal mean; the observed value being 55%. These results are in agreement with the observations based on the crystallographic structure of TTR-Thr109 indicating that the extra atoms in Val as in Thr, which are absent in the Ala of the wild type TTR, widen the ligand binding site.

Adolescent↗
PubMed1995

Adult ADHD and AIDS.

Explore the source record for details and available documents.

AIDS Dementia Complex↗
PubMed1995

Linkage of familial dysalbuminemic hyperthyroxinemia to the albumin gene in a large Amish kindred.

Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasians. Transmitted as an autosomal dominant trait, it is always associated with high serum total T4 (TT4) and more rarely with elevated total T3 (TT3) and/or rT3 (TrT3) concentrations. Free T4, by dialysis, and TSH levels are normal, suggesting the presence of a T4-binding protein abnormality. The abnormal serum T4 carrier shares some physical and immunological properties with albumin, suggesting that it may be albumin itself. Here we show linkage between FDH and the albumin gene in a large Amish family of Swiss descent, using as markers a SacI polymorphism in the coding sequence of the albumin gene and the group-specific component (Gc) gene, located less than 1 centimorgan from the albumin gene. Blood samples were obtained from 160 members of this kindred, and 22 had FDH identified by the pattern of T4 binding to serum proteins separated by isoelectric focusing. Serum TT4 values were above the normal range in all subjects expressing the FDH phenotype, and TrT3 levels were above the normal range in only one half. TT4 concentrations correlated positively with TrT3 and TT3. All TT3 values were, however, within the normal range. Free T4 and TSH levels were normal, confirming the euthyroid state in these subjects. FDH was associated with the albumin SacI(+)/Gc 1S haplotype, yielding a LOD (logarithm of the odds ratio) score of 5.53, with a recombination frequency of 0. These data provide strong support that a variant albumin is the cause of FDH in this kindred.

Base Sequence↗
PubMed1995

Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-beta receptors?

Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone, is linked to mutations in the thyroid hormone receptor-beta (TR beta) gene. The purpose of this study was to determine whether the clinical phenotypes of RTH can be translated in terms of functional impairment of the corresponding mutant TR beta. Data from 124 subjects with RTH representing 18 different mutant TR beta s, showed that serum free T4 levels correlated with the degree of T3-binding impairment of the corresponding TR beta in 12 of these mutant TR beta s (group I), but not in the remaining 6 (group II). In subjects from both groups studied in detail by the administration of incremental doses of T3, the degree of thyrotroph resistance to T3 correlated with the magnitude of endogenous free T4 elevation at baseline, but did not parallel the resistance of peripheral tissues. In transfection studies, all group I mutant TR beta s inhibited positive transactivation by the wild type TR beta s to a similar degree in the presence of 1 nmol/L T3, whereas group II mutant TR beta s exerted a weaker inhibition that was not related to their T3-dependent trans-activation when tested alone. Similar results were obtained with negatively regulated reporter genes. It is concluded that the clinical severity of RTH, determined by thyrotroph resistance, can be predicted from the degree of T3 binding impairment and dominant negative potency of mutant TR beta s, but the degree of peripheral tissue resistance and related clinical manifestations is limited by putative genetic or environmental factors that modulate the effect of thyroid hormone.

Adolescent↗
PubMed1995

Neurocognitive characteristics of individuals with resistance to thyroid hormone: comparisons with individuals with attention-deficit hyperactivity disorder.

Previous studies have demonstrated an association between resistance to thyroid hormone (RTH) and attention-deficit hyperactivity disorder (ADHD). To determine if the neurocognitive characteristics in individuals with RTH are similar to those observed in ADHD, 12 children with RTH from 7 families were matched to 12 children with ADHD without RTH. Subjects were administered standardized intellectual, developmental, and school achievement tests. Parent and teacher ratings of children's hyperactivity and attention were similar for both groups, as were measures of attention, impulsivity, and verbal IQ. Children with RTH displayed lower nonverbal intelligence (performance IQ = 85) and academic achievement (> 1-2 SD below the mean) when compared with those with ADHD only (performance IQ = 99; achievement within 2 SD). Although children with RTH have behavioral characteristics similar to those with ADHD, their significantly weaker abilities of perceptual-organization and lower school achievement suggest a more severe neurobehavioral impairment than ADHD.

Adolescent↗
PubMed1994

An identical missense mutation in the albumin gene results in familial dysalbuminemic hyperthyroxinemia in 8 unrelated families.

Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common form of inherited increase of serum thyroxine in Caucasians. It is the result of increased thyroxine-binding to serum proteins and is inherited as a dominant trait. The entire coding region of the albumin gene of a subject with FDH was sequenced. A single nucleotide substitution, G to A transition in codon 218, was found in one of the two alleles, resulting in the replacement of the normal Arg with His. This mutation was found in 9 affected family members but not in 8 unaffected relatives and 18 unrelated normal individuals. The same missense mutation was found in 12 other subjects with FDH belonging to 7 unrelated families. In every individual with FDH, the mutation was associated with the Sac I+ polymorphism in the albumin gene, strongly suggesting a founder effect.

Arginine↗
PubMed1994

Persistent maternal hydronephrosis after intra-abdominal pregnancy.

Pregnancy presents a wide range of difficult urological management problems. We report a unique case of a term intra-abdominal pregnancy complicated by persistent hydronephrosis after cesarean section. Intra-abdominal placenta degeneration was monitored by serial serum beta-human chorionic gonadotropin values. Hydronephrosis ultimately resolved with conservative management.

Adult↗
PubMed1994

Resistance to thyroid hormone in subjects from two unrelated families is associated with a point mutation in the thyroid hormone receptor beta gene resulting in the replacement of the normal proline 453 with serine.

Resistance to thyroid hormone (RTH) is a condition of impaired tissue responsiveness to thyroid hormone characterized by elevated free thyroid hormone levels in serum accompanied by nonsuppressed TSH. RTH has been associated with mutations in the thyroid hormone receptor (TR) beta gene. We report studies carried out in 9 members of a family (F94) of Jewish ethnic origin and a single subject of Mexican origin. All subjects fulfilling the criteria of RTH (6 of family F94 and one of family F27) had the same point mutation in the T3-binding domain on one of the two alleles of the TR beta gene. This mutation resulted in the replacement of the normal proline-453 with serine (P453S). Nevertheless, the clinical characteristics of affected members of each of the two families differed as did the severity of hormonal resistance in terms of responses to the administration of L-T3. Genetic studies indicate that the same mutation occurred independently in each of the two families.

Adult↗
PubMed1994

A new point mutation (C446R) in the thyroid hormone receptor-beta gene of a family with resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) is a condition of impaired end-organ responsiveness to thyroid hormone characterized by goiter and elevated thyroid hormone levels with an inappropriately normal TSH. RTH has been associated with mutations in the thyroid hormone receptor-beta (TR beta) gene. We report studies carried out in 21 members of a family (F119), 12 of whom exhibited the RTH phenotype. A point mutation was detected in the T3-binding domain of the TR beta gene. It resulted in replacement of the normal cysteine-446 with an arginine (C446R) that has not been previously reported. The clinical characteristics of this family are similar to those reported in other families with RTH, namely goiter, tachycardia, and learning disabilities. Thyroid function tests are also typical of other subjects with RTH. The mean values (+/- SD) in untreated affected subjects compared to those in unaffected family members were: free T4 index, 250 +/- 21 vs. 108 +/- 13; total T3, 4.3 +/- 0.4 vs. 2.4 +/- 0.4 nmol/L; and TSH, 4.5 +/- 1.1 vs. 2.4 +/- 1.1 mU/L. DNA samples from 18 family members were screened for the TR beta mutation, which results in the loss of a BsmI restriction site, and each of the 11 subjects with abnormal thyroid function tests were heterozygous for the mutant allele. The mutant TR beta expressed in Cos-I cells did not bind T3 (Ka of C446R/wild-type, < 0.05). T3 at a concentration up to 100 nmol/L failed to enhance the transactivation of a reporter gene, and the mutant receptor inhibited the T3-mediated transcriptional activation of the wild-type TR beta.

Adolescent↗
PubMed1994

Low intelligence but not attention deficit hyperactivity disorder is associated with resistance to thyroid hormone caused by mutation R316H in the thyroid hormone receptor beta gene.

Resistance to thyroid hormone (RTH) is a syndrome of reduced responsiveness of tissues to thyroid hormone. The clinical manifestations are variable and 46-50% of children with RTH have attention deficit hyperactivity disorder (ADD). We present a new family with RTH (F120) found to have a mutation R316H in the thyroid hormone receptor beta (TR beta) gene identical for that reported in an unrelated family. Assignment of the mutant allele and haplotyping based on CA repeat polymorphism were done on 16 family members. Semistructured diagnostic interviews and psychometric testing were used to determine the psychiatric diagnosis of 12 family members by examiners blinded to the genotype. Three subjects were identified to have the R316H allele as well as mildly elevated free T4 index (168 +/- 12; normal range 77-135) and nonsuppressed TSH (4.1 +/- 1.7 mU/L). Only 2 of the subjects with RTH were found to have ADD, while one family member homozygous for the wild type TR beta and normal thyroid function tests also had ADD. Unaffected family members had higher full scale intelligence quotients (IQ) (93 +/- 7) than any of the 3 family members with RTH (77 +/- 5, p = 0.006). These data do not support the genetic linkage of ADD and RTH, but do suggest that RTH is associated with lower IQ scores that may confer a high likelihood of exhibiting ADD symptoms.

Adolescent↗
PubMed1993

Attention-deficit hyperactivity disorder and thyroid function.

Attention-deficit hyperactivity disorder (ADHD) is thought to have a biologic basis, but the precise cause is unknown. It is one of the neurodevelopmental abnormalities frequently observed in children with generalized resistance to thyroid hormone (GRTH), suggesting that thyroid abnormalities may be related to ADHD. We report a prospective screening study for thyroid abnormalities in 277 children with ADHD by measurement of serum levels of total thyroxine, free thyroxine index, and thyrotropin. Fourteen children with ADHD had thyroid function test abnormalities: six had a normal free thyroxine index and elevated thyroxine level (group 1); three had a high free thyroxine index and a normal thyrotropin level (group 2); and five had a low free thyroxine index with a normal thyrotropin level (group 3). GRTH could not be demonstrated in a detailed study of four of the subjects in whom it was suspected (groups 1 and 2). Although the prevalence of ADHD in subjects with GRTH has been reported to be 46%, the overall prevalence of GRTH must be less than 1:2500 because we failed to detect GRTH in the 277 children with ADHD studied. We conclude that the prevalence of thyroid abnormalities is higher (5.4%) in children with ADHD than in the normal population (< 1%).

Attention Deficit Disorder with Hyperactivity↗
PubMed1993

Covered exstrophy with sequestered colonic remnant.

We report on a woman who presented with urinary incontinence, covered exstrophy and an abdominal mass. Radiographic studies and cystoscopy confirmed that the anterior abdominal mass did not communicate with the bladder or colon and that the gastrointestinal tract was normal. Subsequent surgical resection of the mass and Young-Dees-Leadbetter bladder neck reconstruction were performed. Histological examination of the mass revealed colonic mucosa. The etiology of the covered exstrophy and sequestered colonic remnant is discussed.

Abnormalities, Multiple↗