Clear fluid from a thyroid cyst.
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Adult↗
Biomedical subjects
R E Weiss
Publications and source records attributed to R E Weiss.
Search for abnormalities of nuclear corepressors, coactivators, and a coregulator in families with resistance to thyroid hormone without mutations in thyroid hormone receptor beta or alpha genes.
The syndrome of resistance to thyroid hormone (RTH) is characterized by decreased tissue responsiveness to thyroid hormones. Inheritance is usually autosomal dominant due to mutations in the ligand-binding domain or adjacent hinge region of the thyroid hormone receptor beta (TRbeta) gene. Six of 65 families with the RTH phenotype studied in our laboratory had normal TRbeta1 and TRbeta2 gene sequences. Their clinical characteristics were not different from those of subjects with TRbeta gene mutations. Four of the 6 families were amenable to linkage analysis, and TRalpha involvement was excluded. Candidate genes were then evaluated for their possible involvement in the RTH phenotype in these 4 families: 2 coactivators [NCoA-1 (SRC-1) and NCoA-3 (AIB-1)], 2 corepressors (NCoR and SMRT), and a coregulator (RXRgamma). DNA was obtained from 8 affected subjects and 41 of 45 living first degree relatives. In 2 of the 4 families, the mode of inheritance could be determined by pedigree analysis and was found to be autosomal dominant. Linkage analyses were performed using polymorphic markers near or within the 5 candidate genes. When analyses were not informative or linkage could not be excluded, direct sequencing of the genes in question was performed. Involvement of NCoA-1 was excluded in all four families assuming autosomal dominant inheritance. Roles for NCoR, SMRT, and NCoA-3 were excluded in three and a role for RXRgamma was excluded in two of the four families. However, if the two families without proven dominant mode of inheritance were compound heterozygous, only the involvement of NCoA-1 could be excluded in both. Roles for NCoR, SMRT, and RXRgamma were excluded in one of these two families. Thus, NCoA-1 and RXRgamma genes were not found to be the cause of RTH in subjects without TR gene mutations even though the absence of NCoA-1 and RXRgamma is the cause of RTH in mice. Involvement of other candidate genes in the mediation of thyroid hormone action as well as intracellular hormone transport needs to be explored in these families with non-TRbeta, TRalpha RTH.
Animals↗
Failure of membrane targeting causes the functional defect of two mutant sodium iodide symporters.
Molecular cloning of the sodium/iodide symporter (NIS) allowed identification of NIS gene mutations in patients with iodide trapping defect. Whereas various mutant human (h) NIS molecules display loss of function when expressed by transfection in mammalian cells, the precise mechanism(s) responsible for the functional abnormality of these proteins remains unknown. With the aim to explore these mechanisms in three natural hNIS mutants identified previously in patients with iodide trapping defect (Q267E, S515X, and C272X), we have prepared tools allowing direct measurement of the protein at its normal location in the plasma membrane. A COS-7 cell line was made by transfection that stably expressed high levels of wild-type hNIS. It was used to screen by flow cytometry monoclonal antibodies (mAbs) prepared from mice immunized against hNIS. Genetic immunization was performed by im injection of a wild-type hNIS complementary DNA construct, because this procedure has demonstrated the ability to produce antibodies recognizing native membrane proteins. One mAb that recognized an epitope of hNIS exposed on the extracellular side of the plasma membrane was selected for further studies. The epitope was localized on the sixth putative extracellular loop of the protein on the basis that the mAb did not recognize rat NIS, which exhibits major sequence differences in this segment. When this mAb was used to test by flow cytometry the expression of the three mutant hNIS proteins in transfected COS-7 cells, it detected similar amounts of wild-type, Q267E, and the S515X hNIS molecules in permeabilized cells. In contrast, only the wild-type hNIS was detected at the surface of nonpermeabilized cells. The C272X hNIS truncation mutant was not detected in intact or permeabilized cells. This is consistent with the absence of the mAb epitope from this mutant, which is expected to lack the sixth extracellular loop. Our data demonstrate that faulty membrane targeting is implicated in the mechanisms causing iodide trapping defect in the Q267E and S515X natural hNIS mutants.
Animals↗
Familial dysalbuminemic hyperthyroxinemia in a Swiss family caused by a mutant albumin (R218P) shows an apparent discrepancy between serum concentration and affinity for thyroxine.
Familial dysalbuminemic hyperthyroxinemia (FDH), is the most common cause of inherited increase in serum total T4 (TT4) in the Caucasian population. It is caused by a mutation (R218H) in the human serum albumin (HSA) gene, resulting in 10-fold higher affinity for T4 and, in heterozygous affected subjects, a TT4 level 2-fold higher than that in subjects expressing the wild-type HSA only. We now report FDH in a Swiss family, caused by HSA R218P, previously reported in subjects of Japanese origin. In this form of FDH, serum TT4 levels are 14- to 20-fold the normal mean, confirmed by measurements in serum extracts. TrT3 and TT3, concentrations are 7- and 2-fold above the mean, respectively. Thus, to maintain a normal free T4 level, the calculated affinity constant (Ka) of HSA R218P should be about 16-fold higher than that of HSA R218H. Surprisingly, the Ka values measured at saturation were similar: 5.4 x 10(6) and 6.4 x 10(6) mol/L(-1) for HSA R218H, respectively. To determine how subjects with HSA R218P and R218P maintain a euthyroid state despite the markedly high serum TT4, the concentration of dialyzable T4 was measured at increasing amounts of TT4. At a TT4 level equivalent to that found in the subjects with HSA R218P, the absolute FT4 concentrations were 40, 432, and 1970 pmol/L for sera expressing HSAs R218P, R218H, and wild type, respectively. Thus, the affinity of HSA R218P for T4 must be higher than that of R218H to produce an 11-fold difference in FT4 at the same concentration ofTT4 This difference was obliterated at saturating concentrations of TT4 used for the determination of Ka values by the method of Scatchard.
Amino Acid Substitution↗
Total pelvic exenteration and reconstruction for locally invasive recurrent sarcoma of the perineum.
Extensive primary tumors and locally recurrent tumors of the pelvis or perineum are difficult to manage. We describe the techniques necessary to perform total pelvic exenteration with en bloc resection of the perineum and genitalia for treatment of recurrent sarcoma of the perineum. Wide excision of the sarcoma with negative margins can be achieved by resecting the inferior portion of the pubic symphysis. An absorbable mesh sling may be used to suspend the small bowel above the pelvis, facilitating postoperative radiation. A catheterizable continent urinary reservoir avoids the necessity of two stomas and improves quality of life. Adequate tissue coverage can be attained by myocutaneous gracilis flaps that promote wound healing.
Adult↗
On Bayesian calculations for mixture likelihoods and priors.
We present methodology for calculating Bayes factors between models as well as posterior probabilities of the models when the indicator variables of the models are integrated out of the posterior before Markov chain Monte Carlo (MCMC) computations. Standard methodology would include the indicator functions as part of the MCMC computations. We demonstrate that our methodology can give substantially greater accuracy than the traditional approach. We illustrate the methodology using the model selection prior of George and McCulloch applied to logistic regression and to a mixture model for observations in a hierarchical random effects model.
Bayes Theorem↗
Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone.
Steroid receptor co-activator 1 (SRC-1) is a transcription co-factor that enhances the hormone-dependent action, mediated by the thyroid hormone (TH) receptor (TR) and other nuclear receptors. In vitro studies have shown that SRC-1 is necessary for the full expression of TH effect. SRC-1 knockout mice (SRC-1(-/-)) provide a model to examine the role of this co-activator on TH action in vivo. At baseline, SRC-1(-/-) mice display resistance to TH (RTH) as evidenced by a 2.5-fold elevation of serum TSH levels, despite a 50% increase in serum free TH levels as compared with wild-type (SRC-1(+/+)) mice. When mice were made hypothyroid, TSH levels increased, obliterating the difference between SRC-1(+/+) and SRC-1(-/-) mice observed at baseline. In contrast, the decline of TSH by treatment with L-triiodothyronine was severely blunted in SRC-1(-/-) mice. These data indicate that SRC-1 is not required for the upregulation of TSH in TH deficiency. However, SRC-1 enhances the sensitivity of TSH downregulation by TH. This is the first demonstration of RTH caused by a deficient co-factor other than TR. It supports the hypothesis that a putative defect in the SRC-1 gene or another co-factor could be the cause of RTH in humans without mutations in the TR genes.
Animals↗
Female urethral adenocarcinoma: immunohistochemical evidence of more than 1 tissue of origin.
PURPOSE: Urethral adenocarcinoma is a rare malignancy whose origin remains controversial. The monoclonal antibody mAbDas1 (formerly 7E12H12) was developed against a unique colonic epithelial epitope and is reactive in areas of intestinal metaplasia. Recently the antibody was shown to react in cystitis glandularis as well as adenocarcinoma of the bladder, suggesting that cystitis glandularis may be the precursor of bladder adenocarcinoma. We examined urethral adenocarcinomas and benign urethral specimens using mAbDas1 to determine whether it could provide insight into their histogenesis. MATERIALS AND METHODS: Archival tissue from 12 cases of primary female urethral adenocarcinoma and urethral specimens of inflamed urethral mucosa, urethritis glandularis and transitional cell carcinoma was studied. Immunohistochemical analysis of formalin fixed, paraffin embedded archival tissue was done using the monoclonal antibody mAbDas1. Tumors were also evaluated with a prostate specific antigen (PSA) polyclonal antibody as previous studies have noted PSA reactivity in these tumors. RESULTS: Of the 12 cases 9 were columnar/mucinous adenocarcinoma, 2 clear cell adenocarcinoma and 1 a cribriform pattern resembling adenocarcinoma of the prostate. All columnar/mucinous adenocarcinomas reacted positively (6 strongly and 3 focally) with the mAbDas1 antibody but did not react with the PSA antibody. The tumor with a cribriform pattern reacted strongly with PSA but did not react with mAbDas1. The 2 clear cell adenocarcinomas did not react with either antibody. The benign urethral specimens demonstrated strong reactivity to the mAbDas1 antibody in areas of urethritis glandularis but normal and inflamed urethral mucosa and transitional cell carcinoma did not react. CONCLUSIONS: Primary adenocarcinoma of the female urethra arises from more than 1 tissue of origin. Columnar/mucinous adenocarcinomas of the female urethra and urethritis glandularis demonstrate consistent reactivity with the mAbDas1 antibody, suggesting that these tumors arise from glandular metaplasia analogous to the potential histogenesis previously demonstrated in the bladder. PSA reactivity occurred in 1 tumor with a cribriform pattern and likely represents origin from Skene's glands. Clear cell adenocarcinomas did not react with either antibody, suggesting a third possible pathway in the development of this rare subset of adenocarcinomas.
Adenocarcinoma↗
Behçet's syndrome with left ventricular aneurysm and ruptured renal artery pseudoaneurysm.
A 21-year-old man with Behçet's syndrome presented with both a left ventricular aneurysm and a left renal artery pseudoaneurysm. After successful embolization of the ruptured pseudoaneurysm, the patient underwent successful repair of the left ventricular aneurysm. Although multiple aneurysms have been reported previously, we believe this to be the first reported case of both a ventricular aneurysm and a renal artery pseudoaneurysm afflicting a patient with Behçet's syndrome.
Adult↗
Review of staging modalities in clinically localized prostate cancer.
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Biopsy↗
Primary carcinoid tumour of the testis.
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Adult↗
A novel point mutation in cluster 3 of the thyroid hormone receptor beta gene (P247L) causing mild resistance to thyroid hormone.
Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone (TH), is linked to mutations in the thyroid hormone receptor (TR) beta gene. We report a new family with a heretofore unreported mutation, P247L. The proposita, a 31-year-old female, presented with goiter and palpitations. RTH was suspected because of elevated serum free thyroxine (FT4) level with a normal thyrotropin (TSH). Sequencing the TRbeta gene revealed a mutation causing replacement of a proline at position 247 with leucine. Seven family members were heterozygous for the mutation, two of whom also had evidence of autoimmune thyroid disease. The mutant TRbeta had a Ka for triiodothyronine (T3) 30% that of the wild-type TRbeta, approximately a threefold reduction in T3-induced transactivation and a low level dominant negative activity when tested with a positively regulated reporter gene. In vivo sensitivity to TH was evaluated in three affected subjects by measurement of the responses to graded doses of levotriiodothyronine (LT3). Peak TSH responses to TRH were reduced and were not completely suppressed at even the highest dose of LT3, (0.9, 0.2, and 0.2, compared to < 0.01 microU/mL in unaffected controls), confirming pituitary resistance to TH in all three subjects. In contrast, peripheral tissues responded variably to LT3: serum cholesterol decreased in all by 15%-25%, serum creatine kinase decreased by 15% in two subjects and increased 35% in another, but serum ferritin and sex hormone-binding globulin increased in only one of the three affected individuals that were tested. Basal metabolic rate and sleeping pulse did not change in three and two individuals, respectively. Hyporesponsiveness to exogenous TH established the clinical diagnosis of RTH in one member of the family with a mutant TRbeta but normal tests of thyroid function at baseline. Three affected subjects had an axis I diagnosis of major depression but had Wechsler Intelligence Scale for Children, III (WISC-III) full-scale IQs (FSIQs) in the normal range. This novel TRbeta mutation is associated with a realtively mild RTH. Results of responses to LT3 underscore the variable phenotype of RTH.
Adolescent↗
Improved radioimmunoassay for measurement of mouse thyrotropin in serum: strain differences in thyrotropin concentration and thyrotroph sensitivity to thyroid hormone.
We report an improved heterologous radioimmunoassay (RIA) for the measurement of thyrotropin (TSH) in mouse serum. The assay components are: antirat thyrotropin (rTSH) serum from the National Hormone and Pituitary Program, a commercial [125I]-labeled rTSH and mouse thyrotropin (mTSH) serum standards produced by dilution of a serum pool from hypothyroid mice with high TSH with a serum pool from mice treated with excess levothyroxine (LT4) (mTSH-0). Sensitivity was increased by reducing the amount of antibody and tracer and by taking advantage of the disequilibrium technique. Accuracy was greatly improved by the preparation of mouse serum TSH standards. TSH in serial dilutions of individual mice with high TSH of different etiologies paralleled the mTSH standard curve but not that of rTSH or a crude mouse TSH/luteinizing hormone (LH) reference preparation. The high-mTSH-serum standard contained 20 mU TSH per milliliter, measured in a bioassay utilizing a cell line stably transfected with human TSH receptor cDNA, and a relative TSH concentration of 40 ng/mL. The sensitivity of the RIA is 0.01 to 0.02 ng/mL, depending on the quality of the tracer and the preparation of mTSH-0 serum. The intra-assay and interassay coefficients of variations were, respectively: 16% and 27% at 0.04 ng/mL; 6.3% and 8.2% at 0.4 ng/mL; 5.4% and 9.8% at 1.7 ng/mL; 10% and 24% at 4.0 ng/mL. The mean TSH concentration in serum of 60-80-day-old male mice was four-fold higher than that in females of the same age. The assay was able to distinguish differences in serum TSH concentrations in five different strains of mice. Baseline serum TSH concentrations (mean +/- SD) of 70-day-old male mice were: 0.143 +/- 0.065 ng/mL in the CD-1 strain; 0.229 +/- 0.042 ng/mL in C57BL/6 mice; 0.084 +/- 0.017 ng/mL in SWR/J mice; 0.133 +/- 0.057 ng/mL in NOD SCID mice, and 0.266 +/- 0.122 ng/mL in FVB mice. Mean serum thyroxine (T4) concentrations were also significantly different among the mouse strains but did not correlate with the serum TSH level. Administration of levotriiodothyronine (LT3) suppressed the serum TSH to a greater degree in mice with higher baseline TSH values. Suppression of the thyroidal radioiodide uptake with LT3 correlated with that of serum TSH.
Animals↗
The hypothyroidism in an inbred kindred with congenital thyroid hormone and glucocorticoid deficiency is due to a mutation producing a truncated thyrotropin receptor.
Growth and function of the thyroid and adrenal glands are maintained and controlled by thyrotropin (TSH) and adrenocorticotrophic hormone (ACTH), respectively. The action of these trophic hormones requires the presence of functional TSH and ACTH receptors. We describe a large inbred Bedouin kindred in which profound congenital hypothyroidism and hypoadrenocortisolism occurred alone or together in eight family members belonging to four nuclear families. The high serum TSH and ACTH levels in the presence of normal or hypoplastic thyroid glands and low glucocorticoid, but not mineralocorticoid concentrations, are characteristic of resistance to TSH and ACTH. Linkage analysis, using specific polymorphic markers, excluded the involvement of the ACTH receptor but not thyrotropin receptor (TSHR). A novel point mutation was identified in exon 10 of the TSHR that replaces the normal cytosine in nucleotide 2024 with a thymidine. As a result the normal arginine in codon 609 (CGA) is replaced with a stop codon (TGA). This mutation produces a truncated TSHR lacking the third intracellular and extracellular loops, the sixth and seventh transmembrane segments, and the intracytoplasmic tail. The presence of hypothyroidism did not affect the timing, severity, and manner of clinical manifestation of hypoadrenocortisolism.
Adolescent↗
Virtual reality-based training for the diagnosis of prostate cancer.
Prostate malignancies are the second leading cause of cancer deaths among men. The most common method of detecting this disease is digital rectal examination (DRE). Current DRE training is inadequate, since the number of patients that students can practice on is limited. Furthermore, allied care personnel do not train in screening for prostate cancer. Finally, there is no objective way to follow the improvement in DRE skills for medical personnel. This paper presents a virtual reality-based simulator that addresses the above problems. The prototype consists of a PHANToM haptic interface which provides feedback to the trainee's index finger, a motion restricting board, and an SGI workstation, which renders the patient's anatomy. Four types of prostates were modeled--normal, enlarged with no tumor, incipient malignancy (single tumor), and advanced malignancy (tumor cluster). Human factors studies were conducted on both nonmedical students and urology residents in order to quantify the system usefulness. After only five minutes of training, nonmedical students had a 67% correct diagnosis rate of malignant versus nonmalignant cases. This compared with 56% for urology residents in the same trials. Subjective evaluation by the residents pointed out the need to improve the virtual prostate model realism. A control group formed of urology residents performed the same trials on a modified Merck Procar simulator. The control group scored significantly better (96% correct diagnosis of malignancies). We conclude that the virtual prostate palpation simulator, while promising, needs significant improvement in both model realism and haptic interface hardware.
Computer Simulation↗
Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor beta gene.
Resistance to thyroid hormone (RTH) is a syndrome of variable tissue hyposensitivity to TH. In 191 families, the RTH phenotype has been linked to mutations located in the ligand-binding or hinge domains of the TH receptor (TR) beta gene. The defective TRbeta molecules interfere with the function of the normal TRs to produce dominantly inherited RTH. Of the 65 families with RTH studied in our laboratory, 59 had mutations in the mutagenic region of the TRbeta gene that encompasses exons 7-10. Isolation of a TRbeta PAC (P1 derived artificial chromosome) clone provided the intronic sequences necessary to amplify and sequence the entire TRbeta gene from genomic DNA. Not a single nucleotide substitution, deletion, or insertion was found in all coding and noncoding TRbeta1- and TRbeta2-specific and common exons of the five families with RTH reported herein. Furthermore, linkage analysis using polymorphic markers excluded involvement of the TRbeta and TRalpha genes in two and three of the five families, respectively. The phenotype of RTH in patients without TRbeta gene defects was not different from that in patients with RTH due to TRbeta gene mutations in terms of clinical presentation and reduced responsiveness of the pituitary and peripheral tissues to TH. However, the degree of thyrotroph hyposensitivity to TH appeared to be among the more severe, similar to that of patients with mutant TRbetas that have more than 50-fold reduction of T3 binding affinity and strong dominant negative effect. In these five families and another with non-TRalpha/non-TRbeta RTH, previously identified in our laboratory, evidence for dominant inheritance was secured in two families, and the appearance of a new defect or recessive inheritance was found in the remaining four families. RTH without a structural TRbeta defect occurs in about 10% of families expressing the classic phenotype of TH hyposensitivity, and TRbeta and TRalpha gene involvement has been excluded in 5%. We postulate that a cofactor that interacts with TR is potentially responsible for the manifestation of RTH in these families. As affected subjects are not infertile, the high prevalence of putative neomutations and the low rate of transmission in this non-TR form of RTH may be due to reduced survival of embryos harboring the defect.
Adult↗
Treatment of resistance to thyroid hormone--primum non nocere.
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Animals↗
Two different mutations in the thyroid peroxidase gene of a large inbred Amish kindred: power and limits of homozygosity mapping.
Approximately 10% of newborns with congenital hypothyroidism are unable to convert iodide into organic iodine. This iodide organification defect has a prevalence of 1 in 40,000 newborns and may be caused by defects in the thyroid peroxidase enzyme (TPO), the hydrogen peroxide-generating system, the TPO substrate thyroglobulin, or inhibitors of TPO. We identified a high incidence of severe hypothyroidism due to a complete iodide organification defect in the youngest generation of five nuclear families belonging to an inbred Amish kindred. Genealogical records permitted us to trace their origin to an ancestral couple 7-8 generations back and to identify an autosomal recessive pattern of inheritance. Initial studies of homozygosity by descent using two polymorphic markers within the TPO gene showed no linkage to the phenotype. In fact, 4 of 15 affected siblings from 2 of the nuclear families were heterozygous, resulting in homozygosity values of 73% and 53% in affected and unaffected family members, respectively. A genome-wide homozygosity screen using DNA pools from affected and unaffected family members localized the defect to a locus close to the TPO gene. Linkage analysis using 4 additional polymorphic markers within the TPO gene reduced the number of homozygous unaffected siblings to zero without altering the percent homozygosity initially found in the affected. Sequencing of the TPO gene revealed 2 missense mutations, E799K and R648Q. TPO 779K was found in both alleles of the 11 affected homozygotes, both mutations were present in each of the 3 affected compound heterozygotes, and there were no TPO mutations in 1 subject with hypothyroidism of different etiology. These results demonstrate the power of the DNA pooling strategy in the localization of a defective gene and the pitfalls of linkage analysis when 2 relatively rare mutations coexist in an inbred population.
Child, Preschool↗