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Biomedical subjects

F Brucker-Davis

Publications and source records attributed to F Brucker-Davis.

16 recordsLinked to original sources
PubMed2001

Disruption of gap junctional intercellular communication by lindane is associated with aberrant localization of connexin43 and zonula occludens-1 in 42GPA9 Sertoli cells.

Lindane (gamma-hexachlorocyclohexane) is a lipid-soluble pesticide that exerts carcinogenic and reprotoxic properties. The mechanisms by which lindane alters testicular function are unclear. Sertoli cells control germ cell proliferation and differentiation through cell-cell communication, including gap junction intercellular communication. Using the 42GPA9 Sertoli cell line, we show that lindane, at a non-cytotoxic dose (50 microM), abolished gap junction intercellular communication (GJIC) between adjacent cells. This change was associated with a time-related diminution and redistribution of Cx43 from the membrane to the cytoplasmic perinuclear region. A similar alteration was observed for ZO-1, a tight junction component associated with Cx43, but not for occludin, an integral tight junction protein. After a 24 h lindane exposure, Cx43 and ZO-1 colocalized within the cytoplasm and no modification of non-phosphorylated and phosphorylated isoforms of Cx43 was observed. By double immunofluorescent labelling we demonstrate that the cytoplasmic Cx43 signal was not present in either the endoplasmic reticulum/Golgi apparatus or lysosomes. These results suggest that lindane inhibits GJIC between Sertoli cells and that aberrant Cx43/ZO-1 localization may be responsible for this effect. The alterations in gap junctions induced by lindane in 42GPA9 Sertoli cells are similar to those observed in tumour cells and may be involved in the pathogenesis of neoplastic seminomal proliferation.

Animals↗
PubMed2001

Significant effects of mild endogenous hormonal changes in humans: considerations for low-dose testing.

We review the significant and adverse health effects that can occur with relatively small endogenous hormonal changes in pubertal and adult humans. We discuss the effects of hormonal changes that occur within normal physiologic ranges--such as the rising levels of estrogen in peripuberty, which cause growth spurts at low levels and then the fusion of epiphyses at higher levels--and the hormonal variations during the menstrual cycle and their relation to genital phenotypic changes and intercurrent disease evolution. We turn next to adaptive changes in gonadal and other functions during aging, exercise, stress, starvation, and chronic diseases, which can serve as models for the effects of exogenous, hormonally active compounds. Then we review the states of borderline hormonal imbalances such as subclinical (having few or very mild symptoms, if any) hypothyroidism or hyperthyroidism, glucose intolerance, and other endocrine conditions. Finally, we review the deleterious systemic effects of gonadal imbalance. Information stemming from clinical observations leads to the concept of "no threshold" within the endocrine system and thus illustrates the importance of considering low-dose testing for chemicals that interfere with hormonal activity. We also urge attention to more sensitive, less visible end points such as osteoporosis, increased risk for cardiovascular disease, or cognitive changes.

Adolescent↗
PubMed1999

Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the National Institutes of Health.

We report a large series of 25 patients with TSH-secreting tumors (23 macroadenomas) followed at the NIH. Hyperthyroid symptoms were severe in 14 patients, mild in 8, and absent in 3. Patients were divided into 2 groups according to whether their thyroid had been treated (n = 11) or not (n = 14). In untreated patients, the classical diagnostic criteria (unresponsive TRH test, high alpha-subunit, and high alpha-subunit/TSH ratio) were present, respectively, in 10, 8, and 12 cases (sensitivity, 71%, 75%, and 83%; specificity, 96%, 90%, and 65%). In treated patients, the respective sensitivities of the TRH test, alpha-subunit, and alpha-subunit/TSH ratio were 64%, 90%, and 90%, and their specificities were 100%, 82%, and 73%. Studies of thyroid hormone action revealed no evidence of acquired resistance to thyroid hormone in TSH-secreting tumors. Apparent cure was achieved in 35% of cases by surgery alone and in 22% more by combined therapies. Three deaths occurred, including 1 from metastatic thyrotroph carcinoma. Six patients had residual tumor, with symptoms of hyperthyroidism controlled with octreotide in 5. The size and invasiveness of the tumor, duration of symptoms, and intensity of hyperthyroidism were the main prognostic factors. Thus, early diagnosis and treatment are the keys to a good outcome.

Adenoma↗
PubMed1999

Screening methods for thyroid hormone disruptors.

The U.S. Congress has passed legislation requiring the EPA to implement screening tests for identifying endocrine-disrupting chemicals. A series of workshops was sponsored by the EPA, the Chemical Manufacturers Association, and the World Wildlife Fund; one workshop focused on screens for chemicals that alter thyroid hormone function and homeostasis. Participants at this meeting identified and examined methods to detect alterations in thyroid hormone synthesis, transport, and catabolism. In addition, some methods to detect chemicals that bind to the thyroid hormone receptors acting as either agonists or antagonists were also identified. Screening methods used in mammals as well as other vertebrate classes were examined. There was a general consensus that all known chemicals which interfere with thyroid hormone function and homeostasis act by either inhibiting synthesis, altering serum transport proteins, or by increasing catabolism of thyroid hormones. There are no direct data to support the assertion that certain environmental chemicals bind and activate the thyroid hormone receptors; further research is indicated. In light of this, screening methods should reflect known mechanisms of action. Most methods examined, albeit useful for mechanistic studies, were thought to be too specific and therefore would not be applicable for broad-based screening. Determination of serum thyroid hormone concentrations following chemical exposure in rodents was thought to be a reasonable initial screen. Concurrent histologic evaluation of the thyroid would strengthen this screen. Similar methods in teleosts may be useful as screens, but would require indicators of tissue production of thyroid hormones. The use of tadpole metamorphosis as a screen may also be useful; however, this method requires validation and standardization prior to use as a broad-based screen.

Animals↗
PubMed1998

Effects of environmental synthetic chemicals on thyroid function.

Synthetic chemicals are released into the environment by design (pesticides) or as a result of industrial activity. It is well known that natural environmental chemicals can cause goiter or thyroid imbalance. However, the effects of synthetic chemicals on thyroid function have received little attention, and there is much controversy over their potential clinical impact, because few studies have been conducted in humans. This article reviews the literature on possible thyroid disruption in wildlife, humans, and experimental animals and focuses on the most studied chemicals: the pesticides DDT, amitrole, and the thiocarbamate family, including ethylenethiourea, and the industrial chemicals polyhalogenated hydrocarbons, phenol derivatives, and phthalates. Wildlife observations in polluted areas clearly demonstrate a significant incidence of goiter and/or thyroid imbalance in several species. Experimental evidence in rodents, fish, and primates confirms the potentiality for thyroid disruption of several chemicals and illustrates the mechanisms involved. In adult humans, however, exposure to background levels of chemicals does not seem to have a significant negative effect on thyroid function, while exposure at higher levels, occupational or accidental, may produce mild thyroid changes. The impact of transgenerational, background exposure in utero on fetal neurodevelopment and later childhood cognitive function is now under scrutiny. There are several studies linking a lack of optimal neurological function in infants and children with high background levels of exposure to polychlorinated biphenyls (PCBs), dioxins, and/or co-contaminants, but it is unclear if the effects are caused by thyroid disruption in utero or direct neurotoxicity.

Amitrole↗
PubMed1997

Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma.

BACKGROUND: To detect recurrent disease in patients who have had differentiated thyroid cancer, periodic withdrawal of thyroid hormone therapy may be required to raise serum thyrotropin concentrations to stimulate thyroid tissue so that radioiodine (iodine-131) scanning can be performed. However, withdrawal of thyroid hormone therapy causes hypothyroidism. Administration of recombinant human thyrotropin stimulates thyroid tissue without requiring the discontinuation of thyroid hormone therapy. METHODS: One hundred twenty-seven patients with thyroid cancer underwent whole-body radioiodine scanning by two techniques: first after receiving two doses of thyrotropin while thyroid hormone therapy was continued, and second after the withdrawal of thyroid hormone therapy. The scans were evaluated by reviewers unaware of the conditions of scanning. The serum thyroglobulin concentrations and the prevalence of symptoms of hypothyroidism and mood disorders were also determined. RESULTS: Sixty-two of the 127 patients had positive whole-body radioiodine scans by one or both techniques. The scans obtained after stimulation with thyrotropin were equivalent to the scans obtained after withdrawal of thyroid hormone in 41 of these patients (66 percent), superior in 3 (5 percent), and inferior in 18 (29 percent). When the 65 patients with concordant negative scans were included, the two scans were equivalent in 106 patients (83 percent). Eight patients (13 percent of those with at least one positive scan) were treated with radioiodine on the basis of superior scans done after withdrawal of thyroid hormone. Serum thyroglobulin concentrations increased in 15 of 35 tested patients: 14 after withdrawal of thyroid hormone and 13 after administration of thyrotropin. Patients had more symptoms of hypothyroidism (P<0.001) and dysphoric mood states (P<0.001) after withdrawal of thyroid hormone than after administration of thyrotropin. CONCLUSIONS: Thyrotropin stimulates radioiodine uptake for scanning in patients with thyroid cancer, but the sensitivity of scanning after the administration of thyrotropin is less than that after the withdrawal of thyroid hormone. Thyrotropin scanning is associated with fewer symptoms and dysphoric mood states.

Adult↗
PubMed1997

Thyroid hormones correlate with symptoms of hyperactivity but not inattention in attention deficit hyperactivity disorder.

The diagnostic validity of dividing attention deficit hyperactivity disorder (ADHD) into two distinct subgroups, one with and one without hyperactivity, is controversial since there have been no physiological differences demonstrated between these two subgroups. In this study, the relationship between thyroid hormones and symptoms of hyperactivity was examined in subjects with resistance to thyroid hormone (RTH) and their unaffected family members. Clinical data were collected on 152 subjects; 75 subjects with RTH and 77 family members without RTH. Each subject was assessed using DSM-III-R criterion based, structured psychiatric interviews, and Total T3 (TT3), Total T4 (TT4) and TSH concentrations were measured. The total number of ADHD symptoms were assigned to either inattention or hyperactivity subgroups using DSM-III-R criteria. The total number of ADHD symptoms were then reassigned to inattention or hyperactivity/impulsivity subgroups using DSM-IV criteria. Pearson R correlation coefficients were calculated separately for the RTH and unaffected family members groups in order to determine the relationships between TSH, TT3 and TT4 concentrations, and the DSM-III-R and DSM-IV symptom categories of ADHD in both groups. TSH concentrations were not significantly correlated with any of the symptom categories in either group. However, in the RTH group, both TT3 and TT4 concentrations were significantly and positively correlated with total symptoms of ADHD (DSM-III-R) as well as symptoms of inattention (DSM-III-R) and symptoms of hyperactivity (DSM-III-R). When DSM-IV criteria were used, which reassigns symptoms of impulsivity from the inattention to the hyperactivity category, only the positive correlation between TT3 and TT4 concentrations and symptoms of hyperactivity/impulsivity (DSM-IV) remained significant. In the group of unaffected family members, the relationship between TT3 concentrations and symptoms of hyperactivity/impulsivity (DSM-IV) was the only significant correlation. The data support the hypothesis that thyroid hormones may provide a physiological basis for the dichotomy between symptoms of inattention and symptoms of hyperactivity, particularly when DSM-IV criteria are applied.

Adolescent↗
PubMed1997

Graves' disease following thyrotoxic painless thyroiditis. Analysis of antibody activities against the thyrotropin receptor in two cases.

The exact immunologic mechanisms that lead to the emergence and progression of painless ("silent") thyroiditis remain unclear. We report two cases of painless postpartum thyroiditis followed by Graves' disease, where extensive immunologic evaluation supported a possible pathogenetic association. The time course of changes in thyroid function tests, 123I thyroidal uptake values, and thyrotropin receptor antibodies (TSHRAbs) were documented. The existence of stimulating TSHRAbs (TSAbs) activating the cyclic adenosine monophosphate (cAMP) and phosphatidylinositol 4,5-bisphosphate (PIP2) signal cascades and their functional epitopes, as well as two different thyrotropin-binding inhibitory immunoglobulins (TBII) were documented in both patients at the time of diagnosis of Graves' disease. We suggest that susceptible persons may develop an immunologic response that can trigger the appearance of a mixture of species of TSHRAbs, which in turn may lead to the sequential occurrence of painless thyroiditis and Graves' disease. Additionally, the multiple phases of hyperthyroidism and hypothyroidism that can occur in these patients may reflect the existence and changing spectrum of TSHRAbs in their sera.

Adolescent↗
PubMed1997

MRI-demonstrable regression of a pituitary mass in a case of primary hypothyroidism after a week of acute thyroid hormone therapy.

Although magnetic resonance imaging (MRI) characteristics of pituitary gland hyperplasia in primary hypothyroidism have been previously described, the time span necessary for the regression of the hyperplasia in response to acute thyroid hormone (TH) therapy has not been defined. A 26-yr-old woman underwent 131I ablation 11 yr before admission. Intermittent poor compliance to levothyroxine (LT4) therapy led to inappropriately high serum thyroid-stimulating hormone (TSH) for her triiodothyronine (T3) and thyroxine (T4) levels. The patient was investigated to rule out TSH-secreting pituitary adenoma or resistance to TH. On admission, the patient's clinical features and thyroid function tests, as well as thyrotropin-releasing hormone (TRH) and acute T3 suppression tests, were in favor of profound primary hypothyroidism. MRI revealed symmetrical enlargement of the pituitary gland with distinct morphological characteristics of a macroadenoma. The patient began high-dose TH therapy and was rescanned six days later. The follow-up scan revealed a dramatic shrinkage of the pituitary gland. Four weeks later, serum T4 and TSH were within the normal range, and repeat MRI scan of the pituitary at that time showed a normal gland. This case is the first to document dramatic shrinkage of pituitary hyperplasia in long-standing primary hypothyroidism within one week of acute TH therapy. MRI alone is unable to reliably differentiate between a TSH-secreting pituitary adenoma and hypothyroidism-induced pituitary hyperplasia. Dynamic endocrine testing as well as repeat pituitary MRI after a brief TH trial may provide a firm diagnosis in similar cases.

Adenoma↗
PubMed1996

Screening of candidate oncogenes in human thyrotroph tumors: absence of activating mutations of the G alpha q, G alpha 11, G alpha s, or thyrotropin-releasing hormone receptor genes.

Activating mutations encoding substitutions at positions Arg201 and Gln227 of the alpha-subunit of the stimulatory G protein. G10 have been found in about 40% of pituitary somatotroph tumors. Although the etiology of thyrotroph adenomas is unknown, their autonomous behavior and blunted response to stimulatory hypothalamic hormone superficially resemble those of somatotroph tumors. We hypothesized that a subset of thyrotroph tumors might be caused by dominant somatic mutations that lead to inappropriate activation of the Gq/phospholipase C beta/Ca2+/protein kinase C. pathway normally triggered by occupancy of the TRH receptor (TRHR). We, therefore, screened samples from nine thyrotroph tumors for the presence of activating mutations of the alpha q, alpha 11, and TRHR genes. Fragments of alpha q and alpha 11 complementary DNA encompassing residues (Arg183 and Gln209) that correspond to Arg201 and Gln227 of alpha q were amplified and sequenced. Temperature gradient gel electrophoresis was used to screen for heterozygous mutations in the TRHR coding sequence as well as for known alpha s mutations. No mutations were detected. We conclude that mutations in these regions of the alpha q, alpha 11, alpha s, and TRHR genes occur infrequently, if at all, in human thyrotroph tumors. Alternative mechanisms underlying thyrotroph tumorigenesis, including changes in the expression levels of G protein alpha-subunits or TRHR, dysregulation of downstream components, inappropriate activation of other stimulatory pathways, or loss of inhibitory inputs, remain to be explored.

Adult↗
PubMed1996

Prevalence and mechanisms of hearing loss in patients with resistance to thyroid hormone.

Hearing impairment was anecdotally reported in resistance to thyroid hormone (RTH), a condition caused by mutations in the beta-thyroid hormone receptor (beta TR) gene. Because of its ontogenic distribution in the cochlea, the beta TR may have a pivotal role in the development of auditory function. To assess the prevalence and mechanisms of hearing impairment in RTH, 82 RTH-positive (RTH+) patients and 55 unaffected relatives (RTH-) underwent systematic audiological examination, including puretone and speech reception thresholds, and tests studying middle ear (tympanometry and acoustic reflexes), cochlear (otoacoustic emissions), and retrocochlear integrity (brain stem auditory evoked potentials). Significant hearing loss was present in 21% of RTH+ patients vs. none in RTH- patients. More RTH+ patients had abnormal tympanometry (34% vs. 12%) and abnormal acoustic reflexes (39% vs. 19%). Isolated conductive deficit was found in 7 of 17 RTH+ patients with hearing loss, isolated sensorineural deficit in 7 cases, and mixed deficit in 3 cases. Cochlear dysfunction was found in 50% of all RTH+ patients, with or without hearing loss. Retrocochlear function was normal. No morphological cochlear abnormalities were detected on computed tomography of the temporal bone. In conclusion, hearing loss is a significant problem in RTH, with an equal frequency of conductive (probably related to the frequent ear infections) and sensorineural deficits. Abnormal otoacoustic emissions suggest that the mutant beta TR has a specific negative impact on cochlear function.

Adult↗
PubMed1996

False-positive iodine-131 whole-body scans due to cholecystitis and sebaceous cyst.

False-positive whole-body 131I scans are not frequent but have serious consequences in the management of patients with thyroid cancer. They can be classified in four main groups: elimination of iodine in body fluids, infection or inflammation, cysts or transudates and nonthyroid tumors. We report on two patients with false-positive post-therapy 131I scans. The first patient had uptake projected in the right pelvic area which was later proven to be a large gluteal sebaceous cyst. The second patient had uptake in the gallbladder area that did not disappear after 131I treatment; she underwent exploratory laparotomy which revealed extensive chronic cholecystitis. These cases illustrate two new causes of false-positive 131I whole-body scans (sebaceous cyst and cholecystitis), which highlights two mechanisms (elimination in body fluid and inflammation).

Adenocarcinoma, Follicular↗
PubMed1995

Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study.

OBJECTIVE: To determine the genetic and clinical features of resistance to thyroid hormone in a study from a single institution. DESIGN: Prospective, controlled study. SETTING: National Institutes of Health. PATIENTS: 104 patients with resistance to thyroid hormone from 42 kindreds and 114 unaffected relatives sharing the patients' environmental and genetic backgrounds. MEASUREMENTS: Thyroid, cardiovascular, psychometric, hearing, speech, and growth testing; thyroid tests done at baseline and after TSH-releasing hormone stimulation; and DNA analysis for detection of mutations in the thyroid hormone receptor beta (TR beta) gene (exons 9 and 10). Assessment of tissue-specific compensation for resistance. RESULTS: Inheritance was autosomal dominant in 22 families, sporadic in 14 families, and unknown in 6 families. We found mutations in 25 kindreds (64 patients); 16 mutations were in exon 9 and 9 were in exon 10 of the TR beta gene. In persons with resistance to thyroid hormone, we measured the increased incidence of goiter (65%), attention-deficit hyperactivity disorder (60%), IQ less than 85 (38%), speech impediment (35%), and short stature (18%). We also described new clinical features, such as frequent ear, nose, and throat infections (56%); low weight-for-height in children (32%); hearing loss (21%); and cardiac abnormalities (18%). Genotype, age, whether the mother had resistance to thyroid hormone, and sex influenced the phenotype. Tissue resistance varied from kindred to kindred and involved, in decreasing order, the pituitary gland, the brain, the bone, the liver, and the heart. CONCLUSIONS: This study underscores the incidence of classic features of resistance to thyroid hormone, describes new clinical characteristics of this condition for the first time, and stresses the heterogeneity of the phenotype.

Adolescent↗
PubMed1995

A "hot spot" in the Pit-1 gene responsible for combined pituitary hormone deficiency: clinical and molecular correlates.

Pit-1 is a member of the POU family of transcription factors regulating mammalian development. Pit-1 is thought to be the major cell-specific activator of both the somatotrophs and lactotrophs in the anterior pituitary. When bound to DNA, Pit-1 activates GH and PRL gene expression. Pit-1 is also important for hormonal regulation of the PRL and TSH-beta genes by TRH and cAMP. We studied two unrelated patients with GH, PRL, and TSH deficiencies. Both patients have the same point mutation in the POU homeodomain of the Pit-1 gene (R271W). Patient 1 was studied as an adult and had combined deficiencies of GH, PRL, and TSH. Patient 2, who was studied in infancy, also had GH and PRL deficiencies, but had low thyroid hormone levels with a measurable basal level of TSH and a delayed response of TSH to TRH. Consequently, the current description of Pit-1 gene mutations leading to complete GH, PRL, and TSH deficiencies needs to be expanded to GH and PRL deficiencies associated with a compromise of the thyrotroph's ability to synthesize TSH.

Amino Acid Sequence↗
PubMed1993

[Pulmonary tuberculosis and HIV seropositivity at the Principal Hospital of Dakar (Senegal)].

In a prospective survey conducted in 1990 in the Principal Hospital of Dakar, pulmonary tuberculosis was 2.3 times more frequent in HIV seropositive patients (12.5%) than in HIV seronegative patients. We studied 22 cases of pulmonary tuberculosis in HIV+ patients and compared them with a control group of HIV- patients admitted for pulmonary tuberculosis. Tuberculosis occurred in 6 out of 22 asymptomatic HIV+ patients, in 15 out of 22 patients with clinical AIDS and in 1 patient with ARC syndrome. Clinical signs were the same as in controls, except for patients with advanced AIDS who developed cardinal signs. TB intra-dermal reactions were more often negative in HIV+ patients, notably those with HDV1, expressing immunodepression. Radiological images were typical in 81% of patients and in 86% of controls. However, concomitant infections were common in both groups, with atypical radiology and hyperleukocytosis. At light microscopy, there was no difference in the frequency of acid and alcohol fast bacilli between the two groups. The mortality rate was increased in HIV+ patients, but this was not due to tuberculosis. Relapses were frequent in both groups, due to poor compliance with treatment.

AIDS-Related Opportunistic Infections↗