Non-fatal suicidal behaviour, depression and poverty among young men living in low-resource communities in South Africa.

BACKGROUND: Suicide is a serious public health problem in low- and middle-income countries. Understanding the context- and gender-specific risk factors for non-fatal suicidal behaviour is the cornerstone of evidence-based public health interventions to reduce suicide. Poverty and symptoms of depression are well established risk factors for suicidal behaviour. However, little is understood about how proximal economic factors (such as losing one's job, or food insecurity) may confound the effects of symptoms of depression to increase the risk of non-fatal suicidal behaviour in vulnerable populations, such as young men living under conditions of endemic poverty. The aim of this study was to explore the extent to which a wide range of poverty-related variables account for non-fatal suicidal behaviour independent of, or in addition to, symptoms of depression among young men living in low-resource communities in South Africa (SA). METHODS: Data were collected from a clustered sample of 647 young men living in low-resource communities in the Western Cape province of SA. Multivariate regressions were used to identify the associations between poverty-related measures, symptoms of depression, and past-month prevalence of non-fatal suicidal behaviour. RESULTS: Non-fatal suicidal behaviour in the last month was reported by 47 (6.13%) participants: suicidal ideation (n = 43; 5.97%); suicide plan (n = 5; 0.77%); suicide attempt (n = 4; 0.62%), and deliberate self-harm without intent to die (n = 4; 0.62%). Past-month prevalence of non-fatal suicidal behaviour was significantly associated with particular dimensions of poverty (living in a home without a toilet on the premises, having previously been fired, and food insecurity), but not with other dimensions of poverty (such as prolonged unemployment and low levels of income). However, symptoms of depression were a more significant predictor of non-fatal suicidal behaviour than any measure of poverty (aOR=1.093, 95% CI=1.058-1.129, p < .000). CONCLUSIONS: Depressive symptoms are more strongly associated with non-fatal suicidal behaviour than a range of proximal and distal economic factors among young men living under conditions of endemic poverty in South Africa. This has important public health implications and highlights the importance of increasing young men's access to psychiatric services and targeting depression as an integral component of suicide prevention in low resource communities.

A novel mutation in the TG gene (G2322S) causing congenital hypothyroidism in a Sudanese family: a case report.

BACKGROUND: Congenital hypothyroidism (CH) has an incidence of approximately 1:3000, but only 15% have mutations in the thyroid hormone synthesis pathways. Genetic analysis allows for the precise diagnosis. CASE PRESENTATION: A 3-week old girl presented with a large goiter, serum TSH > 100 mIU/L (reference range: 0.7-5.9 mIU/L); free T4 < 3.2 pmol/L (reference range: 8.7-16 pmol/L); thyroglobulin (TG) 101 µg/L. Thyroid Tc-99 m scan showed increased radiotracer uptake. One brother had CH and both affected siblings have been clinically and biochemically euthyroid on levothyroxine replacement. Another sibling had normal thyroid function. Both Sudanese parents reported non-consanguinity. Peripheral blood DNA from the proposita was subjected to whole exome sequencing (WES). WES identified a novel homozygous missense mutation of the TG gene: c.7021G > A, p.Gly2322Ser, which was subsequently confirmed by Sanger sequencing and present in one allele of both parents. DNA samples from 354 alleles in four Sudanese ethnic groups (Nilotes, Darfurians, Nuba, and Halfawien) failed to demonstrate the presence of the mutant allele. Haplotyping showed a 1.71 centiMorgans stretch of homozygosity in the TG locus suggesting that this mutation occurred identical by descent and the possibility of common ancestry of the parents. The mutation is located in the cholinesterase-like (ChEL) domain of TG. CONCLUSIONS: A novel rare missense mutation in the TG gene was identified. The ChEL domain is critical for protein folding and patients with CH due to misfolded TG may present without low serum TG despite the TG gene mutations.

Anal human papillomavirus infection in a street-based sample of drug using HIV-positive men.

HIV facilitates an increase in human papillomavirus (HPV)-associated conditions. HIV-positive men living in a substance use context in Los Angeles, USA, were recruited using respondent-driven sampling, completed a questionnaire and had biological samples including an anal HPV swab taken. A total of 316 evaluable men were enrolled in the study. The prevalence of any HPV, high-risk (HR) infection and multiple-type infection was highest for men who have sex with men (MSM) (93.9%, 64.6% and 29.7%, respectively). When any HPV and HR-HPV prevalence in all men was stratified by age, the youngest group had 100% and 68.2% prevalence, respectively, with similarly high rates maintained up to age 49 years. The individual's use of alcohol, marijuana, cocaine, methamphetamine or heroin was not significantly associated with anal HPV detection. In this marginalized population, high prevalence rates of anal HPV and HR-HPV occurring over a wide age range may increase the individual's risk for anal dysplasia and anal cancer.

Evaluation of the validity of the Quality of Well-being Scale in Trinidad and Tobago.

Both developing countries in the Caribbean and developed countries face resource allocation challenges. However, cost-effectiveness analysis instruments that may assist in allocation of resources have not been tested in Caribbean countries. Trinidad and Tobago is an advantageous location to test an instrument for potential use in the Caribbean. It has a single payer healthcare system and a literate population. Due to historical and current migration from other Caribbean countries, the population might be a fair representation of English-speaking Caribbean nations. We tested the validity of the Quality of Well-being Scale (QWB) on a sample of the non-institutionalized general population in Trinidad. The survey included reports of chronic conditions and items from the Trinidad and Tobago National Health Interview Survey. Data were analyzed using a multivariable regression model. One adult from each of 235 households consented to the interview. The results are consistent with results obtained in the United States of America. Being older female, more chronic conditions and more symptoms/problems were significantly associated with lower mean QWB scores. These results suggest that the QWB with US-derived weights show evidence of validity in Trinidad and Tobago. Thus, health decision makers can use the QWB to compare the effects of different health conditions and health interventions. In addition, investigators can make cross-cultural comparisons of QWB scores for diseases or health conditions.

Iodine deficiency activates antioxidant genes and causes DNA damage in the thyroid gland of rats and mice.

Because thyroid nodules are frequent in areas with iodine deficiency the aim of this study was to characterise molecular events during iodine deficiency that could explain mutagenesis and nodule formation. We therefore studied gene expression of catalytic enzymes prominent for H(2)O(2) detoxification and antioxidative defence, quantified DNA oxidation and damage as well as spontaneous mutation rates (SMR) in mice and rats fed an iodine controlled diet. Antioxidative enzymes such as superoxide dismutase 3, glutathione peroxidase 4 and the peroxiredoxins 3 and 5 showed increased mRNA expression, which indicates increased radical burden that could be the cause of additional oxidized base adducts found in thyroidal genomic DNA in our experiments of iodine deficiency. Furthermore, the uracil content of thyroid DNA was significantly higher in the iodine-deficient compared to the control group. While SMR is very high in the normal thyroid gland it is not changed in experimental iodine deficiency. Our data suggest that iodine restriction causes oxidative stress and DNA modifications. A higher uracil content of the thyroid DNA could be a precondition for C-->T transitions often detected as somatic mutations in nodular thyroid tissue. However, the absence of increased SMR would argue for more efficient DNA repair in response to iodine restriction.

A case of ACTH-independent bilateral macronodular adrenal hyperplasia and severe congestive heart failure.

Cortisol secretion in ACTH independent bilateral macronodular adrenal hyperplasia (AIMAH) can be regulated by aberrant adrenal receptors. We describe a patient with Cushing's syndrome (CS) due to AIMAH and concomitant Class IV congestive heart failure (CHF). Clinical testing for the presence of aberrant receptors revealed a pronounced serum cortisol (257%) and aldosterone response (212%) to the administration of ACTH and a partial serum cortisol (35%) and aldosterone (106%) response to upright posture. This suggested the possible presence of aberrant hormone receptors for ACTH [melanocortin 2 receptor (MC2-R)], vasopressin, catecholamines or angiotensin II (AT-II) on the patient's adrenal glands. Adrenal tissue from the patient demonstrated an eight-fold increased expression of MC2-R compared to normal adrenal tissue. This increased expression was consistent with the increase in cortisol and aldosterone seen in response to exogenous ACTH. We propose that the severe CHF resulted in activation of the renin-angiotensin system, with an increased production of AT-II. The elevated circulating levels of AT-II may have led to increased expression of MC2-R on the patient's adrenal glands and increased responsiveness to ACTH. This unusual case of CS may elucidate a heretofore unknown mechanism for the development of AIMAH.

Resistance to thyroid hormone associated with autoimmune thyroid disease in a Turkish family.

The syndrome of resistance to thyroid hormone (RTH) is characterized by impaired tissue responses to thyroid hormone. Hashimoto's thyroiditis is the most common thyroid autoimmune disease. We present a Turkish family with both RTH and Hashimoto's thyroiditis. RTH was detected through the presence of point mutation in thyroid hormone receptor (TR), and Hashimoto's thyroiditis was diagnosed due to the presence of thyroid autoantibodies. The proposita, her affected mother as well as her unaffected sister have thyroid autoantibodies consistent with Hashimoto's thyroiditis, and a heterozygous point mutation in exon 10 encoding the ligand (3,3',5-L-T3)-binding domain of the TRbeta gene was detected in both the proposita and the mother. The mutation is a replacement of cytosine for guanine in codon 453 (CCT->GCT) producing a missense mutation substituting a normal proline with an alanine (P453A), which reduces the affinity for T3 to 17% of that of the normal TRbeta. Both also have modest elevation of serum TSH levels. In severe RTH, marked elevation of thyroid hormone concentrations in the absence of suppressed TSH supports the laboratory diagnosis of RTH. However, when RTH is mild and associated with thyroiditis, even a modest thyroid gland insufficiency can obliterate the serum T4 and T3 elevations, typical of RTH. This will manifest as elevated serum TSH. Demonstration of TRbeta gene mutation is then necessary to establish the diagnosis. In addition, under these circumstances, treatment with thyroid hormone should be considered.

A novel splice variant involving the 5' untranslated region of thyroid hormone receptor beta1 (TRbeta1).

The thyroid hormone receptor beta (TRbeta) gene generates two different proteins by use of a different promoter (beta1 and beta2). We now report a novel short TRbeta1 RNA splice variant in humans lacking 35 nucleotides at the 3' end of the non-coding exon 1 due to an alternative 5' splice donor site. This short variant was first identified in sequences of cDNA obtained from cultured human fibroblasts. Both variants were found in human fibroblasts, brain, pituitary, adrenal gland, placenta, muscle, thyroid and lymphocytes. These TRbeta1 variants possess splice donor sites with a sequence score slightly favoring the TRbeta1 long variant. Variant-specific real-time polymerase chain reaction (PCR) showed that their relative proportions were equal except in pituitary and muscle, in which the long form was 3- and 5-fold in excess. T3 treatment of fibroblasts grown in thyroid hormone depleted medium did not affect the absolute or relative expression of the two variants. Furthermore, the expression level in fibroblasts from patients with resistance to thyroid hormone with or without TRbeta gene mutations was not different to that in fibroblasts from normal controls.

Circadian variation in Cushing's disease and pseudo-Cushing states by analysis of F and ACTH pulsatility.

Distinguishing pituitary-dependent Cushing's disease from pseudo-Cushing's states can present a diagnostic challenge. Although many studies potentially discriminate between the 2, only the dexamethasone-suppressed corticotropin-releasing hormone (CRF) stimulation test at 15 minutes is 100% sensitive or specific. We measured baseline profiles of F and ACTH in 31 Cushing's disease patients, 11 with pseudo-Cushing's and 17 controls. Venous blood was collected at 30 minute intervals for 24-h. Subjects also had CRF stimulation tests and 2.0 mg/day dexamethasone suppression tests. F and ACTH profiles were analyzed for circadian rhythmicity, variability, and pulsatility. Relative circadian amplitude was decreased in Cushing's disease compared to both pseudo-Cushing's and normal states. Relative pulse amplitude was reduced in Cushing's disease. Because of this dampening of circadian and pulsatile variations, the overall variability of F and ACTH levels around their mean levels as quantified by the intra-series coefficient of variation (CV), was also decreased in Cushing's disease compared to pseudo-Cushing's and normal states. A F 24-h CV<40% was able to distinguish Cushing's disease from pseudo-Cushing's with 100% sensitivity (95% confidence interval (CI), 88-100%) and specificity (CI, 71-100%). An ACTH CV<40% had 97% sensitivity (CI, 83-100%) and 100% specificity (CI, 71-100%). An overnight 8-h F CV <40% also distinguished Cushing's disease from pseudo-Cushing's with 100% sensitivity (CI, 88-100%) and specificity (CI, 71-100%). These data show that a simple index of total temporal variability (the intra-series CV) derived from the analysis of basal F profiles, provides a useful method to distinguish Cushing's disease from pseudo-Cushing's. A F or ACTH CV <40% discriminates Cushing's disease from pseudo-Cushing's and reflects reduced circadian and pulsatile variations.

Risperidone-induced priapism.

Priapism is well documented as a potential side effect of psychotropic medications. To date, there have been no reports of risperidone-induced priapism in the urologic literature. We report a case of risperidone-induced priapism requiring surgical treatment.

Thyroid function and effect of aging in combined hetero/homozygous mice deficient in thyroid hormone receptors alpha and beta genes.

The maintenance of thyroid hormone (TH) homeostasis is dependent on the synthesis and secretion of TH regulated by TSH. This is achieved, in turn, by the negative feedback of TH on TSH secretion and synthesis, which requires the interaction with TH receptors (TRs). Derived by alternative splicing of two gene transcription products, three TRs (TRbeta1, TRbeta2 and TRalpha1) interact with TH while another, TRalpha2, binds to DNA but not to TH. In this study we compare the results of thyroid function tests in mice with deletions of the TRalpha and TRbeta genes alone and present novel data on mice that are double homozygous and combined heterozygous. Homozygous deletions of both the TRalpha and TRbeta in the same mouse (TRalphao/o; TRbeta-/-) resulted in serum TSH values only slightly lower than those in athyreotic, Pax8 knockout mice. Whereas the absence of TRalpha alone does not cause resistance to TH, the absence of TRbeta in the presence of TRalpha results in a 205, 169, 544% increase in serum thyroxine (T(4)), triiodothyronine (T(3)) and TSH concentrations respectively. However, in the absence of TRbeta, loss of one TRalpha allele can worsen the resistance to TH with a 243 and 307% increase in T(4) and T(3) respectively. Similarly, while the heterozygous mouse with a single TRbeta allele shows no alteration in thyroid function, the concomitant deletion of TRalpha brings about mild but significant resistance to TH. Furthermore, the severity of the resistance to TH was noted to decrease with age in parallel with the decrease in serum free T(4) values also seen in wild-type mice. These results demonstrate that (1) unliganded TRalpha or TRbeta are not absolutely necessary for the upregulation of TSH; (2) TRbeta but not TRalpha is sufficient for TH-mediated downregulation of TSH; and (3) TRalpha may partially substitute for TRbeta in mediating a partial TH-dependent TSH suppression.

Congenital hypothyroidism in a child with unsuspected familial dysalbuminemic hyperthyroxinemia caused by a mutation (R218H) in the human albumin gene.

We found familial dysalbuminemic hyperthyroxinemia (FDH) in a 5-month-old boy with congenital hypothyroidism (CH) who had a blood thyrotropin (TSH) level of 479 mU/L but normal total serum thyroxine (T4) and higher than normal total triiodothyronine (T3) levels. Thyroid hormone substitution began at 5 weeks of age when T4 and T3 concentrations were below normal. Until the age of 5 months, treatment with levothyroxine was suboptimal on the basis of high serum TSH levels despite above-normal T4 levels. FDH was confirmed by isoelectric focusing and testing of other family members. DNA analysis of the patient revealed R218H, a mutation in the serum albumin gene associated with FDH, which was also present in the patient's euthyroid father and brother. Thyroid scans, serum thyroglobulin measurements, and free T4 measurements using equilibrium dialysis or 2-step immunoassay methods can identify thyroid hormone-binding protein defects and simplify the diagnosis and treatment of infants with CH.

In vitro trial of the pilot prototype of the prostate mechanical imaging system.

OBJECTIVES: To compare the sensitivity and accuracy of the mechanical imaging system (MI system) to that of the simulated digital rectal examination (DRE) in detecting nodules within fabricated rubber prostate phantoms. Mechanical imaging is a new technology for visualizing and characterizing tissues using mechanical strain and stress data. METHODS: Twelve rubber phantoms were designed to simulate human prostates. Ten phantoms contained hard nodules in various locations. Two phantoms contained no nodules. Each model was examined with the MI system by a urologist (R.E.W.) and research student. Three-dimensional images of the examined prostate phantoms with and without nodules were generated by the MI system software. Blind DRE was performed on each phantom independently by the urologist and student. The results of the MI examinations and DREs were compared for sensitivity in detecting the presence and location of nodules within the prostate phantoms. RESULTS: Three-dimensional MI images reconstructed from both the student and the urologist examination data demonstrated 100% of the nodules in the appropriate locations. The DREs by the urologist detected 83% of the nodules in the appropriate locations. The DREs by the student detected 67% of the nodules in the appropriate locations. CONCLUSIONS: The prostate MI system allowed the detection of nodules in the prostate phantoms with sensitivity exceeding that of an experienced urologist. In contrast to the DRE, the results of the MI examination appear to be independent of the operator's experience. Therefore, the MI system is a promising means of accurate, sensitive, objective, and recordable detection of hard nodules within the prostate.

Estimation for paired binomial data with application to radiation therapy.

We compare and contrast several different methods for estimating the effect of treatment when responses are paired binomial observations. The ratio of binomial probabilities is the parameter of interest, while the binomial probabilities are nuisance parameters which may vary between pairs. The application is a meta-analysis of the treatment of rectal cancer, with observations in each study indicating the number of recurrences of the cancer in each of two groups, one with radiation therapy and one without. The ratio of the probabilities of recurrence in the radiation to non-radiation groups is of substantive interest, and is modelled as a logistic or complementary log-log function of an unknown linear combination of the covariates. The three methods we consider are maximum likelihood, a Bayesian approach and an approach based on estimating equations. For the MLE and Bayesian approach the potentially large number of nuisance parameters are estimated together with the parameters of interest, whereas for the estimating equation approach only the parameters of interest are estimated. A simulation study is performed to compare the methods and evaluate the impact of overdispersion.

Resistance to thyroid hormone does not abrogate the transient thyrotoxicosis associated with gestation: report of a case.

We report the occurrence of transient thyrotoxicosis during pregnancy in a subject with resistance to thyroid hormone. Before pregnancy, the subject was euthyroid, with normal serum TSH and elevated levels of free T(3) and free T(4) caused by a mutation in the TRbeta gene (R243Q). Beginning at the fourth week of gestation serum levels of free T(3) and T(4) increased in parallel with an increase in hCG. At 6-7 wk gestation she manifested hypermetabolic features, with mild nausea and vomiting. Peak levels of serum hCG and thyroid hormone concentrations were attained at 12 wk gestation, when serum TSH was fully suppressed. In the following weeks of gestation, thyroid hormone levels declined, with amelioration of the symptoms. A baby boy also affected with resistance to thyroid hormone harboring the same TRbeta gene mutation was born by normal vaginal delivery.

Medical mimics. Medical and neurological conditions simulating ADHD.

The medical and neurological conditions that simulate ADHD are reviewed, as well as those disorders frequently presenting as comorbidities with ADHD. The localization of ADHD has invoked multiple areas, including frontal lobes, nondominant parietal lobe, and basal ganglia, and the neural network theory of cortical-subcortical-cortical loops has been implicated in the pathogenesis of ADHD. The medical evaluation of patients presenting with ADHD should be comprehensive, with an emphasis on demonstrating chronic and permeating symptoms since early childhood without a better medical explanation. Associated thyroid disorders are reviewed, including the syndrome of resistance to thyroid hormone. Suggested laboratory studies are provided, depending on the clinical circumstances.

Genetic analysis reveals different functions for the products of the thyroid hormone receptor alpha locus.

Thyroid hormone receptors are encoded by the TRalpha (NR1A1) and TRbeta (NR1A2) loci. These genes are transcribed into multiple variants whose functions are unclear. Analysis by gene inactivation in mice has provided new insights into the functional complexity of these products. Different strategies designed to modify the TRalpha locus have led to strikingly different phenotypes. In order to analyze the molecular basis for these alterations, we generated mice devoid of all known isoforms produced from the TRalpha locus (TRalpha(0/0)). These mice are viable and exhibit reduced linear growth, bone maturation delay, moderate hypothermia, and reduced thickness of the intestinal mucosa. Compounding TRalpha(0) and TRbeta(-) mutations produces viable TRalpha(0/0)beta(-/-) mice, which display a more severe linear growth reduction and a more profound hypothermia as well as impaired hearing. A striking phenotypic difference is observed between TRalpha(0/0) and the previously described TRalpha(-/-) mice, which retain truncated TRDeltaalpha isoforms arising from a newly described promoter in intron 7. The lethality and severe impairment of the intestinal maturation in TRalpha(-/-) mice are rescued in TRalpha(0/0) animals. We demonstrate that the TRDeltaalpha protein isoforms, which are natural products of the TRalpha locus, are the key determinants of these phenotypical differences. These data reveal the functional importance of the non-T3-binding variants encoded by the TRalpha locus in vertebrate postnatal development and homeostasis.

Bayesian selection of continuous-time Markov chain evolutionary models.

We develop a reversible jump Markov chain Monte Carlo approach to estimating the posterior distribution of phylogenies based on aligned DNA/RNA sequences under several hierarchical evolutionary models. Using a proper, yet nontruncated and uninformative prior, we demonstrate the advantages of the Bayesian approach to hypothesis testing and estimation in phylogenetics by comparing different models for the infinitesimal rates of change among nucleotides, for the number of rate classes, and for the relationships among branch lengths. We compare the relative probabilities of these models and the appropriateness of a molecular clock using Bayes factors. Our most general model, first proposed by Tamura and Nei, parameterizes the infinitesimal change probabilities among nucleotides (A, G, C, T/U) into six parameters, consisting of three parameters for the nucleotide stationary distribution, two rate parameters for nucleotide transitions, and another parameter for nucleotide transversions. Nested models include the Hasegawa, Kishino, and Yano model with equal transition rates and the Kimura model with a uniform stationary distribution and equal transition rates. To illustrate our methods, we examine simulated data, 16S rRNA sequences from 15 contemporary eubacteria, halobacteria, eocytes, and eukaryotes, 9 primates, and the entire HIV genome of 11 isolates. We find that the Kimura model is too restrictive, that the Hasegawa, Kishino, and Yano model can be rejected for some data sets, that there is evidence for more than one rate class and a molecular clock among similar taxa, and that a molecular clock can be rejected for more distantly related taxa.

State-of-the-art prostate cancer treatment and research. A report from the Cancer Institute of New Jersey.

Prostate cancer is a devastating disease that will be diagnosed in approximately 200,000 men in 2001. New methods for screening, prevention, and treatment are being developed. In addition, novel agents for the treatment of resistant prostate cancer are being developed in clinical trials. This review summarizes the recent efforts in diet, screening, novel systemic therapies, and alternative medicine for prostate cancer.

Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor alpha.

Only three of the four thyroid hormone receptor (TR) isoforms, alpha1, beta1, and beta2, bind thyroid hormone (TH) and are considered to be true TRs. TRalpha2 binds to TH response elements on DNA, but its role in vivo is still unknown. We produced mice completely deficient in TRalpha (TRalpha(o/o)) that maintain normal serum thyroid-stimulating hormone (TSH) concentration despite low serum thyroxine (T(4)), suggesting increased sensitivity to TH. We therefore examined the effects of TH (L-3,3',5-triiodothyronine, L-T3) given to TH-deprived and to intact TRalpha(o/o) mice. Controls were wild-type (WT) mice of the same strain and mice resistant to TH due to deficiency in TRbeta (TRbeta(-/-)). In liver, T3 produced significantly greater responses in TRalpha(o/o) and smaller responses in TRbeta(-/-) as compared with WT mice. In contrast, cardiac responses to L-T3 were absent or reduced in TRalpha(o/o), whereas they were similar in WT and TRbeta(-/-) mice, supporting the notion that TRalpha1 is the dominant TH-dependent TR isoform in heart. 5-Triiodothyronine (L-T3) given to intact mice produced a greater suppression of serum T(4) in TRalpha(o/o) than it did in WT mice and reduced by a greater amount the TSH response to TSH-releasing hormone. This is an in vivo demonstration that a TR deficiency can enhance sensitivity to TH. This effect is likely due to the abrogation of the constitutive "silencing" effect of TRalpha2 in tissues expressing the TRbeta isoforms.