Evaluation of undergraduate training on tuberculosis at Istanbul Medical School.

SETTING: Undergraduate training on tuberculosis at Istanbul Medical School. OBJECTIVE: To assess whether tuberculosis-related questions asked in chest medicine examinations comply with the World Health Organization's (WHO) learning objectives for tuberculosis training, and to investigate students' skills in interpreting radiology and smears with respect to tuberculosis. DESIGN: Tuberculosis questions set for 4th year medical students (n = 838) were compared with WHO objectives (n = 23): 122 students were each asked to interpret 10 chest X-rays which had been read by three experts as 'typical tuberculosis lesions', 'normal' or 'non-tuberculosis lesions'; 114 students were also each given five smears which had been interpreted by an expert as 'negative' or 'positive' with respect to acid-fast-bacilli (AFB), and were asked to interpret them. RESULTS: Questions covered only nine of the WHO objectives. Among 117 types of questions, 91 (77.8%) were about clinical-radiological findings, treatment and drugs; 334 (65.1%) of 513 X-rays with typical tuberculosis lesions, 77 (21.1%) of 364 normal X-rays and 87 (25.4%) of 343 X-rays with non-tuberculosis lesions were identified as tuberculosis (kappa 0.45). Of 369 AFB-positive smears, 149 (40.4%) were evaluated as false negative, and of 185 AFB-negative smears, 48 (25.9%) were evaluated as false positive (kappa 0.49). CONCLUSION: Examination questions set on tuberculosis at Istanbul Medical School do not adequately reflect WHO learning objectives. Students' skills in interpreting radiology and smears suggest that their practical training on tuberculosis is insufficient.

The frequency of deep venous thrombosis and pulmonary embolus in acute exacerbation of chronic obstructive pulmonary disease.

Infection, pulmonary embolism caused by mostly deep venous thrombosis (DVT), hypoxaemia and drugs, used in the treatment of chronic obstructive pulmonary disease (COPD), related arrhythmia, aspiration are mostly responsible for acute exacerbations of COPD. The incidences of DVT and pulmonary embolus were investigated in 56 hospitalised cases with acute exacerbation of COPD. DVT was diagnosed in six (10.7%) cases with coloured doppler ultrasonography (CDU) and in two cases whose examinations were not sufficient enough to diagnose or refuse DVT. Diagnosis of pulmonary embolus was investigated with ventilation/perfusion scintigraphy in eight cases of clinically medium--high-probable pulmonary embolus. Pulmonary embolus was determined in five cases (8.9%). Age, weight, height, disease course, pulmonary function tests, arterial blood gases and haematocrit values of the cases did not predict the diagnosis of DVT and pulmonary embolus in our cases.

Clinical and molecular analysis of three Mexican families with Pendred's syndrome.

BACKGROUND: The autosomal recessive Pendred's syndrome is defined by congenital sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the Pendred's syndrome (PDS) gene that encodes pendrin, a chloride/iodide transporter expressed in the thyroid, the inner ear, and the kidney. OBJECTIVE: To perform a detailed clinical and molecular analysis of patients with Pendred's syndrome from four patients from three unrelated Mexican families. METHODS: Thyroid function tests, perchlorate test, thyroid scintigraphy, audiometry, computer tomography and magnetic resonance imaging were performed in all affected individuals. Haplotype analyses were performed using microsatellite markers flanking the PDS locus, and the PDS gene was submitted to direct sequence analysis. RESULTS: All patients presented with sensorineural deafness, Mondini malformations of the cochlea, an enlarged vestibular aqueduct, goiter, and a positive perchlorate test. Two patients were hypothyroid, two individuals were euthyroid. Sequence analysis revealed a complex homozygous deletion/insertion mutation at the end of exon 4 in the index patient of family 1 resulting in a premature stop codon at position 138. In family 2, the affected individuals were compound heterozygous for a splice acceptor mutation (IVS2 -1G>A) and a 1231G>C transversion substituting alanine 411 by proline (A411P). In family 3, the index patient was found to be homozygous for a transversion 412G>T in exon 4 replacing valine 138 by phenylalanine (V138F). CONCLUSIONS: All patients included in this study presented with the classic Pendred syndrome triad and molecular analysis revealed pendrin mutations as the underlying cause. The identification of three novel mutations, one of them of complex structure, expands the spectrum of mutations in the PDS gene and emphasizes that they display marked allelic heterogeneity.

Substitutions of tyrosine 601 in the human thyrotropin receptor result in increase or loss of basal activation of the cyclic adenosine monophosphate pathway and disrupt coupling to Gq/11.

Constitutively activating mutations of the thyrotropin (TSH) receptor have been identified as a molecular cause of toxic adenomas, nonautoimmune familial hyperthyroidism, and sporadic congenital hyperthyroidism. By analyzing genomic DNA from a toxic adenoma, we detected a novel somatic mutation in codon 601, tyrosine to asparagine (Y601N), a residue located in the carboxyterminal part of the fifth transmembrane helix. This codon is also notable for the presence of a polymorphic variant, Y601H. These two naturally occurring substitutions (Y601N and Y601H) were analyzed together with an artificial mutation, Y601F, to study the role of this residue for receptor function further. Transient transfection assays revealed that the Y601N mutation results in constitutive activation of the cyclic adenosine monophosphate (cAMP) pathway, but that it is unable to couple to Gq/11. Y601H and Y601F do not display basal activity while retaining responsiveness to TSH, but also lose the ability to induce inositol phosphate accumulation in response to TSH. These studies define Y601N as a mutation that selectively activates the cAMP pathway, and they confirm that Y601H is not a silent polymorphism. In conclusion, residue Y601 has an important role for the characteristic constitutive basal activity of the TSH receptor and coupling to Gq/11.

Thyrotropin receptor mutations in hyperfunctioning thyroid adenomas from Brazil.

Constitutively activating mutations in the thyrotropin (TSH) receptor have been identified as a major molecular cause of hyperfunctioning thyroid adenomas. A smaller subset of these benign tumors is caused by constitutive activation of the adenylyl cyclase cascade by somatic mutations in the Gsalpha gene. In this study, we analyzed hyperfunctioning thyroid adenomas from seven Brazilian patients for TSH receptor and G(s)alpha gene mutations. Solitary autonomous thyroid adenomas were identified by ultrasound and scintigraphy, and DNA was extracted from adenomatous and periadenomatous tissue. Exons 9 and 10 of the TSH receptor gene, and exons 8 and 9 of the G(s)alpha gene, were amplified by polymerase chain reaction (PCR) and subjected to direct sequence analysis. Six of seven adenomas harbored heterozygous mutations known to confer constitutive activity to the TSH receptor. In one case, aspartate 619 was substituted by glycine (D619G). In four adenomas, alanine 623 was replaced by valine (A623V). Both residues are located in the third intracellular loop. In one instance, aspartate 633 located in the sixth transmembrane domain was replaced by tyrosine (D633Y). In this patient, one allele also contained a change of aspartate 727 to glutamate (D727E). This substitution is thought to be a polymorphic variant of the wild-type but it has also been associated with toxic multinodular goiters. Functional comparison of D727 with E727 did not reveal differences in basal or TSH-stimulated cyclic adenosine monophosphate (cAMP)-dependent luciferase activity in transiently transfected cells. These results demonstrate a high prevalence of activating TSH receptor mutations in toxic adenomas in this small series from Brazil (approximately 86%). These findings are in agreement with reports from other countries with a marginal iodine intake but contrast with studies from regions with a high iodine intake where these mutations appear to be less prevalent.

Determination of the etiological organism during acute exacerbations of COPD and efficacy of azithromycin, ampicillin-sulbactam, ciprofloxacin and cefaclor. Turkish Thoracic Society COPD Working Group.

Acute exacerbations, most of which are due to lower respiratory tract infections, cause great morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD) and most of these are due to lower respiratory tract infections. The aim of this study was to determine the causative organism and the effects of azithromycin, ampicillin sulbactam (sultamicillin), ciprofloxacin and cefaclor monohydrate therapy in COPD. One hundred and six patients with COPD in acute exacerbation were randomized into four groups for empiric antibiotic treatment following lung function tests and sputum examination. The most common strains isolated from sputum were Haemophilus influenzae (30.8%), Streptoccocus pneumoniae (12%) and Moraxella catarrhalis (7.7%). Azithromycin, sultamicillin, ciprofloxacin and cefaclor monohydrate were found to be effective in treating COPD exacerbations.

Structural analysis of the thyrotropin receptor in four patients with congenital hypothyroidism due to thyroid hypoplasia.

Sporadic congenital hypothyroidism is most commonly caused by developmental abnormalities of the thyroid gland. More rarely, it is due to defects in gene products involved in the regulation of the hypothalamic-pituitary-thyroid axis or thyroid hormone synthesis. Loss of function mutations in the thyrotropin (TSH) receptor have been shown to result in resistance to biologically active TSH. In complete resistance to TSH, the thyroid gland is hypoplastic and unable to synthesize and secrete sufficient amounts of thyroid hormones. In partial resistance, referred to as euthyroid hyperthyrotropinemia, the size of the gland and the thyroid hormone levels are normal at the expense of an elevated TSH. Four patients with sporadic congenital hypothyroidism and properly located hypoplastic thyroid glands were included in this study. Serum TSH concentrations were 150 mU/L or higher, serum thyroglobulin levels were within normal limits (6.1 to 8.2 ng/mL; normal range: 2.1 to 32 ng/mL), and thyroid autoantibodies were absent. The coding region of the TSHbeta subunit gene, the TSH receptor gene, and exons 8 and 9 of Gsalpha were analyzed by direct sequencing and found to be normal in all patients. One patient was heterozygous for a G to A transition in the TSHbeta gene resulting in a substitution of alanine by threonine at position -7 of the signal peptide. This substitution was also found in her euthyroid father. In addition, Southern analysis of the TSH receptor gene excluded major structural alterations. These findings support previous reports that indicate that TSH resistance is genetically heterogeneous. In addition to mutations in the TSH receptor or the Gsalpha genes, other genetic defects can lead to an identical phenotype. These observations also suggest that TSH receptor mutations might be a relatively rare cause of congenital thyroid hypoplasia.

Phenocopies for deafness and goiter development in a large inbred Brazilian kindred with Pendred's syndrome associated with a novel mutation in the PDS gene.

Pendred's syndrome is an autosomal recessive disease characterized by goiter, impaired iodide organification, and congenital sensorineural deafness. The gene mutated in Pendred's syndrome, PDS (Pendred's syndrome gene), was cloned very recently and encodes the putative sulfate transporter pendrin. Pendred's syndrome may account for up to 10% of the cases with hereditary hearing loss, and pendrin mutations have also been found in a kindred with non-syndromic deafness. In this study, 41 individuals from a large, highly inbred pedigree from Northeastern Brazil were examined for features of Pendred's syndrome. Linkage studies and sequence analysis of the coding region of the PDS gene were performed with DNA from 36 individuals. The index patient, with the classical triad of deafness, positive perchlorate test, and goiter, was found to be homozygous for a deletion of thymidine 279 in exon 3, resulting in a frameshift and a premature stop codon at amino acid 96. This alteration resulted in truncation of the protein in the first transmembrane domain. Two other patients with deafness were found to be homozygous for this mutation; 19 were heterozygous and 14 were homozygous for the wild type allele. Surprisingly, 6 deaf individuals in this kindred were not homozygous for the PDS gene mutation; 3 were heterozygous and 3 were homozygous for the wild type allele, suggesting a probable distinct genetic cause for their deafness. All 3 homozygous individuals for the PDS mutation had goiters. However, goiters were also found in 10 heterozygous individuals and in 6 individuals without the PDS mutation and are most likely caused by iodine deficiency. In conclusion, we identified a novel mutation in the PDS gene causing Pendred's syndrome. The comparison of phenotype and genotype reveals, however, that phenocopies generated by distinct environmental and/or genetic causes are present in this kindred and that the diagnosis of Pendred's syndrome may be difficult without molecular analysis.

The thyroid hormone receptor variant alpha2 is a weak antagonist because it is deficient in interactions with nuclear receptor corepressors.

The thyroid hormone receptor splice variant, alpha2, is unable to bind thyroid hormone (T3) and has been proposed to function as an endogenous inhibitor of T3 action. In this report, we examined further the DNA sequence requirements for alpha2 binding to thyroid hormone response elements (TREs) in an attempt to identify response elements that mediate potent inhibition by alpha2. Heterodimers of alpha2 and retinoid X receptor were found to bind to a subset of TREs (DR4, direct repeats spaced by 4 bp) in which selected flanking and spacer sequences enhanced interactions with the AGGTCA core binding sequence. Despite the optimization of the TRE-binding sites, alpha2 remained a weak dominant negative inhibitor of TRE-driven transcription. A promoter interference assay was also developed for testing inhibition by alpha2. In these studies, alpha2 blocked gene transcription, but it required cotransfected retinoid X receptor, and it was not as potent as unliganded thyroid hormone receptors. These results led to the hypothesis that alpha2 might be deficient in interactions with nuclear receptor corepressors. Consistent with this view, alpha2 did not silence basal transcription in its native form or when linked to Gal4. Alpha2 also failed to interact with corepressors (NCoR and SMRT) in both gel shift assays and mammalian two-hybrid assays. We conclude that alpha2 is a weak antagonist of thyroid hormone action because it binds weakly to a limited repertoire of response elements, and it does not interact with corepressors. Thus, alpha2 may be able to compete with thyroid hormone receptors for binding to a limited group of target sites, but it is not able to actively inhibit transcription.

Bilateral facial paralysis secondary to lymphoma.

We report a patient with bilateral facial palsy due to a non-Hodgkin lymphoma. He was initially diagnosed to have a facial paralysis of unknown aetiology. Three months after this original diagnosis, he developed a non-Hodgkin lymphoma which was treated successfully with chemotherapy, and his palsy consequently returned to normal.

[Exogenous allergic alveolitis caused by mouldy hazel nut leaves]. / Exogene allergische Alveolitis durch schimmelige Haselnusshüllblätter.

A 62-year old farmer woman from the northeastern, very rainy part of Turkey has been collecting large amounts of green and brown involucral hazel-nut leaves for subsequent use as fuel. For the last 20 years she had been complaining of cough, respiratory distress and intermittent fever. In the course of years of continual antigen exposure she developed the clinical and x-ray signs of fibrosis of the lung. Bronchoalveolar lavage produced the typical cell pattern of chronic exogenous allergic alveolitis with predominant CD8 cells. Serum analysis yielded high titres of IgG antibodies against mould fungi partly obtained from hazel-nut husk cultures, as well as thermophilic actinomycetes.