[Death due to tuberculosis requiring treatment or an accompanying disease? A contribution to the lethality and mortality of tuberculosis in Germany]. / Tod an behandlungsbedürftiger Tuberkulose oder an Begleitkrankheiten? Ein Beitrag zur Letalität und Mortalität der Tuberkulose in Deutschland.

BACKGROUND: Tuberculosis (TB) is a curable disease. Nevertheless, patients in Germany also die of TB. Although mortality is decreasing, there are indications for an increase in lethality. This observation provided the impetus for a detailed analysis that sought to investigate the validity of the statistics on deaths caused by TB. METHOD: The study population consists of the 926 fatal cases that were classified either as "death from TB" or as "death due to other causes" out of the 6044 TB patients in the DZK study. For the analysis, health authorities were asked to provide additional information and such documents as the death certificate, the autopsy protocol and the final medical report. In 778 cases, there was at least one additional piece of information available. Three teams of two experts each conducted independent evaluations of the documents. RESULTS: Based on the findings of the experts, every second death caused by TB in 1997 and 1998 was not recorded correctly during the post-mortem examination. Every third TB death was not diagnosed during the patient's lifetime. Patients who died due to TB were, on average, older and more likely to be born in Germany. This indicates that age-related comorbidity among the native German population plays a relevant role. Yet, the unicausal death registration did not acknowledge comorbidity as a contributing factor to the fatal outcome. Pulmonary TB with positive microscopy and culture, miliary TB and meningeal TB were more common among the deaths due to TB than among the general study population, and led more often to a fatal outcome than other organ manifestations. However, the two groups did not differ with regard to multi-drug resistant TB. Alcohol abuse was a leading risk factor for death caused by TB in patients under 65 years. Patient's delay ranged from six to 34 days, and doctor's delay from eight to 46 days. For example, alcohol abusers, on average, visited a physician much later, but were diagnosed more rapidly after the first visit than patients who were not alcohol-dependent. A period of 32 - 200 days elapsed between diagnosis and death caused by TB. CONCLUSIONS: The post-mortem examination often missed TB as the cause of death. Many native German TB patients showed age-related comorbidity. Pulmonary TB with positive microscopy, miliary TB and meningeal TB led more often to a fatal outcome than other organ manifestations. Alcohol abuse was a leading risk factor for TB deaths in patients younger the 65 years. The average period between the onset of symptoms and the diagnosis was significantly longer than the one month generally considered acceptable. The experts could not confirm an increase in lethality for the period under investigation.

[Therapy-resistant otitis externa with additional tympanic membrane perforation: local therapy using N-chlorotaurine and dexamethasone]. / Therapieresistente Otitis externa mit zusätzlicher Trommelfellperforation: Lokaltherapie mit N-Chlortaurin und Dexamethason.

Ear canal infections may not always be clinically distinguished between a bacterial otitis externa, an otomycosis or a mixed infection. In addition, tympanic membrane perforations are often not immediately apparent. The use of a broad-spectrum antiseptic agent without an inner ear toxic effect would therefore be beneficial. We report the case of a female patient suffering from intractable otitis externa with tympanic membrane perforation, who was successfully treated locally with a mixture of 1% NCT and 0.1% dexamethasone.

[Granulomatous bronchiolitis due to aspiration of lycopodium spores by fire-breathing]. / Granulomatöse Bronchiolitis nach Aspiration von Lycopodium-Sporen bei einem Feuerspucker.

BACKGROUND: Lung disease due to aspiration is often unsuspected and represents a diagnostic challenge. CASE REPORT: We report on a 23-year-old male patient with cough, fever and infiltrates on the chest radiograph. The lung biopsy showed granulomatous changes consistent with tuberculosis. The surgical lung biopsy revealed aspiration bronchiolitis with necrosis, granulomatous changes and particulate foreign material. RESULTS: The aspirated matter could be identified only after repeated interrogation specifically directed to the matter. The patient had aspirated Lycopodium spores in the course of occasional fire-breathing. CONCLUSIONS: This is the first report on pulmonary disease due to aspiration of Lycopodium spores in the course of fire-breathing. It shows that the anamnesis is as crucial as histology for the definitive diagnosis of aspiration disease.

[Otitis externa: etiology, diagnostic and therapy]. / Otitis externa: Atiologie, Diagnostik und Therapie.

Otitis externa (OE) occurs during the lifetime in approximately 10% of the population, especially in warm and damp climates or from swimming (swimmer's ear). Females are most often affected around the age of 50 years and males around 70 years of age. Both auditory canals are affected in approximately 10% of cases. Causes of infection are mostly bacteria, and more rarely fungi or viruses. OE can be accompanied not only by relatively slight pain and light swelling of the skin of the auditory canal, but also by severe pain, complete obstruction of the external meatus and retroauricular swelling. An uncomplicated infection can normally be treated by cleaning of the meatus by an ENT specialist and local application of a broad-spectrum antibiotic or an antiseptic supplemented with corticoids as well as antimycotics. Complicated infections, such as necrotizing OE, are rare and normally only occur in elderly patients with diabetes mellitus or in an immunosuppressed condition.

Fibro-osseous lesion of the middle turbinate: ossifying fibroma or fibrous dysplasia?

Benign fibro-osseous tumours of the head and neck region seldom appear in the midface and nasal cavity. Correct differential diagnosis of fibro-osseous tumours is crucial for adequate therapy, as their clinical aggressiveness seems to differ. The rather uncommon case of a 14-year-old boy with a tumour of the middle turbinate is presented. The radiologic appearance of the tumour, on computed tomography and magnetic resonance imaging scans, was consistent with fibrous dysplasia. Angiography revealed extensive vascularisation of the tumour from both the internal and external carotid arteries. To avoid ipsilateral blindness following embolisation, a superselective embolisation of the supplying blood vessels was performed. The tumour was completely resected via an endoscopic approach. Histopathology revealed an ossifying fibroma. This case emphasises the importance of interpretation of the clinical, radiological and histological features before planning definitive treatment. Moreover, when fibro-osseous tumours are suspected, the possibility of extensive, complicated vascularisation must be considered. This case underwent radical resection, with no recurrence after four years' follow up.

Deconfounding microarray analysis - independent measurements of cell type proportions used in a regression model to resolve tissue heterogeneity bias.

OBJECTIVES: Microarray analysis requires standardized specimens and evaluation procedures to achieve acceptable results. A major limitation of this method is caused by heterogeneity in the cellular composition of tissue specimens, which frequently confounds data analysis. We introduce a linear model to deconfound gene expression data from tissue heterogeneity for genes exclusively expressed by a single cell type. METHODS: Gene expression data are deconfounded from tissue heterogeneity effects by analyzing them using an appropriate linear regression model. In our illustrating data set tissue heterogeneity is being measured using flow cytometry. Gene expression data are determined in parallel by real time quantitative polymerase chain reaction (qPCR) and microarray analyses. Verification of deconfounding is enabled using protein quantification for the respective marker genes. RESULTS: For our illustrating dataset, quantification of cell type proportions for peripheral blood mononuclear cells (PBMC) from tuberculosis patients and controls revealed differences in B cell and monocyte proportions between both study groups, and thus heterogeneity for the tissue under investigation. Gene expression analyses reflected these differences in celltype distribution. Fitting an appropriate linear model allowed us to deconfound measured transcriptome levels from tissue heterogeneity effects. In the case of monocytes, additional differential expression on the single cell level could be proposed. Protein quantification verified these deconfounded results. CONCLUSIONS: Deconfounding of transcriptome analyses for cellular heterogeneity greatly improves interpretability, and hence the validity of transcriptome profiling results.

Enhanced fungicidal activity of N-chlorotaurine in nasal secretion.

The antifungal activity of N-chlorotaurine (NCT), a long-lived oxidant produced by stimulated human leucocytes, was investigated. Incubation of Aspergillus spp., Candida spp., Fusarium spp., Penicillium spp. and Alternaria spp. in 1% NCT (55 mM) for 1-4 h produced a log10 reduction in cfu of between 1 and 4. In samples of nasal secretion, killing was significantly hastened (30 min), which may be explained by the formation of monochloramine by halogenation of ammonium, which was found at a concentration of 1 mM in these samples. For these reasons, NCT is of interest as a new agent for treatment of local inflammatory mycosis, e.g. eosinophilic fungal rhinosinusitis.

N-chlorotaurine, a novel endogenous antimicrobial agent: tolerability testing in a mouse model.

OBJECTIVE: To investigate the tolerability of N-chlorotaurine, a new antimicrobial agent, by application to the middle ear in a mouse model. METHODS: Five BALB/c mice were each injected through the tympanic membrane with 5 microL of 0.1%, 1.0%, and 10% N-chlorotaurine and compared with animals in which 0.9% isotonic sodium chloride solution, 0.2% gentamicin sulfate, and 0.25% trimethyltin chloride were instilled. Auditory brainstem responses to clicks were evaluated repeatedly between 4 and 75 days after injection, and histologic investigations of the inner ear were performed subsequently. Three additional groups of mice were injected with isotonic sodium chloride solution, 1.0% N-chlorotaurine, and 0.25% trimethyltin, and brainstem responses to tone bursts of 8, 16, and 32 kHz were tested. In addition, the middle ear was examined histologically. RESULTS: Mice treated with isotonic sodium chloride solution, 0.1% N-chlorotaurine, and 0.2% gentamicin sulfate did not show changes in response threshold. Treatment with 1.0% and 10% N-chlorotaurine caused a reversible increase in auditory brainstem response threshold by 20 dB 4 days after application because of local irritation around the perforation of the tympanic membrane. In contrast, 0.25% trimethyltin showed a permanent elevation of auditory brainstem response threshold of 10 to 15 dB and a scattered loss of outer hair cells predominantly in the apical turn. No alterations of the inner ear were observed in the other treatment groups. The mucous membrane of the middle ear remained unaffected in all test groups. CONCLUSION: Application of N-chlorotaurine to the middle ear is well tolerated without adverse effects and may be a useful new endogenous antimicrobial agent for local treatment of otologic infections.

DNA ploidy determination of early molar pregnancies by image analysis: comparison to histologic classification.

BACKGROUND: To improve histologic diagnosis of molar pregnancies, updated guidelines have been proposed recently. These guidelines take into account that less developed molar gestations differ from their fully developed counterparts. OBJECTIVE: To test the validity of these criteria by correlating histologic diagnosis with ploidy determination accomplished by means of image analysis. DESIGN: Fifty archival cases of early molar pregnancy were reclassified according to the new criteria. The diagnosis had to be changed from partial to complete hydatidiform mole (PM to CM, respectively) in 9 cases and from CM to PM in 4 cases. DNA image cytometry could be performed in 40 cases (CM, n = 21; PM, n = 19). RESULTS: There was 100% agreement between histologic diagnosis and a diploid or polyploid histogram in CM and 79% agreement between triploidy and PM, when the updated diagnostic criteria were used. This represents an improvement compared with diagnoses made with former criteria. Nevertheless, problems of correct classification remain: In 3 cases classified as PMs, fetal remnants were accompanied by the histologic appearance of a CM. These 3 cases could represent either a true embryonic development in CM or a twin gestation with one normal pregnancy and one mole, or they could belong to a (very rare) third type of mole. All of them show the same risk of persistent trophoblastic disease observed in classic CM. CONCLUSIONS: As the groups at risk for developing persistent trophoblastic disease can be identified by their DNA histograms, ploidy analysis would be desirable in addition to histologic examination.

Directly observed intermittent short-course chemotherapy in the Kathmandu valley.

SETTING: Within the national tuberculosis control programme in Nepal, cure rates of only 30%-40% were achieved using standard chemotherapy. High cure rates are particularly difficult to achieve in the Kathmandu valley, because of the mobility of the population and the large numbers of private practitioners. Short-course chemotherapy (SCC) was not used in tuberculosis (TB) control programmes in Nepal before 1991. Therefore we started our pilot programme with a fully supervised, intermittent SCC regimen. In addition we established a mycobacteriological laboratory for routine culture and susceptibility tests. OBJECTIVE: The main objective was to demonstrate the high effectiveness of a three-times weekly SCC regimen and the feasibility of directly observed treatment (DOT). DESIGN: In our new out-patient department we put all active TB patients under SCC. The duration of therapy was 9 months or longer, depending upon bacteriological and radiological needs. The results were well recorded and evaluated by central supervision. Outcome of treatment was recorded at 24-48 months. RESULTS: From January 1990 to December 1993, 771 pulmonary TB patients (618 new cases and 153 old cases) commenced treatment. Of these, 645 (84%) were cured or completed treatment, 84 (11%) defaulted, 15 (2%) died, 15 (2%) were treatment failures and 12 (3.0%) relapsed. CONCLUSION: Directly observed intermittent SCC is highly cost-effective. The results of our service programme showed that it is possible to introduce such a regimen in an urban area of Nepal.

Expression of MHC molecules and ICAM-1 on non-small cell lung carcinomas: association with early lymphatic spread of tumour cells.

Early microdissemination of tumour cells determines the prognosis of patients with apparently localised non-small cell lung cancer (NSCLC). Monoclonal antibodies to epithelial antigens can now be used to detect single carcinoma cells present in mesenchymal secondary organs such as bone marrow or lymph nodes. The present study was designed to obtain insights into the potential role of the immune system in lymphatic and haematogenous microdissemination of NSCLC cells. Using immunohistochemical staining of primary NSCLC, we assessed the expression pattern of molecules mediating an efficient cellular immune response, that is, MHC class I and class II antigens and the intercellular adhesion molecule-1 (ICAM-1). All 58 patients evaluated were staged as free of overt metastases by conventional clinico-pathological screening. Isolated tumour cells in bone marrow or lymph nodes were identified with mAb CK2 to cytokeratin component No. 18 and mAb BerEp-4 to glycoproteins of 34 and 39 kd present on epithelial cells, respectively. MHC class I expression on primary tumours was reduced or absent in 6/10 (60.0%) patients with isolated cancer cells in lymph nodes as compared to 6/33 tumours (18.1%) without such tumour cell dissemination (P = 0.01). MHC class II molecules on primary tumours were detected in 1/10 (10.0%) patients with micrometastases to regional lymph nodes and in 10/33 (30.3%) patients without such a tumour cell spread. None of the 10 patients with nodal microdissemination expressed ICAM-1 on their primary NSCLC, while such expression was detectable in 12/33 (36.4%) patients without this dissemination (P = 0.01). In contrast, the detection of tumour cells in bone marrow was not correlated to the expression of any of these immunoregulatory molecules. Our data suggest that escape caused by deficient expression of MHC class I antigens and ICAM-1 on tumour cells may support homing or survival of disseminated tumour cells in lymphoid tissue.

[HIV-associated histoplasmosis with pulmonary manifestation in Europe]. / HIV-assoziierte Histoplasmose in Europa mit pulmonaler Manifestation.

A 35-year-old man developed weight loss, lower abdominal pain, diarrhoea, cough, fever and general deterioration in his health. He had been born and resident in the USA until 1991, when he moved to Germany. Since 1991 he had known that he was HIV-positive. The chest radiograph showed bilateral diffuse spotty marking and a rounded cardiac silhouette, the latter echocardiographically due to pericardial effusion. Tuberculostatic drugs were started because miliary tuberculosis was suspected. But as his condition worsened and he was thought to have Pneumocystis pneumonia high doses of co-trimoxazole were administered. Perbronchial lung biopsy showed nonspecific chronic inflammatory changes. Periodide acid-Schiff reaction and Grocott staining demonstrated numerous histoplasma in alveolar macrophages and connective tissue. The organism was also cultured from bronchial secretions. Treatment was now changed to itraconazole (400 mg daily), 2 weeks later changed to liposomal amphotericin B (100 mg daily) because of renewed fever. After 6 weeks the patient became free of symptoms and the radiological changes had largely regressed. To prevent recurrence, treatment with itraconazole (400 mg daily) is being continued.

Tinnitus: the hidden epidemic. A patient's perspective.

The author describes his personal experience with tinnitus as well as various medical practitioners. He also discusses possible avenues for tinnitus research and suggests educational efforts that otolaryngology organizations might initiate.

[Control of tuberculosis in Nepal. A project. Initial results, experiences]. / Tuberkulosebekämpfung in Nepal. Ein Projekt. Erste Ergebnisse, Erfahrungen.

2,124 persons were examined in 16 months. 328 of these were tuberculosis patients requiring treatment. When treated, 74%, 81% and 97% of the patients showed conversion of sputum after 2, 4 and 6 months, respectively. Sensitivity tests (n = 223) yielded 19% monoresistances and 5% resistances against 2 drugs. 87% of the patients took their tablets regularly; 8.7% discontinued the treatment.

[Control of tuberculosis in Nepal. A project. Logistics, goals]. / Tuberkulosebekämpfung in Nepal. Ein Projekt. Logistik, Zielsetzung.

The aims of the anti-tuberculosis project are firstly to successfully conclude chemotherapy with few discontinuations of treatment and re-activations, and, secondly, via the determination of resistance, to identify problems in the fight against tuberculosis in Nepal, and to demonstrate therapeutic possibilities in problem patients.

Foregut fermentation in the hoatzin, a neotropical leaf-eating bird.

The only known case of an avian digestive system with active foregut fermentation is reported for the hoatzin (Opisthocomus hoazin), one of the world's few obligate folivorous (leaf-eating) birds. Hoatzins are one of the smallest endotherms with this form of digestion. Foregut fermentation in a flying bird may be explained by increased digestive efficiency by selection of highly fermentable and extremely patchy resources, coupled with microbial nutritional products and secondary compound detoxification. This unexpected digestive system gives a new perspective to the understanding of size limitations of vertebrate herbivores and to the evolution of foregut fermentation.

[Individual field shaping in rotational irradiation]. / Individuelle Feldformung bei der Rotationsbestrahlung.

At the Radiotherapy Department of the University Hospital of Freiburg i.Br., an additional diaphragm controlled by an electronic system in dependence on the angles was developed for the optimization of irradiation planning, i.e. administration of the therapeutically necessary dose to the target volume and, at the same time, sparing of risk organs.