Inhibition of nuclear factor-kappa B activation decreases survival of Mycobacterium tuberculosis in human macrophages.

Nuclear factor-kappa B (NFκB) is a ubiquitous transcription factor that mediates pro-inflammatory responses required for host control of many microbial pathogens; on the other hand, NFκB has been implicated in the pathogenesis of other inflammatory and infectious diseases. Mice with genetic disruption of the p50 subunit of NFκB are more likely to succumb to Mycobacterium tuberculosis (MTB). However, the role of NFκB in host defense in humans is not fully understood. We sought to examine the role of NFκB activation in the immune response of human macrophages to MTB. Targeted pharmacologic inhibition of NFκB activation using BAY 11-7082 (BAY, an inhibitor of IκBα kinase) or an adenovirus construct with a dominant-negative IκBα significantly decreased the number of viable intracellular mycobacteria recovered from THP-1 macrophages four and eight days after infection. The results with BAY were confirmed in primary human monocyte-derived macrophages and alveolar macrophages. NFκB inhibition was associated with increased macrophage apoptosis and autophagy, which are well-established killing mechanisms of intracellular MTB. Inhibition of the executioner protease caspase-3 or of the autophagic pathway significantly abrogated the effects of BAY. We conclude that NFκB inhibition decreases viability of intracellular MTB in human macrophages via induction of apoptosis and autophagy.

p16(INK4a) is superior to high-risk human papillomavirus testing in cervical cytology for the prediction of underlying high-grade dysplasia.

BACKGROUND: The primary goal of this study was to compare the clinical performance of an optimized and rigorously controlled immunocytochemical (ICC) assay for p16(INK4a) to high-risk (HR) human papillomavirus (HPV) detection by polymerase chain reaction (PCR) as diagnostic adjuncts for cytology specimens from colposcopy patients. METHODS: : The study included 403 cervical cytology specimens collected within 3 months of colposcopy. The colposcopic impression and cervical biopsy diagnosis served as the standards for correlation with cytological, p16(INK4a), and HPV data. p16(INK4a) was evaluated using an immunoperoxidase-based assay that was linear over 4 logs for the detection of HeLa-spiked positive control cytology specimens, using a threshold for positive test results that was based on receiver operating characteristic curve analysis. HR-HPV was detected by multiplex PCR using genotype-specific primers. RESULTS: : In all combined diagnostic categories (negative for intraepithelial lesion and malignancy, atypical glandular cells, atypical squamous cells of undetermined significance, atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion, low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion), the p16(INK4a) ICC and HR-HPV assays, respectively, had sensitivity of 81.7% and 83.3% (P = .81) and specificity of 78.1% and 50.9% (P < .001) for the detection of underlying > or =grade 2 cervical intraepithelial neoplasia (CIN) lesions on biopsy. Furthermore, the positive predictive value of p16(INK4a) ICC was greater than that of HR-HPV for patients with biopsies > or =CIN-2 (41.2% and 24.2%, respectively, P = .001). CONCLUSIONS: : This p16(INK4a) immunocytochemical assay has superior specificity but similar sensitivity to HR-HPV testing to predict underlying high-grade dysplastic lesions in patients who are referred for colposcopy. The determination of the overall performance characteristics of p16(INK4a) immunocytochemistry, as an independent test or in combination with HPV testing in low-risk screening populations, however, will require subsequent large-scale prospective clinical trials.

Laboratory diagnosis of urinary tract infections in adult patients.

Urinary tract infections (UTIs) are among the most common bacterial infections and account for a significant part of the workload in clinical microbiology laboratories. Enteric bacteria (in particular, Escherichia coli) remain the most frequent cause of UTIs, although the distribution of pathogens that cause UTIs is changing. More important is the increase in resistance to some antimicrobial agents, particularly the resistance to trimethoprim-sulfamethoxazole seen in E. coli. Physicians distinguish UTIs from other diseases that have similar clinical presentations with use of a small number of tests, none of which, if used individually, have adequate sensitivity and specificity. Among the diagnostic tests, urinalysis is useful mainly for excluding bacteriuria. Urine culture may not be necessary as part of the evaluation of outpatients with uncomplicated UTIs, but it is necessary for outpatients who have recurrent UTIs, experience treatment failures, or have complicated UTIs, as well as for inpatients who develop UTIs.

Infectious diseases detected at autopsy at an urban public hospital, 1996-2001.

Previous studies have demonstrated significant discrepancy rates between clinical and autopsy diagnoses. However, infectious diseases have not received emphasis in these studies. We conducted a study to determine whether the clinical and autopsy diagnoses of infectious diseases are concordant or discrepant and to determine discrepancy rates. Retrospective reviews of the records of 276 patients (adults, 182; fetuses and neonates, 94) who underwent autopsy during the years 1996 through 2001 were performed. Comparison of clinical and autopsy diagnoses was performed using the Goldman classification scheme. Of 182 adult patients, 137 (75.3%) had an infectious disease at autopsy. In 59 (43.1%) of 137 patients, the infectious disease diagnoses were unknown clinically. Of 94 fetuses and neonates, 45 (48%) had an infectious disease at autopsy. In 26 (58%) of 45 patients, the infectious disease diagnoses were unknown before death. There are substantial discrepancies between clinical and autopsy diagnoses of infectious diseases. In adults, acute bronchopneumonia is the infectious disease most often missed clinically; in fetuses and neonates, it is acute chorioamnionitis.

Plasma cell granuloma of the thyroid with Hashimoto's thyroiditis: report of a rare case.

As only eight cases have been previously reported in the literature, plasma cell granuloma of the thyroid gland is a rare entity. This condition can be confused with a benign or malignant neoplastic thyroid process. In this article, we describe a new case of plasma cell granuloma of the thyroid gland that occurred in a 46-year-old man who also had Hashimoto's thyroiditis. This case represents only the second documented instance of a plasma cell granuloma of the thyroid occurring in the setting of Hashimoto's thyroiditis. Moreover, it is only the second case of a plasma cell granuloma that has been reported in a male.