Quantitative association tests of immune responses to antigens of Mycobacterium tuberculosis: a study of twins in West Africa.

There is now considerable evidence that host genetic factors are important in determining the outcome of infection with Mycobacterium tuberculosis (MTB). The aim of this study was to assess the role of several candidate genes in the variation observed in the immune responses to MTB antigens. In-vitro assays of T-cell proliferation, an in-vivo intradermal delayed hypersensitivity response; cytokine and antibody secretions to several mycobacterial peptide antigens were assessed in healthy, but exposed, West African twins. Candidate gene polymorphisms were typed in the NRAMP1, Vitamin D receptor, IL10, IL4, IL4 receptor and CTLA-4 genes. Variants of the loci IL10 (-1082 G/A), CTLA-4 (49 A/G) and the IL4 receptor (128 A/G) showed significant associations with immune responses to several antigens. T-cell proliferative responses and antibody responses were reduced, TNF-alpha responses were increased for subjects with the CTLA-4 G allele. The T-cell proliferative responses of subjects with IL10 GA and GG genotypes differed significantly. IL4 receptor AG and GG genotypes also showed significant differences in their T-cell proliferative responses to MTB antigens. These results yield a greater understanding of the genetic mechanisms that underlie the immune responses in tuberculosis and have implications for the design of therapeutic interventions

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Prevalence and clinical correlates of aortic dilation in hypertrophic cardiomyopathy

BACKGROUND: Aortic dilation has been associated with various cardiac conditions, although its prevalence and clinical correlates in hypertrophic cardiomyopathy (HCM) remain unclear. OBJECTIVES: The purposes of this study were to define the prevalence of ascending aortic dilation in a large referral population of patients with HCM and to determine clinical and echocardiographic correlates of aortic dilation. METHODS: A total of 1,698 patients with HCM underwent echocardiographic measurement of the tubular ascending aorta (proximal and midlevel) during index evaluation at a tertiary HCM referral center. End-diastolic ascending aorta dimension was indexed to body surface area, with dilation defined for the tubular ascending aorta as 2 SD above the mean (\u3e19 mm/m2) and independently as greater than published age-, sex-, and body surface area- adjusted norms (for the sinus of Valsalva and midlevel). Aortic size and presence of aortic enlargement were correlated with clinical and echocardiographic parameters. RESULTS: Tubular ascending aortic dilation \u3e19 mm/m2 was present in 303 patients with HCM (18%), and dilation above adjusted norms was present in 210 patients with HCM (13%). The median indexed tubular ascending thoracic aortic dimension was 16.5 (interquartile range, 14.8-18.2) mm/m2. Indexed dimension increased linearly with age (R = 0.53, P \u3c .0001). Women and patients with a history of systemic hypertension were more likely to have tubular aortic enlargement \u3e19 mm/m2 (29.8% vs 9.9% and 24.1% vs 10.5%, respectively, P \u3c .0001 for both). Patients with obstructive physiology were more likely to have tubular aortic enlargement \u3e19 mm/m2 than those without resting or provocable obstruction (19.6% vs 14.4%, P = .007). Using adjusted norms, aortic enlargement was more frequent at the midlevel compared with the sinus of Valsalva (71% vs 29%), more common in patients with hypertension (15.4% vs 10.6%, P = .009), and more common in patients with paroxysmal atrial fibrillation (16.3% vs 11.5%, P = .036), but no other relationships remained statistically significant. CONCLUSIONS: In this large cohort of patients with HCM, aortic dilation was common. The key correlate of tubular aortic enlargement \u3e19 mm/m2, and aortic enlargement greater than adjusted norms included a history of systemic hypertension. Given an increased prevalence of aortic dilation in HCM, further study is needed on the clinical impact of aortic dilation

The first comprehensive study of the clinical response of a cohort of acromegalic patients with somatostatin responsive headache

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Correction: Mycobacterium tuberculosis Universal Stress Protein Rv2623 Regulates Bacillary Growth by ATP-Binding: Requirement for Establishing Chronic Persistent Infection

Tuberculous latency and reactivation play a significant role in the pathogenesis of tuberculosis, yet the mechanisms that regulate these processes remain unclear. The Mycobacterium tuberculosis universal stress protein (USP) homolog, rv2623, is among the most highly induced genes when the tubercle bacillus is subjected to hypoxia and nitrosative stress, conditions thought to promote latency. Induction of rv2623 also occurs when M. tuberculosis encounters conditions associated with growth arrest, such as the intracellular milieu of macrophages and in the lungs of mice with chronic tuberculosis. Therefore, we tested the hypothesis that Rv2623 regulates tuberculosis latency. We observed that an Rv2623-deficient mutant fails to establish chronic tuberculous infection in guinea pigs and mice, exhibiting a hypervirulence phenotype associated with increased bacterial burden and mortality. Consistent with this in vivo growth-regulatory role, constitutive overexpression of rv2623 attenuates mycobacterial growth in vitro. Biochemical analysis of purified Rv2623 suggested that this mycobacterial USP binds ATP, and the 2.9-Å-resolution crystal structure revealed that Rv2623 engages ATP in a novel nucleotide-binding pocket. Structure-guided mutagenesis yielded Rv2623 mutants with reduced ATP-binding capacity. Analysis of mycobacteria overexpressing these mutants revealed that the in vitro growth-inhibitory property of Rv2623 correlates with its ability to bind ATP. Together, the results indicate that i) M. tuberculosis Rv2623 regulates mycobacterial growth in vitro and in vivo, and ii) Rv2623 is required for the entry of the tubercle bacillus into the chronic phase of infection in the host; in addition, iii) Rv2623 binds ATP; and iv) the growth-regulatory attribute of this USP is dependent on its ATP-binding activity. We propose that Rv2623 may function as an ATP-dependent signaling intermediate in a pathway that promotes persistent infection