Low Sensitivity of T-Cell Based Detection of Tuberculosis among HIV Co-Infected Tanzanian In-Patients

Objective: To evaluate the performance of QuantiFERON-TB GOLD (QFTG) in a resource-poor setting among patients with and without HIV infection.Design: Cross-sectional study.Setting: Two hospitals in Northern Tanzania.Subjects: Eighty three adult male and female inpatients.Intervention: All patients were screened for HIV infection and underwent tuberculin skin test (TST) and QFTG.Results: Eighty-three subjects were enrolled, and 29 (35%) of 83 were HIV-infected. QFTG yielded indeterminate results in 12 (22%; 95%CI 12%-34%) of 54 HIV-uninfected and 13 (45%; 95%CI 26%-64%) of 29 HIV-infected subjects (p=0.0323). Among those with smear-positive pulmonary tuberculosis, TST was positive in 40 (100%; 95%CI 91%-100%) of 40 HIV-uninfected subjects compared with seven (54%; 95%CI 25%- 81%) of 13 HIV-infected subjects (p<0.0001), and QFTG was positive in 28(70%; 95%CI 53%-83%) of 40 HIV-uninfected subjects compared with three (23%; 95%CI 5%-54%) of 13 HIV-infected subjects (p=0.0029). Among medical inpatients at risk for latent tuberculosis infection, TST was positive in seven (50%) of 14 HIV-uninfected patients and three (19%) of 16 HIV-infected patients (p=0.0701) and QFTG was positive among two (14%) of 14 HIV-uninfected patients and three (19%) of 16 HIV-infected patients (p=0.7437).Conclusions: The presence of HIV co-infection was associated with a significant reduction in sensitivity of both the TST (p<0.0001) and QFTG (p=0.0029) for the diagnosis of active M.tuberculosis infection. The high proportion of indeterminate QFTG and lack of sensitivity, particularly among HIV-infected patients, may limit its applicability in settings like Tanzania. Larger studies in resource-poor settings are required.

Etiology of Severe Non-malaria Febrile Illness in Northern Tanzania: A Prospective Cohort Study.

The syndrome of fever is a commonly presenting complaint among persons seeking healthcare in low-resource areas, yet the public health community has not approached fever in a comprehensive manner. In many areas, malaria is over-diagnosed, and patients without malaria have poor outcomes. We prospectively studied a cohort of 870 pediatric and adult febrile admissions to two hospitals in northern Tanzania over the period of one year using conventional standard diagnostic tests to establish fever etiology. Malaria was the clinical diagnosis for 528 (60.7%), but was the actual cause of fever in only 14 (1.6%). By contrast, bacterial, mycobacterial, and fungal bloodstream infections accounted for 85 (9.8%), 14 (1.6%), and 25 (2.9%) febrile admissions, respectively. Acute bacterial zoonoses were identified among 118 (26.2%) of febrile admissions; 16 (13.6%) had brucellosis, 40 (33.9%) leptospirosis, 24 (20.3%) had Q fever, 36 (30.5%) had spotted fever group rickettsioses, and 2 (1.8%) had typhus group rickettsioses. In addition, 55 (7.9%) participants had a confirmed acute arbovirus infection, all due to chikungunya. No patient had a bacterial zoonosis or an arbovirus infection included in the admission differential diagnosis. Malaria was uncommon and over-diagnosed, whereas invasive infections were underappreciated. Bacterial zoonoses and arbovirus infections were highly prevalent yet overlooked. An integrated approach to the syndrome of fever in resource-limited areas is needed to improve patient outcomes and to rationally target disease control efforts

Phosphorylation of the androgen receptor is associated with reduced survival in hormonerefractory prostate cancer patients

Cell line studies demonstrate that the PI3K/Akt pathway is upregulated in hormone-refractory prostate cancer (HRPC) and can result in phosphorylation of the androgen receptor (AR). The current study therefore aims to establish if this has relevance to the development of clinical HRPC. Immunohistochemistry was employed to investigate the expression and phosphorylation status of Akt and AR in matched hormone-sensitive and -refractory prostate cancer tumours from 68 patients. In the hormone-refractory tissue, only phosphorylated AR (pAR) was associated with shorter time to death from relapse (<i>P</i>=0.003). However, when an increase in expression in the transition from hormone-sensitive to -refractory prostate cancer was investigated, an increase in expression of PI3K was associated with decreased time to biochemical relapse (<i>P</i>=0.014), and an increase in expression of pAkt<sup>473</sup> and pAR<sup>210</sup> were associated with decreased disease-specific survival (<i>P</i>=0.0019 and 0.0015, respectively). Protein expression of pAkt<sup>473</sup> and pAR<sup>210</sup> also strongly correlated (<i>P</i><0.001, c.c.=0.711) in the hormone-refractory prostate tumours. These results provide evidence using clinical specimens, that upregulation of the PI3K/Akt pathway is associated with phosphorylation of the AR during development of HRPC, suggesting that this pathway could be a potential therapeutic target

Genetic aberrations of c-myc and CCND1 in the development of invasive bladder cancer

Detrusor muscle invasive transitional cell carcinoma is associated with poor prognosis and is responsible for the majority of bladder cancer related deaths. Amplifications of c-myc and CCND1 are associated with detrusor-muscle-invasive transitional cell carcinoma, however, their precise role in driving disease progression is unclear. Fluorescence in situ hybridisation on archival tissue from 16 patients with primary diagnosis of ⩾pT2 transitional cell carcinoma and 15 cases with primary pTa/pT1 disease subsequently progressing to detrusor-muscle-invasion was performed, in the latter group both pre and post muscle invasive events were studied. No patients presenting with ⩾pT2 had amplification of c-myc, two out of 16 (12.5%) had CCND1 amplification. Of patients who developed ⩾pT2, two out of 15 (13.3%) had amplification of c-myc, both in ⩾pT2, five out of 15 (33.3%) had CCND1 amplification, two in pTa/pT1 tumours, three in ⩾pT2 transitional cell carcinomas. In total, two out of 31 (6.5%) of patients' ⩾pT2 TCCs were amplified for c-myc and six out of 31 (19%) were amplified for CCND1. Eighty-seven per cent (40 out of 46) of tumours were polysomic for chromosome 8 and 80% (37 out of 46) were polysomic for chromosome 11 and this reflected the high copy numbers of c-myc and CCND1 observed. In almost all cases an increase in c-myc/CCND1 copy number occurred prior to invasion and persisted in advanced disease. Amplification of CCND1 or alterations in c-myc/CCND1 early in bladder cancer may have clinical relevance in promoting and predicting progression to detrusor-muscle-invasive transitional cell carcinoma

Behavioral and molecular genetics of reading-related AM and FM detection thresholds

Auditory detection thresholds for certain frequencies of both amplitude modulated (AM) and frequency modulated (FM) dynamic auditory stimuli are associated with reading in typically developing and dyslexic readers. We present the first behavioral and molecular genetic characterization of these two auditory traits. Two extant extended family datasets were given reading tasks and psychoacoustic tasks to determine FM 2 Hz and AM 20 Hz sensitivity thresholds. Univariate heritabilities were significant for both AM (h2 = 0.20) and FM (h2 = 0.29). Bayesian posterior probability of linkage (PPL) analysis found loci for AM (12q, PPL = 81 %) and FM (10p, PPL = 32 %; 20q, PPL = 65 %). Bivariate heritability analyses revealed that FM is genetically correlated with reading, while AM was not. Bivariate PPL analysis indicates that FM loci (10p, 20q) are not also associated with reading

Approaches towards expression profiling the response to treatment

Over the past 8 years there has been a wealth of breast cancer gene expression studies. The majority of these studies have focused upon characterising a tumour at presentation, before treatment, rather than looking at the effects of treatment on the tumour. More recently, a number of groups have moved from predicting prognosis based upon long-term follow-up to alternative approaches of using expression profiling to measure the effect of treatment on breast tumours and potentially predict response to therapy using either post-treatment samples or both pre-treatment and post-treatment samples. Whilst this provides great potential to further our understanding of the mode of action of treatments and to more accurately select which patients will benefit from a particular treatment, serious issues of experimental design must be considered

Introduction of a learning management system at the Kilimanjaro Christian Medical University College

Background. Medical schools in Africa face daunting challenges including faculty shortages, growing class sizes, and inadequate resources. Learningmanagement systems (LMS) may be powerful tools for organising and presenting curricular learning materials, with the potential for monitoring and evaluation functions.Objective. To introduce a LMS for the first-year medical student curriculum at the Kilimanjaro Christian Medical University College (KCMU Co), inMoshi, Tanzania, in partnership with the Duke University School of Medicine (Durham, North Carolina, USA).Methods. Observations were made on the requisite information technology (IT) infrastructure and human resource needs, and participation in trainingexercises. LMS utilisation was recorded, and two (student and faculty) surveys were done.Results. The KCMU Co IT infrastructure was upgraded, and an expert team trained for LMS implementation. An introductory LMS workshop forfaculty had 7 out of 25 invitees, but attendance improved to more than 50% in subsequent workshops. Student attendance at workshops was mandatory. Use of the LMS by students rapidly expanded, and growing faculty utilisation followed later. By the end of the second semester, online examinations were offered, resulting in greater student and faculty  satisfaction owing to rapid availability of results. A year after LMS   introduction, 90% of students were accessing the LMS at least 4 days/week. A student survey identified high levels of satisfaction with the LMS software, quality of content, and learning enhancement.Conclusion. LMS can be a useful and efficient tool for curriculum  organisation, administration of online examinations, and continuous monitoring. The lessons learned from KCMU Co may be useful for similar academic settings

Recent advances in electronic structure theory and their influence on the accuracy of ab initio potential energy surfaces

Recent advances in electronic structure theory and the availability of high speed vector processors have substantially increased the accuracy of ab initio potential energy surfaces. The recently developed atomic natural orbital approach for basis set contraction has reduced both the basis set incompleteness and superposition errors in molecular calculations. Furthermore, full CI calculations can often be used to calibrate a CASSCF/MRCI approach that quantitatively accounts for the valence correlation energy. These computational advances also provide a vehicle for systematically improving the calculations and for estimating the residual error in the calculations. Calculations on selected diatomic and triatomic systems will be used to illustrate the accuracy that currently can be achieved for molecular systems. In particular, the F+H2 yields HF+H potential energy hypersurface is used to illustrate the impact of these computational advances on the calculation of potential energy surfaces