Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restriced glioblastoma

L-Glutamine (Gln) functions physiologically to balance the carbon and nitrogen requirements of tissues. It has been proposed that in cancer cells undergoing aerobic glycolysis, accelerated anabolism is sustained by Gln-derived carbons, which replenish the tricarboxylic acid (TCA) cycle (anaplerosis). However, it is shown here that in glioblastoma (GBM) cells, almost half of the Gln-derived glutamate (Glu) is secreted and does not enter the TCA cycle, and that inhibiting glutaminolysis does not affect cell proliferation. Moreover, Gln-starved cells are not rescued by TCA cycle replenishment. Instead, the conversion of Glu to Gln by glutamine synthetase (GS; cataplerosis) confers Gln prototrophy, and fuels de novo purine biosynthesis. In both orthotopic GBM models and in patients, (13)C-glucose tracing showed that GS produces Gln from TCA-cycle-derived carbons. Finally, the Gln required for the growth of GBM tumours is contributed only marginally by the circulation, and is mainly either autonomously synthesized by GS-positive glioma cells, or supplied by astrocytes

Aneuploidy and prognosis of non-small-cell lung cancer: a meta-analysis of published data

In lung cancer, DNA content abnormalities have been described as a heterogeneous spectrum of impaired tumour cell DNA histogram patterns. They are merged into the common term of aneuploidy and probably reflect a high genotypic instability. In non-small-cell lung cancer, the negative effect of aneuploidy has been a subject of controversy inasmuch as studies aimed at determining the survival–DNA content relationship have reported conflicting results. We made a meta-analysis of published studies aimed at determining the prognostic effect of aneuploidy in surgically resected non-small-cell lung cancer. 35 trials have been identified in the literature. A comprehensive collection of data has been constructed taking into account the following parameters: quality of specimen, DNA content assessment method, aneuploidy definition, histology and stage grouping, quality of surgical resection and demographic characteristics of the analysed population. Among the 4033 assessable patients, 2626 suffered from non-small-cell lung cancer with aneuploid DNA content (overall frequency of aneuploidy: 0.65; 95% CI: (0.64–0.67)). The DerSimonian and Laird method was used to estimate the size effects and the Peto and Yusuf method was used in order to generate the odds ratios (OR) of reduction in risk of death for patients affected by a nearly diploid (non-aneuploid) non-small-cell lung cancer. Survivals following surgical resection, from 1 to 5 years, were chosen as the end-points of our meta-analysis. Patients suffering from a nearly diploid tumour benefited from a significant reduction in risk of death at 1, 2, 3 and 4 years with respective OR: 0.51, 0.51, 0.45 and 0.67 (P< 10−4for each end-point). 5 years after resection, the reduction of death was of lesser magnitude: OR: 0.87 (P = 0.08). The test for overall statistical heterogeneity was conventionally significant (P< 0.01) for all 5 end-points, however. None of the recorded characteristics of the studies could explain this phenomenon precluding a subset analysis. Therefore, the DerSimonian and Laird method was applied inasmuch as this method allows a correction for heterogeneity. This method demonstrated an increase in survival at 1, 2, 3, 4 and 5 years for patients with diploid tumours with respective size effects of 0.11, 0.15, 0.20, 0.20 and 0.21 (value taking into account the correction for heterogeneity;P< 10−4for each end-point). Patients who benefit from a surgical resection for non-small-cell lung cancer with aneuploid DNA content prove to have a higher risk of death. This negative prognostic factor decreases the probability of survival by 11% at one year, a negative effect deteriorating up to 21% at 5 years following surgery. © 2001 Cancer Research Campaign http://www.bjcancer.co

Tuberculosis: A Review of a current concepts and control programme in Nigeria

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Patient knowledge, practices and challenges to health care system in early diagnosis of mycobacterial adenitis

Objective: To assess diagnostic delay, knowledge and practices related to tuberculosis among patients with mycobacterial adenitis. Design: A cross sectional study involving comparison analysis of high-risk groups. Setting: Seven hospitals in rural and semi-rural districts of Arusha. Subjects: Four hundred and twenty six clinically diagnosed adenitis patients. Interventions: Biopsy specimens were processed for culture, histology, and sera for HIV testing. A questionnaire was used to assess knowledge, practice, and diagnostic time. Main outcome measures: Tribal comparisons were made using proportions and means. Results: About 90% (387/423) of patients first visited medical facilities within a mean time of 10.1(SD, 15.7) weeks after becoming aware of their illness, and a diagnosis was made at a mean of 27 (SD, 25) weeks. Non-Iraqw patients, especially the Datoga, practised drinking raw milk (35.2% 43/122), eating raw animal products (18.8% 24/128) and living in houses with poor ventilation (33.6% 44/l3l), more than Iraqw patients. Of the investigations done, 14.5% (60/415) were culture positive, 11.3% (16/142) were HIV positive, and 73.6% (128/174) had histological features consistent with tuberculosis. The knowledge of TB spread by air droplets was poorer in Iraqw (74.1%, 203/274) than in non-lraqw (61.1%, 77/126) patients. About 35.0% (45/129) of non-lraqw and 27.3% (79/289) of Iraqw patients were not aware that TB could be transmitted from animals to humans. Conclusions: The health system diagnostic delay is about twice the patient delay. The knowledge and practices related to both human and bovine TB transmission were poor in all patients, especially in the patients from nomadic tribes. East African Medical Journal Vol.82(4) 2005: 173-18

Mycobacterial adenitis: role of Mycobacterium bovis, non-tuberculous mycobacteria, HIV infection, and risk factors in Arusha, Tanzania

Objective: To assess risk factors and mycobacterial agents in mycobacterial adenitis. Design: Cross sectional involving comparison analysis of high-risk groups. Setting: Seven hospitals in rural and semi-rural districts of Arusha. Subjects: The study comprised of 457 patients of clinically diagnosed mycobacterial adenitis. Interventions: Biopsy materials were cultured and identification of mycobacterial isolates, and HIV infection testing were performed using standard methods. A questionnaire was used to establish information for assessing risk factors. Main outcome measures: Proportions of mycobacterial isolates, risk factors and odds ratios. Results: Of the 457 specimens, 65(14.2%) were culture positive. Isolates identified were M. bovis, 7(10.8%) M. tuberculosis, 27(41.5%) and non-tuberculous mycobacteria 31(47.7%). HIV infection and ingestion of raw milk were linked with increased risk of M. bovis infection by OR of 13.6 (95% CI, 1.7 - 109.9) and 15.28 (3.26 - 71.7), respectively. On multivariate analysis, an OR of 16.2 (1.3 - 201.3) for having M. bovis adenitis was linked to HIV infection, raw milk and houses with poor ventilation. An OR of 5.2 (1.2 - 20.6) for non-tuberculous mycobacterial adenitis was linked to history of TB in the family, HIV infection, raw milk, raw animal products and poor knowledge on transmission of tuberculosis. Conclusions: M. bovis caused one out of ten cases of culture positive mycobacterial adenitis. Non-tuberculous mycobacteria were more common than M. tuberculosis (50% and 40% of the cases, respectively). HIV infection and raw animal products are among the risk factors identified for M. bovis and non-tuberculous mycobacterial adenitis. East African Medical Journal Vol. 81 No. 4 April 2004: 171-17

Mycobacterial adenitis: role of mycobacterium bovis, non-tuberculous mycobacteria, hiv infection, and risk factors in arusha, Tanzania

East African Medical Journal 2004, Vol. 81 (4)Objective: To assess risk factors and mycobacterial agents in mycobacterial adenitis. Design: Cross sectional involving comparison analysis of high-risk groups. Setting: Seven hospitals in rural and semi-rural districts of Arusha. Subjects: The study comprised of 457 patients of clinically diagnosed mycobacterial adenitis. Interventions: Biopsy materials were cultured and identification of mycobacterial isolates, and HIV infection testing were performed using standard methods. A questionnaire was used to establish information for assessing risk factors. Main outcome measures: Proportions of mycobacterial isolates, risk factors and odds ratios. Results: Of the 457 specimens, 65(14.2%) were culture positive. Isolates identified were M. bovis, 7(10.8%) M. tuberculosis, 27(41.5%) and non-tuberculous mycobacteria 31(47.7%). HIV infection and ingestion of raw milk were linked with increased risk of M. bovis infection by OR of 13.6 (95% CI, 1.7 - 109.9) and 15.28 (3.26 - 71.7), respectively. On multivariate analysis, an OR of 16.2 (1.3 - 201.3) for having M. bovis adenitis was linked to HIV infection, raw milk and houses with poor ventilation. An OR of 5.2 (1.2 - 20.6) for non-tuberculous mycobacterial adenitis was linked to history of TB in the family, HIV infection, raw milk, raw animal products and poor knowledge on transmission of tuberculosis. Conclusions: M. bovis caused one out of ten cases of culture positive mycobacterial adenitis. Non-tuberculous mycobacteria were more common than M. tuberculosis (50% and 40% of the cases, respectively). HIV infection and raw animal products are among the risk factors identified for M. bovis and non-tuberculous mycobacterial adenitis

Mycobacterial adenitis: role of mycobacterium bovis, non-tuberculous mycobacteria, hiv infection, and risk factors in arusha, Tanzania

East African Medical Journal 2004, Vol. 81 (4)Objective: To assess risk factors and mycobacterial agents in mycobacterial adenitis. Design: Cross sectional involving comparison analysis of high-risk groups. Setting: Seven hospitals in rural and semi-rural districts of Arusha. Subjects: The study comprised of 457 patients of clinically diagnosed mycobacterial adenitis. Interventions: Biopsy materials were cultured and identification of mycobacterial isolates, and HIV infection testing were performed using standard methods. A questionnaire was used to establish information for assessing risk factors. Main outcome measures: Proportions of mycobacterial isolates, risk factors and odds ratios. Results: Of the 457 specimens, 65(14.2%) were culture positive. Isolates identified were M. bovis, 7(10.8%) M. tuberculosis, 27(41.5%) and non-tuberculous mycobacteria 31(47.7%). HIV infection and ingestion of raw milk were linked with increased risk of M. bovis infection by OR of 13.6 (95% CI, 1.7 - 109.9) and 15.28 (3.26 - 71.7), respectively. On multivariate analysis, an OR of 16.2 (1.3 - 201.3) for having M. bovis adenitis was linked to HIV infection, raw milk and houses with poor ventilation. An OR of 5.2 (1.2 - 20.6) for non-tuberculous mycobacterial adenitis was linked to history of TB in the family, HIV infection, raw milk, raw animal products and poor knowledge on transmission of tuberculosis. Conclusions: M. bovis caused one out of ten cases of culture positive mycobacterial adenitis. Non-tuberculous mycobacteria were more common than M. tuberculosis (50% and 40% of the cases, respectively). HIV infection and raw animal products are among the risk factors identified for M. bovis and non-tuberculous mycobacterial adenitis

Genetic profile of Mycobacterium tuberculosis and treatment outcomes in human pulmonary tuberculosis in Tanzania

Tanzania Journal of Health Research 2014, Vol.16(2)Information on the different spoligotype families of Mycobacterium tuberculosis in Tanzania is limited, and where available, restricted to small geographical areas. This article describes the genetic profile of M. tuberculosis across Tanzania and suggests how spoligotype families might affect drug resistance and treatment outcomes for smear positive pulmonary tuberculosis patients in Tanzania. We conducted the study from 2006 to 2008, and the isolates were obtained from samples collected under the routine drug resistance surveillance system. The isolates were from specimens collected from 2001 to 2007, and stored at the Central and Reference Tuberculosis Laboratory. A total of 487 isolates from 23 regions in the country were spoligotyped. We were able to retrieve clinical information for 446 isolates only. Out of the 487 isolates spoligotyped, 195(40.0%) belonged to the Central Asian (CAS) family, 84 (17.5%) to the Latin American Mediterranean (LAM) family, 49 (10.1%) to the East-African Indian (EAI) family, and 33 (6.8%) to the Beijing family. Other isolates included 1 (0.2%) for H37Rv, 10 (2.1%) for Haarlem, 4 (0.8%) for S family, 58 (11.9%) for T family and 52 (10.7%) for unclassified. No spoligotype patterns were consistent with M. bovis. Regarding treatment outcomes, the cure rate was 80% with no significant variation among the spoligotype families. The overall level of MDR TB was 2.5% (3/121), with no significant difference among the spoligotype families. All Beijing strains (11.8%, 30/254) originated from the Eastern and Southern zones of the country, of which 80% were from Dar es Salaam. Isolates from the CAS and T families were reported disproportionately from the Eastern-Southern zone, and EAI and LAM families from the Northern-Lake zones but the difference was not statistically significant. Five isolates were identified as non-tuberculous Mycobacteria. In conclusion, M. tuberculosis isolates from pulmonary tuberculosis cases in Tanzania were classified mostly within the CAS, LAM, and EAI and T families, while the Beijing family comprised about 7% isolates only. Consistently good treatment outcomes were recorded across these spoligotype families. The proportion of drug resistance strains was low. The findings also suggest variation of spoligotype families with varying geographical localities within the country, and identify this area for further research to confirm this finding