MAF1 is a chronic repressor of RNA polymerase III transcription in the mouse.

Maf1 <sup>-/-</sup> mice are lean, obesity-resistant and metabolically inefficient. Their increased energy expenditure is thought to be driven by a futile RNA cycle that reprograms metabolism to meet an increased demand for nucleotides stemming from the deregulation of RNA polymerase (pol) III transcription. Metabolic changes consistent with this model have been reported in both fasted and refed mice, however the impact of the fasting-refeeding-cycle on pol III function has not been examined. Here we show that changes in pol III occupancy in the liver of fasted versus refed wild-type mice are largely confined to low and intermediate occupancy genes; high occupancy genes are unchanged. However, in Maf1 <sup>-/-</sup> mice, pol III occupancy of the vast majority of active loci in liver and the levels of specific precursor tRNAs in this tissue and other organs are higher than wild-type in both fasted and refed conditions. Thus, MAF1 functions as a chronic repressor of active pol III loci and can modulate transcription under different conditions. Our findings support the futile RNA cycle hypothesis, elaborate the mechanism of pol III repression by MAF1 and demonstrate a modest effect of MAF1 on global translation via reduced mRNA levels and translation efficiencies for several ribosomal proteins

Clinicopathological pattern of benign breast diseases among female patients at a tertiary health institution in Tanzania

Background: Benign breast diseases are a neglected entity in developing countries despite the fact that they constitute the majority of breast complaints. There is a paucity of published information regarding benign breast diseases in Tanzania. This study describes our experience in the management of benign breast diseases outlining the clinicopathological pattern and treatment modalities of these diseases in our local setting.Methods: This prospective descriptive study was conducted between November 2009 and March 2013 at Bugando Medical Centre in Tanzania on female patients aged 10 years and above presenting with benign breast diseases.Results: A total of 346 female patients with benign breast diseases were studied. The majority of patients, 255 (73.7%) were younger than 30 years. Breast lump was the most frequent presentation in 67.6% of patients. Fibroadenoma 95 (60.0%) was the most frequently diagnosed benign breast disease followed by fibrocystic changes (19.0%). Out of 295 patients who had histopathological examination, 64 (21.7%) had proliferative lesions. Of these, 18 (28.1%) had proliferative lesions with atypia while 46(71.9%) had proliferative lesions without atypia. Eight (2.6%) patients were HIV positive with the median CD 4+ count of 258 cells/μl. The majority of patients, 295(85.2%) underwent surgical treatment of which lumpectomy was the most common procedure performed. Conclusion: Benign breast diseases are more common than malignancies in our environment and occur mainly in young women less than 30 years of age and were mostly fibroadenoma and fibrocystic change. Though premalignant lesions of proliferative lesions with atypia were less common in this study, it is advisable that all cases of breast lesions should be carefully evaluated to exclude possibility of breast cancer

Pathological Features of Breast Cancer seen in Northwestern Tanzania: A Nine Years Retrospective Study.

Breast cancer is more common in Western Countries compared to African populations. However in African population, it appears that the disease tends to be more aggressive and occurring at a relatively young age at the time of presentation. The aim of this study was to describe the trend of Breast Cancer in Northwestern Tanzania. This was a retrospective study which involved all cases of breast cancer diagnosed histologically at Bugando Medical Center from 2002 to 2010. Histological results and slides were retrieved from the records in the Pathology department, clinical information and demographic data for patients were retrieved from surgical wards and department of medical records. Histology slides were re-evaluated for the histological type, grade (By modified Bloom-Richardson score), and presence of necrosis and skin involvement. Data was entered and analyzed by SPSS computer software version 15. There were 328 patients histologically confirmed to have breast cancer, the mean age at diagnosis was 48.7 years (+/- 13.1). About half of the patients (52.4%) were below 46 years of age, and this group of patients had significantly higher tendency for lymph node metastasis (p = 0.012). The tumor size ranged from 1 cm to 18 cm in diameter with average (mean) of 5.5 cm (+/- 2.5), and median size of 6 cm. Size of the tumor (above 6 cm in diameter) and presence of necrosis within the tumor was significantly associated with high rate of lymph node metastasis (p = 0.000). Of all patients, 64% were at clinical stage III (specifically IIIB) and 70.4% had lymph node metastasis at the time of diagnosis. Only 4.3% of the patients were in clinical stage I at the time of diagnosis. Majority of the patients had invasive ductal carcinoma (91.5%) followed by mucinous carcinoma (5.2%), Invasive lobular carcinoma (3%) and in situ ductal carcinoma (0.3%). In all patients, 185 (56.4%) had tumor with histological grade 3. Breast cancer in this region show a trend towards relative young age at diagnosis with advanced stage at diagnosis and high rate of lymph node metastasis. Poor Referral system, lack of screening programs and natural aggressive biological behavior of tumor may contribute to advanced disease at the time of diagnosis

Differential overexpression of SERPINA3 in human prion diseases

Prion diseases are fatal neurodegenerative disorders with sporadic, genetic or acquired etiologies. The molecular alterations leading to the onset and the spreading of these diseases are still unknown. In a previous work we identified a five-gene signature able to distinguish intracranially BSE-infected macaques from healthy ones, with SERPINA3 showing the most prominent dysregulation. We analyzed 128 suitable frontal cortex samples, from prion-affected patients (variant Creutzfeldt-Jakob disease (vCJD) n = 20, iatrogenic CJD (iCJD) n = 11, sporadic CJD (sCJD) n = 23, familial CJD (gCJD) n = 17, fatal familial insomnia (FFI) n = 9, Gerstmann-Sträussler-Scheinker syndrome (GSS)) n = 4), patients with Alzheimer disease (AD, n = 14) and age-matched controls (n = 30). Real Time-quantitative PCR was performed for SERPINA3 transcript, and ACTB, RPL19, GAPDH and B2M were used as reference genes. We report SERPINA3 to be strongly up-regulated in the brain of all human prion diseases, with only a mild up-regulation in AD. We show that this striking up-regulation, both at the mRNA and at the protein level, is present in all types of human prion diseases analyzed, although to a different extent for each specific disorder. Our data suggest that SERPINA3 may be involved in the pathogenesis and the progression of prion diseases, representing a valid tool for distinguishing different forms of these disorders in humans

Using the social entrepreneurship approach to generate innovative and sustainable malaria diagnosis interventions in Tanzania: a case study

<p>Abstract</p> <p>Background</p> <p>There have been a number of interventions to date aimed at improving malaria diagnostic accuracy in sub-Saharan Africa. Yet, limited success is often reported for a number of reasons, especially in rural settings. This paper seeks to provide a framework for applied research aimed to improve malaria diagnosis using a combination of the established methods, participatory action research and social entrepreneurship.</p> <p>Methods</p> <p>This case study introduces the idea of using the social entrepreneurship approach (SEA) to create innovative and sustainable applied health research outcomes. The following key elements define the SEA: (1) identifying a locally relevant research topic and plan, (2) recognizing the importance of international multi-disciplinary teams and the incorporation of local knowledge, (3) engaging in a process of continuous innovation, adaptation and learning, (4) remaining motivated and determined to achieve sustainable long-term research outcomes and, (5) sharing and transferring ownership of the project with the international and local partner.</p> <p>Evaluation</p> <p>The SEA approach has a strong emphasis on innovation lead by local stakeholders. In this case, innovation resulted in a unique holistic research program aimed at understanding patient, laboratory and physician influences on accurate diagnosis of malaria. An evaluation of milestones for each SEA element revealed that the success of one element is intricately related to the success of other elements.</p> <p>Conclusions</p> <p>The SEA will provide an additional framework for researchers and local stakeholders that promotes innovation and adaptability. This approach will facilitate the development of new ideas, strategies and approaches to understand how health issues, such as malaria, affect vulnerable communities.</p

An assessment of orofacial clefts in Tanzania

<p>Abstract</p> <p>Background</p> <p>Clefts of the lip (CL), the palate (CP), or both (CLP) are the most common orofacial congenital malformations found among live births, accounting for 65% of all head and neck anomalies. The frequency and pattern of orofacial clefts in different parts of the world and among different human groups varies widely. Generally, populations of Asian or Native American origin have the highest prevalence, while Caucasian populations show intermediate prevalence and African populations the lowest. To date, little is known regarding the epidemiology and pattern of orofacial clefts in Tanzania.</p> <p>Methods</p> <p>A retrospective descriptive study was conducted at Bugando Medical Centre to identify all children with orofacial clefts that attended or were treated during a period of five years. Cleft lip and/or palate records were obtained from patient files in the Hospital's Departments of Surgery, Paediatrics and medical records. Age at presentation, sex, region of origin, type and laterality of the cleft were recorded. In addition, presence of associated congenital anomalies or syndromes was recorded.</p> <p>Results</p> <p>A total of 240 orofacial cleft cases were seen during this period. Isolated cleft lip was the most common cleft type followed closely by cleft lip and palate (CLP). This is a departure from the pattern of clefting reported for Caucasian and Asian populations, where CLP or isolated cleft palate is the most common type. The distribution of clefts by side showed a statistically significant preponderance of the left side (43.7%) (χ²= 92.4, p < 0.001), followed by the right (28.8%) and bilateral sides (18.3%). Patients with isolated cleft palate presented at very early age (mean age 1.00 years, SE 0.56). Associated congenital anomalies were observed in 2.8% of all patients with orofacial clefts, and included neural tube defects, Talipes and persistent ductus arteriosus.</p> <p>Conclusions</p> <p>Unilateral orofacial clefts were significantly more common than bilateral clefts; with the left side being the most common affected side. Most of the other findings did not show marked differences with orofacial cleft distributions in other African populations.</p

Water-loss (intracellular) dehydration assessed using urinary tests, how well do they work? Diagnostic accuracy in older people

Background: Water-loss dehydration (hypertonic, hyperosmotic or intra-cellular dehydration) is due to insufficient fluid intake and distinct from hypovolemia due to excess fluid losses. It is associated with poor health outcomes such as disability and mortality in older people. Urine specific gravity (USG), color and urine osmolality have been widely advocated for screening for dehydration in older adults. Objective: To assess the diagnostic accuracy of urinary measures to screen for water-loss dehydration in older people.Design: This was a diagnostic accuracy study of people aged ≥65years taking part in the Dehydration Recognition In our Elders (DRIE, living in long-term care) or Dietary Strategies for Healthy Ageing in Europe (NU-AGE, living in the community) studies. The reference standard was serum osmolality, index tests included USG, urine color, osmolality, cloudiness, additional dipstick measures, ability to provide a urine sample, and volume of a random urine sample. Minimum useful diagnostic accuracy was set at sensitivity and specificity ≥70% or receiver operating characteristics plot area under the curve ≥0.70. Results: DRIE participants (67% women, mean age 86 years, n=162) had more limited cognitive and functional abilities than NU-AGE participants (64% women, mean age 70 years, n=151). 19% of DRIE and 22% of NU-AGE participants were dehydrated (serum osmolality >300mOsm/kg). Neither USG nor any other potential urinary tests were usefully diagnostic for water-loss dehydration. Conclusions: Although USG, urine color and urinary osmolality have been widely advocated for screening for dehydration in older adults, we show in the largest study to date that their diagnostic accuracy is too low to be useful and these measures should not be used to indicate hydration status in older people (either alone or as part of a wider tranche of tests). There is a need to develop simple, inexpensive and non-invasive tools for the assessment of dehydration in older people

Inhibition of cholesterol recycling impairs cellular PrPSc propagation

The infectious agent in prion diseases consists of an aberrantly folded isoform of the cellular prion protein (PrPc), termed PrPSc, which accumulates in brains of affected individuals. Studies on prion-infected cultured cells indicate that cellular cholesterol homeostasis influences PrPSc propagation. Here, we demonstrate that the cellular PrPSc content decreases upon accumulation of cholesterol in late endosomes, as induced by NPC-1 knock-down or treatment with U18666A. PrPc trafficking, lipid raft association, and membrane turnover are not significantly altered by such treatments. Cellular PrPSc formation is not impaired, suggesting that PrPSc degradation is increased by intracellular cholesterol accumulation. Interestingly, PrPSc propagation in U18666A-treated cells was partially restored by overexpression of rab 9, which causes redistribution of cholesterol and possibly of PrPSc to the trans-Golgi network. Surprisingly, rab 9 overexpression itself reduced cellular PrPSc content, indicating that PrPSc production is highly sensitive to alterations in dynamics of vesicle trafficking