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    Lymphoid leukosis in commercial layers in Morogoro
    (Tanzania Veterinary Association, 2010) Mathew, C.; Matondo, R. B.; Malago, J. J.; Maselle, R. M.; Mwamengele, G. L.
    A total of 25 commercial layer carcases from seven poultry farms in Morogoro municipality were examined for gross and histopathological changes. Grossly, splenomegally, renomegally and hepatomegally were striking features. Both the liver and spleen were almost twice the size of normal organs. The surfaces of the liver, spleen, kidneys, lungs and the heart had yellowish white to grey multifocal and focally extensive patches of variable sizes. The lungs were consolidated. Histologically, the liver, spleen, kidneys, lungs, and the heart had heavy infiltration of large lymphocytes with abundant cytoplasm and poorly stained eosinophilic cytoplasm. There were also small lymphocytes with scant cytoplasm and deeply stained eccentrically placed nuclei and numerous mitotic figures. The history, clinical signs, and pathologic features were suggestive of avian lymphoid leukosis
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    Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration
    (American Physiological Society, 2009-04-01) Matondo, RB; Punt, C; Homberg, J; Toussaint, MJM; Kisjes, R; Korporaal, SJA; Akkerman, JWN; Cuppen, E; de Bruin, A
    The serotonin transporter is implicated in the uptake of the vasoconstrictor serotonin from the circulation into the platelets, where 95% of all blood serotonin is stored and released in response to vascular injury. In vivo studies indicated that platelet-derived serotonin mediates liver regeneration after partial hepatectomy. We have recently generated serotonin transporter knockout rats and demonstrated that their platelets were almost completely depleted of serotonin. Here we show that these rats exhibit impaired hemostasis and contain about 1–6% of wild-type serotonin levels in the blood. Despite the marked reduction of serotonin levels in blood and platelets, efficient liver regeneration and collagen-induced platelet aggregation occur in rats lacking the serotonin transporter. These results provide evidence that liver regeneration is not dependent on the release of serotonin from platelets. Our findings indicate that very low levels of serotonin in blood are sufficient for liver regeneration.
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    Pathogenic Escherichia fergusonii and Staphylococcus gallinarum co-infection in a free-ranging domestic chicken
    (ROAVS, 2012) Misinzo, G; Mathew, C; Matondo, RB; Jumapili, F; Ludosha, M; Masola, S; Munisi, W; Viaene, W; Doorsselaere, J.
    Examination was carried out in an emaciated and depressed free-range domestic chicken from Mpwapwa where multiple cases of a similar condition were observed in 2010. A loosely attached unilateral nodule on the ventral aspect of the right eye and similar other nodules around the base of feathers mainly on dorsal aspects of wings, neck and head were observed. The cut nodules were yellowish with a firm and cheesy consistency surrounded by hyperaemic skin. In addition, multiple grey foci of variable size on liver and localized areas of hyperaemia on duodenal mucosa with mucoid exudates in the lumen were observed. On histopathology, the nodular lesions consisted of hyperplastic feather follicles with broad bands of keratinocytes and extension of follicular epithelium into surrounding dermis. In addition, luminal folliculitis in the skin and hepatic portal vasculitis were observed. Excised lesions from the eye, skin and liver were streaked on bacteriological agar with or without penicillin and streptomycin to isolate bacteria. Bacteria grew in agar without antibiotics but not in agar containing antibiotics. Bacterial colonies were subcultured and passaged four times to obtain pure cultures. Based on colony morphology, two types of bacteria were isolated from each of the organs. DNA was extracted from bacteria followed by amplification and sequencing of the 16S rDNA using 27F and 1492R primers. Sequence similarity search in GenBank showed that the bacteria were Escherichia fergusonii and Staphylococcus gallinarum. The present study shows that the chicken had E. fergusonii and S. gallinarum co-infection sensitive to penicillin and streptomycin
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    Atypical E2f functions are critical for pancreas polyploidization
    (PLOS ONE, 2018-01-12) Matondo, RB; Moreno, E; Toussaint, MJM; Tooten, PCJ; van Essen, SC; van Liere, EA; Youssef, SA; Bongiovanni, L; de Bruin, A
    The presence of polyploid cells in the endocrine and exocrine pancreas has been reported for four decades. In rodents, pancreatic polyploidization is initiated after weaning and the number of polyploid cells increases with age. Surprisingly the molecular regulators and biological functions of polyploidization in the pancreas are still unknown. We discovered that atypical E2f activity is essential for polyploidization in the pancreas, using an inducible Cre/LoxP approach in new-born mice to delete biquitously the atypical E2f transcription factors, E2f7 and E2f8. In contrast to its critical role in embryonic survival, conditional deletion of both of both atypical E2fs in newborn mice had no impact on postnatal survival and mice lived until old age. However, deficiency of E2f7 or E2f8 alone was sufficient to suppress polyploidization in the pancreas and associated with only a minor decrease in blood serum levels of glucose, insulin, amylase and lipase under 4 hours starvation condition compared to wildtype littermates. In mice with fewer pancreatic polyploid cells that were fed ad libitum, no major impact on hormones or enzymes levels was observed. In summary, we identified atypical E2fs to be essential for polyploidization in the pancreas and discovered that postnatal induced loss of both atypical E2fs in many organs is compatible with life until old age.
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    Surgical resection and radiofrequency ablation initiate cancer in cytokeratin-19+-liver cells deficient for p53 and Rb
    (2016-08-23) Matondo, R. B.; Toussaint, M. J. M.; Govaert, K.M.; Vuuren, L. D.; Nantasanti, S.; Nijkamp, M. W.; Pandit, S. K.; Tooten, P. C. J.; Koster, M. H.; Holleman, K.; Schot, A.; Gu, G.; Spee, B.; Roskams, T.; Borel, R. I.; Schotanus, B.; Kranenburg, O.; de Bruin, A.
    The long term prognosis of liver cancer patients remains unsatisfactory because of cancer recurrence after surgical interventions, particularly in patients with viral infections. Since hepatitis B and C viral proteins lead to inactivation of the tumor suppressors p53 and Retinoblastoma (Rb), we hypothesize that surgery in the context of p53/Rb inactivation initiate de novo tumorigenesis. We, therefore, generated transgenic mice with hepatocyte and cholangiocyte/ liver progenitor cell (LPC)-specific deletion of p53 and Rb, by interbreeding conditional p53/Rb knockout mice with either Albumin-cre or Cytokeratin-19-cre transgenic mice. We show that liver cancer develops at the necrotic injury site after surgical resection or radiofrequency ablation in p53/Rb deficient livers. Cancer initiation occurs as a result of specific migration, expansion and transformation of cytokeratin- 19+-liver (CK-19+) cells. At the injury site migrating CK-19+ cells formed small bile ducts and adjacent cells strongly expressed the transforming growth factor β (TGFβ). Isolated cytokeratin-19+ cells deficient for p53/Rb were resistant against hypoxia and TGFβ-mediated growth inhibition. CK-19+ specific deletion of p53/Rb verified that carcinomas at the injury site originates from cholangiocytes or liver progenitor cells. These findings suggest that human liver patients with hepatitis B and C viral infection or with mutations for p53 and Rb are at high risk to develop tumors at the surgical intervention site.
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    E2f8 mediates tumor suppression in postnatal liver development
    (The American Society for Clinical Investigation, 2016-08-01) Machiraju, Raghu; Kent, L. N.; Rakijas, J. B.; Pandit, S. K.; Westendorp, B.; Chen, H.; Huntington, J. T.; Tang, X.; Bae, S.; Srivastava, A.; Senapati, S.; Koivisto, C.; Martin, C. K.; Cuitino, M. C.; Perez, M.; Matondo, R. B.
    E2F-mediated transcriptional repression of cell cycle–dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8’s tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8’s DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development
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    Large induction of type III deiodinase expression after partial hepatectomy in the regenerating mouse and rat liver
    (Oxford University Press, 2008-09-11) Kester, M. H. A.; Matondo, R. B.; Toussaint, M. J. M.; Punt, C. A.; Aarnio, A. M.; Darras, V. M.; Everts, M. E.; Bruin, A.; Visser, T. J.
    The deiodinase types 1 (D1) and 2 (D2) catalyze the activation of T4 to T3, whereas type 3 deiodinase (D3) catalyzes the inactivation of T3 and T4. D3 plays a key role in ontrolling thyroid hormone bioavailability. It is highly expressed during fetal evelopment, but also in other processes with increased cell proliferation, e.g. in vascular tumors. Because tissue regeneration is dependent on cellular proliferation and is associated with activation of fetal genes, we evaluated deiodinase activities and mRNA expression in rat and mouse liver, as well as the local and systemic thyroid hormone status after partial hepatectomy (PH).Weobserved that in rats, D3 activity was increased 10-fold at 20 h and 3-fold at 48 h after PH; D3 mRNA expression was increased 3-fold at 20 h. The increase in D3 expression was associated with maximum 2- to 3-fold decreases of serum and liver T3 and T4 levels at 20 to 24 h after PH. In mice, D3 activity was increased 5-fold at 12 h, 8-fold at 24 h, 40-fold at 36 h, 15-fold at 48 h, and 7-fold at 72 h after PH. In correlation with this, D3 mRNA was highest (6-fold increase), and serum T3 and T4 were lowest at 36 h. Furthermore, as a measure for cell proliferation, 5-bromo-2_-deoxyuridine incorporation peaked at 20–24 h after PH in rats and at 36 h in mice. No significant effect on D1 activity or mRNA expression was found after PH. D2 activity was always undetectable. In conclusion, we found a large induction of hepatic D3 expression after PH that was correlated with an increased cellular proliferation and decreased serum and liver T3 and T4 levels. Our data suggest that D3 is important in the modulation of thyroid hormone levels in the regenerating liver, in which a decrease in cellular T3 permits an increase in proliferation
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    Clinico-pathological findings of the 2011 outbreak of peste des petits ruminants (PPR) in Tandahimba district, southern Tanzania
    (Research Opinions in Animal and Veterinary Sciences, 2012) Matondo, R. B.; Muse, E. A.; Karimuribo, E. D.; Misinzo, G.; Albano, M. O.; Gitao, G. C.
    Although PPR outbreaks were reported in Northern Tanzania since 2008, there has been no description of the clinical or pathological manifestation of the disease, an important criterion in guiding veterinarians and farmers on proper recognition and diagnosis of the disease. A study was therefore conducted to investigate and describe clinical signs and pathological lesions associated with 2011 Peste des petits ruminants (PPR) outbreak in goats and sheep in Tandahimba district located in Southern Tanzania. The investigation involved taking history and conducting clinical examination of PPR suspected cases (25 goats and 3 sheep) in the study district which had neither a history of vaccination against PPR nor previous illness due to PPR. This work was complemented by collection of pathological samples and specimens for laboratory examination. A detailed post-mortem was performed on three sacrificed animals followed by collection of specimens including lungs, liver, spleen and lymph nodes for histopathological examination. Clinical samples from 30 animals which included swabs from ocular, nasal and mouth lesions were also collected for confirmation of PPR through detection of PPR ribonucleic acid using reverse transcription polymerase chain reaction (RT-PCR). Clinical examinations of the cases showed signs suggestive of PPR including severe depression, high fever (41oC), anorexia, muco-pulurent nasal discharge, erosive and necrotic stomatitis, mild diarrhoea and skin nodules. Post mortem examination showed evidence of pneumonia including lung congestion and consolidation, increased thickness of inter-alveolar walls, moderate infiltration of inflammatory cells in bronchiolar subepithelial and perivascular layers. Overall 56.7% of the samples (n=30) tested were positive for PPR by RTPCR. This study has confirmed and described the presence of PPR in southern Tanzania. A more detailed study including other districts is recommended to provide more information regarding the magnitude and factors associated with PPR in Southern Tanzania.