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Most PRKAR1A tumorigenic mutations lead to nonsense mRNA that is decayed; tumor formation has been associated with an increase in type II protein kinase A (PKA) subunits. The IVS6+1G>T PRKAR1A mutation leads to a protein lacking exon 6 sequences [R1A#184-236 (R1A#6)]. We compared in vitro R1A#6 with wild-type (wt) R1A. We assessed PKA activity and subunit expression, phosphorylation of target molecules, and properties of wt-R1A and mutant (mt) R1A; we observed by confocal microscopy R1A tagged with green fluorescent protein and its interactions with Cerulean-tagged catalytic subunit (CA). Introduction of the R1A#6 led to aberrant cellular morphology and higher PKA activity but no increase in type II PKA subunits. There was diffuse, cytoplasmic localization of R1A protein in wt-R1A-and R1A#6-transfected cells but the former also exhibited discrete aggregates of R1A that bound CA; these were absent in R1A#6-transfected cells and did not bind CA at baseline or in response to cyclic AMP. Other changes induced by R1A#6 included decreased nuclear CA. We conclude that R1A#6 leads to increased PKA activity through the mt-R1A decreased binding to CA and does not involve changes in other PKA subunits, suggesting that a switch to type II PKA activity is not necessary for increased kinase activity or tumorigenesis. [Cancer Res 2008;68(9):3133-41]

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Objectives. Despite the availability of services to prevent mother-to-child transmission (PMTCT) of HIV, socio-cultural, health system and operational factors constrain many pregnant women from accessing services or returning for followup thereby increasing the risk of vertical transmission of HIV to newborns. We highlight and describe unique contextual factors contributing to low utilization of PMTCT services in Arba-Minch, Ethiopia. Methods. Qualitative research design was utilized to obtain data through focus group discussions and in-depth interviews with antenatal clinic attendees, health workers health facilities in the study area. Results. Awareness of PMTCT services and knowledge of its benefits was nearly universal, although socioeconomic, cultural and health system factors, including stigma and desire to prevent knowledge of serostatus, impede access to and utilization of services. Health system factors-lack of appropriate followup mechanisms, inadequate access to ARV drugs and poorly equipped manpower also contribute to low utilization of services. Conclusion. Reducing mother-to-child transmission of HIV in sub-Saharan Africa will be more effective when unique contextual factors are identified and addressed. Effectiveness of PMTCT interventions rests on a well functioning health system that recognize the importance of social, economic, cultural contexts that HIV positive pregnant women live in.

Preventing zoonotic diseases requires coordinated actions by government authorities responsible for human and animal health. Constructing the frameworks needed to foster intersectoral collaboration can be approached in many ways. We highlight 3 examples of approaches to implement zoonotic disease prevention and control programs. The first, rabies control in Ethiopia, was implemented using an umbrella approach: a comprehensive program designed for accelerated impact. The second, a monkeypox program in Democratic Republic of the Congo, was implemented in a stepwise manner, whereby incremental improvements and activities were incorporated into the program. The third approach, a pathogen discovery program, applied in the country of Georgia, was designed to characterize and understand the ecology, epidemiology, and pathogenesis of a new zoonotic pathogen. No one approach is superior, but various factors should be taken into account during design, planning, and implementation.

Background The rabies virus causes a fatal encephalitis and can be transmitted through organ transplantation. In 2013, a man developed rabies 18 months after receiving a kidney from a donor with rabies, who was not known to have been infected when the organs were procured. Three additional persons who received organs from the same donor (liver, kidney, heart), all of whom were not vaccinated for rabies before transplantation, received rabies post-exposure prophylaxis (PEP) with rabies immune globulin and 5 doses of rabies vaccine as soon as the diagnosis of rabies was made in the donor (18 months after their transplant surgeries). We describe their clinical management. Methods As the 3 recipients were all on immunosuppressive medications, post-vaccination serologic testing was performed using the rapid fluorescent focus inhibition test to measure rabies virus neutralizing antibodies (RVNAs). An acceptable antibody response to administration of rabies vaccine was defined as detection of RVNAs at a concentration ≥0.1 IU/mL from a serum specimen collected ≥7 days after the fifth vaccine dose. Results All 3 recipients demonstrated an acceptable antibody response despite their immunosuppressed states. More than 36 months have passed since their transplant surgeries, and all 3 recipients have no evidence of rabies. Conclusions The survival of 3 previously unvaccinated recipients of solid organs from a donor with rabies is unexpected. Although the precise factors that led to their survival remain unclear, our data suggest that PEP can possibly enhance transplant safety in settings in which donors are retrospectively diagnosed with rabies.

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Ethiopia is one of the African countries most affected by rabies. A coarse catalog of rabies viruses (RABV) was created as a benchmark to assess the impact of control and elimination activities. We evaluated a 726 bp amplicon at the end of the N-gene to infer viral lineages in circulation using maximum likelihood and Bayesian methods for phylogenetic reconstruction. We sequenced 228 brain samples from wild and domestic animals collected in five Ethiopian regions during 2010–2017. Results identified co-circulating RABV lineages that are causing recurrent spillover infections into wildlife and domestic animals. We found no evidence of importation of RABVs from other African countries or vaccine-induced cases in the area studied. A divergent RABV lineage might be involved in an independent rabies cycle in jackals. This investigation provides a feasible approach to assess rabies control and elimination efforts in resource-limited countries.