Epidemiology of injuries presenting to the national hospital in Kampala, Uganda: implications for research and policy

BackgroundDespite the growing burden of injuries in LMICs, there are still limited primary epidemiologic data to guide health policy and health system development. Understanding the epidemiology of injury in developing countries can help identify risk factors for injury and target interventions for prevention and treatment to decrease disability and mortality.AimTo estimate the epidemiology of the injury seen in patients presenting to the government hospital in Kampala, the capital city of Uganda.MethodsA secondary analysis of a prospectively collected database collected by the Injury Control Centre-Uganda at the Mulago National Referral Hospital, Kampala, Uganda, 2004-2005.ResultsFrom 1 August 2004 to 12 August 2005, a total of 3,750 injury-related visits were recorded; a final sample of 3,481 records were analyzed. The majority of patients (62%) were treated in the casualty department and then discharged; 38% were admitted. Road traffic injuries (RTIs) were the most common causes of injury for all age groups in this sample, except for those under 5 years old, and accounted for 49% of total injuries. RTIs were also the most common cause of mortality in trauma patients. Within traffic injuries, more passengers (44%) and pedestrians (30%) were injured than drivers (27%). Other causes of trauma included blunt/penetrating injuries (25% of injuries) and falls (10%). Less than 5% of all patients arriving to the emergency department for injuries arrived by ambulance.ConclusionsRoad traffic injuries are by far the largest cause of both morbidity and mortality in Kampala. They are the most common cause of injury for all ages, except those younger than 5, and school-aged children comprise a large proportion of victims from these incidents. The integration of injury control programs with ongoing health initiatives is an urgent priority for health and development

Analysis of Mice Lacking DNaseI Hypersensitive Sites at the 5′ End of the IgH Locus

The 5′ end of the IgH locus contains a cluster of DNaseI hypersensitive sites, one of which (HS1) was shown to be pro-B cell specific and to contain binding sites for the transcription factors PU.1, E2A, and Pax5. These data as well as the location of the hypersensitive sites at the 5′ border of the IgH locus suggested a possible regulatory function for these elements with respect to the IgH locus. To test this notion, we generated mice carrying targeted deletions of either the pro-B cell specific site HS1 or the whole cluster of DNaseI hypersensitive sites. Lymphocytes carrying these deletions appear to undergo normal development, and mutant B cells do not exhibit any obvious defects in V(D)J recombination, allelic exclusion, or class switch recombination. We conclude that deletion of these DNaseI hypersensitive sites does not have an obvious impact on the IgH locus or B cell development

Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region.

International audienceB-cell malignancies, such as human Burkitt's lymphoma, often contain translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH, encoded by Igh). The nature of elements that activate oncogenes within such translocations has been a long-standing question. Translocations within Igh involve DNA double-strand breaks initiated either by the RAG1/2 endonuclease during variable, diversity and joining gene segment (V(D)J) recombination, or by activation-induced cytidine deaminase (AID, also known as AICDA) during class switch recombination (CSR). V(D)J recombination in progenitor B (pro-B) cells assembles Igh variable region exons upstream of mu constant region (Cmu) exons, which are the first of several sets of C(H) exons ('C(H) genes') within a C(H) locus that span several hundred kilobases (kb). In mature B cells, CSR deletes Cmu and replaces it with a downstream C(H) gene. An intronic enhancer (iEmu) between the variable region exons and Cmu promotes V(D)J recombination in developing B cells. Furthermore, the Igh 3' regulatory region (Igh3'RR) lies downstream of the C(H) locus and modulates CSR by long-range transcriptional enhancement of C(H) genes. Transgenic mice bearing iEmu or Igh3'RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating that such elements can confer oncogenic c-myc expression. However, in many B-cell lymphomas, Igh-c-myc translocations delete iEmu and place c-myc up to 200 kb upstream of the Igh3'RR. Here we address the oncogenic role of the Igh3'RR by inactivating it in two distinct mouse models for B-cell lymphoma with Igh-c-myc translocations. We show that the Igh3'RR is dispensable for pro-B-cell lymphomas with V(D)J recombination-initiated translocations, but is required for peripheral B-cell lymphomas with CSR-associated translocations. As the Igh3'RR is not required for CSR-associated Igh breaks or Igh-c-myc translocations in peripheral B-cell lymphoma progenitors, we conclude that this regulatory region confers oncogenic activity by long-range and developmental stage-specific activation of translocated c-myc genes

Orientation-specific joining of AID-initiated DNA breaks promotes antibody class switching

During B-cell development, RAG endonuclease cleaves immunoglobulin heavy chain (IgH) V, D, and J gene segments and orchestrates their fusion as deletional events that assemble a V(D)J exon in the same transcriptional orientation as adjacent Cmu constant region exons. In mice, six additional sets of constant region exons (CHs) lie 100-200 kilobases downstream in the same transcriptional orientation as V(D)J and Cmu exons. Long repetitive switch (S) regions precede Cmu and downstream CHs. In mature B cells, class switch recombination (CSR) generates different antibody classes by replacing Cmu with a downstream CH (ref. 2). Activation-induced cytidine deaminase (AID) initiates CSR by promoting deamination lesions within Smu and a downstream acceptor S region; these lesions are converted into DNA double-strand breaks (DSBs) by general DNA repair factors. Productive CSR must occur in a deletional orientation by joining the upstream end of an Smu DSB to the downstream end of an acceptor S-region DSB. However, the relative frequency of deletional to inversional CSR junctions has not been measured. Thus, whether orientation-specific joining is a programmed mechanistic feature of CSR as it is for V(D)J recombination and, if so, how this is achieved is unknown. To address this question, we adapt high-throughput genome-wide translocation sequencing into a highly sensitive DSB end-joining assay and apply it to endogenous AID-initiated S-region DSBs in mouse B cells. We show that CSR is programmed to occur in a productive deletional orientation and does so via an unprecedented mechanism that involves in cis Igh organizational features in combination with frequent S-region DSBs initiated by AID. We further implicate ATM-dependent DSB-response factors in enforcing this mechanism and provide an explanation of why CSR is so reliant on the 53BP1 DSB-response factor