Complications of traditional bonesetting in contemporary fracture care in low- and middle-income countries: A systematic review.

OBJECTIVE: To provide an overview of the evidence on the prevalence and pattern of complications among patients treated by traditional bonesetting presenting for modern orthopaedic services in low- and middle-income countries (LMIC). METHODS: Systematic review following PRISMA guidelines. Articles were identified by searching PubMed, Embase, ScienceDirect, SCOPUS, and Web of Science using the keywords "fracture care", "traditional bonesetters" and "complications". Papers included for review were original articles set in an LMIC that directly reported the prevalence and pattern of musculoskeletal complications of traditional bonesetters' fracture treatment in LMIC settings. RESULTS: A total of 176 papers were screened for eligibility and 15 studies were finally included. Nine were prospective studies, six were retrospective studies. All were hospital-based, observational studies that investigated the outcomes of treatment of fractures by traditional bonesetters published between 1986 and 2018. In total, this review covers 1389 participants with 1470 complications of fracture treatment. CONCLUSION: Traditional bonesetting complications are associated with significant morbidity. However, traditional bonesetters have the potential to contribute positively to primary fracture care when they are trained.

Decreasing Trends in Road Traffic Injury Incidence and Mortality in Nigeria: A Ten-Year Analysis.

BACKGROUND: Road traffic accidents constitute a significant public health burden in Nigeria. In this study, we aim to (1) characterize the temporal burden of road traffic injury (RTI) and mortality rates in Nigeria over a decade, (2) identify regional RTI incidence, mortality trends, and high-risk regions, and (3) assess the impact of state population on injury and mortality. MATERIALS AND METHODS: We retrospectively reviewed aggregate state-level RTI incidence and mortality counts reported by the Federal Road Safety Corps from January 2001 through December 2010. We also reviewed population data from the National Population Commission. In addition to national analyses, regional analyses were performed in Nigeria's six geopolitical zones and one Federal Capital Territory (FCT). Regression analysis was also performed to determine the relationship between population and RTI incidence and mortality. RESULTS: The national median RTI incidence and mortality rates declined by 53% and 75%, respectively, between 2001 and 2010. Analysis by geopolitical zone yielded the greatest increases for both injury and mortality in the FCT and the greatest decreases for both in the South-South region. The average geopolitical zone, apart from the FCT, experienced a 24% decrease in the incidence rate and a 69% decrease in the mortality rate. An analysis of variance, run to assess potential differences in RTI incidence and mortality rates by state population, yielded significant values of P = 0.0023 for injury and P = 0.0002 for mortality. CONCLUSIONS: Acknowledging the potential for underreporting, a more holistic surveillance approach would generate more accurate data for future policy creation to improve clinical outcomes.

Clinical, biochemical, and molecular characterization of macronodular adrenocortical hyperplasia of the zona reticularis: a new syndrome.

CONTEXT: Macronodular adrenocortical hyperplasia classically presents with progressive hypercortisolemia and Cushing syndrome. We describe a 29-yr-old man with massive macronodular adrenocortical hyperplasia without hypercortisolemia but rather markedly elevated and nonsuppressible production of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). OBJECTIVE: To characterize the clinical and molecular features of this case and to determine whether the tissue biochemically resembles the zona reticularis or fetal adrenal. SETTING: University clinic, hospital, and laboratories. DESIGN: Static and dynamic blood and urine testing were performed preoperatively. Tissue was studied by light microscopy, immunoblot, RNA microarray, and enzyme assay. PARTICIPANT: A 29-yr-old man with incidentally discovered bilateral adrenal enlargement. INTERVENTION: Bilateral adrenalectomy. MAIN OUTCOME MEASURES: Molecular studies compared with control samples. RESULTS: Hypercortisolism and 21-hydroxylase deficiency were excluded. DHEA, DHEAS, and 17-hydroxypregnenolone were markedly elevated and did not suppress with dexamethasone 2 mg/d for 4 d. Homogenates of the adrenals demonstrated high 17-hydroxylase, good 17,20-lyase, and low or absent 21-hydroxylase and 3ß-hydroxysteroid dehydrogenase activities. Immunoblots confirmed robust expression of cytochrome P450c17 and AKR1C3 but not P450c21. Microarray analysis demonstrated high CYP11A1 and CYP17A1 expression but low or absent HSD3B1, HSD3B2, and CYP21A2 expression. Expression of mRNA for cytochrome b(5) (CYB5A) and AKR1C3, markers of the zona reticularis, were markedly elevated. CONCLUSION: This is the first case of macronodular hyperplasia of the adrenal zona reticularis confirmed with studies of enzyme activity, mRNA expression, and protein identification. We speculate that this condition can be clinically silent in men but might cause severe hyperandrogenemia in women.

Inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin in an orthotopic model of anaplastic thyroid carcinoma.

Patients with anaplastic thyroid carcinoma (ATC) typically succumb to their disease months after diagnosis despite aggressive therapy. A large percentage of ATCs have been shown to harbor the V600E B-Raf point mutation, leading to the constitutive activation of the mitogen-activated protein kinase pathway. ATC invasion, metastasis, and angiogenesis are in part dependent on the gelatinase class of matrix metalloproteinases (MMP). The explicit targeting of these two tumor markers may provide a novel therapeutic strategy for the treatment of ATC. The MMP-activated anthrax lethal toxin (LeTx), a novel recombinant protein toxin combination, shows potent mitogen-activated protein kinase pathway inhibition in gelatinase-expressing V600E B-Raf tumor cells in vitro. However, preliminary in vivo studies showed that the MMP-activated LeTx also exhibited dramatic antitumor activity against xenografts that did not show significant antiproliferative responses to the LeTx in vitro. Here, we show that the MMP-activated LeTx inhibits orthotopic ATC xenograft progression in both toxin-sensitive and toxin-resistant ATC cells via reduced endothelial cell recruitment and subsequent tumor vascularization. This in turn translates to an improved long-term survival that is comparable with that produced by the multikinase inhibitor sorafenib. Our results also indicate that therapy with the MMP-activated LeTx is extremely effective against advanced tumors with well-established vascular networks. Taken together, these results suggest that the MMP-activated LeTx-mediated endothelial cell targeting is the primary in vivo antitumor mechanism of this novel toxin. Therefore, the MMP-activated LeTx could be used not only in the clinical management of V600E B-Raf ATC but potentially in any solid tumor.

Involvement of TRAF4 in oxidative activation of c-Jun N-terminal kinase.

We previously found that the angiogenic factors TNFalpha and HIV-1 Tat activate an NAD(P)H oxidase in endothelial cells, which operates upstream of c-Jun N-terminal kinase (JNK), a MAPK involved in the determination of cell fate. To further understand oxidant-related signaling pathways, we screened lung and endothelial cell libraries for interaction partners of p47(phox) and recovered the orphan adapter TNF receptor-associated factor 4 (TRAF4). Domain analysis suggested a tail-to-tail interaction between the C terminus of p47(phox) and the conserved TRAF domain of TRAF4. In addition, TRAF4, like p47(phox), was recovered largely in the cytoskeleton/membrane fraction. Coexpression of p47(phox) and TRAF4 increased oxidant production and JNK activation, whereas each alone had minimal effect. In addition, a fusion between p47(phox) and the TRAF4 C terminus constitutively activated JNK, and this activation was decreased by the antioxidant N-acetyl cysteine. In contrast, overexpression of the p47(phox) binding domain of TRAF4 blocked endothelial cell JNK activation by TNFalpha and HIV-1 Tat, suggesting an uncoupling of p47(phox) from upstream signaling events. A secondary screen of endothelial cell proteins for TRAF4-interacting partners yielded a number of proteins known to control cell fate. We conclude that endothelial cell agonists such as TNFalpha and HIV-1 Tat initiate signals that enter basic signaling cassettes at the level of TRAF4 and an NAD(P)H oxidase. We speculate that endothelial cells may target endogenous oxidant production to specific sites critical to cytokine signaling as a mechanism for increasing signal specificity and decreasing toxicity of these reactive species.