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Background: Antivenom is rarely available for the management of snakebites in rural sub-Saharan Africa(sSA)., Objectives: To report clinical management and outcomes of 174 snakebite victims treated with basic intensive-care interventions in a rural sSA hospital., Methods: This cohort study was designed as a retrospective analysis of a database of patients admitted to the intensive care unit (ICU) of St. Mary's Hospital Lacor in Gulu, Uganda (January 2006 - November 2017). No exclusion criteria were applied., Results: Of the 174 patients admitted to the ICU for snakebite envenomation, 60 (36.5%) developed respiratory failure requiring mechanical ventilation (16.7% mortality). Results suggest that neurotoxic envenomation was likely the most common cause of respiratory failure among patients requiring mechanical ventilation. Antivenom (at probably inadequate doses) was administered to 22 of the 174 patients (12.6%). The median (and associated interquartile range) length of ICU stay was 3 (2 - 5) days, with an overall mortality rate of 8%. Of the total number of patients, 67 (38.5%) were younger than 18 years., Conclusion: Results suggest that basic intensive care, including mechanical ventilation, is a feasible management option for snakebite victims presenting with respiratory failure in a rural sSA hospital, resulting in a low mortality rate, even without adequate antivenom being available. International strategies which include preventive measures as well as the strengthening of context-adapted treatment of critically ill patients at different levels of referral pathways, in order to reduce deaths and disability associated with snakebites in sSA are needed. Provision of efficient antivenoms should be integrated in clinical care of snakebite victims in peripheral healthcare facilities. Snakebite management protocols and preventive measures need to consider specific requirements of children., Contributions of the Study: It is estimated that up to 138 000 people die each year following snakebites. Currently, reliable provision of efficient snake-bite antivenom is challenging in many rural health facilities in sub- Saharan Africa (sSA). Our results suggest that basic intensive-care interventions, including mechanical ventilation, is a feasible management option for critically ill snakebite victims in a rural sSA hospital, resulting in a low mortality rate, even without adequate antivenom doses being available., Competing Interests: Conflicts of interest: None.

Autosomal dominant familial Alzheimer's disease (AD) is associated with mutations in the AβPP, PSEN1, and PSEN2 genes. The clinical phenotype associated with AβPP mutations is mainly characterized by dementia or by strokes related to cerebral amyloid angiopathy (CAA). We present a comprehensive clinical, neuropathological, genetic, and biochemical study on a patient affected by familial AD associated with the I716F mutation in the AβPP gene. The clinical phenotype was characterized by early age of onset of 47 years, and rapidly progressive cerebellar ataxia, myoclonic jerks, rigidity, and dementia reminiscent of Creutzfeldt-Jakob disease (CJD), followed by a prolonged persistent vegetative state. Neuropathological evaluation of the proband revealed AD-related pathology but also α-synucleinopathy compatible with dementia with Lewy bodies neocortical stage or Parkinson's disease corresponding to Braak stage 6. Tau-pathology in the form of neurofibrillary degeneration corresponded to stage VI according to the Braak classification. The severe Aβ pathology included CAA, numerous plaques, and deposition of N-truncated pyroglutamate-modified Aβ peptides. Remarkably, pyroglutamate Aβ oligomers were also present intracellularly in Purkinje cells corresponding to the ataxic phenotype. The detection of a CJD-like phenotype expands the spectrum of clinical presentations associated with familial AD. Our study supports the concept that the neuropathology of familial AD expands beyond the classical AD-related pathology as defined by plaques and tangles. Finally, we provide evidence for the first time that oligomeric pyroglutamate Aβ is present in a specific pattern correlating with the clinical symptoms of a patient with AβPP I716F mutation.

Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and multiple system atrophy are characterized by the deposition of disease-associated α-synuclein. In the present study we 1) examined the molecular specificity of the novel anti-α-synuclein 5G4 antibody; 2) evaluated immunoreactivity patterns and their correlation in human brain tissue with micro- and astrogliosis in 57 cases with PD or DLB; and 3) performed a systematic immunoelectron microscopical mapping of subcellular localizations. 5G4 strongly binds to the high molecular weight fraction of β-sheet rich oligomers, while no binding to primarily disordered oligomers or monomers was observed. We show novel localizations of disease-associated α-synuclein including perivascular macrophages, ependyma and cranial nerves. α-Synuclein immunoreactive neuropil dots and thin threads associate more with glial reaction than Lewy bodies alone. Astrocytic α-synuclein is an important component of the pathology. Furthermore, we document ultrastructurally the pathway of processing of disease-associated α-synuclein within neurons and astroglial cells. Interaction of mitochondria and disease-associated α-synuclein plays a key role in the molecular-structural cytopathogenesis of disorders with Lewy bodies. We conclude that 1) the 5G4 antibody has strong selectivity for β-sheet rich α-synuclein oligomers; 2) Lewy bodies themselves are not the most relevant morphological substrate that evokes tissue lesioning; 3) both neurons and astrocytes internalize disease-associated α-synuclein in the human brain, suggesting prion-like cell-to-cell spread of α-synuclein by uptake from surrounding structures, as shown previously in experimental observations., (Copyright © 2014 Elsevier Inc. All rights reserved.)