CT Before Lumbar Puncture in Suspected Meningitis in Botswana: How Established Guidelines May Not Apply / Tomodensitométrie Avant Ponction Lombaire en Cas de Suspicion de Méningite au Botswana: Comment les Directives Classiques Peuvent ne Pas s’Appliquer

English Introduction According to established guidelines from high-income countries, computed tomography of the head (CT) is indicated before lumbar puncture (LP) in the evaluation of suspected meningitis in HIV patients. In Botswana, meningitis in HIV-infected patients is common but CT is not widely available. Objective Develop a rational, evidence-based approach to CT use in the emergency evaluation of suspected meningitis in a population with high HIV prevalence. Methods Emergency center (EC) staff at Princess Marina Hospital in Gaborone, Botswana, reviewed indications for CT and LP in suspected meningitis. The authors considered existing evidence for CT before LP (mostly from high-income countries) and considered the epidemiology of central nervous system infections in Southern Africa. Draft guidelines were circulated to emergency center doctors and nurses, and to specialists in other hospital departments for review and comment before finalization. Result Available literature seems to indicate that in Botswana it would be possible to significantly limit the use of head CT before LP in HIV positive patients without increasing the incidence or risk of herniation. The guideline includes scenarios where an LP might be indicated in the presence of focal neurological findings and in the absence of a CT, in contradiction to established guidelines. Discussion The applicability of established guidelines for CT use in suspected meningitis is dependent on local epidemiology and resources. French Introduction Selon les directives classiques provenant des pays à revenu élevé, la tomodensitométrie (TDM) de la tête est indiquée avant une ponction lombaire (PL) pour l’évaluation d’une possible méningite chez les patients infectés par le VIH. Au Botswana, la méningite chez les patients infectés par le VIH est courante mais la TDM n’est pas souvent disponible. Objectif Développer une approche rationnelle fondée sur des preuves relative à l’utilisation de la TDM en cas d’évaluation d’urgence d’une possible méningite au sein d’une population à forte prévalence du VIH. Méthodes Le personnel du Centre d’Urgences (CU) de l’hôpital Princess Marina à Gaborone, Botswana, a examiné des prescriptions de TDM et de PL en cas de suspicion de méningite. Les auteurs se sont penchés sur les cas existants de TDM avant PL (la plupart provenant de pays à revenus élevés) et ont examiné l’épidémiologie des infections du système nerveux central en Afrique australe. Des directives provisoires ont été distribuées à des médecins et des infirmières de centres d’urgences et à des spécialistes dans d’autres services hospitaliers pour examen et commentaires avant finalisation. Résultat Les publications disponibles semblent indiquer qu’au Botswana, il serait possible de limiter fortement l’utilisation de la TDM de la tête avant une PL chez les patients séropositifs sans augmenter l’incidence ou le risque d’engagement cérébral. La directive comprend des scénarios dans lesquels une PL pourrait être indiquée en présence de signes neurologiques focaux et en l’absence d’une TDM, contrairement à ce que préconisent les directives classiques. Discussion L’applicabilité des directives classiques relatives à l’utilisation de la TDM dans des cas de suspicion de méningite dépend de l’épidémiologie et des ressources locales

Microbiology of Urinary Tract Infections in Gaborone, Botswana

Objective The microbiology and epidemiology of UTI pathogens are largely unknown in Botswana, a high prevalence HIV setting. Using laboratory data from the largest referral hospital and a private hospital, we describe the major pathogens causing UTI and their antimicrobial resistance patterns. Methods This retrospective study examined antimicrobial susceptibility data for urine samples collected at Princess Marina Hospital (PMH), Bokamoso Private Hospital (BPH), or one of their affiliated outpatient clinics. A urine sample was included in our dataset if it demonstrated pure growth of a single organism and accompanying antimicrobial susceptibility and subject demographic data were available. Results A total of 744 samples were included. Greater than 10% resistance was observed for amoxicillin, co-trimoxazole, amoxicillin-clavulanate, and ciprofloxacin. Resistance of E. coli isolates to ampicillin and co-trimoxazole was greater than 60% in all settings. HIV status did not significantly impact the microbiology of UTIs, but did impact antimicrobial resistance to co-trimoxazole. Conclusions Data suggests that antimicrobial resistance has already emerged to most oral antibiotics, making empiric management of outpatient UTIs challenging. Ampicillin, co-trimoxazole, and ciprofloxacin should not be used as empiric treatment for UTI in this context. Nitrofurantoin could be used for simple cystitis; aminoglycosides for uncomplicated UTI in inpatients

Unrepeatered field transmission of 2 Tbit/s multi-banded coherent WDM over 124 km of installed SMF

In this paper we report field transmission of a 2Tbit/s multi-banded Coherent WDM signal over BT Ireland's installed SMF, using EDFA amplification only, with mixed Ethernet (with FEC) and PRBS payloads. To the best of our knowledge, the results obtained represent the highest total capacity transmitted over installed SMF with orthogonal subcarriers. BERs below 10(-5) and no frame-loss were recorded for all 49 subcarriers. Extended BER measurements over several hours showed fluctuations that can be attributed to PMD and to dynamic effects associated with clock instabilities

Methionine 129 variant of human prion protein oligomerizes more rapidly than the valine 129 variant

The human PrP gene (PRNP) has two common alleles that encode either methionine or valine at codon 129. This polymorphism modulates disease susceptibility and phenotype of human transmissible spongiform encyphalopathies, but the molecular mechanism by which these effects are mediated remains unclear. Here, we compared the misfolding pathway that leads to the formation of beta-sheet-rich oligomeric isoforms of the methionine 129 variant of PrP to that of the valine 129 variant. We provide evidence for differences in the folding behavior between the two variants at the early stages of oligomer formation. We show that Met(129) has a higher propensity to form beta-sheet-rich oligomers, whereas Val(129) has a higher tendency to fold into alpha-helical-rich monomers. An equimolar mixture of both variants displayed an intermidate folding behavior. We show that the oligomers of both variants are initially a mixture of alpha- and beta-rich conformers that evolve with time to an increasingly homogeneous beta-rich form. This maturation process, which involves no further change in proteinase K resistance, occurs more rapidly in the Met(129) form than the Val(129) form. Although the involvement of such beta-rich oligomers in prion pathogenesis is speculative, the misfolding behavior could, in part, explain the higher susceptibility of individuals that are methionine homozygote to both sporadic and variant Creutzfeldt-Jakob disease

Demographic and clinical characteristics associated with glomerular filtration rates in living kidney donors

Due to the shortage of organs, living donor acceptance criteria are becoming less stringent. An accurate determination of the glomerular filtration rate (GFR) is critical in the evaluation of living kidney donors and a value exceeding 80 ml/min per 1.73 m2 is usually considered suitable. To improve strategies for kidney donor screening, an understanding of factors that affect GFR is needed. Here we studied the relationships between donor GFR measured by 125I-iothalamate clearances (mGFR) and age, gender, race, and decade of care in living kidney donors evaluated at the Cleveland Clinic from 1972 to 2005. We report the normal reference ranges for 1057 prospective donors (56% female, 11% African American). Females had slightly higher mGFR than males after adjustment for body surface area, but there were no differences due to race. The lower limit of normal for donors (5th percentile) was less than 80 ml/min per 1.73 m2 for females over age 45 and for males over age 40. We found a significant doubling in the rate of GFR decline in donors over age 45 as compared to younger donors. The age of the donors and body mass index increased over time, but their mGFR, adjusted for body surface area, significantly declined by 1.49±0.61 ml/min per 1.73 m2 per decade of testing. Our study shows that age and gender are important factors determining normal GFR in living kidney donors

The Social Effects of Entrepreneurship on Society and Some Potential Remedies: Four Provocations

A rapidly growing research stream examines the social effects of entrepreneurship on society. This research assesses the rise of entrepreneurship as a dominant theme in society and studies how entrepreneurship contributes to the production and acceptance of socio-economic inequality regimes, social problems, class and power struggles, and systemic inequities. In this article, scholars present new perspectives on an organizational sociology-inspired research agenda of entrepreneurial capitalism and detail the potential remedies to bound the unfettered expansion of a narrow conception of entrepreneurship. Taken together, the essays put forward four central provocations: 1) reform the study and pedagogy of entrepreneurship by bringing in the humanities; 2) examine entrepreneurship as a cultural phenomenon shaping society; 3) go beyond the dominant biases in entrepreneurship research and pedagogy; and 4) explore alternative models to entrepreneurial capitalism. More scholarly work scrutinizing the entrepreneurship–society nexus is urgently needed, and these essays provide generative arguments toward further developing this research agenda

The Influence of Huntingtin Protein Size on Nuclear Localization and Cellular Toxicity

Huntington disease is an autosomal dominant neurodegenerative disorder caused by the pathological expansion of a polyglutamine tract. In this study we directly assess the influence of protein size on the formation and subcellular localization of huntingtin aggregates. We have created numerous deletion constructs expressing successively smaller fragments of huntingtin and show that these smaller proteins containing 128 glutamines form both intranuclear and perinuclear aggregates. In contrast, larger NH2-terminal fragments of huntingtin proteins with 128 glutamines form exclusively perinuclear aggregates. These aggregates can form in the absence of endogenous huntingtin. Furthermore, expression of mutant huntingtin results in increased susceptibility to apoptotic stress that is greater with decreasing protein length and increasing polyglutamine size. As both intranuclear and perinuclear aggregates are clearly associated with increased cellular toxicity, this supports an important role for toxic polyglutamine-containing fragments forming aggregates and playing a key role in the pathogenesis of Huntington disease

Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins

Approximately 15 % of human prion disease is associated with autosomal-dominant pathogenic mutations in the prion protein (PrP) gene. Previous attempts to model these diseases in mice have expressed human PrP mutations in murine PrP, but this may have different structural consequences. Here, we describe transgenic mice expressing human PrP with P102L or E200K mutations and methionine (M) at the polymorphic residue 129. Although no spontaneous disease developed in aged animals, these mice were readily susceptible to prion infection from patients with the homotypic pathogenic mutation. However, while variant Creutzfeldt–Jakob disease (CJD) prions transmitted infection efficiently to both lines of mice, markedly different susceptibilities to classical (sporadic and iatrogenic) CJD prions were observed. Prions from E200K and classical CJD M129 homozygous patients, transmitted disease with equivalent efficiencies and short incubation periods in human PrP 200K, 129M transgenic mice. However, mismatch at residue 129 between inoculum and host dramatically increased the incubation period. In human PrP 102L, 129M transgenic mice, short disease incubation periods were only observed with transmissions of prions from P102L patients, whereas classical CJD prions showed prolonged and variable incubation periods irrespective of the codon 129 genotype. Analysis of disease-related PrP (PrPSc) showed marked alteration in the PrPSc glycoform ratio propagated after transmission of classical CJD prions, consistent with the PrP point mutations directly influencing PrPSc assembly. These data indicate that P102L or E200K mutations of human PrP have differing effects on prion propagation that depend upon prion strain type and can be significantly influenced by mismatch at the polymorphic residue 129

Phylogenetic analyses and antimicrobial resistance profiles of Campylobacter spp. from diarrhoeal patients and chickens in Botswana.

Campylobacter spp. are a leading cause of bacterial enteritis worldwide, including countries in Africa, and have been identified by the World Health Organisation (WHO) as one of the high priority antimicrobial resistant pathogens. However, at present there is little knowledge on the prevalence, molecular epidemiology or antimicrobial susceptibility of Campylobacter spp. isolates in Botswana, both in patients and in the zoonotic context. Some data indicate that ~14% of diarrhoeal disease cases in a paediatric setting can be ascribed to Campylobacter spp., urging the need for the magnitude of Campylobacter-associated diarrhoea to be established. In this survey, we have characterised the genomic diversity of Campylobacter spp. circulating in Botswana isolated from cases of diarrhoeal disease in humans (n = 20) and from those that colonised commercial broiler (n = 35) and free-range (n = 35) chickens. Phylogeny showed that the Campylobacter spp. isolated from the different poultry and human sources were highly related, suggesting that zoonotic transmission has likely occurred. We found that for Campylobacter spp. isolated from humans, broilers and free-range chickens, 52% was positive for tetO, 47% for gyrA-T86I, 72% for blaOXA-61, with 27% carrying all three resistance determinants. No 23S mutations conferring macrolide resistance were detected in this survey. In summary, our study provides insight into Campylobacter spp. in poultry reservoirs and in diarrhoeal patients, and the relevance for treatment regimens in Botswana

Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Na v) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Na v channels. Functional characterization of mutant FHF2A co-expressed with wild-type Na v1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Na v channel function