Neurological disorders in HIV in Africa: a review

Background: Neurological disorders in HIV infection are a common cause of morbidity and mortality. The aim of this paper is to provide a narrative overview of up to date information concerning neurological disorders affecting HIV infected persons in Africa.Methods: Seminal research concerning neurological disorders among HIV-infected adults in sub-Saharan Africa from prior to 2000 was combined with an in-depth search of PubMed to identify literature published from 2000 to 2017. The following Mesh terms were used. "Nervous System Diseases” "HIV Infections" and "Africa South of the Sahara" and "Seizures" or "Spinal Cord Diseases" or “Peripheral Nervous System Diseases" or "AIDS Dementia Complex" or “Opportunistic Infections" or "Immune constitution Inflammatory Syndrome” or "Stroke". Only those articles written in English were used. A total of 352 articles were identified, selected and reviewed and 180 were included in the study. These included case series, observational studies, interventional studies, guidelines and reviews with metanalyses. The author also included 15 publications on the subject covering theearlier phase of the HIV epidemic in Africa from 1987 to 1999 making a total of 195 references in the study. This was combined with extensive personal experience diagnosing and treating these neurological disorders.Results: Neurological disorders were common, typically occurring in WHO stages III/IV. These were in three main categories: those arising from opportunistic processes mostly infections, direct HIV infection and autoimmunity. The most common were those arising from direct HIV infection occurring in >50%. These included HIV-associated neurocognitive dysfunction (HAND), neuropathy and myelopathy. Opportunistic infections occurred in >20% and frequently had a 6-9-month mortality rate of 60-70%. The main causes were cryptococcus, tuberculosis, toxoplasmosis and acute bacterial meningitis. Concurrentsystemic tuberculosis occurred in almost 50%.Conclusion: Neurological disorders are common in HIV in Africa and the main CNS opportunistic infections result in high mortality rates. Strategies aimed at reducing their high burden, morbidity and mortality include early HIV diagnosis and anti-retroviral therapy (ART), screening and chemoprophylaxis of main opportunistic infections, improved clinical diagnosis and management and programme strengthening.Keywords: Neurological disorders, HIV, Africa, opportunistic infections, direct HIV infection and inflammatory disorders

Neurological disorders in Northern Tanzania: A 6-year prospective hospital-based case series

Background: The burden of neurological disorders is large and altered by the HIV epidemic. Objectives: We describe the pattern of neurological disorders and their association with HIV infection in adult patients attending a consultant hospital in Northern Tanzania. Methods: In this prospective cross-sectional study, we collected data on adult neurological referrals over a 6-year period between 2007-13. The odds of HIV infection, across neurological categories adjusted for age and sex, was calculated. Results: Of 2037 participants, 54.8% were male and 45.2% were female. The median age of participants was 43 years. The results for HIV screening were available for 992/2037 (48.7%) patients, of whom 306 (30.8%) were seropositive. The most frequent neurological disorders were cerebrovascular disease (19.9%), paraplegia (13.6%), and peripheral neuropathies (8%). Taken together CNS infection accounted for 278/2037 (13.6%). The adjusted odds (aOR) of HIV infection was highest amongst infections; brain abscesses (aOR 107, 95% CI 35.1-470.4) and meningitis/encephalitis (aOR 40.1, 95% CI 13.6-172.9), but also raised in cerebrovascular disease, paraplegia, peripheral neuropathies, cranial nerve palsies, seizures, cerebllar disorders, movement disorders, motor neuron disease and headache. Conclusion: The main pattern of neurological disorders in Northern Tanzania is presented. The odds of HIV infection was highest in CNS infections and in a wide range of non-communicable neurological disorders.publishedVersio

Post-Partum Pituitary Insufficiency and Livedo Reticularis Presenting a Diagnostic Challenge in a Resource Limited Setting in Tanzania: A Case Report, Clinical Discussion and Brief Review of Existing Literature.

Pituitary disorders following pregnancy are an important yet under reported clinical entity in the developing world. Conversely, post partum panhypopituitarism has a more devastating impact on women in such settings due to high fertility rates, poor obstetric care and scarcity of diagnostic and therapeutic resources available. A 37 year old African female presented ten years post partum with features of multiple endocrine deficiencies including hypothyroidism, hypoadrenalism, lactation failure and secondary amenorrhea. In addition she had clinical features of an underlying autoimmune condition. These included a history of post-partum thyroiditis, alopecia areata, livedo reticularis and deranged coagulation indices. A remarkable clinical response followed appropriate hormone replacement therapy including steroids. This constellation has never been reported before; we therefore present an interesting clinical discussion including a brief review of existing literature. Post partum pituitary insufficiency is an under-reported condition of immense clinical importance especially in the developing world. A high clinical index of suspicion is vital to ensure an early and correct diagnosis which will have a direct bearing on management and patient outcome

Sub-Telomere Directed Gene Expression during Initiation of Invasive Aspergillosis

Aspergillus fumigatus is a common mould whose spores are a component of the normal airborne flora. Immune dysfunction permits developmental growth of inhaled spores in the human lung causing aspergillosis, a significant threat to human health in the form of allergic, and life-threatening invasive infections. The success of A. fumigatus as a pathogen is unique among close phylogenetic relatives and is poorly characterised at the molecular level. Recent genome sequencing of several Aspergillus species provides an exceptional opportunity to analyse fungal virulence attributes within a genomic and evolutionary context. To identify genes preferentially expressed during adaptation to the mammalian host niche, we generated multiple gene expression profiles from minute samplings of A. fumigatus germlings during initiation of murine infection. They reveal a highly co-ordinated A. fumigatus gene expression programme, governing metabolic and physiological adaptation, which allows the organism to prosper within the mammalian niche. As functions of phylogenetic conservation and genetic locus, 28% and 30%, respectively, of the A. fumigatus subtelomeric and lineage-specific gene repertoires are induced relative to laboratory culture, and physically clustered genes including loci directing pseurotin, gliotoxin and siderophore biosyntheses are a prominent feature. Locationally biased A. fumigatus gene expression is not prompted by in vitro iron limitation, acid, alkaline, anaerobic or oxidative stress. However, subtelomeric gene expression is favoured following ex vivo neutrophil exposure and in comparative analyses of richly and poorly nourished laboratory cultured germlings. We found remarkable concordance between the A. fumigatus host-adaptation transcriptome and those resulting from in vitro iron depletion, alkaline shift, nitrogen starvation and loss of the methyltransferase LaeA. This first transcriptional snapshot of a fungal genome during initiation of mammalian infection provides the global perspective required to direct much-needed diagnostic and therapeutic strategies and reveals genome organisation and subtelomeric diversity as potential driving forces in the evolution of pathogenicity in the genus Aspergillus

Cosmological implications of baryon acoustic oscillation measurements

We derive constraints on cosmological parameters and tests of dark energy models from the combination of baryon acoustic oscillation (BAO) measurements with cosmic microwave background (CMB) data and a recent reanalysis of Type Ia supernova (SN) data. In particular, we take advantage of high-precision BAO measurements from galaxy clustering and the Lyman-α forest (LyaF) in the SDSS-III Baryon Oscillation Spectroscopic Survey (BOSS). Treating the BAO scale as an uncalibrated standard ruler, BAO data alone yield a high confidence detection of dark energy; in combination with the CMB angular acoustic scale they further imply a nearly flat universe. Adding the CMB-calibrated physical scale of the sound horizon, the combination of BAO and SN data into an “inverse distance ladder” yields a measurement of H0 =67.3 ± 1.1 km s-1 Mpc-1, with 1.7% precision. This measurement assumes standard prerecombination physics but is insensitive to assumptions about dark energy or space curvature, so agreement with CMB-based estimates that assume a flat Λ CDM cosmology is an important corroboration of this minimal cosmological model. For constant dark energy (Λ), our BAO + SN + CMB combination yields matter density Ωm = 0.301 ± 0.008 and curvature Ωk = -0.003 ± 0.003. When we allow more general forms of evolving dark energy, the BAO + SN + CMB parameter constraints are always consistent with flat Λ CDM values at ≈1σ. While the overall χ2 of model fits is satisfactory, the LyaF BAO measurements are in moderate (2–2.5σ) tension with model predictions. Models with early dark energy that tracks the dominant energy component at high redshift remain consistent with our expansion history constraints, and they yield a higher H0 and lower matter clustering amplitude, improving agreement with some low redshift observations. Expansion history alone yields an upper limit on the summed mass of neutrino species, ∑mν (95% confidence), improving to ∑mν if we include the lensing signal in the Planck CMB power spectrum. In a flat Λ CDM model that allows extra relativistic species, our data combination yields Neff = 3.43 ± 0.26; while the LyaF BAO data prefer higher Neff when excluding galaxy BAO, the galaxy BAO alone favor Neff ≈ 3. When structure growth is extrapolated forward from the CMB to low redshift, standard dark energy models constrained by our data predict a level of matter clustering that is high compared to most, but not all, observational estimates

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Neurological disorders in Tanzania. Studies on HIV-I, Guillain-Barré syndrome and konzo

This thesis is the result of clinical studies carried out in Northern Tanzania from 1984-1992 and reports on a number of new clinical entities. These are HIV related neurological disorders, konzo and new forms of existing diseases such as Guillain-Barre Syndrome (GBS). The first and second papers report that neurological disorders were amongst the most common (70%) disorder in AIDS. The Snout and Palmomental reflexes were the most common abnormal neurological finding and increased incrementally with advancing HIV stage and associated neurological disorders. The third paper investigates a consecutive series of GBS cases admitted to Kilimanjaro Christian Medical Centre (KCMC) and to Haukeland University hospital Western Norway and demonstrated that the incidence rate, epidemiological and main clinical fmdings apart from minor differences were similar in the two series. The increased mortality rate (15%) seen in the Tanzanian series is explained mainly by the lack of resources for adequate intensive care. An association between HIV infection and GBS was seen in the Tanzanian but not the Norwegian series and HIV positive GBS patients tended to have more severe neurological disease and increased mortality. The fourth and fifth papers are reports on field surveys in Tarime district in Northern Tanzania investigating an epidemic of unexplained spastic paraparesis which occurred in 1985. The studies showed that the disease is a distinct entity manifested by spastic paraparesis and characterized by a disorder which always affects the distal upper motor neurones to a greater extent than the proximal ones. The disease was named konzo, a local name from the first reported outbreak in Zaire (Trolli 1938). The prevalence of konzo in 15 villages studied ranged from zero cases in the lake shore villages to 1411000 in the inland villages only 5 km away. All patients gave a history of almost complete reliance on bitter cassava as a staple food in the months prior to and during the epidemic. This arose because of the widespread failure of other crops as a result of the severe drought in 1984. In addition the traditional processing methods used for removal of cyanogenic compounds from the roots of bitter cassava appeared to have been shortened. A resulting high cyanide exposure was supported by high serum thiocyanate levels, the mean SCN in May 1985 in 20 cases and 9 controls were 368 and 303 μmoles/l respectively. The geographic and temporal distribution of konzo was also shown to be compatible with cyanide exposure from insufficiently processed cassava roots and there was no evidence of an infectious aetiology. The sixth paper reports on specialized neurological investigations of two patients with konzo who were brought to Sweden which suggests that the site of the pathology in konzo is most probably situated centrally in the motor cortex rather than in the spinal cord

Evidence of the existence of an internal labour market in the Great Eastern Railway Company, 1875-1905

Evidence from promotion ladders and the wage payment system of the GER is evaluated to see if it supports existing claims, primarily based on welfare and pension provision, that by 1900 the railway companies had become the first important adherents in the country to a system of internal labour markets. It is suggested that promotion was internalised and that it was based on merit and seniority, that some form of seniority wage payments system did evolve, and that wage increases were sharpest in the first ten years of employment and were associated with spatial mobility