The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference!

Kinetoplastids are unicellular, eukaryotic, flagellated protozoans containing the eponymous kinetoplast. Within this order, the family of trypanosomatids are responsible for some of the most serious human diseases, including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.), and leishmaniasis (Leishmania spp). Although cAMP is produced during the life cycle stages of these parasites, its signaling pathways are very different from those of mammals. The absence of G-protein-coupled receptors, the presence of structurally different adenylyl cyclases, the paucity of known cAMP effector proteins and the stringent need for regulation of cAMP in the small kinetoplastid cells all suggest a significantly different biochemical pathway and likely cell biology. However, each of the main kinetoplastid parasites express four class 1-type cyclic nucleotide-specific phosphodiesterases (PDEA-D), which have highly similar catalytic domains to that of human PDEs. To date, only TbrPDEB, expressed as two slightly different isoforms TbrPDEB1 and B2, has been found to be essential when ablated. Although the genomes contain reasonably well conserved genes for catalytic and regulatory domains of protein kinase A, these have been shown to have varied structural and functional roles in the different species. Recent discovery of a role of cAMP/AMP metabolism in a quorum-sensing signaling pathway in T. brucei, and the identification of downstream cAMP Response Proteins (CARPs) whose expression levels correlate with sensitivity to PDE inhibitors, suggests a complex signaling cascade. The interplay between the roles of these novel CARPs and the quorum-sensing signaling pathway on cell division and differentiation makes for intriguing cell biology and a new paradigm in cAMP signal transduction, as well as potential targets for trypanosomatid-specific cAMP pathway-based therapeutics

The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa

Transthyretin (TTR) pV142I (rs76992529-A) is one of the 113 variants in the human TTR gene associated with systemic amyloidosis. It results from a G to A transition at a CG dinucleotide in the codon for amino acid 122 of the mature protein (TTR V122I). The allele frequency is 0.0173 in African Americans

Aplastic Crisis as Primary Manifestation of Systemic Lupus Erythematosus

Aplastic crisis is an unusual feature of systemic lupus erythematosus (SLE). We report the case of a 54-year-old woman presenting with both (extravascular) Coombs-positive hemolytic anemia and laboratory findings of bone marrow hyporegeneration with concomitant severe neutropenia. A bone marrow biopsy confirmed aplastic crisis. Diagnostic work-up revealed soaring titers of autoantibodies (anti-nuclear, anti-double-stranded DNA, anti-cardiolipin-IgM, and anti-beta 2-glykoprotein-IgM antibodies), indicating a connective tissue disease as the most plausible reason for bone marrow insufficiency. As the criteria for SLE were fulfilled, we initiated an immunosuppressive therapy by steroids, which led to a rapid complete hematologic and clinical remission in our patient. In this case, we could report on one of the rare cases of SLE-induced aplastic crisis showing that this condition can be entirely reversed by immunosuppressive treatment and that SLE-induced aplastic crisis yields a good prognosis. In conclusion, in a case of aplastic crisis, physicians should be aware that SLE can be a rare cause that is accessible to specific treatment

Mapping the Effects of Anthropogenic Activities in the Catchment of Weija Reservoir using Remote Sensing Techniques

Man has contributed to land cover alteration since time-immemorial through clearing of land for residential, agriculture, recreational and industrial purposes. The emergence of adapting wild plants and animals for human use as well as industrialisation have also contributed to the alteration of land cover. Over the years, anthropogenic activities have had great impact on the Weija catchment. This study seeks to map the catchment and determine the impact of anthropogenic activities using Remote Sensing techniques. Observations and measurements were made on the field as well as classification of land cover using Landsat images of years 1991, 2003 and 2017. Results showed an increase in built-up areas by 18% from 1991 to 2017. Other classes such as shrubs increased due to decrease in dense vegetation. This study confirms the use of Remote Sensing as a valuable tool for detecting change in land cover and determining the impact of anthropogenic activities in the Weija Catchment. Keywords: Land Cover, GIS, Remote Sensing, Weija Catchment, Anthropogenic Activitie

Managing health research capacity strengthening consortia: a systematised review of the published literature

Background Locally relevant research is considered critical for advancing health and development in low- and middle-income countries (LMICs). Accordingly, health research capacity strengthening (HRCS) efforts have intensified, increasingly through consortia. Yet, the knowledge base for managing such consortia is not well defined. This review aimed to ascertain the scope and quality of published literature on HRCS consortium management processes, management-related factors influencing consortium operations and outcomes, and the knowledge gaps. Methods Given the paucity of published HRCS literature, a ‘systematised review’ as outlined by Grant and Booth was conducted, modelling the systematic review process without restriction to research-based publications. A systematic search in PubMed and Scopus was carried out coupled with a manual search for papers using reference checking and citation searching. A quality appraisal of eligible articles using the Mixed Method Appraisal Tool was undertaken. Thematic synthesis was used to analyse the extracted data. Results The search identified 55 papers, made up of 18 empirical papers and 37 commentaries focusing on consortium-based HRCS initiatives involving LMICs and reporting management-related data. The review indicates increasing efforts being made in the HRCS field in reporting consortia outcomes. However, it highlights the dearth of high-quality empirical research on HRCS consortium management and the nascent nature of the field with most papers published after 2010. The available literature highlights the importance of relational management factors such as equity and power relations in influencing consortium success, though these factors were not explored in depth. Operational management processes and their role in the capacity strengthening pathway were rarely examined. Conclusion Findings indicate a weak evidence base for HRCS consortium management both in terms of quantity and conceptual depth, demonstrating the need for an expanded research effort to inform HRCS practice

Pyrimidine biosynthesis is not an essential function for trypanosoma brucei bloodstream forms

<p>Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite.</p> <p>Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 2′deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-5−/− trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line.</p> <p>Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.</p&gt

Case series of six patients diagnosed and managed for idiopathic intracranial hypertension at a tertiary institution eye centre

Background: Idiopathic Intracranial Hypertension (IIH) occurs secondary to raised intracranial pressure (ICP) of unknown etiology and is diagnosed when all other causes of raised ICP have been excluded. It can leave devastating sequelae such as permanent visual loss, hence the need for timely diagnosis and treatment. Anecdotally, one or two cases of idiopathic intracranial hypertension (IIH) previously presented at the Eye Centre, KBTH yearly. However, six cases were seen within a 6-month period, prompting the need to study the clinical features of IIH in this population. Objective: We aim to evaluate the clinical features of patients presenting with IIH at KBTH. Methodology: This is a retrospective case series with contemporaneous collection of data of six patients who presented to the Eye Centre (KBTH) between October 2016 and March 2017 with clinical features suggestive of IIH. The patients were evaluated and diagnosed based on clinical judgement as well as using the modified Dandy criteria. Results: All six patients were female and all except one were obese. The age range was 8 to 40 years with median 22.5 years. Symptoms in the 8-year-old were preceded by oral doxycycline for acne treatment. One patient had a history of using oral contraceptive pills prescribed for irregular menses. Clinical features of blurred vision, headache, and papilloedema were relieved with oral acetazolamide. Conclusion: The upsurge of IIH may be due to the increased incidence of obesity in Ghana. Timely diagnosis and treatment is needed to avoid irreversible blindness. Funding: None Keywords: headaches, idiopathic intracranial hypertension, obesity, blindness, raised intracranial pressure

The restorative role of annexin A1 at the blood–brain barrier

Annexin A1 is a potent anti-inflammatory molecule that has been extensively studied in the peripheral immune system, but has not as yet been exploited as a therapeutic target/agent. In the last decade, we have undertaken the study of this molecule in the central nervous system (CNS), focusing particularly on the primary interface between the peripheral body and CNS: the blood–brain barrier. In this review, we provide an overview of the role of this molecule in the brain, with a particular emphasis on its functions in the endothelium of the blood–brain barrier, and the protective actions the molecule may exert in neuroinflammatory, neurovascular and metabolic disease. We focus on the possible new therapeutic avenues opened up by an increased understanding of the role of annexin A1 in the CNS vasculature, and its potential for repairing blood–brain barrier damage in disease and aging

Predictors of subjective well-being among older Ghanaians

Background: Later years of life are accompanied by many physical, emotional and environmental changes which may impact on the well-being of the individual. Many factors are known to influence the subjectivewell-being of older adults, but most, if not all of this information was the result of studies in the Western world. This study aimed at obtaining and documenting the predictors of subjective well-being (SWB) among older Ghanaians.Methods: Data for the study was obtained from the WHO SAGE study. The single item measure of life satisfaction was used to determine subjective wellbeing. Descriptive statistics as well as logistic regression analysis were carried out to determine the predictors of SWB.Results: A total of 4724 individuals aged 50 years and above responded to the questionnaires. Of these 50.4% were males. Following multivariate logistic regression analysis, age, sex, educational level, income and ethnicbackground were found to significantly affect the SWB of older Ghanaians. Being male was associated with higher level of SWB (OR=1.68; CI: 1.39 – 2.03). For those 50 years and above, being younger (50-59 years) was also associated with a high level of SWB (OR=17.72; CI: 10.13-30.98). Earning a low income and having low educational level were both associatedwith low levels of SWB (OR=0.304; CI: 0.22-0.42; and OR=0.47; CI: 0.37-0.60 respectively). Ewes (p=0.027), Grumas (p=0.002) and  Mole-Dagbons (p=0.04) had significantly higher SWB compared to the other ethnic groups.Conclusion: Among older Ghanaians, factors that positively influence SWB are younger age, male sex, high educational level and high income.Keywords: Subjective well-being, Life satisfaction, Older Ghanaians, SAGE study, Predictor

Anti-proliferative effect of Ficus pumila Linn. on human leukemic cell lines

Background: Cancer is one of the many diseases of global concern due to its high mortality rate with drug resistance becoming a major challenge to chemotherapy and this have propelled many cancer patients to seek alternative and complementary methods of treatment. The objective for this study was, therefore, to determine the antiproliferative activity as well as phytochemical, total phenolic content (TPC), and antioxidant activity of the stem and leaf extracts (FPS and FPL) of Ficus pumila (L.) using standard methods.Methods: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to evaluate anti-proliferative effect and spectrophotometric-based assays for antioxidant and TPC. Phytochemical constituents were accessed by standard methods.Results: The hydroethanolic extracts of the leaves and stems were rich in tannins, general glycosides, saponins, terpenoids, alkaloids, flavonoids (leaves only), and sterols (stem only). Strong total antioxidant activities were observed with FPL and FPS with EC50 values of 0.07 mg/ml and 0.089 mg/ml, respectively. All the crude extracts showed anti-proliferative effect towards the three human leukemic cell lines used (Jurkat, CEM, and HL-60). However, FPL gave the strongest inhibition concentration at 50% values of 130.97 µg/ml (Jurkat) and 56.31 µg/ml (HL-60).Conclusion: These findings suggest that crude extracts of FPS and FPL have anti-proliferative effect on the leukemia cells. The antioxidant properties of the plant including phenolics may be partly responsible for the anti-proliferative activity. Further studies are required to isolate chemical components of the plant and establish their anti-proliferative activities and mechanism of action