An ultraviolet-driven rescue pathway for oxidative stress to eye lens protein human gamma-D crystallin.

Human gamma-D crystallin (HGD) is a major constituent of the eye lens. Aggregation of HGD contributes to cataract formation, the leading cause of blindness worldwide. It is unique in its longevity, maintaining its folded and soluble state for 50-60 years. One outstanding question is the structural basis of this longevity despite oxidative aging and environmental stressors including ultraviolet radiation (UV). Here we present crystallographic structures evidencing a UV-induced crystallin redox switch mechanism. The room-temperature serial synchrotron crystallographic (SSX) structure of freshly prepared crystallin mutant (R36S) shows no post-translational modifications. After aging for nine months in the absence of light, a thiol-adduct (dithiothreitol) modifying surface cysteines is observed by low-dose SSX. This is shown to be UV-labile in an acutely light-exposed structure. This suggests a mechanism by which a major source of crystallin damage, UV, may also act as a rescuing factor in a finely balanced redox system.

Tetralogy of Fallot complicated by multiple cerebral abscesses in a child: a case report.

INTRODUCTION: Brain abscesses are rare but potentially fatal condition and can be associated with cyanotic congenital heart disease of which 5-18.7% of these patients that develop cerebral abscess commonly have tetralogy of Fallot (TOF). CASE PRESENTATION: We report a case of 3-year-old Muganda male that presented with convulsions, cyanosis and difficulty in breathing. The patient had a combination intervention of medical treatment and surgical drainage of the abscess. Post-operative Computerized tomography scan images and pre-operative brain Computerized tomography scans were compared. The multiple rings enhancing lesions were reduced in number and sizes. The largest measured ring was 44 × 22.5×16mm compared to the previous; 42 × 41×36mm. The mass effect had reduced from 16 mm to 7.5 mm. The periventricular hypodensities persisted. Findings showed radiological improvement with residual abscesses, subacute subdural hematoma and pneumocranium. The patient was treated with intravenous ceftriaxone 1 g OD for six weeks and he showed marked improvement and was discharged home after 3 months. CONCLUSION: A comprehensive strategy involving medications, surgical drainage, and early neurosurgical consultation is vital in treating brain abscesses in uncorrected TOF. Early identification of the pathogen, appropriate antibiotic therapy, and vigilant follow-up through clinical assessments and imaging are crucial, potentially spanning a 4-8-week treatment.

Review of Herbal Medicinal Plants Used in the Management of Cancers in the East Africa Region from 2019 to 2023.

BACKGROUND: In the East African region, herbal plants are essential in the treatment and control of cancer. Given the diverse ecological and cultural makeup of the regional states, it is likely that different ethnic groups will use the same or different plants for the same or different diseases. However, since 2019, this has not been compiled into a single study. PURPOSE: The study aimed to compile and record the medicinal plants utilized in East Africa from April 2019 to June 2023 to treat various cancer types. MATERIALS AND METHODS: The study examined 13 original studies that included ethnobotanical research conducted in East Africa. They were retrieved from several internet databases, including Google Scholar, Scopus, PubMed/Medline, Science Direct, and Research for Life. The study retrieved databases on plant families and species, plant parts used, preparation methods and routes of administration, and the country where the ethnobotanical field surveys were conducted. Graphs were produced using the GraphPad Prism 8.125 program (GraphPad Software, Inc., San Diego, CA). Tables and figures were used to present the data, which had been condensed into percentages and frequencies. RESULTS: A total of 105 different plant species from 45 different plant families were identified, including Asteraceae (14), Euphorbiaceae (12), Musaceae (8), and Apocynaceae (7). Uganda registered the highest proportion (46% of the medicinal plants used). The most commonly mentioned medicinal plant species in cancer management was Prunus africana. Herbs (32%), trees and shrubs (28%), and leaves (45%) constituted the majority of herbal remedies. Most herbal remedies were prepared by boiling (decoction) and taken orally (57%). CONCLUSION: East Africa is home to a wide variety of medicinal plant species that local populations and herbalists, or TMP, frequently use in the treatment of various types of cancer. The most frequently used families are Asteraceae and Euphorbiaceae, with the majority of species being found in Uganda. The most frequently utilized plant species is Prunus africana. Studies on the effectiveness of Prunus africana against other malignancies besides prostate cancer are required.

Post-traumatic seizures and factors associated among adult patients with depressed skull fractures at Mulago National Referral hospital; cross-sectional study.

INTRODUCTION: Post-traumatic seizures (PTS) are common among patients with depressed skull fractures (DSF). Understanding the burden of post traumatic seizures and the factors associated among adult patients with DSF is important to improve clinical care. OBJECTIVE: To determine the prevalence and factors associated with post-traumatic seizures among adult patients with DSF at Mulago National Referral hospital (MNRH). METHODS: A cross-sectional study was conducted among 333 study participants between March 2021 and February 2022. Socio-demographic, clinical laboratory factors and anti-seizure medications were collected using a study questionnaire. Data was analysed to determine the prevalence of PTS and factors associated with occurrence of PTS among patients with DSF. RESULTS: The mean age (±SD) of study participants was 31.2, (±10.5) years, with a male to female ratio of 10.4:1. Nearly half of the study participants had attained secondary level of education, while 31.6 % (105) were peasants (subsistence farmers). The overall prevalence of PTS among DSF study participants was 16.2 % (54participants). Late presentation of PTS was the highest at 9.0 % (30) followed by early PTS at 3.9 % [13] and immediate PTS at 3.3 % [11]. Moderate Glasgow coma score (GCS: 9-13), p < 0.015, severe traumatic brain injury (GCS: 3-8), p < 0.026 at the time of admission and midline brain shift (≥5mm), p < 0.009 were associated with PTS. Phenytoin (94.3 %) was the most commonly used ASM followed by phenobarbitone (1.4 %) and Valproate (1.1 %) among study participants. CONCLUSION: Patients with moderate and severe traumatic brain injury and midline brain shift were associated with post traumatic seizures. Early identification and intervention may reduce the burden of posttraumatic seizures in this category of patients.

Common and distinct metabolomic markers related to immune aging in Western European and East African populations.

In old age, impaired immunity causes high susceptibility to infections and cancer, higher morbidity and mortality, and poorer vaccination efficiency. Many factors, such as genetics, diet, and lifestyle, impact aging. This study aimed to investigate how immune responses change with age in healthy Dutch and Tanzanian individuals and identify common metabolites associated with an aged immune profile. We performed untargeted metabolomics from plasma to identify age-associated metabolites, and we correlated their concentrations with ex-vivo cytokine production by immune cells, DNA methylation-based epigenetic aging, and telomere length. Innate immune responses were impacted differently by age in Dutch and Tanzanian cohorts. Age-related decline in steroid hormone precursors common in both populations was associated with higher systemic inflammation and lower cytokine responses. Hippurate and 2-phenylacetamide, commonly more abundant in older individuals, were negatively correlated with cytokine responses and telomere length and positively correlated with epigenetic aging. Lastly, we identified several metabolites that might contribute to the stronger decline in innate immunity with age in Tanzanians. The shared metabolomic signatures of the two cohorts suggest common mechanisms of immune aging, revealing metabolites with potential contributions. These findings also reflect genetic or environmental effects on circulating metabolites that modulate immune responses.

Host genetic regulation of human gut microbial structural variation.

Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established1-6, little is known about how host genetics regulates the genetic diversity of gut microorganisms. Here we conducted a meta-analysis of associations between human genetic variation and gut microbial structural variation in 9,015 individuals from four Dutch cohorts. Strikingly, the presence rate of a structural variation segment in Faecalibacterium prausnitzii that harbours an N-acetylgalactosamine (GalNAc) utilization gene cluster is higher in individuals who secrete the type A oligosaccharide antigen terminating in GalNAc, a feature that is jointly determined by human ABO and FUT2 genotypes, and we could replicate this association in a Tanzanian cohort. In vitro experiments demonstrated that GalNAc can be used as the sole carbohydrate source for F. prausnitzii strains that carry the GalNAc-metabolizing pathway. Further in silico and in vitro studies demonstrated that other ABO-associated species can also utilize GalNAc, particularly Collinsella aerofaciens. The GalNAc utilization genes are also associated with the host's cardiometabolic health, particularly in individuals with mucosal A-antigen. Together, the findings of our study demonstrate that genetic associations across the human genome and bacterial metagenome can provide functional insights into the reciprocal host-microbiome relationship.

Rapid Onsite Evaluation for Specimen Adequacy and Triage of Breast Masses in a Low-Resource Setting.

CONTEXT.­: Rapid onsite evaluation (ROSE) is critical in determining sample adequacy and triaging cytology samples. Although fine-needle aspiration biopsy (FNAB) is the primary method of initial tissue sampling in Tanzania, ROSE is not practiced. OBJECTIVE.­: To investigate the performance of ROSE in determining cellular adequacy and providing preliminary diagnoses in breast FNAB in a low-resource setting. DESIGN.­: Patients with breast masses were recruited prospectively from the FNAB clinic at Muhimbili National Hospital. Each FNAB was evaluated by ROSE for overall specimen adequacy, cellularity, and preliminary diagnosis. The preliminary interpretation was compared to the final cytologic diagnosis and histologic diagnosis, when available. RESULTS.­: Fifty FNAB cases were evaluated, and all were adequate for diagnosis on ROSE and final interpretation. Overall percentage of agreement (OPA) between preliminary and final cytologic diagnosis was 84%, positive percentage of agreement (PPA) was 33%, and negative percentage of agreement (NPA) was 100% (κ = 0.4, P < .001). Twenty-one cases had correlating surgical resections. OPA between preliminary cytologic and histologic diagnoses was 67%, PPA was 22%, and NPA was 100% (κ = 0.2, P = .09). OPA between final cytologic and histologic diagnoses was 95%, PPA was 89%, and NPA was 100% (κ = 0.9, P = <.001). CONCLUSIONS.­: False-positive rates of ROSE diagnoses for breast FNAB are low. While preliminary cytologic diagnoses had a high false-negative rate, final cytologic diagnoses had overall high concordance with histologic diagnoses. Therefore, the role of ROSE for preliminary diagnosis should be considered carefully in low-resource settings, and it may need to be paired with additional interventions to improve pathologic diagnosis.

Genetic and nongenetic drivers of platelet reactivity in healthy Tanzanian individuals.

BACKGROUND: Platelets play a key role in hemostasis, inflammation, and cardiovascular diseases. Platelet reactivity is highly variable between individuals. The drivers of this variability in populations from Sub-Saharan Africa remain largely unknown. OBJECTIVES: We aimed to investigate the nongenetic and genetic determinants of platelet reactivity in healthy adults living in a rapidly urbanizing area in Northern Tanzania. METHODS: Platelet activation and reactivity were measured by platelet P-selectin expression and the binding of fibrinogen in unstimulated blood and after ex vivo stimulation with adenosine diphosphate and PAR-1 and PAR-4 ligands. We then analyzed the associations of platelet parameters with host genetic and nongenetic factors, environmental factors, plasma inflammatory markers, and plasma metabolites. RESULTS: Only a few associations were found between platelet reactivity parameters and plasma inflammatory markers and nongenetic host and environmental factors. In contrast, untargeted plasma metabolomics revealed a large number of associations with food-derived metabolites, including phytochemicals that were previously reported to inhibit platelet reactivity. Genome-wide single-nucleotide polymorphism genotyping identified 2 novel single-nucleotide polymorphisms (rs903650 and rs4789332) that were associated with platelet reactivity at the genome-wide level (P < 5 × 10-8) as well as a number of variants in the PAR4 gene (F2RL3) that were associated with PAR4-induced reactivity. CONCLUSION: Our study uncovered factors that determine variation in platelet reactivity in a population in East Africa that is rapidly transitioning to an urban lifestyle, including the importance of genetic ancestry and the gradual abandoning of the traditional East African diet.

Medicinal plants used in the management of cancers by residents in the Elgon Sub-Region, Uganda.

BACKGROUND: In Uganda, medicinal plants have been utilized to treat a variety of ailments, including cancer. However, there is little information available about the medicinal plants used to treat cancer in the Elgon subregion. As a result, the current study documented the plant species used in the management of cancer in the Elgon sub-region. METHODS: Data were gathered by observation, self-administered questionnaires, interview guides, and guided field trips. Analyzing descriptive statistics and creating graphs were done using SPSS (version 21.0) and GraphPad Prism® version 9.0.0, respectively. Well-established formulae were used to calculate quantitative indices. The narratives were interpreted using major theories and hypotheses in ethnobotany. RESULTS: A total of 50 plant species from 36 families were documented, and herbal knowledge was mainly acquired through inheritance. Fabaceae and Asteraceae comprised more plant species used in herbal preparation. Most plants were collected from forest reserves (63%); herbal therapies were made from herbs (45%); and leaves were primarily decocted (43%). The most frequently used plants were Tylosema fassoglensis, Hydnora abyssinica, Azidarachata indica, Prunus Africana, Kigelia africana, Syzygium cumini, Hydnora africana, Rhoicissus tridentata, Albizia coriaria, and Plectranthus cuanneus. All the most commonly used plants exhibited a high preference ranking (60-86%) and reliability level (74.1-93.9%). Generally, the ICF for all the cancers treated by medicinal plants was close to 1 (0.84-0.95). CONCLUSIONS: The ten most commonly utilized plants were favored, dependable, and most important for treating all known cancers. As a result, more investigation is required to determine their phytochemistry, toxicity, and effectiveness in both in vivo and in vitro studies. This could be a cornerstone for the pharmaceutical sector to develop new anticancer medications.

Burden, risk factors, neurosurgical evacuation outcomes, and predictors of mortality among traumatic brain injury patients with expansive intracranial hematomas in Uganda: a mixed methods study design.

BACKGROUND: Expansive intracranial hematomas (EIH) following traumatic brain injury (TBI) continue to be a public health problem in Uganda. Data is limited regarding the neurosurgical outcomes of TBI patients. This study investigated the neurosurgical outcomes and associated risk factors of EIH among TBI patients at Mulago National Referral Hospital (MNRH). METHODS: A total of 324 subjects were enrolled using a prospective cohort study. Socio-demographic, risk factors and complications were collected using a study questionnaire. Study participants were followed up for 180 days. Univariate, multivariable, Cox regression analyses, Kaplan Meir survival curves, and log rank tests were sequentially conducted. P-values of < 0.05 at 95% Confidence interval (CI) were considered to be statistically significant. RESULTS: Of the 324 patients with intracranial hematomas, 80.6% were male. The mean age of the study participants was 37.5 ± 17.4 years. Prevalence of EIH was 59.3% (0.59 (95% CI: 0.54 to 0.65)). Participants who were aged 39 years and above; PR = 1.54 (95% CI: 1.20 to 1.97; P = 0.001), and those who smoke PR = 1.21 (95% CI: 1.00 to 1.47; P = 0.048), and presence of swirl sign PR = 2.26 (95% CI: 1.29 to 3.95; P = 0.004) were found to be at higher risk for EIH. Kaplan Meier survival curve indicated that mortality at the 16-month follow-up was 53.4% (95% CI: 28.1 to 85.0). Multivariate Cox regression indicated that the predictors of mortality were old age, MAP above 95 mmHg, low GCS, complications such as infection, spasticity, wound dehiscence, CSF leaks, having GOS < 3, QoLIBRI < 50, SDH, contusion, and EIH. CONCLUSION: EIH is common in Uganda following RTA with an occurrence of 59.3% and a 16-month higher mortality rate. An increased age above 39 years, smoking, having severe systemic disease, and the presence of swirl sign are independent risk factors. Old age, MAP above 95 mmHg, low GCS, complications such as infection, spasticity, wound dehiscence, CSF leaks, having a GOS < 3, QoLIBRI < 50, ASDH, and contusion are predictors of mortality. These findings imply that all patients with intracranial hematomas (IH) need to be monitored closely and a repeat CT scan to be done within a specific period following their initial CT scan. We recommend the development of a protocol for specific surgical and medical interventions that can be implemented for patients at moderate and severe risk for EIH.

Differences in the inflammatory proteome of East African and Western European adults and associations with environmental and dietary factors.

Non-communicable diseases (NCDs) are rising rapidly in urbanizing populations in sub-Saharan Africa. Assessment of inflammatory and metabolic characteristics of a urbanizing African population and the comparison with populations outside Africa could provide insight in the pathophysiology of the rapidly increasing epidemic of NCDs, including the role of environmental and dietary changes. Using a proteomic plasma profiling approach comprising 92 inflammation-related molecules, we examined differences in the inflammatory proteome in healthy Tanzanian and healthy Dutch adults. We show that healthy Tanzanians display a pro-inflammatory phenotype compared to Dutch subjects, with enhanced activity of the Wnt/ß-catenin signalling pathway and higher concentrations of different metabolic regulators such as 4E-BP1 and fibroblast growth factor 21. Among the Tanzanian volunteers, food-derived metabolites were identified as an important driver of variation in inflammation-related molecules, emphasizing the potential importance of lifestyle changes. These findings endorse the importance of the current dietary transition and the inclusion of underrepresented populations in systems immunology studies.

Effects of agricultural pesticides on the susceptibility and fitness of malaria vectors in rural south-eastern Tanzania.

BACKGROUND: Agricultural pesticides may exert strong selection pressures on malaria vectors during the aquatic life stages and may contribute to resistance in adult mosquitoes. This could reduce the performance of key vector control interventions such as indoor-residual spraying and insecticide-treated nets. The aim of this study was to investigate effects of agrochemicals on susceptibility and fitness of the malaria vectors across farming areas in Tanzania. METHODS: An exploratory mixed-methods study was conducted to assess pesticide use in four villages (V1-V4) in south-eastern Tanzania. Anopheles gambiae (s.l.) larvae were collected from agricultural fields in the same villages and their emergent adults examined for insecticide susceptibility, egg-laying and wing lengths (as proxy for body size). These tests were repeated using two groups of laboratory-reared An. arabiensis, one of which was pre-exposed for 48 h to sub-lethal aquatic doses of agricultural pesticides found in the villages. RESULTS: Farmers lacked awareness about the linkages between the public health and agriculture sectors but were interested in being more informed. Agrochemical usage was reported as extensive in V1, V2 and V3 but minimal in V4. Similarly, mosquitoes from V1 to V3 but not V4 were resistant to pyrethroids and either pirimiphos-methyl or bendiocarb, or both. Adding the synergist piperonyl butoxide restored potency of the pyrethroids. Pre-exposure of laboratory-reared mosquitoes to pesticides during aquatic stages did not affect insecticide susceptibility in emergent adults of the same filial generation. There was also no effect on fecundity, except after pre-exposure to organophosphates, which were associated with fewer eggs and smaller mosquitoes. Wild mosquitoes were smaller than laboratory-reared ones, but fecundity was similar. CONCLUSIONS: Safeguarding the potential of insecticide-based interventions requires improved understanding of how agricultural pesticides influence important life cycle processes and transmission potential of mosquito vectors. In this study, susceptibility of mosquitoes to public health insecticides was lower in villages reporting frequent use of pesticides compared to villages with little or no pesticide use. Variations in the fitness parameters, fecundity and wing length marginally reflected the differences in exposure to agrochemicals and should be investigated further. Pesticide use may exert additional life cycle constraints on mosquito vectors, but this likely occurs after multi-generational exposures.

Pig and Mouse Models of Hyperlipidemia and Atherosclerosis.

Atherosclerosis is a chronic inflammatory disorder that is the underlying cause of most cardiovascular disease. Resident cells of the artery wall and cells of the immune system participate in atherogenesis. This process is influenced by plasma lipoproteins, genetics, and the hemodynamics of the blood flow in the artery. A variety of animal models have been used to study the pathophysiology and mechanisms that contribute to atherosclerotic lesion formation. No model is ideal as each has its own advantages and limitations with respect to manipulation of the atherogenic process and modeling human atherosclerosis and lipoprotein profile. In this chapter we will discuss pig and mouse models of experimental atherosclerosis. The similarity of pig lipoprotein metabolism and the pathophysiology of the lesions in these animals with that of humans is a major advantage. While a few genetically engineered pig models have been generated, the ease of genetic manipulation in mice and the relatively short time frame for the development of atherosclerosis has made them the most extensively used model. Newer approaches to induce hypercholesterolemia in mice have been developed that do not require germline modifications. These approaches will facilitate studies on atherogenic mechanisms.

Differences in thrombin and plasmin generation potential between East African and Western European adults: The role of genetic and non-genetic factors.

BACKGROUND: Geographic variability in coagulation across populations and their determinants are poorly understood. OBJECTIVE: To compare thrombin (TG) and plasmin (PG) generation parameters between healthy Tanzanian and Dutch individuals, and to study associations with inflammation and different genetic, host and environmental factors. METHODS: TG and PG parameters were measured in 313 Tanzanians of African descent living in Tanzania and 392 Dutch of European descent living in the Netherlands and related to results of a dietary questionnaire, circulating inflammatory markers, genotyping, and plasma metabolomics. RESULTS: Tanzanians exhibited an enhanced TG and PG capacity, compared to Dutch participants. A higher proportion of Tanzanians had a TG value in the upper quartile with a PG value in the lower/middle quartile, suggesting a relative pro-coagulant state. Tanzanians also displayed an increased normalized thrombomodulin sensitivity ratio, suggesting reduced sensitivity to protein C. In Tanzanians, PG parameters (lag time and TTP) were associated with seasonality and food-derived plasma metabolites. The Tanzanians had higher concentrations of pro-inflammatory cytokines, which correlated strongly with TG and PG parameters. There was limited overlap in genetic variation associated with TG and PG parameters between the two cohorts. Pathway analysis of genetic variants in the Tanzanian cohort revealed multiple immune pathways that were enriched with TG and PG traits, confirming the importance of co-regulation between coagulation and inflammation. CONCLUSIONS: Tanzanians have an enhanced TG and PG potential compared to Dutch individuals, which may relate to differences in inflammation, genetics and diet. These observations highlight the importance of better understanding of the geographic variability in coagulation across populations.

A functional genomics approach in Tanzanian population identifies distinct genetic regulators of cytokine production compared to European population.

Humans exhibit remarkable interindividual and interpopulation immune response variability upon microbial challenges. Cytokines play a vital role in regulating inflammation and immune responses, but dysregulation of cytokine responses has been implicated in different disease states. Host genetic factors were previously shown to significantly impact cytokine response heterogeneity mainly in European-based studies, but it is unclear whether these findings are transferable to non-European individuals. Here, we aimed to identify genetic variants modulating cytokine responses in healthy adults of East African ancestry from Tanzania. We leveraged both cytokine and genetic data and performed genome-wide cytokine quantitative trait loci (cQTLs) mapping. The results were compared with another cohort of healthy adults of Western European ancestry via direct overlap and functional enrichment analyses. We also performed meta-analyses to identify cQTLs with congruent effect direction in both populations. In the Tanzanians, cQTL mapping identified 80 independent suggestive loci and one genome-wide significant locus (TBC1D22A) at chromosome 22; SNP rs12169244 was associated with IL-1b release after Salmonella enteritidis stimulation. Remarkably, the identified cQTLs varied significantly when compared to the European cohort, and there was a very limited percentage of overlap (1.6% to 1.9%). We further observed ancestry-specific pathways regulating induced cytokine responses, and there was significant enrichment of the interferon pathway specifically in the Tanzanians. Furthermore, contrary to the Europeans, genetic variants in the TLR10-TLR1-TLR6 locus showed no effect on cytokine response. Our data reveal both ancestry-specific effects of genetic variants and pathways on cytokine response heterogeneity, hence arguing for the importance of initiatives to include diverse populations into genomics research.

Gut microbiome-mediated metabolism effects on immunity in rural and urban African populations.

The human gut microbiota is increasingly recognized as an important factor in modulating innate and adaptive immunity through release of ligands and metabolites that translocate into circulation. Urbanizing African populations harbor large intestinal diversity due to a range of lifestyles, providing the necessary variation to gauge immunomodulatory factors. Here, we uncover a gradient of intestinal microbial compositions from rural through urban Tanzanian, towards European samples, manifested both in relative abundance and genomic variation observed in stool metagenomics. The rural population shows increased Bacteroidetes, led by Prevotella copri, but also presence of fungi. Measured ex vivo cytokine responses were significantly associated with 34 immunomodulatory microbes, which have a larger impact on circulating metabolites than non-significant microbes. Pathway effects on cytokines, notably TNF-α and IFN-γ, differential metabolome analysis and enzyme copy number enrichment converge on histidine and arginine metabolism as potential immunomodulatory pathways mediated by Bifidobacterium longum and Akkermansia muciniphila.