Search

OMGKRP is one of various Karuho poison mysteriously used by unscrupulous individuals to kill people during conflict and animals in Goma City, in DRC. The symptoms and signs of most cases are usually confused with many chronic diseases like tuberculosis and HIV/AIDS; with renal, hepatic and cardiac manifestations as well as blood chemistry changes. The study investigated the toxic effect of OMGKRP poison on blood chemistry, serum enzymes and organ toxicity including the kidney, lung, liver and heart of Wistar albino rats. A laboratory-based experimental study was conducted. Fifty animals in 5 groups each with 10 animals were dosed daily for 28 days with 1.0 mg, 5.0 mg, 20.0 mg and 5000.0 mg/Kg body weight of OMGKRP and normal saline as control group. International standard guidelines, OECD 407 and NIH 2011 were followed during the study period. The blood chemistry analysis, relative organ weight and histopathological changes in the kidney, lung, liver and heart were performed. The findings showed that OMGKRP was associated with increased blood chemistry parameters including total proteins, creatinine, urea, K+ levels, direct albumin levels, a decrease in Cl− levels and albumin levels. Histopathological findings showed an increased relative weight and tissue damages of the lung, kidney, liver and heart. Therefore, OMGKRP Karuho poison caused toxicity on blood chemistry, serum enzymes as well as histopathological changes in the lung, renal, hepatic and cardiac tissue damages in Wistar albino rats.

Background: Pain is a common problem encountered in daily life among humans and animal and it is commonly managed conventionally using modern medicines and traditionally by use of medicinal plants. Phytolacca dodecandra is a common herb in Uganda, used traditionally to alleviate pain and inflammatory conditions. However, its activity in alleviating pain and inflammatory diseases has not been fully scientifically evaluated. Aim of Study: To evaluate the analgesic and anti-inflammatory activity of total crude leaf extracts of P. dodecandra in Wistar albino rats. Materials and Methods: It was a laboratory-based experimental study. Acetic acid-induced writhing test was used to determine the analgesic activity and the histamine-induced paw edema formation for anti-inflammatory activity of the extract. Twenty eight animals were divided into 7 groups each with 4 rats and two (2) sets of data were obtained from each animal per group as per guidance of the refinement rule of 3Rs. For analgesic activity, Group I was dosed with 1.0ml of normal saline (negative control), group II, III, IV, V, VI were dosed with 1000.0, 600.0, 150.0, 40.0 and 5.0 mg/kg bwt of extract respectively. Group VII was dosed 10.0 mg/kg bwt diclofenac sodium (Na) drug (positive control). For anti-inflammatory activity, Group I was dosed with 1.0ml of normal saline (negative control), Group II, III, IV, V, VI were dosed with 1000.0, 600.0, 300.0, 40.0 and 5.0 mg/kg bwt of extract respectively. Group VII was dosed 10.0 mg/kg bwt diclofenac Na. The percentage mean paw volume inhibition and percentage writhing protection were determined. Results: The mean percentage paw volume inhibitions were 29.1%, 74.2% and 32.3% at doses of 5.0, 40.0 mg/kg bwt and 10.0 mg/kg bwt diclofenac Na respectively. The mean percentage writhing protection was 8.9%, 10.4%, 78.5% and 98.7% at doses of 150.0, 600.0, 1000.0 mg/kg of extract and 10.0 mg/kg bwt diclofenac Na respectively. Conclusions: Total crude leaf extracts of P. dodecandra has analgesic and anti-inflammatory activity that may be attributed to the presence of polyphenolic, saponins and many others phytochemicals that are present in the plant.

Background: M. oleifera is a highly valued medicinal plant used widely from time immemorial to treat various ailments. However, with continued un-standardized use of the plant leaves, studies have reported organ toxicity to the liver, kidney and the heart. As communities continue to use M. oleifera leaves for its medicinal and nutritional values, there is need to find an antidote for its hepatotoxicity. Aim: The study established the reversal effect of N-Acetyl Cysteine (NAC) on M. oleifera aqueous leaf extract-induced hepatotoxicity in Wistar albino rats. Methods: Twenty-four (24) rats received a toxic dose (8.05 g/kg bwt) of M. oleifera leaf extract for 28 days to cause sub-acute hepatotoxicity. They were divided into 4 groups of 6 rats each. Group I received 1 ml normal (control group), Group II received 1000 ng/kg NAC, Group III received 1200 mg/kg NAC and Group IV received 1500 mg/kg NAC. Another group of 6 rats (Group V) received 0.75 mg/kg Paracetamol to cause hepatotoxicity. Group V (a positive control) received the prescribed clinical dose of 1200 mg/kg NAC which reverses the hepatotoxicity. All the NAC doses were given once a day intragastric for 7 days. On days: 1, 3 and 7 of receiving NAC, liver serum enzymes and bilirubin were measured. On day 7 the animals were sacrificed and liver tissue harvested for histopathology analysis. Results: A dose of 8.05 g/kg of M. oleifera leaf extract and 0.75 mg/kg Paracetamol were able to induce hepatotoxicity in Wister albino rats in 28 days. The M. oleifera extract induced hepatotoxic rats treated with NAC at doses of 1000 mg/kg, 1200 mg/kg and 1500 mg/kg, had a reduction in mean serum liver enzymes, plus reduced mean serum bilirubin levels. The liver histopathological analysis showed reduced inflammation after treatment with NAC for 3 and 7 days in the M. oleifera and paracetamol induced hepatotoxic rats. Conclusion: NAC can reverse M. oleifera leaf aqueous extract-induced sub-acute hepatotoxicity in Wistar Albino rats.

Introduction: In 2018, there were appropriately 20.6 million [18.2 million–23.2 million] people living with HIV in Eastern and Southern Africa, and an estimated 67% of them were on antiretroviral therapy (ART). A major challenge in the scale-up of ART services in Sub-Saharan Africa is the severe shortage of clinical staff. Methods: We conducted a randomised trial in Tanzania and Zambia to test an innovative intervention that involved the use of lay health workers and screening for cryptococcal meningitis and tuberculosis. Here we describe the model of care with a particular focus on the trained lay worker component. Lay workers carried out home visits to patients in the intervention arm to deliver antiretroviral drugs, provide adherence counselling, and conduct simple monitoring for treatment side effects and other medical conditions. Lay workers were responsible for referring patients with conditions that might require further medical attention as well as discouraging self-referral. A total of 1999 participants were enrolled in the trial. Lay workers were recruited through public advertisements. Results: Six lay workers were recruited in each country and trained for two weeks. Each lay worker was paid a monthly salary of US$ 487.61 in Zambia and US$ 524.61in Tanzania. They were also paid communication and transport expenses for home visits. The median number of visits per patient was 3 for Tanzania and 4 for Zambia. On average a lay worker was responsible for 72.3 patients in Tanzania and 94.5 in Zambia for 1 year. Referrals were made in 9% of the home visits and self-referral was discouraged in 64% of visits. Conclusion: The use of paid lay workers to provide HIV/AIDS services in urban settings where there is a shortage of clinical staff may help to identify ART related side effects/adverse reactions and prevent unnecessary referrals.

The HDL (high-density lipoprotein) Workshop was established in 2009 as a forum for candid discussions among academic basic scientists, clinical investigators, and industry researchers about the role of HDL in cardiovascular disease. This ninth HDL Workshop was held on May 16 to 17, 2019 in Boston, MA, and included outstanding oral presentations from established and emerging investigators. The Workshop featured 5 sessions with topics that tackled the role of HDL in the vasculature, its structural complexity, its role in health and disease states, and its interaction with the intestinal microbiome. The highlight of the program was awarding the Jack Oram Award to the distinguished professor emeritus G.S. Getz from the University of Chicago. The tenth HDL Workshop will be held on May 2020 in Chicago and will continue the focus on intellectually stimulating presentations by established and emerging investigators on novel roles of HDL in cardiovascular and noncardiovascular health and disease states.

Atherosclerosis is the underlying basis for most cardiovascular diseases. It is a chronic inflammation affecting the arterial intima and is promoted by hypercholesterolemia. Cells of both the innate and adaptive immune systems contribute to this inflammation with macrophages and T cells being the most abundant immune cells in the atherosclerotic plaques. In this review, we discuss the studies that examined the role of T cells and T cell subsets in Apoe−/− and Ldlr−/− murine models of atherosclerosis. While there is a general consensus that Th1 cells are pro-atherogenic and regulatory T cells are atheroprotective, the role of other subsets is more ambiguous. In addition, the results in the two models of atherosclerosis do not always yield similar results. Additional studies in the two murine models using cell specific gene manipulations are needed.

Various forms of Karuho poisoning are a common traditional mystery and a public health challenge in Goma city, North Kivu in DRC practiced by unscrupulous people. Its signs and symptoms are commonly mistaken by local communities and medical world with those of tuberculosis, HIV/AIDS and typhoid fever; with neurological and psychological symptoms. Study investigated sub-acute toxicity of Karuho poison on brain of Wistar albino rats. Laboratory based experimental study was conducted at Department of Pharmacology & Therapeutics, Makerere University College of Health Sciences. A total of 4 Karuho poisons (OMGKRP, DLNKRP, CHKRP and BHKRP) were screened for acute and sub-acute toxicity. Fifty animals, 10 in each group were daily dosed for 28 days with 1 mg, 5 mg, 20 mg and 5000 mg/kg bwt of OMGKRP (most active following screening) and normal saline for control group using OECD 407 and NIH 2011 guidelines. Behavioral changes were noted. Histopathological changes in brain regions were analyzed. Treated rats by OMGKRP, most active Karuho poison, were associated with sign of depression, piloerection and shortness of breath. Histopathological changes revealed moderate diffuse congestion and mononuclear inflammatory cells infiltration (plasma cells, lymphocytes and macrophage) in cerebral region with severe inflammation observed in meninges of cerebellum. OMGKRP poison induced inflammation of meninges of cerebellar region of brain.

Objective- To investigate the effect of gut microbiota and diet on atherogenesis. Approach and Results- Here, we investigated the interaction between the gut microbiota and diet on atherosclerosis by feeding germ-free or conventionally raised Apoe

Atherosclerosis is a chronic inflammation associated with increased expression of the acute phase isoforms of serum amyloid A (SAA) and in humans is a plasma biomarker for future cardiovascular events. However, whether SAA is only a biomarker or participates in the development of cardiovascular disease is not well characterized. The purpose of this review is to summarize putative functions of SAA relevant to atherogenesis and in-vivo murine studies that directly examine the effect of SAA on atherosclerosis.Modulation of the expression of SAA1 and/or SAA2 in murine models of atherosclerosis suggests that SAA promotes early atherogenesis. SAA secreted from bone-marrow-derived cells contributes to this antiatherogenic phenotype. SAA also promotes angiotensin-induced abdominal aneurysm in atherogenic mouse models. The reduction in atherosclerosis may be due, at least in part, to remodeling of the acute phase HDL to reduce its capacity to promote cholesterol efflux and reduce its anti-inflammatory ability.SAA is more than a marker of cardiovascular disease and is a participant in the early atherogenic process.

Natural killer T (NKT) cells are a distinct subset of lymphocytes that bridge the innate and adaptive immune response and can be divided into type I invariant NKT cells (iNKT) and type II NKT cells. The objective of this study is to examine the effects of NKT cell on lipid metabolism and the initiation and progression of atherosclerosis in LDL receptor deficient (LDLR&minus, /&minus, ) mice. Mice were fed an atherogenic diet for 4 or 8 weeks and plasma lipids, lipoproteins, and atherosclerosis were measured. The selective absence of iNKT cells in J&alpha, 18&minus, LDLR&minus, mice led to an increase in plasma cholesterol levels in female mice. Transgenic V&alpha, 14tg/LDLR&minus, mice with elevated numbers of iNKT cells had increased late atherosclerosis of the innominate artery, though absence of either iNKT cells or all NKT cells and other CD1d expressing cells had varying effects on atherosclerotic lesion burden in the ascending aortic arch and aortic root. These studies not only highlight the potential modulatory role played by NKT cells in atherosclerosis and lipid metabolism, but also raise the possibility that divergent roles may be played by iNKT and CD1d restricted cells such as type II NKT cells or other CD1d expressing cells.

Addiction to substances of abuse (drugs) and behaviours is a common problem in various communities in Africa. These substances and behaviours influence neurobiological processes in the brain and mainly affect the mesolimbic dopaminergic pathway (reward pathway) that connects two important nuclei, the ventral tegmental area (VTA) and nucleus accumbens (NAc), in the brain, which are responsible for the individual happiness and pleasures. They also affect a multitude of neurons and the neurochemicals they release in the brain, their precursor molecules, synthesis, storage in the vesicles, release, transporters and their metabolizing systems at the synapses, receptors, transcription factors and their effects on the signal transduction pathways. However, race and ethnicity as well as tribal differences among whites, Blacks, Asians, Japanese and Chinese have been reported to play a role in individual responses to alcohol and other substances/drugs of abuse, and behavioural addictions and their effects on the brain. And the differences are mainly due to the pharmacokinetics (PK), pharmacodynamics (PD) and pharmacogenetics (PG), and transporters of the substances/drugs in the body. The chapter aims to ascertain the neurobiology of addiction in African population. It further seeks to interrogate African literature and compare and contrast the neurobiology of substance of abuse (drugs) and behavioural addiction globally.

Apoprotein E (apoE) is a multifunctional protein. Its best-characterized function is as a ligand for low-density lipoprotein (LDL) receptor family members to mediate the clearance of apoB-containing atherogenic lipoproteins. Among its other functions, apoE is involved in cholesterol efflux, especially from cholesterol-loaded macrophage foam cells and other atherosclerosis-relevant cells, and in reverse cholesterol transport. Reverse cholesterol transport is a mechanism by which excess cellular cholesterol is transported via lipoproteins in the plasma to the liver where it can be excreted from the body in the feces. This process is thought to have a role in the attenuation of atherosclerosis. This review summarizes studies on the role of apoE in cellular cholesterol efflux and reverse cholesterol transport and discusses the identification of apoE mimetic peptides that may promote these pathways.

Murine models of atherosclerosis are useful for investigating the environmental and genetic influences on lesion formation and composition. Apoe −/− and Ldlr −/− mice are the 2 most extensively used models. The models differ in important ways with respect to the precise mechanism by which their absence enhances atherosclerosis, including differences in plasma lipoproteins. The majority of the gene function studies have utilized only 1 model, with the results being generalized to atherogenic mechanisms. In only a relatively few cases have studies been conducted in both atherogenic murine models. This review will discuss important differences between the 2 atherogenic models and will point out studies that have been performed in the 2 models where results are comparable and those where different results were obtained.

Anti-HMGB1 autoimmunity plays a role in systemic lupus erythematosus (SLE). Because SLE increases atherosclerosis, we asked whether the same autoimmunity might play a role in atherogenesis.We looked for the induction of HMGB1-specific B and T cell responses by a western-type diet (WTD) in the Apoe(-/-) mouse model of atherosclerosis. We also determined whether modifying the responses modulates atherosclerosis.In the plasma of male Apoe(-/-) mice fed WTD, the level of anti-HMGB1 antibodies (Abs) was detected at ∼50 μg/ml, which was ∼6 times higher than that in either Apoe(-/-) mice fed a normal chow or Apoe(+/+) mice fed WTD (p ≤ 0.0005). The Abs were directed largely toward a novel, dominant epitope of HMGB1 named HMW4; accordingly, compared with chow-fed mice, WTD-fed Apoe(-/-) mice had more activated HMW4-reactive B and T cells (p = 0.005 and p = 0.01, respectively). Compared with mock-immunized mice, Apoe(-/-) mice immunized with HMW4 along with an immunogenic adjuvant showed proportional increases in anti-HMW4 IgG and IgM Abs, HMW4-reactive B-1 and B-2 cells, and HMW4-reactive Treg and Teff cells, which was associated with ∼30% increase in aortic arch lesions (p ≤ 0.01) by two methods. In contrast, Apoe(-/-) mice immunized with HMW4 using a tolerogenic adjuvant showed preferential increases in anti-HMW4 IgM (over IgG) Abs, HMW4-reactive B-1 (over B-2) cells, and HMW4-specific Treg (over Teff) cells, which was associated with ∼40% decrease in aortic arch lesions (p ≤ 0.03).Anti-HMGB1 autoimmunity may potentially play a role in atherogenesis.

ApoE is a multifunctional protein that is expressed by many cell types that influences many aspects of cardiovascular physiology. In humans, there are three major allelic variants that differentially influence lipoprotein metabolism and risk for the development of atherosclerosis. Apoe-deficient mice and human apoE isoform knockin mice, as well as hypomorphic Apoe mice, have significantly contributed to our understanding of the role of apoE in lipoprotein metabolism, monocyte/macrophage biology, and atherosclerosis. This brief history of these mouse models will highlight their contribution to the understanding of the role of apoE in these processes. These Apoe(-/-) mice have also been extensively utilized as an atherosensitive platform upon which to assess the impact of modulator genes on the development and regression of atherosclerosis.

HIV/AIDS has remained a challenge in Uganda among adolescent despite the ABC strategy used globally to prevent HIV infection. The study assessed the knowledge, attitudes and perceptions of secondary school teenagers towards HIV transmission and prevention in rural and urban schools of central Uganda. A cross sectional study using self-administered questionnaires and structured interviews was used to collect data from adolescents in secondary schools in Kampala and Buikwe districts. Eight schools were randomly selected with 4 schools in each district. A total of 245 students from schools were recruited in the study with 120 and 125 students from urban Kampala and rural Buikwe district schools respectively. Data were analyzed using SPSS version 11. The results were expressed as percentages in a 2 × 2 tables. The mean age of the participants was 15.9 ± 2.5 years. Results showed that 95.1% participants had knowledge on HIV/AIDS in both urban and rural schools and 27.4% knew all the modes of HIV transmission. About 83.7% knew the ABC strategy for HIV prevention and 37.6% would talk about HIV/AIDS mainly with friends. For HIV cure, 62.0% of study participants reported non-cure and 24.9% were not sure. The remaining 13.1% of the study participants in both urban and rural schools reported that HIV can be cured. And the modes of curing HIV that were mentioned by participants included spiritual healing, transmitting it to others through sexual intercourse and that antiretroviral (ARVs) drugs can cure it as well as that it can be cured abroad. About 65.7% of participants reported recognition of one with HIV/ AIDS and by having red lips, being sickly; weight loss, skin rash and being very rich were mentioned. About 39.2% of the study participants mentioned that they cannot get infected with HIV and can't contract HIV at all and 18.4% believed that chances of getting HIV infection were high. On perception and attitude on condoms and their use, participants reported that it is a sign of mistrust, reduces sexual pleasures and they are embarrassing to buy. Majority of the participants in both urban and rural schools had some knowledge on HIV/AIDS and the ABC strategy for HIV prevention. However, there was a knowledge gap on the various modes of HIV transmission and prevention. There was misconception of the participants on HIV/AIDS cure, condom use and on the chances of contracting HIV. About the source of HIV/AIDS information, majority of the participants were getting information on HIV/AIDS from friends of which some information was misleading. This false information could be the reason for the increased HIV prevalence reported among the adolescents in the schools. Generally, participants had some knowledge on HIV/AIDS though they had knowledge gap on HIV transmission and prevention.

Purpose of review Macrophage foam cells are important cells in the vascular wall that contribute to the inflammation associated with atherosclerotic lesions. Recent studies have demonstrated the heterogeneity of macrophages in lesions. In this review, advances in our understanding of the formation of foam cells by macrophage subsets in atherosclerotic plaques will be discussed. Recent findings Macrophage subsets develop in response to the microenvironment in the arterial wall. The uptake of lipoproteins, particularly oxidized LDL, has been considered the major mechanism of foam cell formation. However, native and aggregated LDL can also be taken up by macrophages and M2 macrophages have been shown to be efficient in the uptake of apoptotic cells that can contribute lipids to the cells. The ability of the macrophage subsets to respond to bioactive lipids in the artery wall to either promote macrophage subset polarization and/or to promote foam cell formation is only beginning to be understood. Summary Although we are beginning to appreciate the heterogeneity of macrophages present in atherosclerotic plaques, further work is required to fully understand the molecular basis for the differential ability of macrophage subsets to form foam cells and to respond to bioactive lipids.

Background: Vernonia amygdalina is a common medicinal plant that is widely used by local communities and traditional herbalists in central Uganda in management of various conditions including hypertension that occurs as a result of changes in heart contractility. However, there is limited scientific information of V. amygdalina effects on the force and rate of contractility of the heart. The study evaluated the inotropic and chronotropic effect of methanol, aqueous, ether and total crude leaf extracts of V. amygdalina on isolated perfused rabbit heart.Methods: An experimental laboratory based study determined the effects of V. amygdalina extracts on the rate and force of contraction isolated perfused rabbit using the Langendorff’s heart perfusion experiment and methods. The heart rate (beats/minute) was counted per minute. The force of contraction of the heart was determined measuring the height of each peak on the kymogram.Results: The findings showed that the force and rate of heart contractility reduced with increasing doses of methanol, aqueous ether and total crude leaf extracts at doses of 0.5, 8.0, 62.0 and 250.0 mg/ml. The force and rate of heart contractility at a dose of 250.0 mg/ml for all the extracts were comparable to that of acetylcholine drug to almost causing cardiac arrest.Conclusions: The leaf extracts of V. amygdalina contain compounds that reduced the force and rate of contraction of an isolated rabbit heart.

Loneliness is the feeling of distress that arises when an individual perceives his or her social relationships as being less satisfying than what is desired. Life satisfaction is a global assessment of an individual's quality of life based on his chosen criteria. This descriptive cross sectional study assessed loneliness, life satisfaction and psychological distress among 480 out of school adolescents using the UCLA loneliness scale, the Satisfaction with life scale (SWLS) and the General Health questionnaire. Reasons for out of school are poverty (45.0%), eager to do business (30.0%) and death of parents (20.0%). 25.8% experienced frequent loneliness while 24.2% had psychological distress. Findings were discussed in line with literature reviewed and recommendations made.

Background Hypercholesterolemia‐induced decreased availability of nitric oxide ( NO ) is a major factor in cardiovascular disease. We previously established that cholesterol suppresses endothelial inwardly rectifying K + (Kir) channels and that Kir2.1 is an upstream mediator of flow‐induced NO production. Therefore, we tested the hypothesis that suppression of Kir2.1 is responsible for hypercholesterolemia‐induced inhibition of flow‐induced NO production and flow‐induced vasodilation ( FIV ). We also tested the role of Kir2.1 in the development of atherosclerotic lesions. Methods and Results Kir2.1 currents are significantly suppressed in microvascular endothelial cells exposed to acetylated–low‐density lipoprotein or isolated from apolipoprotein E–deficient ( Apoe −/− ) mice and rescued by cholesterol depletion. Genetic deficiency of Kir2.1 on the background of hypercholesterolemic Apoe −/− mice, Kir2.1 +/− /Apoe −/− exhibit the same blunted FIV and flow‐induced NO response as Apoe −/− or Kir2.1 +/− alone, but while FIV in Apoe −/− mice can be rescued by cholesterol depletion, in Kir2.1 +/− /Apoe −/− mice cholesterol depletion has no effect on FIV . Endothelial‐specific overexpression of Kir2.1 in arteries from Apoe −/− and Kir2.1 +/− /Apoe −/− mice results in full rescue of FIV and NO production in Apoe −/− mice with and without the addition of a high‐fat diet. Conversely, endothelial‐specific expression of dominant‐negative Kir2.1 results in the opposite effect. Kir2.1 +/− /Apoe −/− mice also show increased lesion formation, particularly in the atheroresistant area of descending aorta. Conclusions We conclude that hypercholesterolemia‐induced reduction in FIV is largely attributable to cholesterol suppression of Kir2.1 function via the loss of flow‐induced NO production, whereas the stages downstream of flow‐induced Kir2.1 activation appear to be mostly intact. Kir2.1 channels also have an atheroprotective role.

Obesity is a chronic inflammatory state characterized by altered levels of adipose tissue immune cell populations. Natural killer T (NKT) cells are CD1d restricted lymphocyte subsets that recognize lipid antigens whose level decreases in obese adipose tissue. However, studies in mice with deficiency or increased levels of NKT cells have yielded contradictory results, so the exact role of these cells in obesity and adipose tissue inflammation is not yet established. We previously showed that Ldlr-/- mice with excess invariant NKT (iNKT) cells demonstrate significant weight gain, adiposity, metabolic abnormalities, and atherosclerosis. The current study evaluates the effects of NKT cell deficiency on obesity, associated metabolic changes, and atherosclerosis in Jα18-/-Ldlr-/- (lacking iNKT cells) and Cd1d-/-Ldlr-/- (lacking invariant and type II NKT cells) mice, and control mice were fed an obesogenic diet (high fat, sucrose, cholesterol) for 16 weeks. Contrary to expectations, Ja18-/-Ldlr-/- mice gained significantly more weight than Ldlr-/- or Cd1d-/-Ldlr-/- mice, developed hypertriglyceridemia, and had worsened adipose tissue inflammation. All the mice developed insulin resistance and hepatic triglyceride accumulation. Ja18-/-Ldlr-/- mice also had increased atherosclerotic lesion area. Our findings suggest that iNKT cells exacerbates the metabolic, inflammatory, and atherosclerotic features of diet-induced obesity. Further work is required to unravel the paradox of an apparently similar effect of iNKT cell surplus and depletion on obesity.

Using genetic and biochemical approaches, we investigated proteins that regulate macrophage cholesterol efflux capacity (CEC) and ABCA1-specific CEC (ABCA1 CEC), 2 functional assays that predict cardiovascular disease (CVD). Macrophage CEC and the concentration of HDL particles were markedly reduced in mice deficient in apolipoprotein A-I (APOA1) or apolipoprotein E (APOE) but not apolipoprotein A-IV (APOA4). ABCA1 CEC was markedly reduced in APOA1-deficient mice but was barely affected in mice deficient in APOE or APOA4. High-resolution size-exclusion chromatography of plasma produced 2 major peaks of ABCA1 CEC activity. The early-eluting peak, which coeluted with HDL, was markedly reduced in APOA1- or APOE-deficient mice. The late-eluting peak was modestly reduced in APOA1-deficient mice but little affected in APOE- or APOA4-deficient mice. Ion-exchange chromatography and shotgun proteomics suggested that plasminogen (PLG) accounted for a substantial fraction of the ABCA1 CEC activity in the peak not associated with HDL. Human PLG promoted cholesterol efflux by the ABCA1 pathway, and PLG-dependent efflux was inhibited by lipoprotein(a) [Lp(a)]. Our observations identify APOA1, APOE, and PLG as key determinants of CEC. Because PLG and Lp(a) associate with human CVD risk, interplay among the proteins might affect atherosclerosis by regulating cholesterol efflux from macrophages.

Background: Chronic obstructive pulmonary disease (COPD) is well known for its cardiovascular co-morbidities. Increased platelet-monocyte interaction is found in COPD and may reflect altered platelet function and a potential role for anti-platelet therapy. Objectives: The objectives were to investigate platelet-monocyte interaction, platelet activation and reactivity and plasmatic coagulation in stable COPD. Methods: Platelet-monocyte interaction and platelet activation were determined by flow cytometry in 30 stable COPD patients and 25 controls. Platelet activation was measured by binding of fibrinogen to the activated fibrinogen receptor and platelet P-selectin expression at baseline and after platelet stimulation with platelet agonists. Plasmatic coagulation was measured by D-dimer and thrombin generation. Results: Platelet-monocyte interaction was increased in stable COPD (median fluorescence intensity of platelet CD61 was 19.8 [IQR 14.0-33.2] vs. 10.0 [IQR 8.7-16.7], p = 0.002). In contrast, platelet activation and reactivity, reflected by fibrinogen binding and P-selectin expression, were the same in both groups. Plasma P-selectin and interleukin-6 were increased in COPD (p = 0.01 and p = 0.02, respectively), whereas soluble fibrinogen, D-dimer and thrombin generation were similar. Conclusions: Increased platelet-monocyte interaction was found in the absence of platelet hyper-reactivity and activation of plasmatic coagulation in stable COPD. Future clinical evaluation of the effects of different anti-platelet drugs in COPD is warranted, as anti-platelet therapy may interfere with platelet-monocyte interaction.

Atherosclerosis is a chronic inflammatory disorder that develops in response to hyperlipidaemia. Cells from both the innate and adaptive immune systems contribute to the development of atherosclerotic lesions. The role of natural killer T (NKT) cells in response to microbial pathogens and inflammatory disorders such as atherosclerosis has received increasing attention in the past 10-15 years. Endogenous self-lipid antigens and exogenous lipid antigens, including those on microorganisms can activate NKT cells. CD1d molecules on antigen-presenting cells present these lipids to the T-cell receptor on NKT cells, which results in the rapid production of cytokines and cytotoxic proteins. NKT cells can also be activated in a CD1d-independent manner. Numerous studies have shown that NKT cells can promote atherogenesis. Various NKT cell sublineages have been described, but the participation of each in atherogenesis requires further characterization. In this Review, we provide an overview of NKT cells in the immune system, discuss CD1 molecules and lipid antigen presentation, and describe the interaction of the CD1d-NKT cell network with gut microbiota and its effect in modulating the activity or levels of NKT cells, which might in turn influence atherosclerosis. Although the exact mechanisms by which NKT cells promote atherosclerosis have not been fully elucidated, several potential mechanisms are proposed.

Atherosclerosis is a chronic inflammatory disorder that is the underlying cause of most cardiovascular disease. Both cells of the vessel wall and cells of the immune system participate in atherogenesis. This process is heavily influenced by plasma lipoproteins, genetics, and the hemodynamics of the blood flow in the artery. A variety of small and large animal models have been used to study the atherogenic process. No model is ideal as each has its own advantages and limitations with respect to manipulation of the atherogenic process and modeling human atherosclerosis or lipoprotein profile. Useful large animal models include pigs, rabbits, and nonhuman primates. Due in large part to the relative ease of genetic manipulation and the relatively short time frame for the development of atherosclerosis, murine models are currently the most extensively used. Although not all aspects of murine atherosclerosis are identical to humans, studies using murine models have suggested potential biological processes and interactions that underlie this process. As it becomes clear that different factors may influence different stages of lesion development, the use of mouse models with the ability to turn on or delete proteins or cells in tissue specific and temporal manner will be very valuable.

High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) have been shown in epidemiological studies and in animal models to reduce the risk of atherosclerosis. Synthetic peptides modeling the repeating amphipathic a-helices in apoA-I, the major apoprotein of HDL, were originally designed to study the lipid binding and other physical properties of the helices. The interest in apoA-I mimetic peptides was greatly stimulated by the observation that some, but not all, of the peptides significantly reduce atherosclerosis in animal models. Both monohelical and tandem helical peptides have been studied in vitro and in vivo for properties that mimic the antiatherogenic functional properties of HDL and apoA-I, particularly their ability to promote cholesterol efflux and reduce inflammation and oxidation. Mimetic peptides related to apoE, another apoprotein with repeating amphipathic helices, have also been shown to be antiatherogenic. Both peptide families likely function via common mechanisms and unique mechanisms. The understanding of how the structural properties of the various mimetic peptides relate to their mechanism of action will facilitate the development of optimal antiatherogenic therapeutic mimetic peptides.

The immunosuppressant dexamethasone was shown to preferentially deplete CD4+ effector T cells while sparing regulatory T cells (Tregs) in vivo. In the current study, we show that it also preferentially depletes B-2 cells while sparing B-1 cells. In the ApoE−/− mouse model of atherosclerosis, in which both Tregs and B-1 cells are thought to play an atheroprotective role, we show that HSP60-targeted immunization in the presence of dexamethasone raises Ag-reactive Tregs and B-1 cells concomitantly and reduces the severity of atherosclerosis. These results indicate that dexamethasone is an adjuvant that potentiates both the Treg and B-1 responses to immunogens. This study shows that B-1 cells with a specificity for a disease-relevant Ag can be raised in vivo by immunization.

During the post-antibiotic golden age, it has seen a massive antibiotic/antibacterial production and an increase in irrational use of these few existing drugs in the medical and veterinary practice, food industries, tissue cultures, agriculture and commercial ethanol production globally. The irrational drug use has been further exacerbated by the increased marketing and promotion of these drugs by the pharmaceutical companies thus increasing their accessibility in the public and hence their improper use. The lack of production and introduction of the newer and effective antibiotic/antibacterial drugs in clinical practice in the post-antibiotic golden age has seen an increase in the emergence of the resistant pathogenic bacterial infections creating a significant problem in the global health of humankind. The massive productions of the antibiotic/antibacterial drugs have contributed to the poor disposal of these drugs and hence many of them are discharged in various water bodies contributing to the environmental antibiotic/antibacterial drug pollution. In the environment, these drugs exert pressure on the environmental bacteria by destroying useful bacteria that are responsible for the recycling of the organic matter and as well as promoting the selection of the resistant pathogenic bacteria that can spread in human and animal population thus causing an increase in the observed bacterial disease burden and hence a significant global public health problem. The resistant bacterial diseases lead to the high cost, increased occurrence of adverse drug reactions, prolonged hospitalization, the exposure to the second- and third-line drugs like in MDR-TB and XDR-TB that leads to toxicity and deaths as well as the increased poor production in agriculture and animal industry and commercial ethanol production.

Chronic alcohol use is a common problem globally among the HIV-infected patients on ARV treatment regimens, leading to severe liver damage and increase in serum enzymes. The study determined effect of chronic alcohol intake on serum enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyl transferase (GGT)) in HIV-infected patients on d4T/3TC/NVP treatment regimen in Uganda using the WHO alcohol use disorders’ identification test (AUDIT) tool and chronic alcohol use biomarkers (ALT, AST, GGT, AST/ALT ≥ 2.0 and mean corpuscular volume (MCV)). A case control study using repeated measure design with serial measurements model was used. Alcohol use biomarkers were used to standardize the gender differences in alcohol use. A total of 41 patients (21 alcohol group and 20 control group) were followed up for 9 months with blood sampling done at 3 month intervals. The serum enzymes’ levels were determined by using the Cobas Intergra 400 Plus analyzer system. The mean GGT levels were higher in chronic alcohol use group as compared to control group in both groups. The levels were above reference ranges during 6 month and three times higher during 9-month follow-up period for both chronic alcohol use self reporting WHO AUDIT tool and biomarkers’ groups. Generally, the mean AST, ALT and AST/ALT levels were slightly higher in alcohol use group as compared to control group and were slightly higher in both groups as compared to reference ranges during the 9 month follow-up period. Chronic alcohol consumption by HIV-infected patients on d4T/3TC/NVP drug regimen increased GGT and AST/ALT serum enzyme levels and hence was used as chronic alcohol use biomarkers.

Sustained heavy ethanol drinking is a common problem globally and ethanol is one of the most abused drugs among individuals of different socio-economic status including the HIV-infected patients on antiretroviral drugs. Ethanol is reward drug and a CNS depressant especially at high doses. The study determined the effect of sustained heavy ethanol drinking by HIV-infected patients on d4T/3TC/NVP regimen on CD4+ cell counts in Uganda using WHO AUDIT tool and chronic alcohol-use biomarkers. A case control study using repeated measures design with serial measurements model was used. The patients on stavudine (d4T) 30 mg, lamivudine (3TC) 150 mg and nevirapine (NVP) 200 mg and chronic alcohol use were recruited. A total of 41 patients (20 in alcohol group and 21 in control group) were screened for chronic alcohol use by WHO AUDIT tool and chronic alcohol use biomarkers. They were followed up for 9 months with blood sampling done at 3 months intervals. CD4+ cell count was determined using Facscalibur Flow Cytometer system. Results were then sorted by alcohol-use biomarkers (GGT, MCV and AST/ ALT ratio). Data were analysed using SAS 2003 version 9.1 statistical package with repeated measures fixed model and the means were compared using student t-test. The mean CD4+ cell counts in all the groups were lower than the reference ranges at baseline and gradually increased at 3, 6 and 9 months of follow-up. The mean CD4+ cell counts were higher in the control group as compared to the chronic alcohol use group in both WHO AUDIT tool group and chronic alcohol-use biomarkers group though there was no significant difference (p > 0.05). Chronic alcohol use slightly lowers CD4+ cell count in HIV-infected patients on d4T/3TC/NVP treatment regimen.

Atherosclerosis is a chronic inflammation initiated by the accumulation of low-density lipoproteins (LDL) in the subendothelial space of the artery wall in spatially selected regions of the artery. The LDL is derived from circulating plasma lipoproteins. The passage of macromolecules across the endothelial barrier may involve one of three mechanisms—diffusional, paracellular or transcellular.

BackgroundCentral nervous system infections, including meningitis, continue to cause significant morbidity in Africa. HIV has contributed to the epidemiology of CNS infections in this setting. Notable advances in the study of CNS infections by several groups have demonstrated the utility of new diagnostic strategies and impact of novel treatment strategies. However, efforts to coordinate meningitis research in Africa, and between Africa and the rest of the world remain very limited.MethodsIn a bid to promote a coordinated study of CNS infections across Africa, and in collaboration with other meningitis groups globally, the researchers of the AMBITION study (High Dose Ambisome on a Fluconazole Backbone for Cryptococcal Meningitis Induction Therapy in Sub-saharan Africa: A Randomised Controlled Non-inferiority Trial) are leveraging the EDCTP support for the AMBITION trial to set up an Africa Meningitis Trials Network.ResultsThe Africa Meningitis Trials Network (AMNET) was launched in Malawi in early 2018. Main achievements since the launch of the network, include an internal review of meningitis research across network sites and launch of the network website. The network also has two study protocols pending ethics review at all sites. These studies will provide much needed information on resources available for meningitis care, research and provide a baseline epidemiology of meningitis in Africa.ConclusionAMNET provides a rare opportunity for investigators interested in meningitis research to leverage the ongoing AMBITION trial to conduct Africa-wide preliminary research on meningitis. The network is recruiting additional members in Africa and globally to collaborate on meningitis research, and also apply for research funding to support meningitis work. Anyone interested in knowing more about the network should contact the AMNET communications officer, Ms Phum’lani Machao, phumlani.machao@gmail.com

BackgroundThe REMSTART trial identified an effective package (cryptococcal antigen (CrAg) screening and enhanced antiretroviral therapy (ART) adherence support) that reduced all-cause mortality in advanced HIV (CD4 ≤200 cells/mm3) by 28% compared to standard of care. The introduction of this package at clinic level has been necessary to impact routine care practices in Tanzania.MethodsThe TRIP study is cluster-randomised. The intervention package was implemented in 16 routine care facilities (early arm) whilst 8 facilities continued with standard of care (deferred arm). At the end of 12 months follow-up, the intervention was implemented in the deferred facilities. The primary endpoint is all-cause mortality at 1 year.ResultsImplementation of the REMSTART intervention into routine care services has highlighted the following challenges: 1) Baseline CD4 testing: half (4/8) of rural facilities had no CD4 machines and in a further 3/8 there was a lack of reagents needed for CD4 testing. Clinical staging has replaced inclusion criterion where CD4 testing is not available; 2) Heavy staff workload in routine care; regular discussion with policymakers and workshops enhanced the take-up of the package; 3) Timing of ART: the Ministry of Health has updated national guidelines to include the package and delay ART by 2 weeks in CrAg-positives.ConclusionIt has proven essential to engage with policymakers and programme managers from the outset, i.e. during the REMSTART trial itself and the following TRIP implementation study. The Ministry of Health has now changed the national HIV guidelines to include the REMSTART package and develop training modules for CrAg screening in all regional hospitals. The TRIP study has revealed key issues that must be addressed to allow scaling up the interventions.

BackgroundDREAMM is an implementation study aiming to reduce meningo-encephalitis related mortality. Delays in diagnosis and treatment through poor access to diagnostics and treatments are significant contributing factors to the ongoing high mortality of HIV-associated central nervous system (CNS) infections, causing up to 25% of all HIV-related deaths in sub-Saharan Africa.MethodsA before-after design is being implemented across 3 sites in Africa; Lilongwe, Malawi, Dar Es Salaam, Tanzania and Yaoundé, Cameroon. The study is composed of 3 phases: Observation, Training and Implementation.ResultsThe observation phase (audit of practice) happened between November 2016 – May 2017 in Malawi and Tanzania. Overall, 110 patients were included. Ten-week all-cause mortality was 64% (42/66) in Tanzania and 37% (13/35) in Malawi. Approximately 75% of patients were ART experienced. Across sites, 76.6% of patients presented with abnormal mental status, with a median baseline CD4 count of 50 cells/µL. Only 2/75 patients in Tanzania had a lumbar puncture ordered compared to 27/35 in Malawi. All patients in Tanzania received empirical Fluconazole monotherapy whereas almost 1/3 patients in Malawi (11/35) were treated with Amphotericin B which is not readily available in both countries.The training phase (completed in November 2017 for Malawi and Tanzania) used the train-the-trainer approach. Interactive workshops on using rapid diagnostic tests (RDTs), performing basic microbiological techniques and safe administration of medicines were chosen as the most pertinent to reducing mortality. Patient and laboratory pathways were optimised afterwards by increasing the routine laboratory capacity, performing CSF analysis, providing infectious diseases mentorship for clinicians and procuring RDTs and reagents not locally available.Implementation is underway in Malawi and Tanzania and the audit phase is scheduled for autumn in Cameroon. Upon completion, the project is expected to create a sustainable approach to reduce the high mortality of HIV-related meningo-encephalitis with the optimised patient and laboratory pathways embedded within routine care.

BackgroundWhile user fees in healthcare systems have been associated with quality improvement, a substantial increase may have a detrimental effect. This paper reports on the effects of increasing user fees on utilisation of TB diagnostic services in Tanzania.MethodsWe retrospectively analysed data on TB diagnostic services utilisation between July 2013 and June 2015 in Mnazi Mmoja Zanzibar (MMZ), Musoma and Sumbawanga hospitals. In July 2014, user fees in Musoma were increased substantially from 2 to 5 US dollar; Sumbawanga increased the fees stepwise, from 1 to 2 US dollar in July 2014, and from2 to 3 US dollar in January 2015 MMZ did not raise the fees. We compared TB services utilisation before and after introduction of user fees.ResultsOut of 7483 presumptive TB patients registered in all sites, 50.2% were males. Over half (3969) were registered before the user fee was increased. Among 3969, 1579 (39.8%) were from Musoma, 922 (23.2%) from Sumbawanga and 1468 (37.0%) from MMZ. Of the 3514 patients registered after the introduction of user fees, 983 (28%), 952 (27.1%) and 1579 (44.9%) patients were from Musoma, Sumbawanga and MMZ, respectively. The number of presumptive TB patients seeking TB diagnostic services at Musoma decreased significantly by 38% from 1579 to 983 after the increase of user fees (p=0.001). More females (817; 51.8% vs 458, 35.9%) attended Musoma before user fees were increased as compared to males whose attendance did not differ much (761; 48.2% vs 525; 53.4%); (p=0.01). There was no significant decrease of patients at Sumbawanga and MMZ.ConclusionThere was a significant decrease in the number of presumptive TB patients who accessed new TB diagnostic services in Musoma after a substantial increase of user fees, the effect was stronger among women. Although user fees are beneficial, they should be increased stepwise so as not to affect service utilisation.

Obesity is a chronic inflammatory state characterized by infiltration of adipose tissue by immune cell populations, including T lymphocytes. Natural killer T (NKT) cells, a specialized lymphocyte subset recognizing lipid antigens, can be pro- or anti-inflammatory. Their role in adipose inflammation continues to be inconclusive and contradictory. In obesity, the infiltration of tissues by invariant NKT (iNKT) cells is decreased. We therefore hypothesized that an excess iNKT cell complement might improve metabolic abnormalities in obesity. Vα14 transgenic (Vα14tg) mice, with increased iNKT cell numbers, on a LDL receptor-deficient (Ldlr(-/-)) background and control Ldlr(-/-) mice were placed on an obesogenic diet for 16 weeks. Vα14tg.Ldlr(-/-) mice gained 25% more weight and had increased adiposity than littermate controls. Transgenic mice also developed greater dyslipidemia, hyperinsulinemia, insulin resistance, and hepatic triglyceride accumulation. Increased macrophage Mac2 immunostaining and proinflammatory macrophage gene expression suggested worsened adipose inflammation. Concurrently, these mice had increased atherosclerotic lesion area and aortic inflammation. Thus, increasing the complement of iNKT cells surprisingly exacerbated the metabolic, inflammatory, and atherosclerotic features of obesity. These findings suggest that the reduction of iNKT cells normally observed in obesity may represent a physiological attempt to compensate for this inflammatory condition.

Malaria is a fatal disease caused by different Plasmodium species of parasites and has remained the major killer of humans worldwide especially the children under five years of age and pregnant women. In this study, the anti-Plasmodia activities of the crude leaf ether extracts of Aloe dawei (AD) and Justicia betonica (JB) on Plasmodium falciparum were investigated, with chloroquine diphosphate as a positive control. The results showed that ether extracts of JB had EC50 of 13.36 (95% CI: 8.032 to 22.23) µg/ml and AD had 7.965 (95% CI: 3.557 to 17.84) µg/ml. The chloroquine diphosphate had EC50 of 24.86 (95% CI: 9.239 to 66.89) µg/ml. The qualitative phytochemical analysis of the ether extract showed that JB contains steroids and triterpenoids, alkaloids and saponins while AD contained steroids and triterpenoids, anthraquinolones, alkaloids and saponins. The results provides evidence that JB and AD contain compounds with anti-P. falciparum activity and hence their use by the traditional herbalist and local communities in treatment of malaria. Key words: Anti-Plasmodium falciparum, activity, EC50, Aloe dawei, Justicia betonica.

Medicinal herbs are commonly used worldwide as immune boosters and immunomodulators in the management of various disease conditions. Many of these herbs commonly used have not been scientifically evaluated for their immune modulating activities. The study investigated the immunomodulatory activity of the total crude leaf extract of Hibiscus sabdariffa in Wistar albino rats. It was an experimental study that was conducted on four groups of animals each with 6 healthy adult rats. Group I was dosed each with 1mL of normal saline. Groups II, III and IV were dosed 1mL of 125, 250 and 500 mg/Kg bwt of total crude extract, daily for 14 days respectively. On the 15th day, whole blood was collected into a clean ethlenediaminetetracetic acid (EDTA)-vacutainer. The complete blood count (CBC), immune blood cell count, hemagglutination antibody (HA) titers, neutrophil adhesion and delayed-type hypersensitivity (DTH) response were determined. All the doses caused an increase in mean red blood cell (RBC) counts as compared to control group. Similarly, the mean percentage neutrophils, monocytes, basophils and eosinophils increased with dose while the opposite was true for percentage lymphocytes. The mean HA titers for the herb were higher than control though no statistical difference (p≥0.05) was observed. Similar effects were observed with neutrophil adhesions response as that of HA titers. For DTH, the highest footpad thickness (175.2% increment) was observed at a dose of 500 mg/Kg bwt after 12 h and was statistically significant (p≤0.05) as compared to control. H. sabdariffa contain compounds with immunomodulatory activity in Wistar albino rats. Key words: Immunomodulation, Hibiscus sabdariffa, total crude extracts.