Corrigendum to "Crinum jagus (J. Thomps. Dandy): Antioxidant and protective properties as a medicinal plant on toluene-induced oxidative stress damages in liver and kidney of rats" [Toxicol. Rep. 9 (2022) 699-712].

[This corrects the article DOI: 10.1016/j.toxrep.2022.03.026.].

A protein restricted diet induces a stable increased fat storage phenotype in flies.

Background: Scientific evidence has revealed possible confounders in diet induced obesity models of Drosophila melanogaster. High Sugar Diet (HSD) induction of obesity in flies has been associated with fly hyperosmolarity and glucotoxicity, while High Fat Diet (HFD) induction has been associated with lipotoxicity. The objective of this study was to assess for a healthy obesity phenotype by comparison of fly survival, physio-chemical and biochemical changes associated with HSD, HFD and Protein Restricted Diet (PRD) obesity induction models of male Drosophila melanogaster. Here, we provide information on a PRD as the plausible option in obesity research not involving cancer, diabetes, glucotoxicity and lipotoxicity studies. Methods: Obesity was induced by exposing Drosophila melanogaster white mutant w1118 to four experimental diets for four weeks. Group 1 was fed regular food (control), group 2 was fed a 0.5% less yeast than in regular feed (PRD), group 3 was fed a 30% w/v sucrose to regular cornmeal food (HSD) and group 4 was fed a 10% w/v food-grade coconut oil to regular cornmeal food (HFD). Peristaltic waves were measured on 3rd instar larvae of all experimental groups. Negative geotaxis, fly survival, body mass, catalase activity, triglycerides (TG/TP), sterol, and total protein were measured in adult Drosophila melanogaster after four weeks. Results: Triglycerides (TG/TP) and total protein levels were significantly higher in HSD phenotype. Sterols were higher in HFD phenotype. Though catalase enzyme activity was highest in PRD phenotype, this activity was not statistically significant when compared to that of HSD and HFD phenotypes. However, PRD phenotype had the lowest mass, highest survival rate and the highest negative geotaxis, thus demonstrating a balanced, stable and more viable metabolic status in the experimental model. Conclusion: A protein restricted diet induces a stable increased fat storage phenotype in Drosophila melanogaster.

Knowledge, Attitude, and Practice Toward Cervical Cancer Screening Among Female University Students in Ishaka Western Uganda.

Purpose: Cervical cancer (CC) is the leading cause of cancer-related death among women living in third-world countries. CC is preventable, with the possibility of complete treatment if detected early. The objective of the study was to assess the level of knowledge, attitude, and practice on CC screening (CCS) among female university students (FUS) in Ishaka, western Uganda. Methods: The study was a descriptive cross-sectional study among FUS (n = 407) in western Uganda conducted after the first nationwide lockdown in Uganda. Information was collected using a questionnaire and descriptively presented as frequency and percentages. Results: The majority of our respondents were medical students 283 (69.5%), below 25 years 339 (83.3%), with Anglican Christian religious background 150 (36.9%). Respondents above the age of 25 years (p = 0.0052) and those in the medical profession (p < 0.001) had more knowledge. More medical students had a better attitude (p = 0.0043) and favorable practices (0.0134) compared to their non-medical counterparts. There is a weak correlation between attitude (r = 0.206, p < 0.001) and practice (r = 0.181, p = 0.0003) with knowledge on CCS. Conclusion: Observation from the present study suggests the need for more efforts in the fight against cervical cancer and encouragement of positive attitude and practice towards cervical cancer screening and uptake of vaccination.

Multivariate analysis of heavy metals content of beef from Soroti, Uganda.

Information about food hygiene and quality in the sub-Saharan African countries remains scarce at a time when many of their citizenry are beginning to acquire the much coveted middle income status. Confounding this are challenges linked to monitoring on a continuous basis the safety of food produced by such lucrative industries as the beef industry. The objective of the current study was to initiate a process of encouraging changes in the status quo, by showing how a first step in that direction might look like. Using heavy metal contents of representative beef samples from butcheries in Soroti, Uganda, typical of a sub-Saharan country, we demonstrate how relationships and common sources of metals in food could be identified in a multivariate space. Beef samples from 40 sites were analyzed by atomic absorption spectrometry for iron (Fe), zinc (Zn), nickel (Ni), chromium (Cr), lead (Pb), copper (Cu), cobalt (Co) and cadmium (Cd). The study showed that all beef samples contained these metals, the extent of which were in the order: Fe > Zn >> Ni, Cr > Pb > Cu, Co > Cd. By correlation analysis, the pairs Ni and Cr, Cd and Co, Ni and Fe or Cr and Fe were found to be most likely coming from similar sources. At least three distinct characteristics of beef consumed in Soroti were also found, a distinction perhaps arising from three major categories of feedlots used to raise donor cattle. The incremental risk of children or adults developing cancer over a lifetime was estimated and found to fall into three categories, two of which are separately explained by the presence of Cr or Ni. The sources of these metals remain a matter of speculation on our part. More studies are needed to determine these sources and to understand the nature of cancer risk in the three categories of beef identified here.

Green tea silver nanoparticles improve physiological motor and cognitive function in BALB/c mice during inflammation.

Information on the basic changes associated with green tea small molecules in acute inflammation is deficient. The purpose of the study was to characterize and establish the effects of green tea silver nanoparticles (AgNPs) following inflammation in BALB/c male mice. In this study, green tea silver nitrate nanoparticles were characterized and the extract were made up to constitute high (100%), medium (10%), and low (1%) concentrations for administration. Acute inflammation was induced in groups I-V of the experimental rodents by injecting 0.5 ml/kg of fresh egg albumin on the subplantar surface of the right hind paw and animals were monitored for 36 h. Group I-III were administered 100%, 10%, 1% green tea nanoparticles extract while group IV was given diclofenac. Group V was the positive control while group VI was the negative control that received the vehicle. Paw edema was measured at a 2 h interval for 3 days, while the pain was assessed by measuring the locomotion activity using the voluntary wheel running and the anxiety-like behavior. Hypersensitivity was measured through the temperature sensation experiment and a non-linear regression analysis was done. Here, synthesized green tea AgNPs registered an absorbance band at 460 nm, phytochemicals due to presence of organic functional groups of O[bond, double bond]C[bond, double bond]O of oxycarbons, of C[bond, double bond]C of a conjugate alkene, C[bond, double bond]O of a stretching bond of a secondary alcohol. The silver green tea nanoparticles were spherical, covered by a slimy layer, capped and stable. Green tea AgNPs significantly decreased temperature hypersensitivity in BALB/c male mice and this demonstrated their protective effects. Low concentrations of green tea nanoparticles inhibited edema thus mimicking effects of diclofenac, however, the percentage of inhibition was highest in medium and high silver-tea nanoparticles concentrations demonstration the importance of concentration in therapeutics. Anxiety was lowest in BALB/c male mice treated with high concentrations of silver green tea nanoparticles, and this led to increased locomotory activity in mice. Green tea AgNPs have strong anti-inflammatory effects at high concentrations. Concentrations of green tea AgNPs modulated basic sensory and motor behaviors in BALB/c male mice demonstrating their importance in complementary and integrative medical practice.

Attenuation of Seizures, Cognitive Deficits, and Brain Histopathology by Phytochemicals of Imperata cylindrica (L.) P. Beauv (Poaceae) in Acute and Chronic Mutant Drosophila melanogaster Epilepsy Models.

Imperata cylindrica is a globally distributed plant known for its antiepileptic attributes, but there is a scarcity of robust evidence for its efficacy. The study investigated neuroprotective attributes of Imperata cylindrica root extract on neuropathological features of epilepsy in a Drosophila melanogaster mutant model of epilepsy. It was conducted on 10-day-old (at the initiation of study) male post-eclosion bang-senseless paralytic Drosophila (parabss1) involved acute (1-3 h) and chronic (6-18 days) experiments; n = 50 flies per group (convulsions tests); n = 100 flies per group (learning/memory tests and histological examination). Administrations were done in 1 g standard fly food, per os. The mutant flies of study (parabss1) showed marked age-dependent progressive brain neurodegeneration and axonal degeneration, significant (P < 0.05) bang sensitivity and convulsions, and cognitive deficits due to up-regulation of the paralytic gene in our mutants. The neuropathological findings were significantly (P < 0.05) alleviated in dose and duration-dependent fashions to near normal/normal after acute and chronic treatment with extract similar to sodium valproate. Therefore, para is expressed in neurons of brain tissues in our mutant flies to bring about epilepsy phenotypes and behaviors of the current juvenile and old-adult mutant D. melanogaster models of epilepsy. The herb exerts neuroprotection by anticonvulsant and antiepileptogenic mechanisms in mutant D. melanogaster due to plant flavonoids, polyphenols, and chromones (1 and 2) which exert antioxidative and receptor or voltage-gated sodium ion channels' inhibitory properties, and thus causing reduced inflammation and apoptosis, increased tissue repair, and improved cell biology in the brain of mutant flies. The methanol root extract provides anticonvulsant and antiepileptogenic medicinal values which protect epileptic D. melanogaster. Therefore, the herb should be advanced for more experimental and clinical studies to confirm its efficacy in treating epilepsy.

Trypanocide usage in the cattle belt of southwestern Uganda.

Background: Systematic infrastructure and regulatory weaknesses over many decades, in communities struggling with animal African trypanosomiasis (AAT) would be expected to create an environment that would promote drug misuse and risk development of drug resistance. Here, we explore rural community practices of livestock keepers, livestock extension officers and drug shop attendants to determine whether appropriate practice was being followed in administration of trypanocides and other drugs. Methods: A questionnaire-based survey was undertaken in southwestern Uganda in 2022 involving 451 farmers who kept cattle, sheep or goats and 79 "professionals" who were either livestock extension officers or drug shop attendants. Results: Respondents reported using one or more type of trypanocidal drug on 80.1% of the 451 farms in the last 30 days. Diminazene aceturate was used on around three-quarters of farms, while isometamidium chloride was used on around one-fifth. Homidium bromide was used on less than 1% of farms. Cattle were significantly more likely to be treated with trypanocides than sheep or goats. On around two-thirds of farms, trypanocides were prepared and injected by farmers, with extension officers administering these drugs on most of the other third, especially on cattle farms. Almost all drugs were obtained from privately-owned drug shops. For treatment of AAT with trypanocides, prescription-only medicines were routinely used by farmers without professional supervision and in the absence of a definitive diagnosis. While a far greater proportion of professionals had a better education and had received training on the use of trypanocides than farmers, there was relatively little difference in their ability to use these drugs correctly. Farmers were more likely than professionals to use only DA to treat trypanosomiasis and were more likely to use antibiotics as well as trypanocidal drugs to treat the animal. Furthermore, they estimated, on average, that twice the recommended dose of either diminazene aceturate or isometamidium chloride was needed to treat a hypothetical 400 kg bovine. A minority of both farmers and professionals reported that they observed the recommended withdrawal times following injection of trypanocidal drugs and very few of either group knew the recommended withdrawal times for milk or meat. Only one in six farmers reported using the sanative pair (alternating use of diminazene aceturate and isometamidium chloride), to reduce the risk of drug resistant trypanosome strains emerging, while this approach was more widely used by professionals. Farmers reported using antibiotics more commonly than the professionals, especially in sheep and goats, raising concerns as to overuse and misuse of this critical class of drugs. In addition to using trypanocides, most farmers also reported using a topical veterinary pesticide for the control of ticks and tsetse. On average, farmers spent 12.2% of their income from livestock sales on trypanocides. Conclusion: This study highlights the complexity of issues involved in the fight against AAT using drug treatment. A multistakeholder campaign to increase awareness among farmers, drug shop attendants, and extension workers of the importance of adherence to recommended drug dosing, using the sanative pair and following recommended drug withdrawal guidance would promote best practice, reduce the risk of emergence of resistant strains of trypanosomes, and support enhanced food safety.

Systematic Review and Meta-Analysis on Human African Trypanocide Resistance.

Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of increased monotherapy drug treatment failures against Trypanosoma brucei gambiense and T. b. rhodesiense that are associated with changes in pathogen receptors. Methods: Electronic searches of 12 databases and 3 Google search websites for human African trypanocide resistance were performed using a keyword search criterion applied to both laboratory and clinical studies. Fifty-one publications were identified and included in this study using the PRISMA checklist. Data were analyzed using RevMan and random effect sizes were computed for the statistics at the 95% confidence interval. Results: Pentamidine/melarsoprol/nifurtimox cross-resistance is associated with loss of the T. brucei adenosine transporter 1/purine 2 gene (TbAT1/P2), aquaglyceroporins (TbAQP) 2 and 3, followed by the high affinity pentamidine melarsoprol transporter (HAPT) 1. In addition, the loss of the amino acid transporter (AAT) 6 is associated with eflornithine resistance. Nifurtimox/eflornithine combination therapy resistance is associated with AAT6 and nitroreductase loss, and high resistance and parasite regrowth is responsible for treatment relapse. In clinical studies, the TbAT1 proportion of total random effects was 68% (95% CI: 38.0−91.6); I2 = 96.99% (95% CI: 94.6−98.3). Treatment failure rates were highest with melarsoprol followed by eflornithine at 41.49% (95% CI: 24.94−59.09) and 6.56% (3.06−11.25) respectively. HATr-resistant phenotypes used in most laboratory experiments demonstrated significantly higher pentamidine resistance than other trypanocides. Conclusion: The emergence of drug resistance across the spectrum of trypanocidal agents that are used to treat HAT is a major threat to the global WHO target to eliminate HAT by 2030. T. brucei strains were largely resistant to diamidines and the use of high trypanocide concentrations in clinical studies have proved fatal in humans. Studies to develop novel chemotherapeutical agents and identify alternative protein targets could help to reduce the emergence and spread of HATr.

Systematic Review and Meta-Analysis on Knowledge Attitude and Practices on African Animal Trypanocide Resistance.

BACKGROUND: African trypanocide resistance is an emerging public health emergency whose control requires a revisit on farmer's knowledge, attitudes, and practices in developing countries. African animal trypanocide resistance (AATr) is rife in an environment where drug use and policy decisions are disjointed. The objective of the study was to identify community factors responsible for the development of AATr. This was important since diminazene aceturate (DA), isometamidium chloride (ISM), and homidium bromide (HB) have existed for over 30 years and no new drugs have been provided to farmers. METHODS: An electronic keyword search across 12 databases was conducted using a search criterion from 1806 to June 2022. This generated a total of 24 publications, but after removing duplicates, review articles, and nonrelated articles, a total of eight papers were included in the analysis by following the PRISMA checklist. A meta-analysis was conducted on the data extracted and the risk ratio and inverse variance at 95% confidence interval were calculated using RevMan®. RESULTS: All the eight articles in the study showed that DA was the most preferred trypanocide in both West and Eastern Africa. Poor farmer knowledge of AATr and limited drug options were major drivers for trypanocide resistance. In addition, farmer treatments, use of untrained personnel, poor administration, poor dosing, and preparation of trypanocides were major drivers for the development of AATr and similarities were identified in DA and ISM practices (P = 0.13). CONCLUSIONS: AATr is spread in developing countries due to a lack of community knowledge, attitudes, and drug-use practices. This situation could be reversed through interdisciplinary collaborations in endemic communities by promoting effective treatments and responsible drug handling.

Tamarindus indica ameliorates behavioral and cytoarchitectural changes in the cerebellar cortex following prenatal aluminum chloride exposure in Wistar rats.

Aluminium exposure has been linked with developmental neurotoxicity in humans and experimental animals. The study aimed to evaluate the ameliorative effect of Tamarindus indica on the developing cerebellar cortex, neurobehavior, and immunohistochemistry of the cerebellar cortex following prenatal aluminum chloride (AlCl3) exposure. Pregnant timed Wistar rats were divided into 5 groups (n=4). Group I (negative control) was given distilled water, group II was treated with 200 mg/kg of AlCl3, group III were given 200 mg/kg of AlCl3 and 400 mg/kg of ethyl acetate leaf fraction of Tamarindus indica (EATI), group IV were given 200 mg/kg of AlCl3 and 800 mg/kg of EATI, and group V were treated with 200 mg/kg of AlCl3 s/c and 300 mg/kg of vitamin E for 14 days (prenatal day 7-21) via the oral route. Male pups (n=6) were randomly selected and taken for neurobehavioral studies, and humanely sacrificed via intraperitoneal injection of thiopental sodium. The cerebellum was removed, fixed and tissue processed for histological and immunohistochemical studies. The results revealed that prenatal AlCl3 exposure impacted neurodevelopment and neurobehaviour among exposed pups. Prenatal AlCl3 exposure was marked with delayed cytoarchitectural development of the cerebellar cortex and increased GFAP expression in the cerebellar cortex. On the other hand, treatment with EATI and vitamin E were marked with significant improvements. The present study therefore concluded treatment with EATI shows an ameliorative effect to prenatal AlCl3 exposure.

Anti-obesity effects of Erythrina abyssinica stem bark extract in flies exposed to a high fat diet.

Background: An in vitro assay on Sigmoidin A from Erythrina abyssinica stem bark revealed its potency to inhibit pancreatic lipase. However, studies indicate activity of extract bioactive compounds in combination far exceed the favorable effects of each individual compound due to synergy and additive effects. In this study, we provide information on the effect of E. abyssinica stem bark extract in Drosophila melanogaster. The objective of the study was to determine the safety and effects of E. abyssinica stem bark extract on fly survival, body weight, triglycerides, sterol, total protein, and catalase activity of obese male D. melanogaster. Methods: Obesity was induced by exposing D. melanogaster white mutant w 1118 to coconut food for two weeks. Groups 1-3 were fed on coconut food + fenofibrate at 25 mM, 50 mM, and 75 mM. Groups 4-6 were fed on coconut food + E. abyssinica stem bark extract at concentrations of 2.5 g/ml, 5.0 g/ml, and 7.5 g/ml. The positive control was exposed to only coconut food while the negative control was on regular food. Fly survival observations were done for 15 days, while acute and chronic effects were done at 30 min and after 48 h respectively following treatment. Body mass, negative geotaxis, reducing power of the extract, triglycerides (TG/TP), sterol, total protein levels, and catalase activity were measured after 10 days of exposure to the experimental diets. Results: Fly survival changes were observed after 10 days and E. abyssinica stem bark extract had the strongest reducing power at 7.5 g/ml extract concentration. E. abyssinica stem bark extract reduced body mass, triglyceride levels (TG/TP), sterol levels, and modulated catalase activity at 7.5 g/ml extract concentration. Though the standard drug fenofibrate had the highest fat accumulation reduction potential, the extract at 7.5 g/ml was much safer in reducing fat accumulation in obese male D. melanogaster than other concentration used. Conclusion: Antioxidants in E. abyssinica stem bark extract are responsible for the observed anti-obesity activity.

Cerebral Cortical Activity During Academic Stress Amongst Undergraduate Medical Students at Kampala International University (Uganda).

Background: Stress among medical students is related to their academic lifespan; however, information on brain health among medical students from developing countries continues to be scarce. The objective of this study was to establish perceived academic stress levels, assess the ability to cope with stress, and investigate its effects on the visual reaction time (VRT), audio reaction time (ART), and tactile reaction time (TRT) in the somatosensory cortex among medical students of Uganda. Methods: This was a cross-sectional study conducted among preclinical (n = 88) and clinical (n = 96) undergraduate medical students at Kampala International University Western Campus. A standard Perceived Stress Scale (PSS) was used to categorize stress into low, moderate, and severe while the ability to cope with stress was categorized into below average, average, above average, and superior stresscoper (SS). Data on reaction time were acquired through VRT, ART, and TRT using the catch-a-ruler experiment, and this was analyzed using SPSS version 20. Results: This study shows that preclinical students are more stressed than clinical students (PSS prevalence for low stress = preclinical; clinical: 40, 60%). Moderate stress was 48.4 and 51.6% while high perceived stress was 75 and 25% among preclinical and clinical students. Among male and female students in preclinical years, higher TRT and VRT were found in clinical students showing that stress affects the tactile and visual cortical areas in the brain, although the VRT scores were only significantly (P = 0.0123) poor in male students than female students in biomedical sciences. Also, highly stressed individuals had higher TRT and ART and low VRT. SS had high VRT and ART and low TRT in preclinical students, demonstrating the importance of the visual cortex in stress plasticity. Multiple regression showed a close relationship between PSS, ability to cope with stress, age, and educational level (P < 0.05), demonstrating the importance of social and psychological support, especially in the biomedical sciences. Conclusion: Preclinical students suffer more from stress and are poorer SS than clinical students. This strongly impairs their cortical regions in the brain, thus affecting their academic productivity.

Crinum jagus (J. Thomps. Dandy): Antioxidant and protective properties as a medicinal plant on toluene-induced oxidative stress damages in liver and kidney of rats.

Crinum jagus (C. jagus; J. Thomps.) Dandy (Liliaceae) is a pantropical plant known for its medicinal values and pharmacological properties. The study assessed the protective effects and changes in oxidative stress indices due to C. jagus leaf extracts on the toluene-induced liver and kidney injuries in rats. The study was conducted on 8-week-old male Wistar rats (n = 80), weighing 243.3 ± 1.42 g. Group I, 1 ml/kg distilled water for 7 days; Group II, 4.5 ml/kg toluene once, 1 ml/kg distilled water for 7 days; Group III, 4.5 ml/kg toluene once, 500 mg/kg methanolic extract for 7 days; Group IV, 4.5 ml/kg toluene once, 500 mg/kg aqueous extract for 7 days; Group V, 500 mg/kg methanolic extract for 7 days; Group VI, 500 mg/kg aqueous extract for 7 days; Group VII, 500 mg/kg of vitamin C for 7 days; Group, VIII, 4.5 ml/kg toluene once, 500 mg/kg vitamin C for 7 days, all administrations were given by oral gavage. The phytochemical contents, absolute and relative organ weights of liver and kidneys, liver and kidney function tests, antioxidant status, as well as histological tests were analyzed using standard protocols. The tannins, flavonoids, and polyphenols were in highest concentration in both extracts, content in methanol extract (57.04 ± 1.51 mgg-1, 35.43 ± 1.03 mgg-1, 28.2 ± 0.34 mgg-1 respectively) > aqueous extract (18.74 ± 1.01 mgg-1, 13.43 ± 0.47 mgg-1, 19.65 ± 0.21 mgg-1 respectively). In the negative control group (II), bodyweights significantly (P < 0.05) reduced by 22%, liver weight and kidney weight significantly (P < 0.05) increased by 42% and 83% respectively, liver-to-bodyweight and kidney-to-bodyweight ratios increased significantly (P < 0.05); serum liver function tests (LFTs) i.e., bilirubin, alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyl transferase (GGT), and serum kidney function tests (creatinine and urea) were significantly (P < 0.05) elevated; oxidant status (tissue malondialdehyde; MDA) was significantly (P < 0.05) elevated, antioxidant status i.e., tissue superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels was significantly (P < 0.05) reduced; with markedly visible renal and hepatic histopathological findings, compared to the normal control group. In C. jagus extract test groups (III and IV), the parameters were significantly (P < 0.05) alleviated and reversed to normal/near normal compared to the negative control. The LFTs, kidney function tests, and antioxidant status were significantly (P < 0.05) more improved with the methanol extract test and standard control groups compared to the aqueous extract test group; Also, the methanol extract test group showed better histological features than the aqueous extract test and standard control groups. The methanolic extract shows better antioxidant potential due to the availability of more nonenzymatic antioxidants (tannins, flavonoids, and polyphenols). The findings showed that toluene is a very aggressive xenobiotic due to the promotion of oxidative stress and peroxidation of cellular lipids, but C. jagus leaves provide significant protection through the reducing power of nonenzymatic antioxidants and their ability to induce endogenous antioxidant enzymes (SOD, CAT, and glutathione reductase or GR) causing reduced cellular lipid peroxidation and tissue damages, quickened tissue repair, and improved cell biology of liver and kidneys during toluene toxicity. The methanol leaf extract provides better protection and should be advanced for more experimental and clinical studies to confirm its efficacy in alleviating oxidative stress tissue injuries, specifically due to toluene.

An Update on African Trypanocide Pharmaceutics and Resistance.

African trypanosomiasis is associated with Trypanosoma evansi, T. vivax, T. congolense, and T. brucei pathogens in African animal trypanosomiasis (AAT) while T. b gambiense and T. b rhodesiense are responsible for chronic and acute human African trypanosomiasis (HAT), respectively. Suramin sodium suppresses ATP generation during the glycolytic pathway and is ineffective against T. vivax and T. congolense infections. Resistance to suramin is associated with pathogen altered transport proteins. Melarsoprol binds irreversibly with pyruvate kinase protein sulfhydryl groups and neutralizes enzymes which interrupts the trypanosome ATP generation. Melarsoprol resistance is associated with the adenine-adenosine transporter, P2, due to point mutations within this transporter. Eflornithine is used in combination with nifurtimox. Resistance to eflornithine is caused by the deletion or mutation of TbAAT6 gene which encodes the transmembrane amino acid transporter that delivers eflornithine into the cell, thus loss of transporter protein results in eflornithine resistance. Nifurtimox alone is regarded as a poor trypanocide, however, it is effective in melarsoprol-resistant gHAT patients. Resistance is associated with loss of a single copy of the genes encoding for nitroreductase enzymes. Fexinidazole is recommended for first-stage and non-severe second-stage illnesses in gHAT and resistance is associated with trypanosome bacterial nitroreductases which reduce fexinidazole. In AAT, quinapyramine sulfate interferes with DNA synthesis and suppression of cytoplasmic ribosomal activity in the mitochondria. Quinapyramine sulfate resistance is due to variations in the potential of the parasite's mitochondrial membrane. Pentamidines create cross-links between two adenines at 4-5 pairs apart in adenine-thymine-rich portions of Trypanosoma DNA. It also suppresses type II topoisomerase in the mitochondria of Trypanosoma parasites. Pentamidine resistance is due to loss of mitochondria transport proteins P2 and HAPT1. Diamidines are most effective against Trypanosome brucei group and act via the P2/TbAT1 transporters. Diminazene aceturate resistance is due to mutations that alter the activity of P2, TeDR40 (T. b. evansi). Isometamidium chloride is primarily employed in the early stages of trypanosomiasis and resistance is associated with diminazene resistance. Phenanthridine (homidium bromide, also known as ethidium bromide) acts by a breakdown of the kinetoplast network and homidium resistance is comparable to isometamidium. In humans, the development of resistance and adverse side effects against monotherapies has led to the adoption of nifurtimox-eflornithine combination therapy. Current efforts to develop new prodrug combinations of nifurtimox and eflornithine and nitroimidazole fexinidazole as well as benzoxaborole SCYX-7158 (AN5568) for HAT are in progress while little comparable progress has been done for the development of novel therapies to address trypanocide resistance in AAT.

African animal trypanocide resistance: A systematic review and meta-analysis.

Background: African animal trypanocide resistance (AATr) continues to undermine global efforts to eliminate the transmission of African trypanosomiasis in endemic communities. The continued lack of new trypanocides has precipitated drug misuse and overuse, thus contributing to the development of the AATr phenotype. In this study, we investigated the threat associated with AATr by using the major globally available chemotherapeutical agents. Methods: A total of seven electronic databases were screened for an article on trypanocide resistance in AATr by using keywords on preclinical and clinical trials with the number of animals with treatment relapse, days taken to relapse, and resistant gene markers using the PRISMA checklist. Data were cleaned using the SR deduplicator and covidence and analyzed using Cochrane RevMan®. Dichotomous outputs were presented using risk ratio (RR), while continuous data were presented using the standardized mean difference (SMD) at a 95% confidence interval. Results: A total of eight publications in which diminazene aceturate (DA), isometamidium chloride (ISM), and homidium chloride/bromide (HB) were identified as the major trypanocides were used. In all preclinical studies, the development of resistance was in the order of HB > ISM > DA. DA vs. ISM (SMD = 0.15, 95% CI: -0.54, 0.83; I 2 = 46%, P = 0.05), DA vs. HB (SMD = 0.96, 95% CI: 0.47, 1.45; I 2 = 0%, P = 0.86), and HB vs. ISM (SMD = -0.41, 95% CI: -0.96, 0.14; I 2 = 5%, P = 0.38) showed multiple cross-resistance. Clinical studies also showed evidence of multi-drug resistance on DA and ISM (RR = 1.01, 95% CI: 0.71-1.43; I 2 = 46%, P = 0.16). To address resistance, most preclinical studies increased the dosage and the treatment time, and this failed to improve the patient's prognosis. Major markers of resistance explored include TbAT1, P1/P2 transporters, folate transporters, such as F-I, F-II, F-III, and polyamine biosynthesis inhibitors. In addition, immunosuppressed hosts favor the development of AATr. Conclusion: AATr is a threat that requires a shift in the current disease control strategies in most developing nations due to inter-species transmission. Multi-drug cross-resistance against the only accessible trypanocides is a major public health risk, justifying the need to revise the policy in developing countries to promote control of African trypanosomiasis.

Effects of ß-Blockers on the Sympathetic and Cytokines Storms in Covid-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. ß2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. ß-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, ß-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of ß-blockers in the management of Covid-19.

COVID-19-Related Mental Health Burdens: Impact of Educational Level and Relationship Status Among Low-Income Earners of Western Uganda.

Objective: The study aimed to investigate the relationship between mental health with the level of education, relationship status, and awareness on mental health among low-income earners in Western Uganda. Methods: This was a cross-sectional descriptive study carried out among 253 participants. Anxiety, anger, and depression were assessed using a modified generalized anxiety disorder (GAD-7), Spielberger's State-Trait Anger Expression Inventory-2, and Beck Depression Inventory item tools, respectively. Results: The majority of our respondents were male (n = 150/253, 59.3), had a secondary level of education (104/253, 41.1), and were single (137/253, 54.2). No formal education and primary education (r2 = 47.4% and 6.4%, respectively) had a negative correlation with awareness of mental health care. In addition, no formal education had a positive correlation with anger and depression (r2 = 1.9% and 0.3%, respectively). Singleness in this study had a negative correlation with awareness of mental health care, anger, and depression (r2 = 1.9, 0.8, and 0.3%, respectively), and a positive correlation with anxiety (r2 = 3.9%). Conclusion: It is evident that education and relationship status influenced awareness on mental health care and mental health state among low-income earners in Western Uganda during the first COVID-19 lockdown. Therefore, policymakers should strengthen social transformation through the proper engagement of low-income earners in this COVID-19 era.

Anxiety, Anger and Depression Amongst Low-Income Earners in Southwestern Uganda During the COVID-19 Total Lockdown.

Background: Low-income earners are particularly vulnerable to mental health, consequence of the coronavirus disease 2019 (COVID-19) lockdown restrictions, due to a temporary or permanent loss of income and livelihood, coupled with government-enforced measures of social distancing. This study evaluates the mental health status among low-income earners in southwestern Uganda during the first total COVID-19 lockdown in Uganda. Methods: A cross-sectional descriptive study was undertaken amongst earners whose income falls below the poverty threshold. Two hundred and fifty-three (n = 253) male and female low-income earners between the ages of 18 and 60 years of age were recruited to the study. Modified generalized anxiety disorder (GAD-7), Spielberger's State-Trait Anger Expression Inventory-2 (STAXI-2), and Beck Depression Inventory (BDI) tools as appropriate were used to assess anxiety, anger, and depression respectively among our respondents. Results: Severe anxiety (68.8%) followed by moderate depression (60.5%) and moderate anger (56.9%) were the most common mental health challenges experienced by low-income earners in Bushenyi district. Awareness of mental healthcare increased with the age of respondents in both males and females. A linear relationship was observed with age and depression (r = 0.154, P = 0.014) while positive correlations were observed between anxiety and anger (r = 0.254, P < 0.001); anxiety and depression (r = 0.153, P = 0.015) and anger and depression (r = 0.153, P = 0.015). Conclusion: The study shows the importance of mental health awareness in low resource settings during the current COVID-19 pandemic. Females were identified as persons at risk to mental depression, while anger was highest amongst young males.

The Rise of SARS-CoV-2 Variants and the Role of Convalescent Plasma Therapy for Management of Infections.

Novel therapies for the treatment of COVID-19 are continuing to emerge as the SARS-Cov-2 pandemic progresses. PCR remains the standard benchmark for initial diagnosis of COVID-19 infection, while advances in immunological profiling are guiding clinical treatment. The SARS-Cov-2 virus has undergone multiple mutations since its emergence in 2019, resulting in changes in virulence that have impacted on disease severity globally. The emergence of more virulent variants of SARS-Cov-2 remains challenging for effective disease control during this pandemic. Major variants identified to date include B.1.1.7, B.1.351; P.1; B.1.617.2; B.1.427; P.2; P.3; B.1.525; and C.37. Globally, large unvaccinated populations increase the risk of more and more variants arising. With successive waves of COVID-19 emerging, strategies that mitigate against community transmission need to be implemented, including increased vaccination coverage. For treatment, convalescent plasma therapy, successfully deployed during recent Ebola outbreaks and for H1N1 influenza, can increase survival rates and improve host responses to viral challenge. Convalescent plasma is rich with cytokines (IL-1ß, IL-2, IL-6, IL-17, and IL-8), CCL2, and TNFα, neutralizing antibodies, and clotting factors essential for the management of SARS-CoV-2 infection. Clinical trials can inform and guide treatment policy, leading to mainstream adoption of convalescent therapy. This review examines the limited number of clinical trials published, to date that have deployed this therapy and explores clinical trials in progress for the treatment of COVID-19.

Epidemiology of Trypanosomiasis in Wildlife-Implications for Humans at the Wildlife Interface in Africa.

While both human and animal trypanosomiasis continue to present as major human and animal public health constraints globally, detailed analyses of trypanosome wildlife reservoir hosts remain sparse. African animal trypanosomiasis (AAT) affects both livestock and wildlife carrying a significant risk of spillover and cross-transmission of species and strains between populations. Increased human activity together with pressure on land resources is increasing wildlife-livestock-human infections. Increasing proximity between human settlements and grazing lands to wildlife reserves and game parks only serves to exacerbate zoonotic risk. Communities living and maintaining livestock on the fringes of wildlife-rich ecosystems require to have in place methods of vector control for prevention of AAT transmission and for the treatment of their livestock. Major Trypanosoma spp. include Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, and Trypanosoma cruzi, pathogenic for humans, and Trypanosoma vivax, Trypanosoma congolense, Trypanosoma evansi, Trypanosoma brucei brucei, Trypanosoma dionisii, Trypanosoma thomasbancrofti, Trypanosma elephantis, Trypanosoma vegrandis, Trypanosoma copemani, Trypanosoma irwini, Trypanosoma copemani, Trypanosoma gilletti, Trypanosoma theileri, Trypanosoma godfreyi, Trypansoma simiae, and Trypanosoma (Megatrypanum) pestanai. Wildlife hosts for the trypansomatidae include subfamilies of Bovinae, Suidae, Pantherinae, Equidae, Alcephinae, Cercopithecinae, Crocodilinae, Pteropodidae, Peramelidae, Sigmodontidae, and Meliphagidae. Wildlife species are generally considered tolerant to trypanosome infection following centuries of coexistence of vectors and wildlife hosts. Tolerance is influenced by age, sex, species, and physiological condition and parasite challenge. Cyclic transmission through Glossina species occurs for T. congolense, T. simiae, T. vivax, T. brucei, and T. b. rhodesiense, T. b. gambiense, and within Reduviid bugs for T. cruzi. T. evansi is mechanically transmitted, and T. vixax is also commonly transmitted by biting flies including tsetse. Wildlife animal species serve as long-term reservoirs of infection, but the delicate acquired balance between trypanotolerance and trypanosome challenge can be disrupted by an increase in challenge and/or the introduction of new more virulent species into the ecosystem. There is a need to protect wildlife, animal, and human populations from the infectious consequences of encroachment to preserve and protect these populations. In this review, we explore the ecology and epidemiology of Trypanosoma spp. in wildlife.