Artemisinin drug resistance and monitoring: a narrative review

Artemisinin drug resistance is one of the major reasons for malaria treatment failures in the sub-Saharan African countries where artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated malaria. The occurrence of single nucleotide polymorphisms (SNPs) is found to correlate with antimalarial drug resistance. With artemisinin, the SNPs occurs at the Kelch 13-propeller gene locus on chromosome 13. The artemisinin drug resistance surveillance strategy involves continuous monitoring of Kelch 13-propeller biomarker to detect emergence of mutations which could herald drug resistance in the region. In this narrative review paper, we examined existing literature to bridge the knowledge gap and accentuate the importance of routine surveillance for artemisinin resistance in sub-Saharan Africa. We conducted our search on PubMed database and Google Scholar to identify peer-reviewed articles, reports, and abstracts on artemisinin drug resistance using the following keywords; 'artemisinin drug resistance', 'antimalarial drug resistance', 'artemisinin-based combination therapy', 'Kelch 13-propeller', 'K13- propeller gene', and 'K13 molecular marker'. The review provided pertinent information on artemisinin derivatives, artemisinin-based combination therapy, molecular action of artemisinin, definition of artemisinin resistance, genetic basis of artemisinin drug resistance and discovery of Kelch 13, and the importance of artemisinin resistance surveillance. Molecular surveillance can provide healthcare policy makers a forecast of impending threats to malaria treatment. This is more so when drugs are in combination therapy, for instance, molecular surveillance can give a hint that one drug is failing despite the fact that in combination, it is still apparently clinically effective.

Genotypic characterization of aminoglycoside resistance genes from bacteria isolates in selected municipal drinking water distribution sources in Southwestern Nigeria

BACKGROUND: Multi-drug Resistant (MDR) bacteria could lead to treatment failure of infectious diseases and could be transferred by non-potable water. Few studies have investigated occurrence of Antibiotic Resistance Genes (ARGs) among bacteria including Aminoglycoside Modifying Genes (AMGs) from Drinking Water Distribution Systems (DWDS) in Nigeria. Here, we aimed at characterization of AMGs from DWDS from selected states in southwestern Nigeria. METHODS: One hundred and eighty one (181) MDR bacteria that had been previously characterized using 16S rDNA and showed resistance to at least one aminoglycoside antibiotic were selected from treated and untreated six water distribution systems in southwestern Nigeria. MDR bacteria were PCR genotyped for three AMGs:aph (3´´)c, ant (3´´)b and aph(6)-1dd. RESULTS: Out of 181 MDR bacteria genotyped, 69(38.12%) tested positive for at least one of the genotyped AMGs. Highest (50, 27.62%) detected gene was ant (3")c followed by aph (3")c(33,18.23%). Combination of aph(3")c and ant (3")b in a single bacteria was observed as the highest (14, 7.73%) among the detected gene combination. Alcaligenes sp showed the highest (10/20) occurrence of ant (3")b while aph(3")c was the highest detected among Proteussp (11/22). Other bacteria that showed the presence of AMGs include: Acinetobacter, Aeromonas, Bordetella, Brevundimonas, Chromobacterium, Klebsiella, Leucobacter, Morganella, Pantoae, Proteus, Providencia, Psychrobacter and Serratia. CONCLUSIONS: High occurrence of ant (3")c and aph (3")c among these bacteria call for urgent attention among public health workers, because these genes can be easily disseminated to consumers of these water samples if present on mobile genetic elements like plasmids, integrons and transposons

Gene and cell therapy in South Africa: current status and future prospects

South Africa has a high disease burden resulting from communicable and non-communicable diseases. Current therapeutic interventions rarely result in a cure and the associated lifelong treatment places a considerable strain on an overburdened health sector. Gene and cell therapies present novel alternatives to disease management, offering the promise of a single treatment and a lifelong cure. Although challenges remain, investment in the field has started to bear fruit, with a number of gene and cell therapeutics reaching the market in the past decade. To take full advantage of these developments, it is important that a proactive approach to nurturing appropriate human and material resources is adopted in the country

Efflux Pump-Mediated resistance in Chemotherapy

Efflux pump mechanisms perform important physiological functions such as prevention of toxin absorption from the gastrointestinal tract; elimination of bile from the hepatocytes; effective functioning of the blood-brain barrier and placental barrier; and renal excretion of drugs. They exist in all living cells; but those in the bacterial and mammalian cells are more important to the clinician and pharmacologist; as they constitute an important cause of antimicrobial drug resistance; which contributes to treatment failure; high medical bills; and increased mortality / morbidity. This review was aimed at highlighting the role of efflux pump mechanisms in microbial resistance to chemotherapeutic agents. It was also aimed to elucidate their structure and mechanisms of action so as to integrate the efflux pump mechanisms in the design and development of novel antimicrobial agents.Findings from previous studies and research on this subject assessed through Google search; Pubmed; Hinari websites; as well as standard textbooks on chemotherapy; provided the needed information in the process of this review. Efflux pump inhibitors are promising strategies for preventing and reverting efflux-mediated resistance to chemotherapeutic agents. They are usually employed as adjuncts in antimicrobial and cancer chemotherapy. Toxicity; more common with the older-generation inhibitors such as verapamil and reserpine; constitutes the greatest impediment to their clinical applications. No efflux pump inhibitor has been approved for routine clinical use; as a result of doubtful clinical efficacy and unacceptably high incidence of adverse effects; particularly inhibition of the P-450 drug metabolizing enzyme. At present; their applications are mainly restricted to epidemiological studies. Nonetheless; the search for efficacious and tolerable efflux pump inhibitors continues because of the potential benefits. There is a need to consider efflux pump substrate selectivity in the design and development of novel chemotherapeutic agents

p53 Expression in Colorectal Carcinoma in Relation to Histopathological Features in Ugandan Patients

Background: It has been shown that colorectal carcinoma is increasing in incidence in African countries. This could be due to change in life style. Molecular patho- genesis of colorectal cancer commonly involves mutation in p53 gene which leads to expression of p53 protein in tumor cells. Expression of p53 protein has been associated with poor clinical outcome and reduced survival in patients. Objective: This was a retrospective laboratory based study carried out in the Department of Pathology Makerere University; Kampala; Uganda. The aim of the study was to evaluate the expression of p53 protein in colorectal carcinoma in Ugandan patients; specifically its association with histological types; degree of differentiation; sites of the tumor and demographic characteristics of the patients. Methods: Immuno- histochemistry was carried out on 109 patient's paraffin embedded tissue blocks of colorectal carcinoma diagnosed in the Pathology Department; Faculty of Medicine Makerere University Kampala during the period 1995 to 2005. The indirect immunoperoxidase method using monoclonal antibody p53 DO-7 and Envision + Dual link system-HRP to detect p53 expression was used. Haematoxylin and eosin stain was used for evaluation of histological types and degree of differentiation of the tumors. Topography of the tumors and demographic data were obtained from accompanying histological request forms. Results: Out of 109 patient's tissue blocks that were studied; 61 cases (56) expressed p53 protein in the nucleus of malignant cells. Right sided colonic tumors were commoner (53.2) than left sided colonic tumors (46.8). p53 protein was expressed more in left sided colonic tumors with a significant difference (p0.05); it was also expressed more in well differentiated tumors and non mucinous adenocarcinomas but with no significant difference (p0.05). p53 expression was not affected by age or sex. Conclusion: Frequency of p53 protein expression in Ugandan patients did not differ from that reported in the other parts of the world. It was expressed more in the left sided colonic tumors and this could support the hypothesis that right and left colonic tumors could have different pathogenesis and probably also responsible for difference in prognosis in these two topographic sites

The Prevalence of the Alpha Thalassaemia Gene among Sicklers attending the Sickle Cell Clinic at Mulago Hospital

Across sectional study to determine the prevalence of the alpha-thal gene among sicklers attending the out=patient clinic at Mulago Hospital in Uganda was carried out during the period 19th December; 1994 to 31st January 1995 inclusive. one hundred and forty two subjects were recruited and studied. Blood collected on filter papers was analysed for alpha-thalassaemia using multiplex polymerase chain reaction techniques. Out of 142 patients; 110(77.5) had alpha-thal-2 deletion;while 32(25.5) patients had normal alpha globin genotype. The gene frequency of(-) among the sicle cell patients studied was recorded as 0.425; which is almost twice that recorded in other parts of Africa such as Kenya which was 0.26(Ojwang;1987). Almost all the patients with alpha-thal; (100/110) were heterozygous (/) whilst 10 were homozygous (_/_). A comparison of the alpha- thal and the non-alpha-thal groups suggested that alpha thal has little or no effect on homozygous sickle cell disease. Among patients more than sixty months of age; those without concurrent alpha-thal had a significant hepatomegaly of more than four centimetres as compared to those with alpha-thal. There is need for a larger longitudinal case controlled study to clarify further the effect of alpha-thal gene on sicle cell anaemia

Extensive genetic diversity in the HLA class II region of Africans; with a focally predominant allele; DRB1*1304

Molecular HLA class II typing of greater than 1700 individuals from The Gambia in West Africa and Malawi in South-Central Africa revealed a striking diversity of HLA DRB-DQB haplotypes as defined by restriction fragment length polymorphism (RFLP); this diversity is twice as extensive as that found in northern Europeans. Despite this diversity; sequence and PCR/oligonucleotide analysis showed that the recently described variant DRB1*1304 is the commonest DRB1 allele in The Gambia. The sequence; geographical distribution; and RFLP association of this allele; together with homozygosity test results; suggest that DRB1*1304 may have arisen from DRB1*1102 and have reached its remarkably high frequency as a result of recent directional selection. The prevalence of this unusual allele has implications for trials of subunit vaccines in this area. The extensive and distinctive HLA class II region polymorphism in sub-Saharan Africans is consistent with evidence from other genetic loci implying an African origin of modern Homo sapiens