Browsing by Author "Mbai, Fiona N"

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Changes in genotypes of Plasmodium falciparum human malaria parasite following withdrawal of chloroquine in Tiwi, Kenya
(Elsevier, 2012) Mang’era, Clarence M.; Mbai, Fiona N; Omedo, Irene A; Mireji, Paul O; Omar, Sabah A
Chloroquine (CQ) drug was withdrawn in 1998 as a first-line treatment of uncomplicated malaria in Kenya. This was in response to resistance to the drug in Plasmodium falciparum malaria parasite. Investigations were conducted to determine prevalence of CQ resistance genotypes in the parasites in Tiwi, a malaria endemic town in Kenya, before and about a decade after the withdrawal of the drug. Blood samples were collected and spotted on filter papers in 1999 and 2008 from 75 and 77 out-patients respectively with uncomplicated malaria. The sampling was conducted using finger pricking technique. DNA was extracted from individual spots in the papers and screened for the presence of P. falciparum chloroquine resistance transporter (Pfcrt) and multi drug resistance (Pfmdr-1) markers using nested PCR. Nature of mutations (haplotypes) in the Pfcrt and Pfmdr-1 markers in the samples were confirmed using dot blot hybridization technique. Changes in pattern of CQ resistance in the parasite samples in 1999 and 2008 were assessed by Chi Square test. There was a significant (P < 0.05) reduction in CQ resistant genotypes of the parasite between 1999 and 2008. Pfmdr and Pfcrt CQ resistant genotypes in 2008 reduced to 54.10 and 63.64% respectively, from 75.39 and 88.0% respectively in 1999. This reduction was accompanied by emergence of Pfcrt specific CQ sensitive (IEK) and intermediate/partially CQ resistant (MET) haplotypes. Results suggest significant reversal of the phenotype of the parasite from chloroquine resistant to wild/sensitive type. The novel haplotypes indicates transitional phase of the parasite to the wild type. Current prevalence of chloroquine resistant genotype is definitely above the threshold for efficacious re-introduction of chloroquine for treatment of malaria in Tiwi.
Characterisation of Murine Endometrial Epithelium in Vitro: Effects of Epidermal Growth Factor.
(1997) Mbai, Fiona N
Effects of Dietary Decosahexaenoic Acid (DHA) on eNOS in Human Coronary Artery Endothelial Cells
(2008) Stebbins, Charles L; Stice, James P; Hart, Michael; Mbai, Fiona N; Knowlton, Anne A
Endothelial dysfunction occurs in heart disease and may reduce functional capacity via attenuations in peripheral blood flow. Dietary decosahexaenoic acid (DHA) may improve this dysfunction, but the mechanism is unknown. This study determined if DHA enhances expression and activity of eNOS in cultured human coronary artery endothelial cells (HCAEC). HCAEC from 4 donors were treated with 5 nM, 50 nM, or 1 μM DHA for 7 days to model chronic DHA exposure. A trend for increased expression of endothelial nitric oxide synthase (eNOS) and phospho-eNOS was observed with 5 and 50 nM DHA. DHA also enhanced expression of 2 proteins instrumental in activation of eNOS: phospho-Akt (5 and 50 nM) and HSP90 (50 nM and 1 μM). Vascular endothelial growth factor–induced activation of Akt increased NOx in treated (50 nM DHA) versus untreated HCAEC (9.2 ± 1.0 vs 3.3 ± 1.1 μmol/μg protein/μL). Findings suggest that DHA enhances eNOS and Akt activity, augments HSP90 expression, and increases NO bioavailability in response to Akt kinase activation
Efforts to identify early spontaneous embryo mortality in the rhesus monkey (Macaca mulatta)
(1989) Mbai, Fiona N
Evaluation of the Anticonvulsant Activity of the Leaf Methanol Extract of Crassula arborescens (Mill.) Willd. (Crassulaceae) in Mice
(2014) Amabeoku, George Jimboyeka; Mbamalu, Oluchi Nneka; Davids, Tasneem; Fakude, Samukelisiwe; Gqwaka, Anda; Mbai, Fiona N; Pieterse, Reighman; Shaik, Aneesa
Crassula arborescens (Mill.) Willd. subsp. Arborescens is widely used for the treatment of various ailments including diarrhoea, corns, epilepsy and as a purgati ve. However, no information exists in any literature to verify the acclaimed effecti veness of C. arborescens in the treatment of the various ailments. The study, therefore, intended to investigate the anticonvulsant activity of the leaf methanol extract of C. arborescens in mice. Acute toxicity study and phytochemical qualitative analysis of the plant extracts were also carried out. Chemically-induc ed convulsion methods were used to assess the anticonvulsant activity of C. arborescens . Standard methods were used for the acute t oxicity study and phytochemical analysis of the chemical compone nts of the plant extr act. PTZ (pentylenetetrazole), bicuculline, picrotoxin, NMDLA (N-methy l-DL-aspartic acid) or strychnine produced tonic convulsions i n all the mice used. Leaf methanol extract of Crassula arborescens , muscimol, phenobarbitone or di azepam significantly antagonised PTZ, bicuculline or picr otoxin-induced convulsion. C. arborescens or LY233053 significantly antagonised NMDLA-induced tonic convulsion. C. arborescens or phenobarbitone signifi cantly antagonised strychni ne-elicited tonic convulsi on. Phenytoin or DMSO (dimethylsulfoxide) did not significantly affect the tonic convulsion produced by PTZ, bicuculline, picrotoxin, NMDLA or strychnine. The LD 50 value obtained from intraperitoneal administration of C. arborescens was 781.6 mg/kg while that following oral administration of the plant extract was over 4,000 mg/kg. The phytochemical qualitativ e analysis done showed the presence of flavonoids, tannins, reducing sugar, saponins and triterpene steroids. The data obta ined in the study show that the leaf methan ol extract of Crassula arborescens has anticonvulsant activity which may be underpinned by GABAergic, glutaminergic and glycinergic mechanisms. The high LD 50 value obtained following the oral administra tion of the plant extract shows that the leaf methanol extract is non-toxic to animals.
Gender differences in cardiovascular disease: The effects of estrogen
(2005) Mbai, Fiona N; Hamilton, Karyn L; Knowlton, Anne A
Estrogen and its therapeutic application in cardiovascular disease are highly controversial. There has been a paucity of basic research on estrogen and its molecular effects, which has weakened the underpinnings of clinical trials of estrogen treatment. In the past 10 years, much has been discovered about both the genomic and nongenomic effects of estrogen. The identification of at least three distinct receptors for estrogen, as well as the development of drugs with varying binding affinities for different receptors, has created exciting therapeutic possibilities.
Impact of aging vs. estrogen loss on cardiac gene expression: estrogen replacement and inflammation
(2011) Pechenino, Angela S; Lin, Li; Mbai, Fiona N; Lee, Alison R; He, Xian-Min; Stallone, John N; Knowlton, AA
Despite an abundance of evidence to the contrary from animal studies, large clinical trials on humans have shown that estrogen administered to postmenopausal women increases the risk of cardiovascular disease. However, timing may be everything, as estrogen is often administered immediately after ovariectomy (Ovx) in animal studies, while estrogen administration in human studies occurred many years postmenopause. This study investigates the discrepancy by administering 17β-estradiol (E2) in a slow-release capsule to Norway Brown rats both immediately following Ovx and 9 wk post-Ovx (Late), and studying differences in gene expression between these two groups compared with age-matched Ovx and sham-operated animals. Two different types of microarray were used to analyze the left ventricles from these groups: an Affymetrix array (n = 3/group) and an inflammatory cytokines and receptors PCR array (n = 4/group). Key genes were analyzed by Western blotting. Ovx without replacement led to an increase in caspase 3, caspase 9, calpain 2, matrix metalloproteinase (MMP)9, and TNF-α. Caspase 6, STAT3, and CD11b increased in the Late group, while tissue inhibitor of metalloproteinase 2, MMP14, and collagen I α1 were decreased. MADD and fibronectin were increased in both Ovx and Late. TNF-α and inducible nitric oxide synthase (iNOS) protein levels increased with Late replacement. Many of these changes were prevented by early E2 replacement. These findings suggest that increased expression of inflammatory genes, such as TNF-α and iNOS, may be involved in some of the deleterious effects of delayed E2 administration seen in human studies
Rapid Activation of Nuclear Factor-κB by 17β-Estradiol and Selective Estrogen Receptor Modulators: Pathways Mediating Cellular Protection
(2012) Stice, James P; Mbai, Fiona N; Chen, Le; Knowlton, Anne A
17 β -estradiol (E2) treatment activates a set of protective response that have been found to protect cells from injury and more importantly to significantly abate the injuries associated with trauma- hemorrhage in vivo . Rapid NF κ B activation has been found to be an important signaling step in E2 mediated protection in cell culture, in vivo ischemia and trauma-hemorrhage. In the current study, we investigated the signaling cascades linking E2 signaling with NF κ B activation and the protective response, and compared them with the effects of two selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen. Two candidate pathways, mitogen activated protein kinases (MAPK), and phosphatidylinositol-3-kinase (PI3-K) were studied. Selective inhibitors were used to identify each pathway's contribution to NF κ B activation. Treatment of HCAECs with E2 activated PI3-K/Akt, p38, and JNK, all of which activated ERK 1/2 followed by NF κ B activation. The combined activation of Akt, p38 and JNK was essential to activate NF κ B. The two SERMs activated PI3-K and p38, which then phosphorylated ERK 1/2 and activated NF κ B independent of the JNK pathway. NFkB activation by these compounds protected cells from hypoxia/reoxygenation injury. However, E2, unlike either SERM, led to modest increases in apoptosis through the JNK pathway. SERM treatment led to increased expression of the protective proteins, Mn-superoxide dismutase and endothelial nitric oxide synthase, that was not seen with E2. These results provide new insight into the pathways activating NFkB by E2 and SERMS and demonstrate that SERMs may have greater protective benefits than E2 in adult endothelial cells and potentially in vivo , as well
Reply to “Letter to the Editor: ‘Understanding the WHI gap’
(2012) Pechenino, Angela S; Lee, Alison R; Lin, Li; Mbai, Fiona N; Stallone, John N; Knowlton, AA
This is a reply in response to Drs. Kerber's and Turner's commentary about our article (10) in Physiological Genomics. We thank Kerber and Turner for their enthusiastic response to our article and are pleased that they found it useful in their practice (10). However, we would like to point out that the link between estrogen therapy postmenopause and a decrease in dementia in older women is tenuous at best. Few studies indicate definitively that hormone replacement therapy (HRT) results in a decrease in dementia, and most only point toward a possibility that has yet to be realized (5). Basic studies in rodent models suggest that estrogen replacement can reduce brain injury in models of stroke, but more work is needed before taking these findings to the clinical setting (1). Additionally, the Women's Health Initiative (WHI) and the Million Woman Study indicate that breast cancer risk increases significantly when women are put on HRT, specifically with estrogen and progesterone taken in combination, a finding that should limit the use of HRT to those women who do not already manifest a high risk for breast cancer (2, 9). In contrast to chronic estrogen replacement, there is a small, but growing, literature supporting a role for a protective role of estrogen in acute injury (11–13). We and others have found that treatment with a high concentration of 17β-estradiol at the time of injury can greatly reduce inflammation and apoptosis (3, 4, 6, 14). Such limited use of E2 will not increase the risk of cancer but does have the possibility of greatly reducing tissue injury. We feel that a more promising area for the treatment of postmenopausal symptoms comes from the selective estrogen receptor modulators (SERMs). For example, raloxifene improved verbal memory in postmenopausal women when given over a period of 5 yr.(7) In contrast tamoxifen, a SERM that is primarily an estrogen antagonist, was associated with poorer performance on letter fluency and manual dexterity in women with breast cancer compared with untreated controls (8). Many SERMs have been synthesized, and some may have the positive, protective effects of estrogen without promoting cell proliferation and cancer. More work will be needed identifying the specific effects of these compounds before this type of treatment can be applied in the clinic to ameliorate aging-associated changes such as cardiovascular disease and dementia
A Venue-Based Approach to Reaching MSM, IDUs and the General Population with VCT: A Three Study Site in Kenya
(2012) Singh, Kavita; Brodish, Paul; Mbai, Fiona N; Kingola, Nzioki; Rinyuri, Agnes; Njeru, Carol; Mureithi, Patrick; Sambisa, William; Weir, Sharon
A venue-based HIV prevention study which included Voluntary Counseling and Testing (VCT) was conducted in three diverse areas of Kenya—Malindi, Nanyuki and Rachounyo. Aims of the study were to: (1) assess the acceptability of VCT for the general population, men who have sex with men (MSM), and injecting drug users (IDUs) within the context of a venue-based approach; (2) determine if there were differences between those agreeing and not agreeing to testing; and (3) study factors associated with being HIV positive. Approximately 98% of IDUs and 97% of MSM agreed to VCT, providing evidence that populations with little access to services and whose behaviors are stigmatized and often considered illegal in their countries can be reached with needed HIV prevention services. Acceptability of VCT in the general population ranged from 60% in Malindi to 48% in Nanyuki. There were a few significant differences between those accepting and declining testing. Notably in Rachuonyo and Malindi those reporting multiple partners were more likely to accept testing. There was also evidence that riskier sexual behavior was associated with being HIV positive for both men in Rachounyo and women in Malindi. Overall HIV prevalence was higher among the individuals in this study compared to individuals sampled in the 2008–2009 Kenya Demographic and Health Survey, indicating the method is an appropriate means to reach the highest risk individuals including stigmatized populations.