10 research outputs found
A prospective study of mortality from cryptococcal meningitis following treatment induction with 1200 mg oral fluconazole in Blantyre, Malawi.
No full textOBJECTIVE: We have previously reported high ten-week mortality from cryptococcal meningitis in Malawian adults following treatment-induction with 800 mg oral fluconazole (57% [33/58]). National guidelines in Malawi and other African countries now advocate an increased induction dose of 1200 mg. We assessed whether this has improved outcomes.
DESIGN: This was a prospective observational study of HIV-infected adults with cryptococcal meningitis confirmed by diagnostic lumbar puncture. Treatment was with fluconazole 1200 mg/day for two weeks then 400mg/day for 8 weeks. Mortality within the first 10 weeks was the study end-point, and current results were compared with data from our prior patient cohort who started on fluconazole 800 mg/day.
RESULTS: 47 participants received fluconazole monotherapy. Despite a treatment-induction dose of 1200 mg, ten-week mortality remained 55% (26/47). This was no better than our previous study (Hazard Ratio [HR] of death on 1200 mg vs. 800 mg fluconazole: 1.29 (95% CI: 0.77-2.16, p = 0.332)). There was some evidence for improved survival in patients who had repeat lumbar punctures during early therapy to lower intracranial pressure (HR: 0.27 [95% CI: 0.07-1.03, p = 0.055]).
CONCLUSION: There remains an urgent need to identify more effective, affordable and deliverable regimens for cryptococcal meningitis
The impact of foreign direct investment on the economic growth and development of sub-Saharan African countries, 1998
No full textThis study examines the social and economic effects of multinational corporations (MNCs), the main purveyors of foreign direct investment (EDI), on the countries of sub-Saharan Africa. The study is based on the rift in empirical and theoretical findings concerning the actual effects of multinational presence in a developing country. On one hand, those who believe in the efficiency of MNCs in bringing about global development have produced studies and theories to support their view of multinationals as the great equalizers among nations. On the other hand, those in disagreement with this view of the multinational have also produced studies and theories, which contend that the MNC has adverse effects on political and economic sovereignty and the fulfillment of basic needs in developing economies. A regression analysis was used to investigate the effects of foreign direct investment (EDI), foreign aid (ODA) and political stability (PS) on the economic growth and economic development of thirty sub-Saharan African countries during two time periods: 1980-1989 and 1990-1995. Foreign aid and political stability were also used in the study due to the fact that both have been known to affect the direction of growth and development. The time periods were chosen to analyze the effects of the end of the Cold War (1989) on sub-Saharan African countries. The researcher found that political stability had the most significant impact on economic growth in period 2 and economic development in both time periods. The conclusions drawn from the findings suggest that the small amount of foreign investment that sub-Saharan Africa receives probably accounts for its insignificant effects on economic growth and development. They also suggest that cormption concerning the misuse of foreign aid probably accounts for the insignificant effects that foreign aid had on economic growth and economic growth and development
Three epidemics of invasive multidrug-resistant salmonella bloodstream infection in Blantyre, Malawi, 1998-2014
No full textBackground. The Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW) has routinely collected specimens for blood culture from febrile patients, and cerebrospinal fluid from patients with suspected meningitis, presenting to Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi, since 1998. Methods. We present bloodstream infection (BSI) and meningitis surveillance data from 1998 to 2014. Automated blood culture, manual speciation, serotyping, and antimicrobial susceptibility testing were performed at MLW. Population data for minimum-incidence estimates in urban Blantyre were drawn from published estimates. Results. Between 1998 and 2014, 167 028 blood cultures were taken from adult and pediatric medical patients presenting to QECH; Salmonella Typhi was isolated on 2054 occasions (1.2%) and nontyphoidal Salmonella (NTS) serovars were isolated 10 139 times (6.1%), of which 8017 (79.1%) were Salmonella Typhimurium and 1608 (15.8%) were Salmonella Enteritidis. There were 392 cases of NTS meningitis and 9 cases of Salmonella Typhi meningitis. There have been 3 epidemics of Salmonella BSI in Blantyre; Salmonella Enteritidis from 1999 to 2002, Salmonella Typhimurium from 2002 to 2008, and Salmonella Typhi, which began in 2011 and was ongoing in 2014. Multidrug resistance has emerged in all 3 serovars and is seen in the overwhelming majority of isolates, while resistance to third-generation cephalosporins and fluoroquinolones is currently uncommon but has been identified. Conclusions. Invasive Salmonella disease in Malawi is dynamic and not clearly attributable to a single risk factor, although all 3 epidemics were associated with multidrug resistance. To inform nonvaccine and vaccine interventions, reservoirs of disease and modes of transmission require further investigation
Mediation of radiation-induced bystander effect and epigenetic modification: The role of exosomes in cancer radioresistance
No full textExosomes are nano-sized extracellular vesicles produced by almost all mammalian cells. They play an important role in cell-to-cell communication by transferring biologically active molecules from the cell of origin to the recipient cells. Ionizing radiation influences exosome production and molecular cargo loading. In cancer management, ionizing radiation is a form of treatment that exerts its cancer cytotoxicity by induction of DNA damage and other alterations to the targeted tissue cells. However, normal bystander non-targeted cells may exhibit the effects of ionizing radiation, a phenomenon called radiation-induced bystander effect (RIBE). The mutual communication between the two groups of cells (targeted and non-targeted) via radiation-influenced exosomes enables the exchange of radiosensitive molecules. This facilitates indirect radiation exposure, leading, among other effects, to epigenetic remodeling and subsequent adaptation to radiation. This review discusses the role exosomes play in epigenetically induced radiotherapy resistance through the mediation of RIBE
Comparison of baseline variables between patients initiated on fluconazole 800mg and those initiated on fluconazole 1200mg.
No full texta<p>Continuous variables analysed by Wilcoxon test, categorical variables analysed by χ<sup>2</sup>-test test.</p>b<p>Includes blindness, cranial nerve palsies or focal weakness.</p><p>Comparison of baseline variables between patients initiated on fluconazole 800mg and those initiated on fluconazole 1200mg.</p
Kaplan-Meier Survival plot of patients on fluconazole.
No full text<p>A: 800mg induction dose. B: Kaplan-Meier Survival plot of patients on fluconazole 1200mg induction dose.</p
MicroRNA-376a-3p sensitizes CPT-11-resistant colorectal cancer by enhancing apoptosis and reversing the epithelial-to-mesenchymal transition (EMT) through the IGF1R/PI3K/AKT pathway
No full textColorectal cancer (CRC) remains the third most prevalent type of cancer worldwide contributing to an estimated 10 % of all cancer cases. CPT-11 is one of the first-line drugs for CRC treatment. Unfortunately, the development of drug resistance significantly exacerbates the adverse impact of CRC. Consequent tumor recurrences and metastasis, years after treatment are the frequently reported incidences. MicroRNAs (miRNA) are short non-coding RNA with the functionality of gene suppression. The insulin-like growth factor type 1 receptor (IGF1R) is a tyrosine kinase receptor frequently upregulated in cancers and is associated with cell survival and drug resistance. MiRNAs are frequently reported to be dysregulated in cancers including CRC. Evidence suggests that dysregulated miRNAs have direct consequences on the biological processes of their target genes. We previously demonstrated that miRNA-376a-3p is upregulated in CPT-11responsive, CRC cells upon treatment with CPT-11. We therefore aimed to investigate the involvement of miRNA-376a-3p in CPT-11 resistance and its probable association with IGF1R-mediated cancer cell survival. Our experimental approach used knockdown and overexpression experiments supplemented with western blot, RT-qPCR, flow cytometry, MTT, and migration assays to achieve our aim. Our data reveals the mechanism through which IGF1R and miRNA-376a-3p perpetrate and attenuate CPT-11 resistance respectively. MiRNA-376a-3p overexpression negatively regulated the IGF1R-induced cell survival, PI3K/AKT pathway, and reversed the epithelial-mesenchymal transition, hence sensitizing resistant cells to CPT-11. Our findings suggests that the miRNA-376a-3p/IGF1R axis holds promise as a potential target to sensitize CRC to CPT-11 in cases of drug resistance
Alveolar T-helper 17 responses to streptococcus pneumoniae are preserved in ART-untreated and treated HIV-infected Malawian adults
No full textWe explored if HIV infection is associated with impaired T-Helper 17 responses against Streptococcus pneumoniae in the lung. We recruited 30 HIV-uninfected healthy controls, 23 asymptomatic HIV-infected adults not on ART, and 40 asymptomatic HIV-infected adults on ART (Median time 3.5yrs), in whom we collected bronchoalveolar lavage fluid. We measured alveolar CD4+ T cell immune responses following stimulation with pneumococcal cell culture supernatant using flow cytometry-based intracellular cytokine staining. We found that the proportion of alveolar CD4+ T cells producing IL-17A following stimulation with pneumococcal cell culture supernatant (CCS) was similar between HIV-uninfected controls and ART-naïve HIV-infected adults (0.10% vs. 0.14%; p = 0.9273). In contrast, the proportion and relative absolute counts of CD4+ T cells producing IL-17A in response to pneumococcal CCS were higher in ART-treated HIV-infected adults compared HIV-uninfected controls (0.22% vs. 0.10%, p = 0.0166; 5420 vs. 1902 cells/100 ml BAL fluid; p = 0.0519). The increase in relative absolute numbers of IL-17A-producing alveolar CD4+ T cells in ART-treated individuals was not correlated with the peripheral blood CD4+ T cell count (r=-0.1876, p = 0.1785). Alveolar Th17 responses against S. pneumoniae are preserved in HIV-infected adults. This suggests that there are other alternative mechanisms that are altered in HIV-infected individuals that render them more susceptible to pneumococcal pneumonia. [Abstract copyright: Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.]</p
Genomic identification of a novel co-trimoxazole resistance genotype and its prevalence amongst Streptococcus pneumoniae in Malawi.
No full textOBJECTIVES: This study aimed to define the molecular basis of co-trimoxazole resistance in Malawian pneumococci under the dual selective pressure of widespread co-trimoxazole and sulfadoxine/pyrimethamine use. METHODS: We measured the trimethoprim and sulfamethoxazole MICs and analysed folA and folP nucleotide and translated amino acid sequences for 143 pneumococci isolated from carriage and invasive disease in Malawi (2002-08). RESULTS: Pneumococci were highly resistant to both trimethoprim and sulfamethoxazole (96%, 137/143). Sulfamethoxazole-resistant isolates showed a 3 or 6 bp insertion in the sulphonamide-binding site of folP. The trimethoprim-resistant isolates fell into three genotypic groups based on dihydrofolate reductase (encoded by folA) mutations: Ile-100-Leu (10%), the Ile-100-Leu substitution together with a residue 92 substitution (56%) and those with a novel uncharacterized resistance genotype (34%). The nucleotide sequence divergence and dN/dS of folA and folP remained stable from 2004 onwards. CONCLUSIONS: S. pneumoniae exhibit almost universal co-trimoxazole resistance in vitro and in silico that we believe is driven by extensive co-trimoxazole and sulfadoxine/pyrimethamine use. More than one-third of pneumococci employ a novel mechanism of co-trimoxazole resistance. Resistance has now reached a point of stabilizing evolution. The use of co-trimoxazole to prevent pneumococcal infection in HIV/AIDS patients in sub-Saharan Africa should be re-evaluated
