Abstract
Background
Few data exist on cardiac fibrosis and inflammation in youth with HIV, particularly in sub-Saharan Africa.
Purpose
Our objective was to assess the association between HIV status ...and cardiovascular magnetic resonance (CMR) measures of subclinical cardiac fibrosis, inflammation, and function.
Methods
We performed CMR on a cross-section of youth in South Africa: youth with perinatally acquired HIV (YPHIV), youth with non-perinatally acquired HIV (YNPHIV), and HIV-seronegative youth (YHIV-). Subclinical fibrosis late gadolinium enhancement (LGE) mass and fraction, extracellular volume (ECV), inflammation native T1 and T2 mapping, and cardiac function (cine, strain, and strain rate) were assessed. CD4, viral load (VL), and fasting glucose, insulin for Homeostatic Model Assessment-Insulin Resistance (HOMA) and lipids were obtained. Unadjusted and adjusted quantile regression models were used to assess the association between HIV status and CMR outcomes. In sub-group analyses of youth with HIV, we additionally adjusted for HIV factors.
Results
Of 464 youth, 287 were YPHIV, 87 YNPHIV, and 90 YHIV-. YNPHIV were older with a higher proportion self-identifying as female than YPHIV and YHIV- (median age 20 vs 18 and 17 years; 85% vs 50% and 49%, respectively). YPHIV had lower body surface area (1.6 vs 1.7 and 1.7m2) and a higher proportion with prior TB disease (70% vs. 20% vs 8%) compared to YNPHIV and YHIV-. Tobacco use, HOMA, total cholesterol, and low-density lipoproteins were similar between groups. Among youth with HIV, YPHIV had a higher proportion with CD4<200 cells/mm3 (10% vs 4%) or VL>50 copies/mL (39% vs 13%) but lower proportion on integrase inhibitors (33% vs 84%). LGE mass (0.13 vs 0.12 vs 0.07g respectively) and fraction (0.3% vs 0.3% vs. 0.2% respectively) were higher in YPHIV and YNPHIV than YHIV-; native T1 was highest in YNPHIV compared to YPHIV and YHIV- (Table). In adjusted analyses, compared to YHIV-, median LGE mass was higher in YPHIV and YNPHIV (β:0.06, p=0.01 for YPHIV, β:0.05, p=0.03 for YNPHIV) and LGE% was higher in YPHIV (β:0.14, p=0.02); native T1 and ECV did not differ between groups in adjusted analyses. Among youth with HIV, CMR outcomes did not differ significantly for persons with perinatal vs non-perinatal HIV. Findings did not vary in analyses restricted to females.
Conclusion
In one of the largest studies of CMR among youth with HIV in sub-Saharan Africa, we found that despite their young age, YPHIV and YNPHIV appear to have higher subclinical cardiac fibrosis than YHIV- and healthy adults in South Africa. Youth with HIV may benefit from early screening and long-term monitoring for cardiovascular disease.TableFigure
The dual-action HIV-1 protease and reverse transcriptase inhibition potential of coumarin–AZT conjugates has been explored using saturation transfer difference (STD) NMR, computer modelling and ...enzyme inhibition techniques.
Baylis–Hillman-derived 3-(benzylaminomethyl)coumarins have been treated, sequentially, with chloroacetyl chloride and propargylamine to afford alkynylated coumarins as substrates for Click Chemistry reactions with azidothymidine (AZT) in the presence of a Cu(I) catalyst. The dual-action HIV-1 protease (PR) and reverse transcriptase (RT) inhibition potential of the resulting N-benzylated cycloaddition products, and a series of non-benzylated analogues, has been explored using saturation transfer difference (STD) NMR, computer modelling and enzyme inhibition techniques.
Vernonia adoensis is a folk herbal medicine traditionally used to treat tuberculosis and tuberculosis-related ailments. The study aimed to determine the antitubercular activity of V. adoensis and its ...possible mode of action against Mycobacterium smegmatis. Extracts and phytochemicals were tested for growth inhibitory and bactericidal activities against M. smegmatis. The effects of the most effective plant extract on drug transport across the membrane and its ability to cause membrane and protein leakage in mycobacterial cells were determined. Its capacity to quench DPPH (2, 2-diphenyl-1-picryl-hydrazyl) was also evaluated. The ethyl acetate extract from Vernonia adoensis leaf was most effective against M. smegmatis with a minimum inhibitory concentration and minimum bactericidal concentration of 63 μg/ml and 125 μg/ml respectively. The most active phytochemical was the alkaloid fraction with an MIC of 125 μg/ml. Significant nucleic acid and protein leakage in M. smegmatis was observed after exposure to the leaf extract. The extract did not possess significant free radical scavenging activity and did not affect drug transport in mycobacterial cells. Results showed that the ethyl acetate leaf extract exhibited potential antimycobacterial activity against M. smegmatis. Cell membrane disruption resulting in protein and nucleic acid leakage could be the plant's possible mode of action.
3-Hydroxy-3-phenylpropanoate ester–AZT conjugates have been prepared and their potential as dual-action HIV-1 Integrase and Reverse Transcriptase inhibitors has been explored and compared with their ...cinnamate ester analogues. Display omitted
Novel 3-hydroxy-3-phenylpropanoate ester–azidothymidine (AZT) conjugates have been prepared using Baylis–Hillman methodology, and their potential as dual-action HIV-1 Integrase and Reverse Transcriptase inhibitors has been explored using enzyme inhibition and computer modelling techniques; their activity and HeLa cell toxicity have been compared with those of their cinnamate ester analogues.
Current tuberculosis regimens have failed to combat the issue of drug resistance and ethno medicines may represent a possible source of antimycobacterial agents. Combretum species are well known in ...African traditional medicines and used for various ailments including pneumonia, venereal diseases like syphilis, mental problems, relief of sore throats and colds, fever, and chest coughs associated with tuberculosis. Alkaloids function as either hydrogen-acceptor or hydrogen-donor in hydrogen bonding critical for the interaction between targets thus, potentiating effects of curative agents on diseases. Alkaloid extracts from leaves of Combretum zeyheri, Combretum platypetalum, Combretum molle and Combretum apiculatum, were assessed for antimycobacterial activity to establish rationale for their use in traditional medicines for various ailments including pneumonia, relief of sore throats and colds, fever, and chest coughs associated with tuberculosis.
Alkaloids were extracted from the leaves of Combretum zeyheri, Combretum platypetalum, Combretum molle and Combretum apiculatum. The broth microdilution method was used for the screening of growth inhibitory activity. The standard drug rifampicin was used as the positive control. Alkaloid extracts from the most potent plant species, Combretum zeyheri were further investigated for time-kill dependency effects on drug transport in Mycobacterium smegmatis.
Using the broth microdilution susceptibility method, C. zeyheri alkaloid extract, was found to have the most antimycobacterial effects with an MIC value of 125 μg/ml whilst MICs for C. molle and C. platypetalum were above 1000 μg/ml. An MBC value of 250 μg/ml was observed with alkaloid extracts from Combretum zeyheri whilst the remaining three Combretum species showed no bactericidal activity. It was also shown that C. zeyheri had potential efflux pump inhibitory activity. Determination of the time-kill kinetics of extracts from C. zeyheri showed not only a concentration-dependent activity but time-dependent bactericidal effect as well.
Alkaloid extracts from the leaves of C. zeyheri have potential as a source of lead compounds that may be developed further into antimycobacterial compounds. The mechanism of action of may be due to inhibition of transport across the cell membrane. Further work needs to be done to isolate the active components in these extracts.
DESIGN OF AN ANIMAL DRAWN DISC RIDGER Mautsa, M. L.
JOURNAL of the JAPANESE SOCIETY of AGRICULTURAL MACHINERY,
2001, Letnik:
63, Številka:
Supplement
Journal Article
The signal transducer and activator of transcription (STAT) and protein inhibitor of STAT(PIAS) system represent an elegant regulatory mechanism of transcriptional control IN mammalian cytokine ...signalling. Abnormal activation of the system is associated with immune disorders and a large group of diverse tumours. PIAS3 is a multiple domain protein with distinct functions involved in regulation of cytokine-mediated gene activation pathways.Its over-expression significantly inhibits cell growth and renders cancer cells more sensitive to drugs. The objective of this study was to structurally and biochemically characterise the function of the PIAS3 protein using in silico, in vivo and in vitro analysis approaches.The conservation pattern of the PIAS protein family and critical conserved residues in the PINIT (Proline, Isoleucine, Asparagine, Isoleucine, Tyrosine) domain were identified. The PINIT domain model was generated based on the PINIT domain structure of yeast PIAS3 homologue Siz1 and structural determinants in the PIAS3-STAT3 interaction were evaluated.Guided by the in silico findings, in vivo analysis of the localisation of the PIAS3, mutantderivatives of PIAS3 (PIAS3-L97A, PIAS3-R99N, PIAS3-R99Q), PINIT and acidic domain was conducted. PIAS3 was completely localised in the nucleus while PIAS3 mutants appeared to exhibit diffuse cytoplasmic distribution. The PINIT domain was predominantly localised in the nucleus with some apparent perinuclear staining while the acidic domain exhibited a predominantly perinuclear staining pattern. Further analysis of the PINIT domain and the effect of the mutants on PIAS3-STAT3 interaction were assessed by in vitro analysis. Guided by in silico analysis, the PINIT domain and mutant derivatives of PINIT domain (PINIT-L97A, PINIT-R99N, and PINIT-R99Q) were heterologously expressed in Escherichia coli and subsequently purified using a combination of immobilized metal affinity and size exclusion based chromatography. The size and structural elements of the PINIT domain and its mutants were characterised. The 23 kDa PINIT domain was found to exist as a monomer in solution and its secondary structure was shown to consist of 66 % β-sheets by fourier transformed infrared spectroscopy consistent with the generated homology model.Using surface plasmonresonance spectroscopy (SPR) the PINIT domain was shown to bind to STAT3 in a specific concentration dependent manner. Recombinant PINIT-L97A,PINITR99N and PINIT-R99Q mutants, which exhibited similar structural integrity to the wildtype, were found to abrogate binding to STAT3. These findings suggest that these residues form part of a potential binding surface for stat3. In conclusion, this study has provided evidence that the PINIT domain is an important determinant of PIAS3 interaction with STAT3 and that the interaction is mediated by defined conserved residues directly involved in the PINITSTAT3 interaction.
Community participation is an effective strategy for strengthening health systems and progressively realising health rights. For meaningful community participation to occur, the capacity of formal or ...informal community organisations and mechanisms involved in addressing social determinants of health needs to be strengthened. One way of doing this is through training. There is minimal research on the efforts of community structures set up to address social determinants of health and health needs in communities, following training to strengthen their capacity. This study sought to evaluate the successes and challenges of a particular Community Systems Strengthening Project which, between 2016 and 2019, set out to train health committee members and community health activists in Gugulethu, South Africa. In so doing, it investigated whether and how the health committee members and Community Health Activists assumed an activist role in the community and are engaging in meaningful community participation. A mixed methods evaluative study was conducted in two phases during 2020-2021. The first phase was a scoping review of available literature, followed by an evaluative study including review of project documents, observation by attending events organised by the project and other community organisations, and in-depth interviews with health committee members (2), community health activists (4) and project staff (4). The training intervention was found to have influenced the health committee members and Community Health Activists thinking, understanding and practice in their community efforts to address social determinants of health. Therefore, adequate support, training, and an enabling environment can facilitate meaningful community participation in health. Ultimately, these measures will contribute to the progressive realisation of the right to health and the right to community participation, and ultimately health system transformation. The limited adaptability of the intervention, limited resources, participant perceptions and sustainability were found to be obstacles to meaningful community participation. This dissertation consists of two parts. The study protocol, Part A, outlines the rationale of undertaking this research and the proposed methods. Part B consists of the journal ready manuscript which presents the results and discussion of the research findings.
PDF
