Structures of HIV-1 gp120 envelope glycoproteins from laboratory-adapted and primary isolates

BACKGROUND: The gp120 exterior envelope glycoprotein of HIV-1 binds sequentially to CD4 and chemokine receptors on cells to initiate virus entry. During natural infection, gp120 is a primary target of the humoral immune response, and it has evolved to resist antibody-mediated neutralization. We previously reported the structure at 2.5 A of a gp120 core from the HXBc2 laboratory-adapted isolate in complex with a 2 domain fragment of CD4 and the antigen binding fragment of a human antibody. This revealed atomic details of gp120-receptor interactions and suggested multiple mechanisms of immune evasion. RESULTS: We have now extended the HXBc2 structure in P222, crystals to 2.2 A. The enhanced resolution enabled a more accurate modeling of less-well-ordered regions and provided conclusive identification of the density in the central cavity at the crux of the gp120-CD4 interaction as isopropanol from the crystallization medium. We have also determined the structure of a gp120 core from the primary clinical HIV-1 isolate, YU2, in the same ternary complex but in a C2 crystal lattice. Comparisons of HXBc2 and YU2 showed that while CD4 binding was rigid, portions of the gp120 core were conformationally flexible; overall differences were minor, with sequence changes concentrated on a surface expected to be exposed on the envelope oligomer. CONCLUSIONS: Despite dramatic antigenic differences between primary and laboratory-adapted HIV-1, the gp120 cores from these isolates are remarkably similar. Taken together with chimeric substitution and sequence analysis, this indicates that neutralization resistance is specified by quaternary interactions involving the major variable loops and thus affords a mechanism for viral adaptation. Conservation of the central cavity suggests the possibility of therapeutic inhibitors. The structures reported here extend in detail and generality our understanding of the biology of the gp120 envelope glycoprotein.     

CoQ9 potentiates green tea antioxidant activities in Wistar rats

Green tea (Camellia sinensis), and CoQ(9 )when given to Wistar rats produced a partial reversal on reserpine induced oxidative stress and liver damage. Green tea, with its abundant polyphenol (-)Epigallocatechin 3-gallate (ECGC) and other catechins, is known for its antioxidative characteristics influencing lipid metabolism. Ubiquinone, abundant in heart muscle, is also a potent antioxidant with known effects in numerous pathologies. However the combined effect of ECGC and ubiquninone has not been reported. In the present study we found that green tea extract, when given in combination with CoQ(9) to Wistar rats subjected to oxidative stress, showed a statistically significant antioxidative effect. Liver cholesterol level in rats receiving combination treatment was also significantly lower than control or rats receiving green tea extract alone. Reserpine induced liver damage in Wistar rats was also partially reversed by a treatment of green tea extract when combined with CoQ(9). These results may have important clinical implications and may be extrapolated for the treatment of patients suffering from liver damage due to hepatitis B/C or liver cirrhosis.     

Curcumin as a therapeutic agent in leukemia

Leukemia comprises a group of hematological malignancies responsible for 8% of all cancers and is the most common cancer in children. Despite significant improvements in leukemia treatment, the efficacy of conventional chemotherapeutic agents is low and the disease carries a poor prognosis with frequent relapses and high mortality. Curcumin is a yellow polyphenol compound with diverse pharmacological actions including anticancer, antioxidant, antidiabetic, anti-inflammatory, immunomodulatory, hepatoprotective, lipid-regulating, antidepressant, and antiarthritic. Many cellular and experimental studies have reported the benefits of curcumin in treating leukemia. Curcumin's anticancer effects are exerted via various mechanisms. Here, we review the effects of curcumin on various types of leukemia whilst considering its mechanisms of action.     

Impact of Universal Health Insurance Coverage on Hypertension Management: A Cross-National Study in the United States and England

Background

The Patient Protection and Affordable Care Act (ACA) galvanised debate in the United States (US) over universal health coverage. Comparison with countries providing universal coverage may illustrate whether the ACA can improve health outcomes and reduce disparities. We aimed to compare quality and disparities in hypertension management by socio-economic position in the US and England, the latter of which has universal health care.

Method

We used data from the Health and Retirement Survey in the US, and the English Longitudinal Study for Aging from England, including non-Hispanic White respondents aged 50–64 years (US market-based v NHS) and >65 years (US-Medicare v NHS) with diagnosed hypertension. We compared blood pressure control to clinical guideline (140/90 mmHg) and audit (150/90 mmHg) targets; mean systolic and diastolic blood pressure and antihypertensive prescribing, and disparities in each by educational attainment, income and wealth, using regression models.

Results

There were no significant differences in aggregate achievement of clinical targets aged 50 to 65 years (US market-based vs. NHS- 62.3% vs. 61.3% [p = 0.835]). There was, however, greater control in the US in patients aged 65 years and over (US Medicare vs. NHS- 53.5% vs. 58.2% [p = 0.043]). England had no significant socioeconomic disparity in blood pressure control (60.9% vs. 63.5% [p = 0.588], high and low wealth aged ≥65 years). The US had socioeconomic differences in the 50–64 years group (71.7% vs. 55.2% [p = 0.003], high and low wealth); these were attenuated but not abolished in Medicare beneficiaries.

Conclusion

Moves towards universal health coverage in the US may reduce disparities in hypertension management. The current situation, providing universal coverage for residents aged 65 years and over, may not be sufficient for equality in care.     

Synthesis and in vivo diuretic activity of some novel pyrimidine derivatives

A series of 1,6-dihydropyrimidine-2-amine derivatives and 1,6-dihydropyrimidine-2-thiol derivatives were synthesized by the reaction of substituted 1,3-diphenylprop-2-en-1-one (chalcones) with guanidine hydrochloride and thiourea, respectively. All the synthesized compounds were in good agreement with elemental and spectral data. The synthesized compounds were screened in vivo for diuretic activity. The four compounds 2d, 2e, 3d and 3e, which showed moderate to good diuretic activity, were evaluated for their toxicity studies and none of the compounds showed any toxicity of the liver as compared with control. However, compounds 3e and 3d showed diuretic properties more than that of standard (acetazolamide) and were long acting. Overall, compound 3e, 6-(2,6-dichlorophenyl)-4-(pyridin-2-yl)-1,6-dihydropyrimidine-2-thiol, was found to be the most promising candidate of the series.     

The effects of pay for performance on disparities in stroke, hypertension, and coronary heart disease management: interrupted time series study

Background

The Quality and Outcomes Framework (QOF), a major pay-for-performance programme, was introduced into United Kingdom primary care in April 2004. The impact of this programme on disparities in health care remains unclear. This study examines the following questions: has this pay for performance programme improved the quality of care for coronary heart disease, stroke and hypertension in white, black and south Asian patients? Has this programme reduced disparities in the quality of care between these ethnic groups? Did general practices with different baseline performance respond differently to this programme?

Methodology/Principal Findings

Retrospective cohort study of patients registered with family practices in Wandsworth, London during 2007. Segmented regression analysis of interrupted time series was used to take into account the previous time trend. Primary outcome measures were mean systolic and diastolic blood pressure, and cholesterol levels. Our findings suggest that the implementation of QOF resulted in significant short term improvements in blood pressure control. The magnitude of benefit varied between ethnic groups with a statistically significant short term reduction in systolic BP in white and black but not in south Asian patients with hypertension. Disparities in risk factor control were attenuated only on few measures and largely remained intact at the end of the study period.

Conclusions/Significance

Pay for performance programmes such as the QOF in the UK should set challenging but achievable targets. Specific targets aimed at reducing ethnic disparities in health care may also be needed.