Potential risks and benefits of HIV treatment simplification: a simulation model of a proposed clinical trial.

BACKGROUND: In recent studies, subjects who had achieved suppression of the human immunodeficiency virus (HIV) RNA level while receiving an initial 3-drug antiretroviral regimen successfully maintained suppression while receiving treatment with a "boosted" protease inhibitor (PI) alone. We projected the long-term outcomes of this treatment simplification strategy to inform the design of a proposed multicenter, randomized clinical trial. METHODS: We used published studies to estimate the efficacy, adverse effects, and cost of a sequence of HIV drug regimens for the simplification strategy, compared with those outcomes for the current standard-of-care (SOC) strategy. Using a published simulation model of HIV disease, we projected life expectancy, discounted quality-adjusted life expectancy (QALE), and discounted lifetime medical costs for each strategy. RESULTS: Subjects who have not developed PI-resistant HIV infection at the time of failure of the simplification regimen have a greater life expectancy (27.9 vs. 27.1 years) and QALE (14.9 vs. 14.7 years), compared with SOC subjects, because they receive an additional line of therapy without negative consequences for future treatment options. The QALE for the simplification strategy remains higher than that for the SOC, unless a large proportion of patients experiencing virologic failure while receiving the simplification regimen develop PI resistance. Depending on the probability of simplification regimen failure, the advantage is maintained even if HIV develops PI resistance in 42%-70% of subjects. Projected lifetime costs are $26,500-$72,400 per person lower for the simplification strategy than for the SOC strategy. CONCLUSIONS: An HIV treatment simplification strategy involving use of a boosted PI alone may lead to longer survival overall at lower cost, compared with the SOC combination therapy, because the simplification strategy potentially adds an additional line of therapy. The risk of emergence of PI resistance during treatment with a simplified regimen is a critical determinant of the viability of this strategy.     

Epstein Barr virus latent membrane protein-1 in Hodgkin's lymphoma in Nigerians

Background

The burden of lymphomas on the health care system in Nigeria is enormous. Correct diagnosis and identification of aetiological factor are important steps in reducing this burden.

Methods

Eight cases diagnosed as HL within a period of six years at the Obafemi Awolowo University teaching Hospital, Ile-Ife, Nigeria by haematoxylin and eosin (Hand E) only were immunophenotyped using the indirect immunoperoxidase method. Epstein-Barr virus latent membrane protein-1 (LMP-1), CD15 and CD30 immunohistochemistry was also performed. The clinical characteristics of each patient were documented.

Objectives

To document the frequency of involvement of Epstein-Barr virus in cases of HL seen in a university hospital in Nigeria.

Results

Out of the eight cases diagnosed by H&E as HL immunophenotyping showed only five were HL. The rest were non-Hodgkin''s lymphoma (2 diffuse large B-cell and 1 null cell ALCL). All were cases of classical HL with 60% being of the mixed cellularity (MC) subtype. There were 2 males and 3 females with ages ranging from 7 years to 40 years. All presented with cervical lymphadenopathy and three had splenomegaly in addition. 60% of the tumour was EBV positive, all of the MC subtype. Three patients had chemotherapy. Eventually all were lost to follow-up. There was no case of the nodular lymphocyte predominance variant.

Conclusion

Mixed cellularity is the most common subtype and is the only subtype associated with EBV positivity in this study. Epstein-Barr virus probably plays an important role in the aetiology of HL in Nigerians.Running title: Epstein-Barr virus, Hodgkin''s lymphoma in Nigerians     

Multiple granular cell tumors are an associated feature of LEOPARD syndrome caused by mutation in PTPN11

We report a patient with a clinical and molecular diagnosis of LEOPARD syndrome (LS) associated with multiple granular cell tumors (MGCT). Bidirectional sequencing of exons 7, 12, and 13 of the PTPN11 gene revealed the T468M missense mutation in exon 12. This mutation has been previously reported in patients with LS. To our knowledge, this is the first report of MGCT associated with molecularly characterized LS and provides the first molecular evidence linking granular cell tumors (GCT) to the Ras/mitogen-activated protein (MAP) kinase pathway. We propose that MGCT can be associated with LS. Analysis of GCT from this case tested negatively for loss of heterozygosity (LOH) at the PTPN11 and NF1 loci and did not show deletions of the PTEN gene. The absence of LOH of PTPN11 supports published functional data that T468M is a dominant-negative mutation.     

Desensitization of endothelial P2Y1 receptors by PKC-dependent mechanisms in pressurized rat small mesenteric arteries

Background and purpose:

Extracellular nucleotides play a crucial role in the regulation of vascular tone and blood flow. Stimulation of endothelial cell P2Y1 receptors evokes concentration-dependent full dilatation of resistance arteries. However, this GPCR can desensitize upon prolonged exposure to the agonist. Our aim was to determine the extent and nature of P2Y1 desensitization in isolated and pressurized rat small mesenteric arteries.

Experimental approach:

The non-hydrolyzable selective P2Y1 agonist ADPβS (3 µM) was perfused through the lumen of arteries pressurized to 70 mmHg. Changes in arterial diameter and endothelial cell [Ca²⁺]_i were obtained in the presence and absence of inhibitors of protein kinase C (PKC).

Key results:

ADPβS evoked rapid dilatation to the maximum arterial diameter but faded over time to a much-reduced plateau closer to 35% dilatation. This appeared to be due to desensitization of the P2Y1 receptor, as subsequent endothelium-dependent dilatation to acetylcholine (1 µM) remained unaffected. Luminal treatment with the PKC inhibitors BIS-I (1 µM) or BIS-VIII (1 µM) tended to augment concentration-dependent dilatation to ADPβS (0.1–3 µM) and prevented desensitization. Another PKC inhibitor, Gö 6976 (1 µM), was less effective in preventing desensitization. Measurements of endothelial cell [Ca²⁺]_i in pressurized arteries confirmed the P2Y1 receptor but not M₃ muscarinic receptor desensitization.

Conclusions and implications:

These data demonstrate for the first time the involvement of PKC in the desensitization of endothelial P2Y1 receptors in pressurized rat mesenteric arteries, which may have important implications in the control of blood flow by circulating nucleotides.     

损伤性癫痫模型大鼠海马和额叶突触蛋白的动态表达

Objective To observe the time course of changes in synaptophysin (P38) expression in the cortex and hippocampus of rats with posttraumatic epilepsy (PTE), and explore the role of synaptic plasticity in the epileptogenesis of PTE. Methods Thirty-seven male Sprague-Dawley rats were randomized into normal control group (n=5), sham-operated group (n=12) with intracortical saline injection, and PTE model group (n=20) with stereotactic FeCl<,2> injection (0.1 mol/L, 10 μ1) into the motor cortex. The expression of P38 in the brain cortex and hippocampus of the rats was detected immunohistochemically at 1 h and 7, 14 and 30 days after the injections. Results Most of the rats with FeCl<,2> injection developed isolated epileptiform discharges soon alter the injection. Compared with the sham-operated groups, the rats in PTE group showed significantly decreased P38 expression in the right frontal cortex at all the time points of measurement (P<0.05). At 1 h after FeCl<,2> injection, P38 expression in the polymorphic layer, stratum lacunosum and stratum radiatum of the right hippocampai CA3 area and DG molecular layer underwent no significant changes (P>05), but at 7 days, the expression increased significantly in all the stratum regions of the right hippocampal CA3 area, and this high expression level was maintained till 30 days after the injection. Conclusion Synaptic plasticity alterations in relation to P38 expression changes in the cortex and hippocampus may play an important role in the epileptogenesis of PTE in this rat model.     

Utilities derived from visual analog scale scores in patients with HIV/AIDS.

BACKGROUND: Visual analog scale (VAS) scores are used as global quality-of-life indicators and, unlike true utilities (which assess the desirability of health states v. an external metric), are often collected in HIV-related clinical trials. The purpose of this study was to derive and evaluate transformations relating aggregate VAS scores to utilities for current health in patients with HIV/AIDS. METHODS: HIV-specific transformations were developed using linear and nonlinear regression to attain models that best fit mean VAS and standard gamble (SG) utility values directly derived from 299 patients with HIV/AIDS participating in a multicenter study of health values. The authors evaluated the transformations using VAS and SG utility values derived directly from patients in other HIV/AIDS studies. Derived transformations were also compared with published transformations. RESULTS: A simple linear transformation was derived (u = 0.44v + 0.49), as was the exponent for a curvilinear model (u = 1 - [1 - v]1.6), where u = the sample mean utility and v the sample mean VAS score. The curvilinear transformation predicted values within 0.10 of the actual SG utility in 5 of 8 estimates and within 0.05 in 3 of 8 estimates (absolute error ranged from -0.01 to +0.21). The linear transformation performed somewhat better, predicting within 0.10 of the actual SG value in 6 of 8 cases and within 0.05 in 5 of 8 estimates (absolute error ranged from -0.05 to +0.13). An alternative linear model (u = v + 0.018) derived from the literature performed similarly to our linear model (7 of 8 predictions within 0.10, 1 of 8 estimates within 0.05, and absolute error ranging from -0.15 to +0.10), whereas an alternative published curvilinear model (u = 1 - [1 - v]2.3) performed the least well (2 of 8 estimates within 0.10 of the actual values and no estimates within 0.05). CONCLUSIONS: Predicted utilities are a reasonable alternative for use in HIV/AIDS decision analyses and cost-effectiveness analyses. Linear transformations performed better than curvilinear transformations in this context and can be used to convert aggregate VAS scores to aggregate SG values in large HIV/AIDS studies that collect VAS data but not utilities.