Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects

BACKGROUND: Intensive therapy of HIV infection with highly active antiretroviral therapy (HAART) dramatically reduces viral loads and improves immune status. Abnormalities of lipid levels, body fat distribution, and insulin resistance have been commonly reported after starting HAART. Whether the lipid abnormalities result from changes in metabolism after an improvement in HIV status or are partly attributable to the effects of protease inhibitor use is unknown. METHODS: Twenty-one healthy volunteers participated in a 2 week double-blind, placebo-controlled study on the effect of the protease inhibitor ritonavir on total lipids, apolipoproteins, and post-heparin plasma lipase activities. RESULTS: Those taking ritonavir (n = 11) had significantly higher levels of plasma triglyceride, VLDL cholesterol, IDL cholesterol, apolipoprotein B, and lipoprotein (a) compared with placebo (n = 8). HDL cholesterol was lower with therapy as a result of a reduction in HDL3 cholesterol. Post-heparin lipoprotein lipase (LpL) activity did not change but hepatic lipase activity decreased 20% (P < 0.01) in those taking ritonavir-compared with placebo. Although all lipoprotein subfractions became triglyceride enriched, most of the increase in triglyceride was in VLDL and not in IDL particles. CONCLUSION: Treatment with ritonavir in the absence of HIV infection or changes in body composition results in hypertriglyceridemia that is apparently not mediated by impaired LpL activity or the defective removal of remnant lipoproteins, but could be caused by enhanced formation of VLDL. Long-term studies of patients with HIV infection receiving HAART will be necessary to determine the impact of these drugs and associated dyslipidemia on the risk of coronary artery disease.     

Comparison of the Goldmann-Weekers Dark Adaptometer™ and LKC Technologies Scotopic Sensitivity Tester-1™

The standard for dark adaptation has long been the Goldmann-Weekers Dark Adaptometer (Haag-Streit). More recently, portable, relatively inexpensive LED-based dark adaptometers have become commercially available. These devices have potential use in areas with limited resources to screen for night-blindness, commonly caused worldwide by vitamin A deficiency. In order to determine the sensitivity to detecting changes in night vision, this study compared one such device, LKC Technologies Scotopic Sensitivity Tester-1 (SST- 1) to the Goldmann-Weekers in patients with hereditary retinal degeneration and loss of rod function. Dark-adapted final thresholds and rod full-field ERG responses were obtained from 87 patients and 24 normal subjects. Linear regression analysis, discrepancy analysis, and receiver operator characteristic curves for both devices show that the SST-1 quantifies psychophysical rod function nearly as well as the Goldmann-Weekers, within some limitations. We conclude, therefore, that the SST-1 is a viable alternative to the Goldmann-Weekers for the screening of night-blinding retinal disorders.     

Shape discrimination in age-related macular degeneration

PURPOSE: Recent studies suggest that a global shape-discrimination task is sensitive to neural undersampling and/or irregular sampling, but is not affected by normal aging. In this study, the ability of patients with age-related macular degeneration (AMD) to perform the shape-discrimination task was examined. METHODS: Twenty patients with AMD (age range, 66-81 years) were selected on the basis of Snellen visual acuity of 20/50 or better in at least one eye and prior clinical documentation. A control group consisted of 10 older subjects (age range, 61-93 years) with normal findings in a fundus examination. Radial frequency (RF) patterns were used as stimuli. A spatial paradigm and a temporal two-alternative, forced-choice (2AFC) staircase paradigm were used. In each trial, two RF patterns (one deformed and one undeformed) were presented, and patients were asked to identify the deformed pattern. The peak spatial frequency of RF patterns was 5 cyc/deg; the radial modulation frequency was 8 cyc/360 degrees; mean radii were 0.5 degrees, 1 degrees, 2.0 degrees, or 2.5 degrees; and stimulus contrast was 80%. Thresholds for detecting the deformation were estimated by a maximum-likelihood fitting procedure. RESULTS: Thirty-five of 40 eyes with AMD had 20/50 or better acuity. Among them, 29 eyes had early AMD (drusen, hyperpigmentation, hypopigmentation), 5 had extrafoveal geographic atrophy, and 1 had exudative AMD. With the spatial 2AFC, 91% (32/35) of eyes with AMD showed significant elevation of the threshold for detecting radial deformation of RF patterns when compared with normal control eyes. With the temporal 2AFC, 97% (31/32) of eyes with AMD showed significant threshold elevations, and the degree of the deficit in the shape discrimination did not correlate significantly with visual acuity loss (r = 0.3, P = 0.094). Comparison of the severity of AMD with shape-discrimination performance revealed that the average detection threshold of the eyes with extrafoveal geographic atrophy was significantly higher than that of the eyes with drusen only (P < 0.01), even though average acuity showed no significant difference. CONCLUSIONS: Patients with AMD had significant deficits in performing the global shape-discrimination task. The dissociation of shape discrimination with visual acuity suggests that the shape-discrimination task may provide distinguishable information about the integrity of the photoreceptor mosaic in AMD.     

Accurate prediction of BRCA1 and BRCA2 heterozygous genotype using expression profiling after induced DNA damage.

PURPOSE: In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells. EXPERIMENTAL DESIGN: Short-term primary fibroblast cultures were established from skin biopsies from 10 BRCA1 and 10 BRCA2 mutation carriers and 10 controls, all of whom had previously had breast cancer. The cells were subjected to 15 Gy ionizing irradiation to induce DNA damage. RNA was extracted from all cell cultures, preirradiation and at 1 hour postirradiation. For expression profiling, 15 K spotted cDNA microarrays manufactured by the Cancer Research UK DNA Microarray Facility were used. Statistical feature selection was used with a support vector machine (SVM) classifier to determine the best feature set for predicting BRCA1 or BRCA2 heterozygous genotype. To investigate prediction accuracy, a nonprobabilistic classifier (SVM) and a probabilistic Gaussian process classifier were used. RESULTS: In the task of distinguishing BRCA1 and BRCA2 mutation carriers from noncarriers and from each other following radiation-induced DNA damage, the SVM achieved 90%, and the Gaussian process classifier achieved 100% accuracy. This effect could not be achieved without irradiation. In addition, the SVM identified a set of BRCA genotype predictor genes. CONCLUSIONS: We conclude that after irradiation-induced DNA damage, BRCA1 and BRCA2 mutation carrier cells have a distinctive expression phenotype, and this may have a future role in predicting genotypes, with application to clinical detection and classification of mutations.     

Use of topical misoprostol to reduce radiation‐induced mucositis: Results of a randomized,double‐blind,placebo‐controlled trial

Radiation‐induced mucositis is an acute reaction of the mucosa of patients undergoing head and neck radiotherapy. It can have debilitating and dose‐limiting consequences. There is no consensus on an accepted intervention that significantly reduces its severity. Misoprostol is a synthetic prostaglandin E₁ analogue, with properties of a mucosal cytoprotectant. We designed a randomized, double‐blind, placebo‐controlled trial of misoprostol in patients with head and neck cancer. The aim of this study was to determine if topical misoprostol was effective in reducing the severity of radiation‐induced mucositis in patients receiving radical dose radiotherapy. The effect of this intervention on a patient’s general well‐being was also investigated. The primary end‐point of the study was the incidence of Radiation Therapy Oncology Group grade 3 mucositis. Between 1999 and 2002, 83 patients were recruited into the study at Westmead and Nepean Hospitals, Sydney. Forty‐two patients were randomized to receive misoprostol and 41 to receive a placebo. Most patients received radiotherapy in the adjuvant setting (52 of the 83) and had either an oral cavity (42 of the 83) or an oropharyngeal (16 of the 83) cancer. We could not identify any significant difference in the incidence of severe mucositis based on whether patients were allocated to receive misoprostol or placebo. There was no significant difference in the mean area under the mucositis curve (13.2 vs 16.6; P = 0.1). Patients allocated to misoprostol did report slightly increased soreness (7.6 vs 6.9; P = 0.04) and a greater use of analgesics. However, this difference did not translate into a worse feeling of general well‐being as measured by a simple visual analogue scale (5.8 vs 5.2; P = 0.3). In conclusion, we were unable to identify a reduction in radiation‐induced mucositis in patients receiving misoprostol. There is a paucity of high‐level evidence on potentially useful interventions and a continued need for new and innovative research, incorporating quality‐of‐life measurements, in patients experiencing radiation‐induced mucositis.     

Vega library for processing DICOM data required in Monte Carlo verification of radiotherapy treatment plans

Monte Carlo (MC) methods provide the most accurate to-date dose calculations in heterogeneous media and complex geometries, and this spawns increasing interest in incorporating MC calculations into treatment planning quality assurance process. This involves MC dose calculations for clinically produced treatment plans. To perform these calculations, a number of treatment plan parameters specifying radiation beam and patient geometries need to be transferred to MC codes, such as BEAMnrc and DOSXYZnrc. Extracting these parameters from DICOM files is not a trivial task, one that has previously been performed mostly using Matlab-based software. This paper describes the DICOM tags that contain information required for MC modeling of conformal and IMRT plans, and reports the development of an in-house DICOM interface, through a library (named Vega) of platform-independent, object-oriented C++ codes. The Vega library is small and succinct, offering just the fundamental functions for reading/modifying/writing DICOM files in a C++ program. The library, however, is flexible enough to extract all MC required data from DICOM files, and write MC produced dose distributions into DICOM files that can then be processed in a treatment planning system environment. The library can be made available upon request to the authors.     

Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study

The prevalence of comorbid alcohol, other drug, and mental disorders in the US total community and institutional population was determined from 20,291 persons interviewed in the National Institute of Mental Health Epidemiologic Catchment Area Program. Estimated US population lifetime prevalence rates were 22.5% for any non-substance abuse mental disorder, 13.5% for alcohol dependence-abuse, and 6.1% for other drug dependence-abuse. Among those with a mental disorder, the odds ratio of having some addictive disorder was 2.7, with a lifetime prevalence of about 29% (including an overlapping 22% with an alcohol and 15% with another drug disorder). For those with either an alcohol or other drug disorder, the odds of having the other addictive disorder were seven times greater than in the rest of the population. Among those with an alcohol disorder, 37% had a comorbid mental disorder. The highest mental-addictive disorder comorbidity rate was found for those with drug (other than alcohol) disorders, among whom more than half (53%) were found to have a mental disorder with an odds ratio of 4.5. Individuals treated in specialty mental health and addictive disorder clinical settings have significantly higher odds of having comorbid disorders. Among the institutional settings, comorbidity of addictive and severe mental disorders was highest in the prison population, most notably with antisocial personality, schizophrenia, and bipolar disorders.     

Influence of posture on the serum concentration of calcium

Experiments were designed to study the effects of change in posture on the serum concentrations of total calcium, plasma ionic calcium, magnesium, protein-bound calcium, total protein, albumin, and globulin. Plasma ionic calcium and serum magnesium were not influenced by changes in posture. All the remaining constituents responded in a consistent manner, namely, on changing from the lying to the erect position, their concentrations rose significantly. On sitting or on lying down, their values fell reaching minimal levels after about $\text{1}\text{2}\text{hr}$ and showing little change thereafter. All the values attained on lying were significantly lower than those reached on sitting in the same time periods. Variations in the concentrations of calcium and protein due to alteration in posture could amount to as much as 47% and 71%, respectively, of their normal range spans. These variations were considerably reduced by the use of protein corrections developed by Dent and in particular by Parfitt. A sex difference was noted in the concentrations of both serum total calcium and total protein, more marked in the latter. The difference in calcium appears due to a difference in its protein-bound component. It is clear that the influence of posture must be considered when interpreting serum calcium concentrations. Failure to recognize this influence has undoubtedly contributed to the variations in the normal ranges of serum calcium proposed by different workers.