Acute leukemia associated with valproic acid treatment: A novel mechanism for leukemogenesis?

Valproic acid has been previously associated with hematologic toxicity, including a reversible myelodysplasia-like syndrome without chromosomal abnormalities. We now report three cases of acute leukemia with features of secondary leukemia associated with valproic acid therapy: two cases of acute myelogenous leukemia with multilineage dysplasia, one with trisomy 8 and one with monosomy 7, and one case of secondary acute lymphoblastic leukemia with del (7) (q22q34), del (9) (q21.11q22), del (11) (q12q23). One patient had a previous myelodysplastic syndrome while on valproic acid. Valproic acid has been previously shown to be a histone deacetylase inhibitor. Inhibition of histone deacetylase causes a relaxation of chromatin structure and thus increases susceptibility to DNA damage and sensitizes cells to radiation. We propose that valproic acid therapy may lead to secondary leukemia by increasing DNA damage through chronic inhibition of histone deacetylase.     

Reasons for drinking less and their relationship to sustained remission from problem drinking

AIMS: To compare representative general population and treated samples on their reasons for drinking less and whether particular reasons were related to sustained remission from problem drinking for either group. PARTICIPANTS AND DESIGN: A total of 659 problem drinking adults in a Northern California county identified through a probability survey in the general population (n = 239) and a survey of consecutive admissions to public and private alcohol and drug programs (n = 420), who reported drinking less at the one-year follow-up and provided reasons for reducing their drinking, were assessed 1-, 3-, and 5-years post-baseline regarding their problem drinking status. MEASUREMENTS: Logistic regression models were used to predict sustained remission from problem drinking. RESULTS: While the treated sample endorsed a majority of reasons in significantly higher proportions than the general population sample, the same three reasons were significant for both groups in predicting sustained remission from problem drinking: hitting rock bottom, experiencing a traumatic event and undergoing a spiritual awakening. Interventions by medical personnel and family members were either non-significant predictors or significantly negatively related to sustained improvement for both general population and treated problem drinkers. CONCLUSIONS: General population and treatment samples have similar reasons for cutting down as they relate to sustained remission from problem drinking.     

Effects of managed care on alcohol and other drug (AOD) treatment

The article represents the proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada. The organizer/chair was Stephen Magura. The presentations examined: (1) How managed care organization policies may affect enrollees' use of alcohol and other drug (AOD) treatment, by Constance Horgan and associates; (2) The determinants of patients' access to and utilization of AOD treatment in a large health maintenance organization, by Jennifer R. Mertens and Constance Weisner; (3) The impact on treatment access and costs of a statewide carve-out for AOD treatment for Medicaid, by Donald Shepard and associates; and (4) The predictive validity of a new patient assessment technology developed, in part, to better justify AOD treatment in response to the demands of managed care, by Stephen Magura and associates.     

The cross-clade neutralizing activity of a human monoclonal antibody is determined by the GPGR V3 motif of HIV type 1

Both polyclonal and monoclonal human antibodies (Abs) to the V3 domain of HIV-1 gp120 display cross-clade neutralizing activity against primary isolates and T cell-adapted virus strains. The most broadly neutralizing of the human anti-V3 monoclonal Abs (mAbs), 447-52D, recognizes 14 amino acids, including the GPxR core epitope at the tip of the V3 loop. Monoclonal Ab 447-52D neutralized 92% of 38 primary isolates carrying the GPGR V3 motif regardless of whether the viruses belonged to clades A, B, F, or H; in contrast, none of 19 viruses with the GPGQ and other non-GPGR/Q sequences at the tip of the V3 loop was sensitive to mAb 447-52D. These data are consistent with the crystallographic resolution of a complex of the Fab fragment of mAb 447-52D with a V3 peptide that shows that the binding specificity of the mAb is due to recognition of the GPGR motif at the tip of the loop. The critical role of the Arg residue in this motif was determined using viruses pseudotyped with the envelope of primary isolate CA1 containing the GPGR motif or with a mutated envelope with a Gln (Q) replacing the Arg (R) at the tip of the loop. While the wild-type pseudovirus was neutralized by mAb 447-52D, the pseudovirus carrying the point mutation was resistant to neutralization. These data illuminate the structural basis for both the breadth and specificity of a broadly neutralizing human mAb and contribute to our understanding of the epitopes recognized by Abs that protect against infection with HIV-1.     

Automated clinical trial eligibility prescreening: increasing the efficiency of patient identification for clinical trials in the emergency department

Objectives (1) To develop an automated eligibility screening (ES) approach for clinical trials in an urban tertiary care pediatric emergency department (ED); (2) to assess the effectiveness of natural language processing (NLP), information extraction (IE), and machine learning (ML) techniques on real-world clinical data and trials.Data and methods We collected eligibility criteria for 13 randomly selected, disease-specific clinical trials actively enrolling patients between January 1, 2010 and August 31, 2012. In parallel, we retrospectively selected data fields including demographics, laboratory data, and clinical notes from the electronic health record (EHR) to represent profiles of all 202795 patients visiting the ED during the same period. Leveraging NLP, IE, and ML technologies, the automated ES algorithms identified patients whose profiles matched the trial criteria to reduce the pool of candidates for staff screening. The performance was validated on both a physician-generated gold standard of trial–patient matches and a reference standard of historical trial–patient enrollment decisions, where workload, mean average precision (MAP), and recall were assessed.Results Compared with the case without automation, the workload with automated ES was reduced by 92% on the gold standard set, with a MAP of 62.9%. The automated ES achieved a 450% increase in trial screening efficiency. The findings on the gold standard set were confirmed by large-scale evaluation on the reference set of trial–patient matches.Discussion and conclusion By exploiting the text of trial criteria and the content of EHRs, we demonstrated that NLP-, IE-, and ML-based automated ES could successfully identify patients for clinical trials.     

Branching out: a molecular fingerprint of endothelial differentiation into tube-like structures generated by Affymetrix oligonucleotide arrays

The process of endothelial differentiation into a network of tube-like structures with patent lumens requires an integrated program of gene expression. To identify genes upregulated in endothelial cells during the process of tube formation, RNA was prepared from several different time points (0, 4, 8, 24, 40, and 48 hours) and from three different experimental models of human endothelial tube formation: in collagen gels and fibrin gels driven by the combination of PMA (80), bFGF (40 ng/ml) and bFGF (40 ng/ml) or in collagen gels driven by the combination of HGF (40 ng/ml) and VEGF (40 ng/ml). Gene expression was evaluated using Affymetrix Gene Chip oligonucleotide arrays. Over 1000 common genes were upregulated greater than twofold over baseline at one or more time points in the three different models. In the present study, we discuss the identified genes that could be assigned to major functional classes: apoptosis, cytoskeleton, proteases, matrix, and matrix turnover, pumps and transporters, membrane lipid turnover, and junctional molecules or adhesion proteins.     

Continuous positive airway pressure therapy in sleep apnoea

Sleep apnoea is associated with increased mortality and morbidity. The treatment goal is to reduce the neurocognitive and cardiovascular sequelae. CPAP therapy in sleep apnoea is discussed in two parts in the article. The first part will consider CPAP therapy in the more common form of sleep apnoea (i.e. obstructive or mixed sleep apnoea) and the second part will consider CPAP therapy in central sleep apnoea. Alternative positive airway pressure modalities are discussed. CPAP therapy has been extensively studied and it remains the mainstay of treatment in obstructive sleep apnoea, as it is still the most consistently efficacious and safe option. However, its major disadvantage is that it does not confer a cure to this disorder and hence therapy is generally life long with its usual treatment compliance problems. As such, there are continuous improvement strategies. The role of CPAP therapy in central sleep apnoea is more limited. There has been increasing data on the beneficial effect of CPAP on central sleep apnoea/Cheyne-Stokes respiration in congestive heart failure. Evidence for CPAP therapy in sleep apnoea has evolved significantly over the last decade. However, more research and publication of large-scale long-term randomized trials of treatment in sleep apnoea to assess patient-orientated outcomes and preferences are necessary.     

Stability of local brain levels of insulin-like growth factor-I in two well-characterized models of decreased plasma IGF-I

Insulin-like growth factor-I (IGF-I), a functionally important neurotrophic factor, impacts tissues throughout the body including the central nervous system. In addition to the significant proportion of IGF-I that is synthesized in the liver and released into the plasma, IGF-I is expressed locally in tissues. The present study investigated the relationship between plasma and local brain levels of IGF-I in two well-characterized models of decreased IGF-I. The first is an adult-onset growth hormone deficiency (AOGHD) model, and the second is a caloric restriction (CR) model. In the first cohort of animals from both models, the hippocampus was removed from the brain immediately following decapitation, and in the second cohort, the animals were perfused transcardially with phosphate buffered saline to remove cerebral blood prior to harvesting the hippocampus. Our results demonstrated that although the plasma IGF-I levels were decreased in the CR and AOGHD rats compared to controls, the hippocampal IGF-I levels did not differ among the groups. These data suggest that local brain IGF-I levels are regulated in a different manner than plasma IGF-I levels.