Rash Impulsiveness and Reward Sensitivity as predictors of treatment outcome in male substance dependent patients

Recent theories hypothesize that the impulsivity observed in addictive behaviors is a two-factor construct, consisting of Rash Impulsiveness and Reward Sensitivity. There is some evidence for this distinction, but it is unknown what the clinical relevance of this distinction is. The present study examines the predictive value of the two-factor model regarding drop-out from treatment and relapse into substance use in a clinical population of male substance dependent patients. Both behavioral and self-report measures of Rash Impulsiveness and Reward Sensitivity were measured during treatment while substance use relapse was measured after 90 days. Results indicate that treatment drop-out could be predicted by a behavioral index of Reward Sensitivity (Card Playing Task); self-reported Rash Impulsiveness only approached significance as predictor drop-out. In contrast, relapse could not be predicted in the present study. These findings might have implications for the early identification and treatment of patients at risk of treatment drop-out.     

Safety and immunogenicity of a canarypox-vectored human immunodeficiency virus Type 1 vaccine with or without gp120: a phase 2 study in higher- and lower-risk volunteers

Live attenuated viral vectors that express human immunodeficiency virus (HIV) antigens are being developed as potential vaccines to prevent HIV infection. The first phase 2 trial with a canarypox vector (vCP205, which expresses gp120, p55, and protease) was conducted in 435 volunteers with and without gp120 boosting, to expand the safety database and to compare the immunogenicity of the vector in volunteers who were at higher risk with that in volunteers at lower risk for HIV infection. Neutralizing antibodies to the MN strain were stimulated in 94% of volunteers given vCP205 plus gp120 and in 56% of volunteers given vCP205 alone. CD8(+) cytotoxic T lymphocyte cells developed at some time point in 33% of volunteers given vCP205, with or without gp120. Phase 3 field trials with these or similar vaccines are needed, to determine whether efficacy in preventing HIV infection or in slowing disease progression among vaccinees who become infected is associated with the level and types of immune responses that were induced by the vaccines in this study.     

Selection for animal cells that express the Escherichia coli gene coding for xanthine-guanine phosphoribosyltransferase.

Cultured monkey (TC7) and mouse (3T6) cells synthesize an Excherichia coli enzyme, xanthine-guanine phosphoribosyltransferase (XGPRT; 5-phospho-alpha-D-ribose-1-diphosphate:xanthine phosphoribosyltransferase, EC 2.4.2.22), after transfection with DNA vectors carrying the corresponding bacterial gene, Ecogpt. In contrast to mammalian cells, which do not efficiently use xanthine for purine nucleotide synthesis, cells that produce E. coli XGPRT can synthesize GMP from xanthine via XMP. After transfection with vector-Ecogpt DNAs, surviving cells producing XGPRT can be selectively grown with xanthine as the sole precursor for guanine nucleotide formation in a medium containing inhibitors (aminopterin and mycophenolic acid) that block de novo purine nucleotide synthesis. Cells transformed for Ecogpt arise with a frequency of 10(-4) to 10(-5); they appear to be genetically stable in as much as there is no discernible decrease in XGPRT formation or loss on their ability to grow in selective medium after propagation in nonselective medium. Although several of the vector-gpt DNAs can replicate in monkey and mouse cells, none of the transformants contain autonomously replicating vector-gpt DNA. Rather, the gpt transformants contain one to five copies of the transfecting DNA associated with, and most probably integrated into, cellular DNA sequences. In several transformants, vector-coded gene products for which there was no selection are also synthesized. This suggests that recombinant DNAs containing Ecogpt as a selective marker can be useful for cotransformation of nonselectable genes.     

Simian virus 40 DNA directs synthesis of authentic viral polypeptides in a linked transcription-translation cell-free system.

A linked cell-free system has been developed which is capable of transcribing and translating mamalian viral DNA, and its characteristics and requirements are outlined. In this system, simian virus 40 (SV40) DNA Form I (supercoiled) directed the synthesis of discrete polypeptides up to 85,000 daltons in size. One of these products was indistingusihable from authentic major virus capsid protein VPI, as judged by mobility on sodium dodecyl sulfate/polyacrylamide gels, antibody predipitation, and peptide analyses. The cell-free products larger than VPI comprised a number of polypeptides ranging in molecular weight from 50,000 to 85,000. These polypeptides demonstrated no immunological relationship whatsoever to the structural protein VPI. However, two of these products, along with one of approximately 25,000 dlatons, were precipitated with antiserum to SV40 tumor antigen. Linear SV40 DNA generated by the cleavage of Form I DNA with the restriction endonuclease EcoR1 was an efficient template in this system and also directed the synthesis of a polypeptide migrating with VPI on polyacrylamide gels. The potential of this system for defining a functional map of a DNA genome is discussed.     

Proteopathic tau seeding predicts tauopathy in vivo

Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer’s disease, this model predicts that tau seeds propagate pathology through the brain via cell–cell transfer in neural networks. The critical role of tau seeding activity is untested, however. It is unknown whether seeding anticipates and correlates with subsequent development of pathology as predicted for a causal agent. One major limitation has been the lack of a robust assay to measure proteopathic seeding activity in biological specimens. We engineered an ultrasensitive, specific, and facile FRET-based flow cytometry biosensor assay based on expression of tau or synuclein fusions to CFP and YFP, and confirmed its sensitivity and specificity to tau (∼300 fM) and synuclein (∼300 pM) fibrils. This assay readily discriminates Alzheimer’s disease vs. Huntington''s disease and aged control brains. We then carried out a detailed time-course study in P301S tauopathy mice, comparing seeding activity versus histological markers of tau pathology, including MC1, AT8, PG5, and Thioflavin S. We detected robust seeding activity at 1.5 mo, >1 mo before the earliest histopathological stain. Proteopathic tau seeding is thus an early and robust marker of tauopathy, suggesting a proximal role for tau seeds in neurodegeneration.Protein aggregation characterizes many neurodegenerative disorders, including Alzheimer’s disease (AD) and the related tauopathies. These disorders feature the accumulation of fibrillar deposits of the microtubule-associated protein tau with progressive deterioration of the central nervous system. Tau pathology and its associated brain atrophy do not appear randomly throughout the brain, but rather progress along distinct neural networks (1–5). This aspect suggests a role for transcellular spread of a pathogenic agent via neural connections. Our laboratory and others have previously hypothesized that tau aggregates—or seeds—serve as this agent of spread, transmitting the aggregated state from cell to cell via prion-like mechanisms (6–15).Mounting fundamental insights support this hypothesis. Tau seeds applied to the outside of cells bind the cell surface by attaching to heparan sulfate proteoglycans, triggering uptake by macropinocytosis (13). Upon internalization, tau seeds nucleate the fibrillization of endogenous tau monomer via templated conformational change, or seeding (8, 10). Tau seeding requires a critical unit of size for activity, as only particular species propagate the aggregated state (16). In vivo studies have described tau protein spreading from local sites to distant regions, presumably via transsynaptic movement (11, 12, 17–19). Finally, our laboratory and another recently demonstrated that tau propagates discrete amyloid conformations through the brains of animals that give rise to unique neuropathologies (18, 20).Despite this evidence, it remains unclear whether the development of proteopathic tau seeding represents a causal process of tauopathy, a downstream consequence of tau fibril accumulation, a coincident trait of neurodegeneration, or even an epiphenomenon. If proteopathic seeds are indeed a causal agent of disease, then their activity should exist in the brains of tauopathy mouse models and human subjects, precede other forms of pathology, and correlate with disease progression.To test these hypotheses, we created a highly sensitive and quantitative assay using a novel FRET-based biosensor cell line that specifically reports tau seeding activity. With this assay, we profiled the temporal evolution of tau seeding activity in the brains of P301S transgenic mice, a model of human tauopathy, and compared it to standard measurements of histopathology taken from the same animals. We find that tau seeding marks incipient tauopathy, occurring far before the onset of several standard histopathological markers. This finding implicates proteopathic tau seeding as a proximal cause of neurodegeneration, and establishes a highly quantitative and sensitive seed detection method.     

Face Validity of Observed Meal Patterns Reported with 7-Day Diet Diaries in a Large Population-Based Cohort Using Diurnal Variation in Concentration Biomarkers of Dietary Intake

In a cross-sectional analysis of a population-based cohort (United Kingdom, N = 21,318, 1993–1998), we studied how associations between meal patterns and non-fasting triglyceride and glucose concentrations were influenced by the hour of day at which the blood sample was collected to ascertain face validity of reported meal patterns, as well as the influence of reporting bias (assessed using formula of energy expenditure) on this association. Meal size (i.e., reported energy content), mealtime and meal frequency were reported using pre-structured 7-day diet diaries. In ANCOVA, sex-specific means of biomarker concentrations were calculated by hour of blood sample collection for quartiles of reported energy intake at breakfast, lunch and dinner (meal size). Significant interactions were observed between breakfast size, sampling time and triglyceride concentrations and between lunch size, sampling time and triglyceride, as well as glucose concentrations. Those skipping breakfast had the lowest triglyceride concentrations in the morning and those skipping lunch had the lowest triglyceride and glucose concentrations in the afternoon, especially among acceptable energy reporters. Eating and drinking occasion frequency was weakly associated with glucose concentrations in women and positively associated with triglyceride concentrations in both sexes; stronger associations were observed for larger vs. smaller meals and among acceptable energy reporters. Associations between meal patterns and concentration biomarkers can be observed when accounting for diurnal variation and underreporting. These findings support the use of 7-day diet diaries for studying associations between meal patterns and health.     

Nucleotide sequence of a multiple-copy gene for the B protein of photosystem II of a cyanobacterium

Chloroplast photogene 32 codes for the 32-kilodalton triazine herbicide-binding protein at the B site of electron transport in photosystem II of the photosynthetic apparatus—its product is the B protein and the gene is accordingly designated ps2B here. The cyanobacteria Anacystis nidulans R2, Fremyella diplosiphon, and Nostoc sp. MAC each contain several copies of ps2B. The sequence of one copy of ps2B from Fremyella, ps2B-1, has been determined. The longest open reading frame would code for a protein of 360 amino acids. Although the deduced amino acid sequence of ps2B-1 is highly homologous overall to that of the corresponding spinach protein [Zurawski, G., Bohnert, H. J., Whitfeld, P. R. & Bottomley, W. (1982) Proc. Natl. Acad. Sci. USA 79, 7699-7703] and, excluding neutral substitutions, the homology is 95% for an internal segment of 309 amino acids, there are a number of nonneutral amino acid substitutions. Most of the differences in net charge and polarity occur in the first 20 amino acids at the amino terminus and in the amino acid composition at the carboxyl terminus. The nucleotide sequences are 76% homologous overall. Conserved sequences resembling prokaryotic “-10” and “-35” regions are found at remarkably similar positions in the spinach and F. diplosiphon sequences although the surrounding sequences show only occasional homologies.     

Alcohol consumption and blood lipids in elderly coronary patients

Alcohol may have a beneficial effect on coronary heart disease (CHD) that could be mediated by elevation of high-density lipoprotein cholesterol (HDLC). Data on alcohol consumption and blood lipids in coronary patients are scarce. We studied whether total ethanol intake and consumption of specific types of beverages are associated with blood lipids in older subjects with CHD. Blood lipids were measured in 1052 myocardial infarction patients aged 60 to 80 years (78% male). Intake of alcoholic beverages, total ethanol, and macronutrients was assessed by food frequency questionnaire. Seventy percent of the subjects used lipid-lowering medication. Total cholesterol was on average 5.14 mmol/L, and HDLC was on average 1.28 mmol/L. Among men, total ethanol intake was positively associated with HDLC (difference of 0.094 mmol/L for ≥15 g/d vs 0 g/d, P = .024), whereas the association with HDLC among women was not significant (difference of 0.060 mmol/L for ≥5 g/d vs 0 g/d, P = .560) after adjustment for dietary, lifestyle, and CHD risk factors. Liquor consumption was weakly positively associated with HDLC in men (P = .045). Beer consumption in men and wine consumption in women were also positively associated with HDLC, but were not significant in the fully adjusted model. In conclusion, moderate alcohol consumption may elevate HDLC in treated post-myocardial infarction patients. This may be due to ethanol and not to other beneficial substances in alcoholic beverages. Based on this finding, further research needs to be done to examine the effects of the residual substances from different types of alcoholic beverages on HDLC.