The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

Contextualizing is not nullifying: Reply to Mills (2005).

In omitting crucial words and sentencees, neglecting relevant citations, and overlooking important distinctions, Jon Mills' (see record 2005-04819-001) critique of relational psychoanalysis significantly misrepresents the authors' viewpoint. This viewpoint seeks to contextualize, but not to nullify, individual worlds of experience and their limiting horizons. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Roles for Psychologists in End-of-Life Care: Emerging Models of Practice.

Professional psychologists are increasingly likely to encounter opportunities to work with patients and families facing end-of-life issues. Psychologists can provide psychological assessment, intervention for patients and families, consultation with and support of health care team members, grief therapy, and program development and evaluation. Psychological services are useful for healthy individuals who wish to make thoughtful plans about their own future care, patients with life-limiting illnesses, families stressed by providing end-of-life care, bereaved individuals, and health care providers who face issues of burnout and strain. Several challenges for psychologists working in end-of-life care are noted, including training, development of clear roles, and reimbursement. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Potentiation by specific short-chain fatty acids of differentiation and apoptosis in human colonic carcinoma cell lines

The architecture of normal colonic mucosa suggest that terminally differentiated epithelial cells near the top of the crypt are extruded into the colonic lumen. Morphological studies have identified apoptotic cells among the differentiated phenotypes near the crypt-lumen interface, suggesting a link between pathways of differentiation, apoptosis, and cellular shedding. We studied these processes in HT29 and SW620 cells and found that compared to adherent cells, those cells which were shed during standard, uninduced culture conditions exhibited nonrandom DNA fragmentation characteristic of apoptosis. Moreover, these apoptotic cells, which accumulate in the media, exhibited a more differentiated phenotype. Because short-chain fatty acids (SCFAs) are natural effectors of colonic cell differentiation in vivo, we investigated the specificity of three 4-carbon atom SCFAs on potentiating differentiation and apoptosis, and thus accumulation of shed cells in the conditioned media, in these colonic carcinoma cell lines. Whereas the unbranched SCFA butyrate induced a more differentiated phenotype and enhanced apoptosis, two derivatives of butyrate, branched isobutyric acid and a nonmetabolizable fluorine-substituted analogue, heptafluorobutyric acid, were ineffective in inducing either differentiation or apoptosis. Thus, potentiated differentiation and apoptosis in colonic carcinoma cells were linked to SCFA structure and, most likely, utilization.     

Continuous infusion of porcine factor VIII in the management of patients with factor VIII inhibitors

Increased detection thresholds for pure tones were observed in a large cohort of children exposed to lead environmentally while smaller studies in lead-exposed workers have reported conflicting results on assessments of auditory function. Pure tone detection thresholds were determined in a group of monkeys (Macaca fascicularis) dosed with 2 mg/kg/day of lead from birth through testing at 13 years of age. Blood lead concentrations were stable at about 30 micrograms/dl until monkeys were 10-11 years of age at which time they increased to between 50 and 70 micrograms/dl. Five age- and rearing-matched monkeys served as controls. Detection thresholds were determined at six frequencies between 0.125 and 31.5 kHz. Ear phones were fit over both ears, and thresholds were determined for each ear separately. The monkey signaled detection of the tone by breaking contact with a stainless steel bar. Three lead-exposed monkeys exhibited normal pure tone detection functions. Three monkeys had thresholds outside of the control range at some frequencies; there was a tendency for higher frequencies to be differentially more affected. These findings are consistent with reports of elevated pure tone thresholds in humans exposed to lead developmentally, although the effect is smaller than might have been predicted given the concurrent blood lead concentrations of these monkeys.     

Special issue on women, psychoanalysis, and gender: Editors' introduction.

Introduces this special issue of Psychoanalytic Psychology. This special issue on Women, Psychoanalysis, and Gender is a commemoration of the capability, influence, acceptance, and authority of women in the community of psychoanalysis. In this issue, we turn to both new and more established voices in an expanded arena of gender, culture, and psychoanalysis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Typicality effects in attitudes toward social policies: A concept-mapping approach.

Social typicality effects occur when people apply their attitudes more consistently toward typical than toward atypical category members presumably because attitudes are directed toward the prototypic category member. Four studies tested whether individuals also apply social policy attitudes more consistently toward typical than toward atypical persons affected by the policy. Study 1 used attitude concept maps to assess how extensively individuals spontaneously reference the typical person affected by a social policy. Death penalty proponents did so more than did opponents; welfare proponents and opponents did so equally. In 3 other studies, death penalty proponents displayed greater typicality effects in sentencing "convicted murderers" than did opponents, welfare proponents and opponents displayed equal typicality effects in evaluating cases of suspected welfare fraud, and individuals whose attitude concept maps about welfare referred more to persons displayed greater typicality effects than did individuals whose maps referred more to principles. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Surface leakage currents in SiN/sub x/ passivated AlGaN/GaN HFETs

A novel guarded surface leakage test structure is used to isolate the surface and bulk leakage contributions to gate current in AlGaN/GaN HFETs. Passivation with various recipes of SiN/sub x/ always resulted in the commonly observed increase in gate leakage, which was found to be dominated by bulk leakage through the AlGaN. However, high temperature deposited SiN/sub x/ recipes gave a 1-2 orders reduction in surface leakage, whereas low temperature deposition gave an increase. Gate lag measurements were found to correlate closely with the surface leakage component, giving direct evidence that the key device problem of current slump is associated with current flow at the AlGaN surface.     

Effect of prior knowledge on good and poor readers' memory of text.

We investigated how prior knowledge influences the amount of short-term nonverbal and verbal memory and long-term retention in students of high and low ability in reading comprehension. Sixty-four junior high students were divided into four equal-sized groups on the basis of preassessed reading ability (high and low) and preassessed amount of existing prior knowledge about baseball (high and low). Each subject silently read an account of a half inning of a baseball game. After reading, each subject recalled the account nonverbally by moving figures and verbally by retelling the story. After an interpolated task, they summarized the game and sorted passage sentences for idea importance. There was a significant main effect for prior knowledge on all measures. No interactions between prior knowledge and ability were found. These results delineate the powerful effect of prior knowledge. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dietary disinhibition, perceived stress, and glucose control in young, Type 1 diabetic women.

Examining the relationship of stress, dietary disinhibition, and blood glucose control in diabetic young women was the goal of this study. 65 diabetic girls and women, ranging in age from 12 to 26 yrs, completed eating behaviors and perceived stress scales during regular clinic visits. Blood glucose control was assessed by concurrent glycosylated hemoglobin measurements. Multiple regression analyses indicated that high levels of perceived stress predicted dietary disinhibition and that within the age range studied, young women were more likely than early adolescent girls to perceive their life as stressful. Contrary to previous findings that failed to show that stress can indirectly affect glucose control by interfering with compliance behaviors, the present work indicated a Stress?×?Dietary Disinhibition interaction in predicting glucose control. Blood glucose control was poorest in those diabetic women who both perceived their lives as stressful and reported medium to high disinhibition. Blood glucose control was unrelated to stress in young women who reported low levels of disinhibition. These results have implications for the development of specific interventions for young diabetic women who perceive their lives as stressful and who may respond to stress by eating. (PsycINFO Database Record (c) 2010 APA, all rights reserved)