Mechanism of Ethanol-Enhanced Estradiol Permeation Across Human Skin in Vivo

The influence of ethanol on the permeation of 17-estradiol (estradiol) across viable human skin in vivo was investigated with the human skin sandwich flap model. Maintaining continuous delivery of a constant concentration of the solute in phosphate-buffered saline, pH 7.4 (PBS), or mixtures of ethanol in PBS to the skin surface revealed that steady-state flux of estradiol was achieved within 30–60 min and maintained throughout 4 hr. The 10-fold decrease in in vivo flux and permeability coefficient (K _p) of tracer estradiol solutions in ethanol or ethanol solutions compared with PBS vehicle reflected the 10-fold difference in the apparent partition coefficients (K _m) of estradiol from the respective vehicles into isolated human stratum corneum. Neither the stratum corneum thickness nor the diffusion coefficient of estradiol was significantly different among the vehicles tested. In vivo flux of estradiol in ethanol or ethanol solutions across viable human skin was increased with saturated solutions of estradiol. Further, in vivo flux of estradiol from vehicles such as PBS, ethanol, and ethanol mixtures, which minimally alter the rate-limiting barrier, can be successfully predicted with knowledge of only two physicochemical parameters, the estradiol concentration in the vehicle and the K _m of estradiol from the vehicle into isolated human stratum corneum.     

The use of a deuterium tracer technique to follow the fate of fluids ingested by human subjects: effects of drink volume and tracer concentration and content

Deuterium oxide (2H2O) has been added to drinks as a tracer for water to estimate the availability to the body water pool of ingested fluids, but doubts have been raised as to the reliability of the method. The present investigation evaluated the effects of systematic variations in the volume of fluid consumed and the amount and concentration of added tracer on the rate of accumulation of tracer in arterialized blood after ingestion of a labelled drink. Three separate experiments were undertaken. In expt 1, six healthy men ingested on separate occasions 200, 400 and 800 ml of a dilute glucose-electrolyte solution: all test drinks contained the same concentration (40 g l-1) of 2H2O. In expt 2, six healthy men ingested 200, 400 and 800 ml of the same glucose-electrolyte drink: each drink contained 8 g of 2H2O so that the concentration, but not the amount, of 2H2O differed between treatments. In expt 3, six healthy men ingested 400 ml of the same drink on three separate occasions: each drink contained 8, 16 or 32 g of tracer so that amount and concentration of 2H2O both varied. Arterialized venous blood samples were collected for the determination of deuterium (2H) concentration before ingestion of the test drink and at intervals for 120 min after ingestion. All trials for each of the experiments were conducted in the morning after an overnight fast and trials were in randomized order and separated by 7 days. In expt 1, the blood 2H concentration at all time points from 2 min after ingestion of the test drink onwards was higher for the drink containing 32 g 2H2O than for the drink containing 16 g 2H2O, which in turn was higher than after ingestion of the drink containing 8 g of 2H2O. In expt 2, no significant differences between treatments were observed at any time. In expt 3, the rate of 2H accumulation was greater after ingestion of the drink containing 32 g of 2H2O than after either of the other two drinks, and the 2H accumulation rate was greater after ingestion of the drink containing 16 g of 2H2O than after the drink containing 8 g of 2H2O. When data from all three experiments were combined, significant correlations were observed between the rate of accumulation of 2H in the circulation (p.p.m. min-1) and the amount (rs = 0.75, P < 0001) and concentration (rs = 0.69, P < 0001) of 2H2O in the test drink, but there was no relationship (rs = 0.09, P = 0.5) between the rate of 2H accumulation in the blood and the volume of the drink consumed. The results suggest that the rate of tracer accumulation in the blood after ingestion of different volumes of test drinks is not a reliable indication of the availability of the ingested fluid, but that the method gives at least a qualitative measure of the sum of the effects of gastric emptying and intestinal water absorption.     

A new GTP-cyclohydrolase I mutation in an unusual dopa-responsive dystonia, familial form

We found a new mutation in the GTP cyclohydrolase gene involved in dopa-responsive dystonia. We sequenced the GTP cyclohydrolase gene in a family with four siblings affected by this disorder and identified an A-T mutation in exon 2, leading to a non conservative amino acid substitution at codon 135 of the protein (Ile135Lys), which may change the conformation of the binding site of this enzyme. The clinical evolution was heterogeneous among carriers of the same mutation, underlining the involvement of other determinants modulating the occurrence of the disease such as genetic or environmental susceptibility factors.     

Assessing clinical significance: proposed extensions to method

Jacobson, Follette, and Revenstorf's (1984) proposal for assessing clinical significance provides a needed convention for psychotherapy outcome research. Several limitations that exists in this method (Jacobson & Revenstorf, 1988) are addressed in this paper and extensions are proposed. Specifically, limitations regarding the operationalization of the underlying social validation methodology in the derivation of normative samples and the resultant standards they set are discussed. Extensions and guidelines are proposed for specifying normative samples, determining the distinctness of these samples, and expanding procedures to accommodate multiple samples. This paper initially assumes a psychometric perspective and presents extensions, based on the Symptom Checklist 90-R. Then it shifts to a clinician perspective and applies reliable change estimates and cutoff scores to actual outcome data by analyzing the progress of four patients during and after therapy. The overall merit and utility of extensions to clinical significance are then discussed.     

Clinically significant change: practical indicators for evaluating psychotherapy outcome

Developing procedures to evaluate the clinical significance of psychotherapy outcome is imperative. We see social validation as the most promising, viable methodology in this endeavor. Several concerns have been raised, however, about our proposed extensions. In this article, we illuminate and reassert the importance of generating and using multiple normative samples, and the utility of our statistical extensions. We address the limitations of procedural error and skewed sample distributions. Finally we see our commentary as a call for extensive study of the relationship between scores on standard outcome instruments and client's life functioning. We trust our commentary will continue to stimulate healthy dialogue on this crucial topic.