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.     

Structural studies on tazobactam.

Tazobactam (3, C10H12N4O5S) is an effective inhibitor of bacterial beta-lactamases. It crystallizes with unit cell dimensions a = 10.230 (2) A, b = 14.396 (2) A, and c = 17.291 (2) A in space group P2(1)2(1)2(1). Compared to the related inhibitor sulbactam (2), which lacks the triazole ring, crystalline tazobactam exhibits very similar beta-lactam geometry and the same S(1) envelope conformation of the thiazolidine ring. However, in both independent molecules of 3 a triazole ring nitrogen atom accepts an intermolecular hydrogen bond; similar interaction by this moiety of 3 with a hydrogen-bond donor on the enzyme, which is impossible for 2, could account for its enhanced inhibitory power. Semiempirical molecular orbital calculations show pronounced negative potential there. Molecular mechanics supports the hypothesis that the carboxyl group can rotate freely and the triazole ring can "flip".     

Depression of the fast IPSP underlies paired-pulse facilitation in area CA1 of the rat hippocampus.

1. Intracellular recordings from CA1 pyramidal neurons in the rat hippocampal slice have been used to study synaptic transmission after maximal orthodromic stimulation of the Schaffer collateral-commissural fibers. Paired-pulse stimulation was used to investigate how the first (conditioning) stimulation influenced the response to the second (test) stimulation. 2. When the test stimulation was delivered up to approximately 4 s after the conditioning stimulation, the late phase of the excitatory postsynaptic synaptic potential (EPSP) was increased ("late-phase facilitation") whereas the fast (f-) and the slow (s-) inhibitory postsynaptic potentials (IPSPs) were depressed. 3. In terms of appearance and time course, facilitation of the intracellularly recorded EPSP was similar to that of the extracellularly recorded field EPSP in stratum radiatum. 4. The s-IPSP is not involved in facilitation of the EPSP. To show this, we counteracted the s-IPSP either by repolarizing the membrane potential to the resting level or by intracellularly injecting the quaternary lignocaine derivative QX 314. Facilitation of the late phase of the EPSP was unaffected by either procedure. 5. The conditioned response was modified in two ways when the stimulation was delivered at the equilibrium potential for the f-IPSP (Ef-IPSP) and the s-IPSP had been blocked by intracellular injection of QX 314. The amplitude of the EPSP was increased, and the repolarizing phase was delayed with an apparent depolarizing shift of Ef-IPSP. This effect was present at pulse intervals greater than 20 ms and was maximal after 150 ms. Facilitation could be detected at interpulse intervals of up to 4 s. 6. The gamma-aminobutyric acid-B (GABAB) agonist baclofen (1 microM) reduced late-phase facilitation by preferentially increasing the unconditioned response, such that this came to resemble a conditioned response in control medium. 7. The f-IPSP was isolated pharmacologically to investigate its role in the facilitation of the EPSP. This was done by blocking the s-IPSP with QX314 and the EPSP with a mixture of the N-methyl-D-aspartate (NMDA) receptor blocker, 2-amino-5-phosphonovaleric acid (APV, 50 microM), and the non-NMDA receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM). An f-IPSP was then evoked by stimulating the interneurons directly. This potential could be blocked by the GABAA receptor antagonist bicuculline (20 microM), thereby confirming the successful isolation of GABAAergic transmission. 8. With paired-pulse stimulation, the amplitude of the conditioned f-IPSP was depressed.(ABSTRACT TRUNCATED AT 400 WORDS)