Autonomy and dependence: chronic physical illness and decision-making capacity

In this article some of the presuppositions that underly the current ideas about decision making capacity, autonomy and independence are critically examined. The focus is on chronic disorders, especially on chronic physical disorders. First, it is argued that the concepts of decision making competence and autonomy, as they are usually applied to the problem of legal (in)competence in the mentally ill, need to be modified and adapted to the situation of the chronically (physically) ill. Second, it is argued that autonomy and dependence must not be considered as two mutually exclusive categories. It is suggested that decision making may take on the form of a more or less conscious decision not to be involved in making all kinds of explicit and deliberate decisions. Elaborating on Agich's distinction between ideal and actual autonomy, the concept of “Socratic autonomy” is introduced. This revised version was published online in July 2006 with corrections to the Cover Date.     

Stages of Change Assessments in Alcohol Problems: Agreement Across Self- and Clinician-Reports

A number of self-report scales and algorithms have been developed to measure stage of change in alcohol problems. These methods rely on client self-reports, but an alternative approach is to use clinician judgments. The purpose of this investigation was to compare approaches including a newly developed Readiness to Change Questionnaire – Clinician Version (RCQ-CV). Clients being assessed for alcohol treatment (N = 64) completed SOCRATES, the Readiness to Change Questionnaire (RCQ), a social desirability scale, and a stage of change algorithm. Clinicians completed the RCQ-CV and provided a simple assessment of stage of change. The agreement among the alternative methods was generally good with the continuous measures, including agreement between scales, between clients and clinicians, and between experienced clinicians and trainees. Agreement among categorical stage assignments was poor. The RCQ-CV shows promise as a clinical and research tool.     

NK2 tachykinin receptors mediate contraction of the pig intravesical ureter: tachykinin-induced enhancement of non-adrenergic non-cholinergic excitatory neurotransmission

The current study was designed to characterize the functionally active tachykinin receptors involved in tachykinin-elicited contractions in the pig intravesical ureter, and to investigate the possible modulation exerted by the natural tachykinins substance P (SP) and neurokinin A (NKA) on the non-adrenergic non-cholinergic (NANC) excitatory ureteral neurotransmission. In pig intravesical ureteral strips pretreated with phosphoramidon (10(-5) mol/L) to block the endopeptidase activities, isometric force recordings showed that SP, NKA, and the NK2 receptor selective agonist [beta-Ala(8)]-NKA (4-10), all three induced contractions, with the following potency order: NKA > [beta-Ala(8) ]-NKA (4-10) > SP. [Sar(9), Met(O(2))(11)]-SP and senktide, selective agonists of the NK1 and NK3 receptors, respectively, failed to modify the ureteral tone. Urothelium removal and incubation with tetrodotoxin (10(-6) mol/L), phentolamine (10(-7) mol/L), propranolol (3 x 10(-6) mol/L), atropine (10(-7) mol/L) and indomethacin (3 x 10(-6) mol/L), did not alter the contraction induced by a submaximal (10(-7) mol/L) dose of [beta-Ala(8)]-NKA (4-10). MEN 10,376 (10(-8)-10(-7) mol/L), a NK2 receptor antagonist, reduced the contraction to 3 x 10(-8) mol/L NKA. GR 82334 (10(-6) -10(-5) mol/L) and SR 142801 (10(-8)-10(-7) mol/L), selective antagonists of the NK1 and NK3 receptors, respectively, did not modify that contraction. In pig intravesical ureteral strips in NANC conditions, SP and NKA induced a potentiation of the contractions to electrical field stimulation (EFS) and to exogenous ATP. The results suggest that the tachykinins evoke a direct contraction of pig intravesical ureteral strips through NK2 receptors located in the smooth muscle. SP and NKA exert an enhancement of the NANC excitatory neurotransmission of the pig intravesical ureter.     

Usefulness of the Kohlrausch-Williams-Watts Stretched Exponential Function to Describe Protein Aggregation in Lyophilized Formulations and the Temperature Dependence Near the Glass Transition Temperature

Purpose. We studied the feasibility of using the Kohlrausch-Williams-Watts stretched exponential function (KWW equation) to describe protein aggregation in lyophilized formulations during storage. Parameters representing mean aggregation time (_a) and stretched exponential constant (_a) were calculated according to the KWW equation by assuming that the time required for protein molecules to aggregate () varies because of the fact that protein aggregation occurs at a rate that depends on the degree of protein deformation resulting from stresses created during freeze-drying. The temperature dependence of the parameters near the glass transition temperature was examined to discuss the possibility of predicting protein aggregation by accelerated testing. Methods. Protein aggregation in lyophilized bovine serum -globulin (BGG) formulations containing dextran or methylcellulose, at temperatures ranging from 10 to 80°C, was followed by size-exclusion chromatography. Results. Non-exponential BGG aggregation in lyophilized formulations could be described by the KWW equation. The _a and _a parameters changed abruptly around the NMR relaxation-based critical mobility temperature for formulations containing dextran and methylcellulose. In the glassy state, in contrast, the _a parameter of these formulations exhibited continuous temperature dependence. The parameter , as calculated from _a and _a, reflected differences in values between the two excipients. Conclusions. The results indicate that the parameter _a is reflective of physical changes wihtin lyophilized formulations. Within the temperature range, during which no abrupt changes in _a were observed, knowledge regarding the _aand _a parameters allows the rate of protein aggregation to be predicted. The parameter was found to be useful in comparing the protein aggregation behavior of formulations having different _a and _a values.     

Acute and chronic caffeine administration differentially alters striatal gene expression in wild-type and adenosine A(2A) receptor-deficient mice

In order to assess for the respective involvement of adenosine A(1) and A(2A) receptors (A(2A)-R) in the consequences of short- and long-term caffeine exposure on gene expression, the effects of acute caffeine administration on striatal, cortical, and hippocampal expression of immediate early genes (IEG), zif-268 and arc, and the effects of long-term caffeine or 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) exposure (once daily for 15 days) on striatal gene expression of substance P, enkephalin, and glutamic acid decarboxylase isoforms, GAD65 and GAD67, were evaluated in wild-type and A(2A)-R-deficient (A(2A)-R(-/-)) mice. In situ hybridization histochemistry was performed using oligonucleotides followed by quantitative image analysis. Our results demonstrated that a biphasic response of IEG expression to acute caffeine observed in the wild-type striatum was resumed in a monophasic response in the mutant striatum. In the cerebral cortex and hippocampus, the effect of caffeine was weak in wild-type, whereas in mutant mice it induced a 2-3-fold increase in the IEG expression to restore a level similar to the wild-type basal expression. Chronic caffeine and DPCPX-mediated regulation in neuropeptide and GADs striatal gene expression typically showed the mimicking of alterations resulting from the A(2A)-R genetic deficiency in 25 mg/kg caffeine-treated wild-type mice as well as the dose-dependent normalization of substance P and enkephalin expression in A(2A)-R(-/-) mice. These results indicate that, depending on the dose, the blockade of A(2A)-R or A(1) receptors by caffeine is preferentially revealed leading to highly differential alterations in striatal gene expression and they also suggested the central role of these two receptors on the control of dopaminergic functions.     

Inhibition of morphine withdrawal by the NMDA receptor antagonist MK-801 in rat is age-dependent

This study investigated the effects of the NMDA receptor antagonist MK-801 on the development of morphine dependence in 7-, 14-, and 21-day-old rat pups. For 6.5 days, starting at 1, 8, or 15 days of age, rats were pretreated with MK-801 (0.03 or 0.1 mg/kg, bid) or saline; 15 min later, morphine sulfate (10 mg/kg) or saline was injected to induce opiate dependence. On the afternoon of the seventh day, pups were injected with MK-801 (0.1 mg/kg) or saline and 15 min later with naltrexone (1 mg/kg) to precipitate withdrawal. Pups were then placed in a warm chamber with the litter and their behavior scan-sampled every 15 sec for a total of 15 min. MK-801 failed to inhibit morphine withdrawal in the 7-day-old rat, but did attenuate the development of morphine dependence in both the 14- and 21-day-old rats. These results suggest that the NMDA receptor is not functionally active in opiate withdrawal until around the second to third week of postnatal life in the rat and that there exists a transition period for the NMDA receptor to play a role in the development of opiate dependence and withdrawal.     

Severely mentally ill substance abusers: an 18-month follow-up study

  Background: The aims of this study were to investigate initial characteristics and improvement after 18 months in patients with comorbidity of severe mental illness and substance dependence. These patients took part in a multicentre study aimed at improving co-operation between psychiatric health care units and social services. Methods: A total of 358 patients, 66% men, were included. There were four diagnostic subgroups: psychosis 29%, depression 17%, borderline personality disorder 23%, and other diagnoses of equal severity 31%. Initially and at follow-up the following measurements were used: global functioning axis V DSM-III-R (GAF), seven areas of Addiction Severity Index (ASI) and psychological symptoms (SCL-90). The outcome of substance use during the past 6 months was estimated by the Clinical Rating Scale (CRS). Results: Most patients were single (77%) and few (10%) had income from employment. Many (61%) had made suicide attempts, and 52% had somatic diseases before entering this project. After 18 months, 14 patients (3.9%) had died, and 288 patients (84%) could be interviewed. There were significant improvements in all but one ASI area (employment), in psychological symptoms and in global functioning. There was a positive correlation between the reductions in severity of alcohol abuse, drug abuse, psychiatric symptoms, relationships (ASI) and psychological symptoms. Forty-eight percent of patients with mainly alcohol-related problems, and 57% of those with mainly drug-related problems were either “abstinent” or using drugs “without impairment” (CRS) after 18 months. Improvement did not differ between psychiatric subgroups. Conclusion: These patients have weak social integration. Alcohol dependence was the most common substance use disorder. In most areas investigated, patients had improved. No substance abuse was found in half of the patients at follow-up. Accepted: 24 October 2000     

Delta9-tetrahydrocannabinol releases and facilitates the effects of endogenous enkephalins: reduction in morphine withdrawal syndrome without change in rewarding effect

Recent studies have suggested that cannabinoids might initiate the consumption of other highly addictive substances, such as opiates. In this work, we show that acute administration of Delta9-tetrahydrocannabinol in mice facilitates the antinociceptive and antidepressant-like responses elicited by the endogenous enkephalins protected from their degradation by RB 101, a complete inhibitor of enkephalin catabolism. This emphasizes the existence of a physiological interaction between endogenous opioid and cannabinoid systems. Accordingly, Delta9-tetrahydrocannabinol increased the release of Met-enkephalin-like material in the nucleus accumbens of awake and freely moving rats measured by microdialysis. In addition, this cannabinoid agonist displaced the in vivo [3H]diprenorphine binding to opioid receptors in total mouse brain. The repetitive pretreatment during 3 weeks of Delta9-tetrahydrocannabinol in mice treated chronically with morphine significantly reduces the naloxone-induced withdrawal syndrome. However, this repetitive administration of Delta9-tetrahydrocannabinol did not modify or even decrease the rewarding responses produced by morphine in the place preference paradigm. Taken together, these behavioural and biochemical results demonstrate the existence of a direct link between endogenous opioid and cannabinoid systems. However, chronic use of high doses of cannabinoids does not seem to potentiate the psychic dependence to opioids.     

增生性瘢痕成纤维细胞P物质表达的研究

目的研究P物质（substance P，SP）在人增生性瘢痕体外培养的成纤维细胞的表达情况及其与正常皮肤之间的差异，探讨增生性瘢痕组织SP表达增高的原因。方法以酶消化法体外培养成人增生性瘢痕以及正常皮肤的成纤维细胞，将SP（终浓度为10^-7mol／L）加入培养液中刺激成纤维细胞，分别于刺激前和刺激后1、3、6、12、24h采用RT—PCR检测细胞内SP基因的表达情况，ELISA检测培养液中SP浓度。正常皮肤对照组及瘢痕对照组除不应用SP外，余处理均相同。结果未受SP刺激时，人增生性瘢痕及正常皮肤体外培养的成纤维细胞均能分泌一定浓度的SP，两者之间差异有统计学意义（P〈0．01）。SP刺激后，正常皮肤体外培养的成纤维细胞SP基因和蛋白表达均在1～3h内达到高峰，随后迅速下降，24h后仍高于其正常水平；而增生性瘢痕体外培养的成纤维细胞SP基因和蛋白表达在3～6h内达到高峰，随后缓慢下降，24h后仍高于其正常水平。两种成纤维细胞SP的分泌差异有统计学意义（P〈0．05）。结论外源性SP可诱使成纤维细胞内SP的分泌增加，而增生性瘢痕与正常皮肤成纤维细胞SP的分泌情况有明显差异。     

Talking to Youth About Drugs: What Do Late Adolescents Say About Parental Strategies?

Abstract: This research, comprised of 2 studies, extends current knowledge of parent‐child communication about drugs. The first study developed a typology of parental strategies used to deter children’s substance use. The second study examined relationships among the parental strategies identified in the first study, which included family communication environments and self‐reported substance use. Results revealed that parental communication strategies to deter substance use may be employed in different ways by laissez‐faire, pluralistic, consensual, and protective families. Of the 7 identified types of strategies, very few actually impacted substance use in the previous 30 days. The only strategy to have a significant effect on the use of all drug types was a “no tolerance rule.” Prevention efforts and programs may target parents so as to enhance parental communication competence and offer parents an array of strategies to choose from that might best fit with their family communication environment.