Outcomes,performance, and quality-What's the difference?

Calls for greater accountability within the addiction treatment field have led to a wide range of efforts designed to improve treatment performance, quality, and outcomes. However, efforts with conceptually and methodologically different approaches have used the same umbrella terms such as “quality,” “performance indicators,” and “outcome domains,” causing substantial confusion among providers and policymakers. This article provides operational definitions of the terms used in discussing quality, performance, and outcomes, as well as a discussion of ways to integrate efforts to measure treatment system performance and quality during treatment with patient outcomes during and following treatment. This article thus helps build a common understanding about how these efforts to bring greater accountability can be combined and integrated to improve the attractiveness and effectiveness of addiction treatments.     

Is it the Taste or the Buzz? Alexithymia,Caffeine, and Emotional Eating

Background: Alexithymia, a relatively stable personality trait characterized by difficulties identifying and describing feelings and externally oriented thinking, has been linked to both substance use disorders and eating disorders. In nonclinical samples, alexithymia is associated with heavier consumption of alcohol and caffeine. Both are psychoactive drugs, but unlike most drugs they are typically consumed in the context of palatable and calorie-rich products. Objectives: Given the association of alexithymia with disordered eating, the present study evaluated the hypothesis that heavier consumption of caffeine by those with high levels of alexithymia may be motivated by the palatable and caloric aspects of common caffeine products rather than by drug-seeking. Methods: There were 224 participants aged 17–63?years who completed instruments assessing demographics, alexithymia, emotional eating, caffeine consumption, alcohol consumption, negative moods, and reward sensitivity. Results: As predicted, alexithymia was positively related to emotional eating as well as consumption of caffeine and alcohol, and alexithymia was a significant predictor of caffeine intake in regression models. However, there was no indication of mediation by emotional eating. Conclusions: Alexithymia is characterized by deficient emotion regulation and negative moods, hence use of drugs and/or foods to regulate emotions, combined with poor interoceptive awareness, may account for excessive consumption of drugs or foods as alternative emotion regulation strategies in those with high levels of this trait.     

Naltrexone and β-funaltrexamine antagonism of the antinociceptive and response rate-decreasing effects of morphine, dezocine, and d-propoxyphene

  Rationale: Patterns of competitive and insurmountable antagonism provide important data to guide the classification and characterization of different types of opioid agonists as well as infer the mechanism of action for agonists. Objective: Experiments with the competitive antagonist, naltrexone, and the insurmountable antagonist, β-funaltrexamine (β-FNA), were conducted to determine whether the antinociceptive and rate-decreasing effects of the opioid agonists dezocine and d-propoxyphene are 1) mediated through μ opioid receptors in rats, and 2) differ from morphine with respect to relative efficacy. Methods: The rat tail-withdrawal assay was used to measure antinociception and a fixed ratio 20 (FR20) schedule of food delivery was used to measure rate suppression. Results: Naltrexone (0.01–1.0 mg/kg) was approximately equipotent as an antagonist of the antinociceptive and rate-decreasing effects of both morphine and dezocine and as an antagonist of the antinociceptive effects of d-propoxyphene. Naltrexone failed to block the rate-decreasing effects of d-propoxyphene. β-FNA (5 and 10 mg/kg) also antagonized the antinociceptive and rate-decreasing effects of morphine and dezocine as well as the antinociceptive effects of d-propoxyphene. β-FNA failed to produce a dose-dependent antagonism of the rate-decreasing effects of d-propoxyphene. Conclusions: These data suggest that the antinociceptive effects of morphine, dezocine, and d-propoxyphene and the rate-decreasing effects of morphine and dezocine are mediated through μ opioid receptors. Overall, high doses of β-FNA produced a greater degree of antagonism of the behavioral effects of dezocine than morphine or d-propoxyphene, confirming other reports that dezocine is a lower efficacy agonist than morphine. Additionally, the degree of antagonism produced by β-FNA was greater for the antinociceptive effects of all three compounds than for the rate-decreasing effects. Received: 14 August 1998 / Final version: 4 December 1998     

Toxicology, Environmental Health, and the “One Health” Concept

The One Health concept promotes collaboration among veterinarians, physicians, scientists, and other professions to promote human, animal, and ecosystem health. One Health illustrates the interconnectedness and interdependence of human, animal, and ecosystem health. This concept has traditionally focused on zoonoses that are infectious diseases, not on chemical- or poison-related illnesses in animals and their relationship to the detection and prevention of human illness. The purpose of this article is to describe key experiences of scientists in the Health Studies Branch within the National Center for Environmental of Health of the Centers for Disease Control and Prevention in which the study of animal illness facilitated a public health investigation into an outbreak of chemicalassociated human disease. The experiences highlight how utilizing the One Health approach may improve chemical-associated outbreak investigations and facilitate appropriate intervention strategies. An appropriate One Health approach in toxicology and environmental health in outbreak settings should include consideration of the common environments and food sources shared by humans and animals and consideration of the potential for contaminated animal products as food sources in human exposures.     

Thiol reactivity and its impact on the ciliate toxicity of α,β-unsaturated aldehydes, ketones, and esters

A recently introduced chemoassay has been used to determine second-order rate constants of the electrophile-nucleophile reaction of 15 α,β-unsaturated aldehydes with glutathione. The respective kGSH values vary for more than 3 orders of magnitude, and are within the range determined previously for 31 α,β-unsaturated ketones and esters. Structure-reactivity analyses yield distinct relationships between kGSH and structural features of the compounds. Moreover, increasing kGSH increases the aldehyde toxicity toward ciliates in terms of 48 h-EC50 values (effective concentration yielding 50% growth inhibition of Tetrahymena pyriformis within 48 h). A respective log-log regression equation including both kGSH and the octanol/water partition coefficient, Kow, yields a squared correlation coefficient of 0.96. Comparative analysis with corresponding data for 15 ketones and 16 esters reveals systematic differences between the three compound classes with regard to the individual contributions of hydrophobicity and electrophilic reactivity to aquatic toxicity. The former is particularly pronounced for aldehydes, while the ester toxicity is largely governed by reactivity, with ketones showing an intermediate pattern that is more similar to the one of esters than of aldehydes. It follows that within the Michael acceptor domain of α,β-unsaturated carbonyls, a distinction between aldehydes and nonaldehydic derivatives appears necessary when employing electrophilic reactivity as a component for the quantitative prediction of their reactive toxicity toward aquatic organisms.     

Patient‐perceived problems, compliance, and the outcome of hypertension treatment

Objective: To study the associations between the outcome of antihypertensive therapy with both patient-perceived problems and patient initiated modification of dosage instructions. Design and methods: In this cross-sectional survey, all chronic hypertensives aged less than 75 years (n = 971) visiting nine Finnish pharmacies between May and September of 1996 were asked to participate. Of the 866 agreeing to participate, 482 returned the questionnaire (56%). After excluding persons with missing data, the final study population consisted of 428 hypertensive patients. Information on problems with treatment, the modification of dosage instructions, and blood pressure levels was based on patient self-reports.Results: Two-thirds (68%) of the study population reported suffering from one or more problems. The most common problems were symptoms of high blood pressure and adverse drug effects. Thirty-one percent of the male respondents and 21% of the female respondents reported having modified their dosage instructions. Only 36% of the patients had reached the goal blood pressure (<160/90 mmHg). Patients having problems with hypertension treatment were significantly more likely to have modified their dosage instructions than those without problems (3+ problems, adjusted OR=4.8). Not reaching goal blood pressure levels was sigfinicantly associated with both high number of patient-perceived problems (3+ problems, adjusted OR=2.1) and modification of dosage instructions (adjusted OR=1.9).Conclusion: The poor outcome in antihypertensive therapy is associated with both patient-perceived problems and patient initiated modification of dosage instructions.     

The family relationships of Antoine Brulon, apothecary to the king, and his wife, Anne de Furnes, in Auvergne and Paris in the 17th century. Anne de Furnes and Molière in Paris and the village of Auteuil

This article presents the biography of Anne de Fumes, wife of Antoine Brulon, the king's apothecary. Due to the successive deaths of her husband and her only daughter, Geneviève, her sisters-in-law, Géraude and Anne Brulon, living in Auvergne, inherited the property of their niece. Anne de Fumes, who inherited the movable assets, carried out a series of transactions to acquire the totality of the property rights, which she obtained, but at the considerable cost of 100,000 pounds. After her death, her five nephews and nieces, her sole legatees, inherited her estate. From 1666, Molière was the tenant of an apartment in a building in the Rue Saint-Thomas-du-Louvre, Place du Palais-Royal, in Paris, which belonged to Anne de Fumes. She lived in the neighbouring house in the Rue Saint-Honoré of which she was also the owner. Three apothecaries, Philibert Boudin, Jean Morel and Pierre Frapin, successively rented the shop and entresol of the house in the Rue Saint-Thomas-du-Louvre. Pierre Frapin, tenant of the shop from 1668, supplied Molière with medicine. Like Molière, Anne de Fumes rented accommodation in a house in the village of Auteuil belonging to Jacques de Grout de Beaufort and his wife Marie Filz. Reports show that the famous actor and Anne de Fumes cohabited in Auteuil during the period 1667 to 1672.     

Cellular and paracellular calcium transport in the rat ileum and the influence of 1α,25-dihydroxyvitamin D3 and dexamethasone

Summary Concentration dependence of unidirectional calcium fluxes across the rat ileum freed from the serosa and the muscularis externa were measured in a modified Ussingchamber. Mucosa (m) to serosa (s) calcium flux showed a saturable component, whereas s to m calcium flux was linearly related to the calcium concentration between 0.125 mmol/1 and 5 mmol/1. At all calcium concentrations used net secretion of calcium was observed. The s to m flux of the simultaneously measured paracellular marker mannitol at all calcium concentrations was remarkably higher than the m to s flux, resulting in net mannitol secretion. The results obtained from the calcium fluxes when clamping the transepithelial electrical potential agree well with those of the concentration dependence of the calcium fluxes: 1. Only m to s flux has a voltage independent, transcellular component. 2. Calcium s to m flux is totally voltage dependent, i.e. diffusive. 3. Diffusional s to m calcium flux is about 80% greater than the diffusional fraction of the m to s flux. Omitting glucose from the bathing solution effected a decrease of the transepithelial electrical potential and of the short circuit current by 91% and 85% respectively; net calcium secretion was almost abolished and net mannitol secretion remarkably reduced. Addition of glucose, which stimulates water absorption in the ileum as a metabolic substrate, activated m to s but significantly more pronounced s to m calcium flux parallel to that of mannitol. Dexamethasone, known to stimulate sodium and water absorption in the ileum by activation of the Na,K-ATPase, effected an increase of the transepithelial electrical potential difference and of the short circuit current by about 100% but had no influence on tissue resistance; m to s and more pronounced s to m calcium flux was stimulated after the induction by dexamethasone and net calcium secretion was increased by 70%. After pretreatment with 1,25-dihydroxyvitamin D3 tissue resistance was decreased by about 42%. The vitamin had no effect on net calcium or mannitol secretion but significantly increased bidirectional calcium and mannitol fluxes. Flux measurements in clamped preparations revealed: 1. 1,25-dihydroxyvitamin D₃ and dexamethasone has no effect on the cellular-mediated m to s calcium transport; 2. diffusive calcium flux in m to s and in the opposite direction, from s to m, is increased by the vitamin and by the hormone. In conclusion the net ileal calcium and mannitol secretion is the consequence of an asymmetry of the paracellular flux with a prevalence of the s to m flux over that in m to s direction. It is hypothesized that this prevalence is caused by an anomalous solvent drag effect. Paracellular calcium flux in both directions is increased by 1,25-dihydroxyvitamin D3 and dexamethasone by different mechanisms, as indicated by the changes in the electrical parameters of the tissue. Send offprint requests to U. Karbach at the above address     

Comparative effects of the α7 nicotinic partial agonist,S 24795, and the cholinesterase inhibitor,donepezil, against aging-related deficits in declarative and working memory in mice

Introduction The comparative effects of a newly described specific α7 nAChR partial agonist, S 24795, and a cholinesterase inhibitor, donepezil, currently used as a symptomatic Alzheimer’s disease treatment were studied in two mouse models of aging-related memory deficits. Materials and methods We employed radial arm-maze paradigms assessing short-term working memory (STWM, experiment A) and mnemonic flexibility, a cardinal property of long-term declarative (LTDM, experiment B). Both compounds were administered daily at 0.3 and 1 mg/kg subcutaneously (∼3 weeks). Results In the STWM experiment, vehicle-treated aged mice displayed a severe and persistent deficit in the retention of successive arm visits in comparison to younger controls. S 24795 at 1 mg/kg (trends at 0.3 mg/kg) and donepezil at 0.3 mg/kg (but not 1 mg/kg) exerted beneficial effects on this deficit: The performance of aged mice treated with these drugs remarkably increased across the testing days and almost reached young adult performance level. In the critical test trials of memory flexibility (i.e., LTDM), in experiment B, S 24795 at 1 mg/kg (trends at 0.3 mg/kg) and donepezil at the dose of 1 mg/kg (but not 0.3 mg/kg) improved aged mice performance. Conclusion This preclinical demonstration that S 24795 restored specific age-related memory deficits with as much efficacy as donepezil adds to recent literature in highlighting the potential interest of an α7 nAChR drug as a symptomatic AD therapeutic.     

Is Na+ required for the binding of dopamine, amphetamine, tyramine, and octopamine to the human dopamine transporter?

The role of Na(+) in the recognition of blockers by the dopamine transporter is accomodated by a model with a cation site that overlaps with the blocker binding domain, and a distal Na(+) site that interacts with this cation site and perhaps with the blocker binding domain itself. The present study addresses the application of this model to the recognition of substrates by the dopamine transporter, focusing on conditions that should reveal a stimulatory effect, if present, of Na(+) on substrate binding. Recognition was studied via the inhibition of binding of [(3)H]WIN 35,428 (2beta-carbomethoxy-3beta-(4-fluorophenyl) [(3)H]tropane), a cocaine analog, to the human dopamine transporter in human embryonic kidney 293 cells. Little or no changes in binding were noted for dopamine, d-amphetamine, p-tyramine, or dl-octopamine by increasing [Na(+)] from 2 mM to 20 mM with co-varying Br(-), both at pH 7.4 and 7.0. In 74-mM Tris-HBr or -HCl, only dopamine and d-amphetamine showed binding increases upon raising Na(+), leveling off with NO(3)(-) or SO(4)(2-) but not Br(-) as anion at approximately 60 mM Na(+), consonant with a partly stimulatory action of Br(-). An Na(+) free, low 5-mM Tris-HEPES buffer was used for studying Na(+) curves truly starting at 0 mM, and, with SO(4)(2-) as the anion, no stimulation of binding by Na(+) was observed. This suggested that the stimulations observed in high (74 mM) Tris(+) buffer by Na(+) were not a direct effect of Na(+) but rather a disinhibitory effect of Na(+) in removing Tris(+) inhibition that depended upon substrate. Tris(+) IC(50) values in Na(+) free buffer were not lower for dopamine and d-amphetamine than p-tyramine and dl-octopamine. No evidence was found for a stronger inhibitory effect of Na(+) for dopamine and dl-octopamine potentially offsetting Tris(+) disinhibition. All results together support the existence of a substrate domain overlapping with a cation site that also binds Tris(+); a distal Na(+) site interacts with this cation site and with the substrate domain by negative allosterism and is additionally impacted by Cl(-). Importantly, interactions between sites vary with the type of substrate, and, in membrane preparations, Na(+) is not required for, or stimulatory to, the binding of any of the four substrates studied unlike the binding of the cocaine analog WIN 35,428.     

Study of the genotoxic and cytotoxic effects of the α-, β-, and γ- Hexachlorocyclohexane isomers in human lymphocyte cells using the cytokinesis-block micronucleus assay

The genotoxic potential of hexachlorocyclohexane (HCH) isomers (α-, β-, and γ-) which are organochlorine pesticides was tested in peripheral blood lymphocyte cultures from two donors by using the cytokinesis-block micronucleus assay. Micronucleus (MN) frequency, binucleated cells with micronucleus (BNMN), and cytokinesis-blocked proliferation index (CBPI) were determined as genotoxic and cytotoxic endpoints. At the concentration ranges tested (12.5–100?μg.L?^?1), all HCH isomers induced dose-dependent cytotoxic effects, γ-HCH being the most toxic. This isomer was also able to induce significant increase in MN frequency and BNMN cells indicating a genotoxic potential at 50 and 100?μg.L?^?1. The genotoxic test of β-HCH showed a positive induction of MN and BNMN cells at the highest concentration of 100?μg.L?^?1 and a significant cytotoxicity at 50?μg.L?^?1. Under the experimental condition used, α-HCH was unable to induce any significant increase in MN frequency confirming that α-HCH is a non-genotoxic agent.     

Antagonism of γ-aminobutyric acid and muscimol by picrotoxin,bicuculline, strychnine,bemegride, leptazol,d-tubocurarine and theophylline in the isolated olfactory cortex

Summary -Aminobutyric acid (GABA) applied to neurones in the olfactory cortex slice in vitro, increases input conductance and produces a small depolarization, which mimicks the action of the inhibitory transmitter. In previous experiments it was shown that this inhibition could be blocked by picrotoxin, bicuculline, strychnine, leptazol, bemegride, theophylline and d-tubocurarine. In the present study the effects of the above blockers on the action of bathapplied GABA were assessed. These blockers all antagonised the action of GABA at concentrations similar to those required to block synaptic inhibition. However, the amount of antagonism of GABA action was variable and this variability was attributed to the cellular uptake of GABA. The variability was circumvented by using muscimol, a GABA agonist not subjected to uptake. This GABA antagonism explains the convulsant action of many of the agents studied and reinforces the idea that GABA mediated inhibitory transmission in the olfactory cortex.     

Differential Effects of Anionic,Cationic, Nonionic,and Physiologic Surfactants on the Dissociation, α-Chymotryptic Degradation,and Enteral Absorption of Insulin Hexamers

Various surfactants were investigated to compare their effects on insulin dissociation, -chymotryptic degradation, and rat enteral absorption. With a circular dichroism technique, sodium dodecyl sulfate (SDS) at a 5 mM concentration was found to completely dissociate procine-zinc insulin hexamers (0.5 mg/ml) into monomers. The catalytic activity of -chymotrypsin (0.5 µM) was also abolished by 5 mM SDS. When insulin was injected into the distal jejunum/ proximal ileum segment of the rat, 5 mM SDS greatly enhanced its pharmacological availability, from a negligible value to 2.8%. Being a cationic surfactant, hexadecyl trimethylammonium bromide (CTAB) also efficiently dissociated insulin hexamers at concentrations of 1–5 mM. However, extensive charge–charge interaction was observed below a CTAB concentration of 0.6 mM, leading to insulin precipitation at a molar CTAB:insulin ratio of 1:1 to 2:1. An -chymotryptic degradation study also revealed near-complete dissociation of insulin hexamers at 1 mM CTAB. Above 1 mM, however, CTAB acted as an enzyme inhibitor, most likely by means of charge repulsion. Enteral absorption studies showed a much lower pharmacological availability, only 0.29%. Nonionic surfactants such as Tween 80 and polyoxyethylene 9 lauryl ether were ineffective in dissociating insulin hexamers. Tween 80, at 5 mM, neither significantly altered the -chymotryptic degradation pattern nor enhanced the enteral absorption of insulin. The relative effectiveness of different species of bile salts on insulin hexamer dissociation appeared to be similar. Sodium glycocholate at a 30 mM concentration also significantly increased insulin pharmacological availability, to 2.3%. A morphological study did not reveal any significant alteration of the rat intestinal mucosal integrity after exposure to 5 mM SDS for 30 min. The results further emphasize the importance of the degree of insulin aggregation on its enteral transport.     

Zaprinast activates MAPKs, NFκB, and Akt and induces the expressions of inflammatory genes in microglia

Previously, the authors reported that zaprinast, an inhibitor of cGMP-selective phosphodiesterases, induced the secretions of TNF-α and IL-1β by microglia and enhanced the induction of iNOS by lipopolysaccharide (LPS). In this study, the signaling mechanism responsible for microglial activation by zaprinast was investigated and the effects of zaprinast and LPS on microglial activation were compared. Zaprinast was found to activate ERK1/2, p38 MAPK, JNK, NFκB, and PI3K/Akt, and subsequently, induce the mRNA expressions of IL-1α, IL-1β, TNF-α, CCL2, CCL4, CXCL1, CXCL2, and CD14. Associations between signaling pathways and gene expressions were examined by treating microglia with signal inhibitors. PDTC inhibited the induction of all the above genes by zaprinast, and SB203580 inhibited all genes except CXCL1. SP600125, PD98059, and LY294002 inhibited the induction of at least CCL2. Microglial activation by zaprinast was then compared with full-blown activation by LPS. The zaprinast-induced phosphorylations of MAPKs and IκB were less prompt than LPS-induced phosphorylations. IκB degradation by LPS was significant at 10min and did not return to normal, whereas zaprinast induced a later, transient degradation. LPS induced the mRNA expressions of IL-1β, TNF-α, IL-6, CCL2, iNOS, and COX-2, and although zaprinast significantly induced the expressions of all except IL-6 and iNOS, these inductions were far less than those induced by LPS. Collectively, zaprinast was found to upregulate microglial activity mainly via NFκB and p38 MAPK signaling and the subsequent expressions of inflammatory genes. Although, zaprinast was found to have obvious effects on microglia, these were weaker than the effects of LPS.     

A comparison of the content-, construct- and predictive validity of the cigarette dependence scale and the Fagerström test for nicotine dependence

BACKGROUND: Research showed that the widely used Fagerstrom test for nicotine dependence (FTND) does not cover important aspects of dependence. A new test, the cigarette dependence scale (CDS-12), covers the main elements in DSM-IV and ICD-10 definitions of dependence. We compared the psychometrics of CDS-12, FTND, and CDS-5 and the heaviness of smoking index (HSI), which are short versions of CDS-12 and FTND, respectively. METHODS: Internet survey in 2002-2003. Participants were invited one month after answering the first survey to answer a second survey on smoking status and withdrawal symptoms. RESULTS: Eight hundred two smokers answered both surveys. Cronbach's alpha coefficients were higher for CDS-12 (0.91) and CDS-5 (0.77) than for FTND (0.68) and HSI (0.63). Among 231 smokers who quit smoking at follow-up, higher baseline CDS-12 scores predicted higher withdrawal ratings at follow-up, for all withdrawal symptoms except appetite. FTND and HSI predicted higher craving in quitters, but did not predict the intensity of other withdrawal symptoms. Neither CDS-5, FTND or HSI predicted smoking cessation, but higher CDS-12 scores marginally predicted smoking cessation at follow-up (area under the receiver operating characteristic (ROC) curve = 0.55, 95% confidence interval = 0.51-0.59). CONCLUSIONS: CDS-12 had better content validity and internal consistency than FTND and was a slightly better predictor of withdrawal symptoms. Unexpectedly, higher (not lower) CDS-12 scores predicted subsequent smoking cessation, perhaps because endorsement of some CDS-12 items implies accepting that one is dependent, which in turn could reflect motivation to quit. CDS-12 may represent an alternative to FTND for measuring cigarette dependence.