BACKGROUND

Abnormal patterns of metabolite levels have been detected by magnetic resonance spectroscopy in frontostriatal regions of individuals meeting DSM-IV criteria for methamphetamine dependence, but less is known about the effects of drug abstinence on metabolite levels.

OBJECTIVE

To assess the effects of long-term methamphetamine use and drug abstinence on brain metabolite levels.

METHODS

To assess regional specific metabolite levels using magnetic resonance spectroscopy imaging techniques in 2 groups of currently abstinent methamphetamine users: methamphetamine users who recently initiated abstinence and methamphetamine users who had initiated abstinence more than 1 year prior to study.

METHODS

Participants were recruited from outpatient substance abuse treatment centers.

METHODS

Eight methamphetamine users with sustained abstinence (1 year to 5 years) and 16 recently abstinent methamphetamine users (1 month to 6 months) were compared with 13 healthy, non-substance-using controls.

METHODS

Magnetic resonance spectroscopy measures of N-acetylaspartate-creatine and phosphocreatine (NAA/Cr), choline-creatine and phosphocreatine (Cho/Cr), and choline-N-acetylaspartate (Cho/NAA) ratios were obtained in the anterior cingulate cortex as well as in the primary visual cortex, which served as a control region.

RESULTS

The absolute values of Cr did not differ between controls and methamphetamine users. Methamphetamine users had abnormally low NAA/Cr levels within the anterior cingulate cortex, regardless of the time spent abstinent (F(2,34) = 12.61; P<.001). No NAA/Cr group differences were observed in the primary visual cortex (F(2,33) = 0.29; P = .75). The Cho/NAA values for the anterior cingulate cortex were abnormally high in the methamphetamine users who recently initiated abstinence but followed a normal pattern in the methamphetamine users who had initiated abstinence more than 1 year prior to study (F(2,34) = 7.31; P = .002).

CONCLUSIONS

The relative choline normalization across periods of abstinence suggests that following cessation of methamphetamine use, adaptive changes occur, which might contribute to some degree of normalization of neuronal structure and function in the anterior cingulum. More research is needed to elucidate the mechanisms underlying these adaptive changes.

The innervation of cerebral blood vessels by nerve fibers containing calcitonin gene-related peptide (CGRP) and the vasomotor effects of this peptide are described for a number of different mammalian species. CGRP-immunoreactive nerve fibers were present in the adventitia of cerebral arteries in all species examined (guinea pig, cat, rabbit, rat, and mouse). Numerous perikarya containing CGRP immunoreactivity are demonstrable in the trigeminal ganglion of all species. In the cerebral perivascular nerve fibers and in trigeminal perikarya, CGRP is often colocalized with substance P and neurokinin A. Marked interspecies differences exist both in the density of CGRP-immunoreactive nerve fibers and in the cerebrovascular levels measured with radioimmunoassay. The highest concentrations were observed in cerebral vessels from guinea pigs, the lowest concentration in rabbit vessels, and intermediate levels in the feline and human cerebral vasculature. CGRP is a potent dilator of cerebral arteries in all species examined (human pial, feline middle cerebral, rabbit, guinea pig and rat basilar arteries). The concentration of CGRP eliciting half-maximal responses ranged from 0.4 nM (human pial artery) to 3 nM (rat and rabbit basilar arteries). Pretreatment of cerebral arteries with low concentrations of either substance P (0.1 nM) or neurokinin A (3 nM) attenuated slightly the CGRP-induced relaxations of guinea pig basilar arteries. Calcitonin was found to be a very weak dilator of cerebral arteries from human and guinea pig. Thus, cardiovascular nerve fibers containing CGRP appear to be present in all mammalian species (although to varying degrees) and CGRP is invariably a potent dilator of the cerebral arteries for all species.

Heme is an important immunostimulating agent and oxidative factor contributing to endothelial cell activation. To investigate the mechanism of heme-induced endothelial cell activation, we analyzed the effect of heme and the inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), on the expression of the heme-degrading stress protein, heme oxygenase (HO), and adhesion molecules in human umbilical vein endothelial cells (HUVEC). Indirect immunofluorescence double labeling studies demonstrated a simultaneous increase of ICAM-1 and HO-1 after exposure of cells to heme for 24 hr. Co-expression of HO-1 and ICAM-1 was also demonstrated in TNF-alpha-exposed cells. Dot blot immunoassay and quantitative analysis by ELISA demonstrated that heme treatment for 24 hr caused a 2-fold increase in ICAM-1 expression (P < 0.002) compared with quiescent cells, while in cells stimulated by TNF-alpha for 24 hr ICAM-1 gene expression increased by 5-fold. Moreover, heme exposure also resulted in a marked increase in VCAM-1 and E selectin expression (three and four times over control levels, respectively). On the other hand, TNF-alpha treatment showed similar expression levels for VCAM-1 and E selectin, compared with stimulation by heme (100 microM). The level of HO activity in endothelial cells exposed to heme or TNF-alpha was increased from 24.7 +/- 5.7 pmol bilirubin/mg protein/min in control to 70.0 +/- 9.5 and 36.7 +/- 3.1 pmol bilirubin/mg protein/min in heme- and TNF-alpha-stimulated cells, respectively. These results suggest that upregulation of ICAM-1, VCAM-1, and E selectin expression is associated with oxidative stress induced by hemoglobin/heme and that HO-1 may play a modulating role via its ability to degrade heme to a substance with antioxidant properties.

NMDA receptors have the potential to produce complex activity-dependent regulation of transmitter release when localized presynaptically. In the somatosensory system, NMDA receptors have been immunocytochemically detected on presynaptic terminals of primary afferents, and these have been proposed to drive release of substance P from central terminals of a subset of nociceptors in the spinal cord dorsal horn. Here we report that functional NMDA receptors are indeed present at or near the central terminals of primary afferent fibers. Furthermore, we show that activation of these presynaptic receptors results in an inhibition of glutamate release from the terminals. Some of these NMDA receptors may be expressed in the preterminal axon and regulate the extent to which action potentials invade the extensive central arborizations of primary sensory neurons.

Cannabinoid compounds have been shown to produce antinociception and antihyperalgesia by acting upon cannabinoid receptors located in both the CNS and the periphery. A potential mechanism by which cannabinoids could inhibit nociception in the periphery is the activation of cannabinoid receptors located on one or more classes of primary nociceptive neurons. To address this hypothesis, we evaluated the neuronal distribution of cannabinoid receptor type 1 (CB1) in the trigeminal ganglion (TG) of the adult rat through combined in situ hybridization (ISH) and immunohistochemistry (IHC). CB1 receptor mRNA was localized mainly to medium and large diameter neurons of the maxillary and mandibular branches of the TG. Consistent with this distribution, in a de facto nociceptive sensory neuron population that exhibited vanilloid receptor type 1 immunoreactivity, colocalization with CB1 mRNA was also sparse (<5%). Furthermore, very few neurons (approximately 5%) in the peptidergic (defined as calcitonin gene-related peptide- or substance P-immunoreactive) or the isolectin B4-binding sensory neuron populations contained CB1 mRNA. In contrast, and consistent with the neuron-size distribution for CB1, nearly 75% of CB1-positive neurons exhibited N52-immunoreactivity, a marker of myelinated axons. These results indicate that in the rat TG, CB1 receptors are expressed predominantly in neurons that are not thought to subserve nociceptive neurotransmission in the noninjured animal. Taken together with the absence of an above background in situ signal for CB2 mRNA in TG neurons, these findings suggest that the peripherally mediated antinociceptive effects of cannabinoids may involve either as yet unidentified receptors or interaction with afferent neuron populations that normally subserve non-nociceptive functions.

Sieve tubes of legumes (Fabaceae) contain characteristic P-protein crystalloids with controversial function. We studied their behavior by conventional light, electron, and confocal laser scanning microscopy. In situ, crystalloids are able to undergo rapid (<1 sec) and reversible conversions from the condensed resting state into a dispersed state, in which they occlude the sieve tubes. Crystalloid dispersal is triggered by plasma membrane leakage induced by mechanical injury or permeabilizing substances. Similarly, abrupt turgor changes imposed by osmotic shock cause crystalloid dispersal. Because chelators generally prevent the response, divalent cations appear to be the decisive factor in crystalloid expansion. Cycling between dispersal and condensation can be induced in opened cells by repetitive exchange of bathing media containing either Ca(2)+ or chelators. Sr(2)+ and Ba(2)+, but not Mg(2)+, are equally active. In conclusion, the fabacean P-protein crystalloids represent a novel class of mechanically active proteinaceous structures, which provide an efficient mechanism with which to control sieve tube conductivity.

After neonatal treatment of rats with capsaicin, the spinal cord, the spinal trigeminal nucleus and spinal and trigeminal ganglia were analysed with immunohistochemistry using antisera to several peptides and 5-hydroxytryptamine. A marked decrease was observed in substance P-, cholecystokinin-, somatostatin- and VIP-like immunoreactivity present in the central branches of primary sensory neurons in the spinal cord and in substance P- and somatostatin-like immunoreactivity in sensory ganglion cells. No definite depleting effect of capsaicin could be established on 5-hydroxytryptamine and peptides, such as enkephalin and neurotensin, present in centrally originating fibres in the dorsal horn of the spinal cord. The results demonstrate that the effects of capsaicin are not confined to substance P immunoreactive primary sensory neurons. The possibility is discussed that capsaicin effects specifically functioning rather than chemically specific primary sensory neurons.

Many known painkillers are not always effective in the therapy of chronic neuropathic pain manifested by hyperalgesia and tactile allodynia. The mechanisms underlying neuropathic pain appear to be complicated and to differ from acute and inflammatory pain. Recent advances in pain research provide us with a clear picture for the molecular mechanisms of acute pain, and substantial information is available concerning the plasticity that occurs under conditions of neuropathic pain. The most important changes responsible for the mechanisms of neuropathic pain are found in the altered gene/protein expression in primary sensory neurons. After damage to peripheral sensory fibers, up-regulated expression of the Ca(v)alpha(2)delta-(1) channel subunit, the Na(v)1.3 sodium channel, and bradykinin (BK) B1 and capsaicin TRPV1 receptors in myelinated neurons contribute to hyperalgesia; while the down-regulation of the Na(v)1.8 sodium channel, B2 receptor, substance P (SP), and even mu-opioid receptors in unmyelinated neurons is responsible for the phenotypic switch in pain transmission. Clarification of the molecular mechanisms for such complicated plasticity would be extremely valuable when considering the therapeutic design of pain relieving drugs. Although many reports deal with the changes in expression of key molecules related to neuropathic pain, the initiation and the mechanisms that follow remain to be determined. The current study using lysophosphatidic acid (LPA) receptor knockout mice revealed that LPA produced by nerve injury initiates neuropathic pain and demyelination following partial sciatic nerve ligation (PSNL). A single injection of LPA was found to mimic PSNL in terms of neuropathic pain and its underlying mechanisms. This discovery may lead to the subsequent discovery of LPA-induced secondary genes, which would be therapeutic targets for neuropathic pain.

Ependymal overexpression of brain-derived neurotrophic factor (BDNF) stimulates neuronal addition to the adult striatum, from subependymal progenitor cells. Noggin, by suppressing subependymal gliogenesis and increasing progenitor availability, potentiates this process. We asked whether BDNF/Noggin overexpression might be used to recruit new striatal neurons in R6/2 huntingtin transgenic mice. R6/2 mice injected with adenoviral BDNF and adenoviral Noggin (AdBDNF/AdNoggin) recruited BrdU(+)betaIII-tubulin(+) neurons, which developed as DARPP-32(+) and GABAergic medium spiny neurons that expressed either enkephalin or substance P and extended fibers to the globus pallidus. Only AdBDNF/AdNoggin-treated R6/2 mice harbored migrating doublecortin-defined neuroblasts in their striata, and the new neurons expressed p27 as a marker of mitotic quiescence after parenchymal integration. AdBDNF/AdNoggin-treated R6/2 mice sustained their rotarod performance and open-field activity and survived longer than did AdNull-treated and untreated controls. Neither motor performance nor survival improved in R6/2 mice treated only with AdBDNF, and intraventricular infusion of the mitotic inhibitor Ara-C completely blocked the performance and survival effects of AdBDNF/AdNoggin, suggesting that the benefits of AdBDNF/AdNoggin derived from neuronal addition. Thus, BDNF and Noggin induced striatal neuronal regeneration, delayed motor impairment, and extended survival in R6/2 mice, suggesting a new therapeutic strategy in Huntington disease.

BACKGROUND

Accumulating evidence indicates important gender differences in substance use disorders. Little is known, however, about gender differences and opioid use disorders.

OBJECTIVE

To compare demographic characteristics, substance use severity, and other associated areas of functioning (as measured by the Addiction Severity Index-Lite (ASI-Lite)) among opioid-dependent men and women participating in a multisite effectiveness trial.

METHODS

Participants were 892 adults screened for the National Institute on Drug Abuse Clinical Trials Network investigation of the effectiveness of two buprenorphine tapering schedules.

RESULTS

The majority of men and women tested positive for oxycodone (68% and 65%, respectively) and morphine (89% each). More women than men tested positive for amphetamines (4% vs. 1%, p < .01), methamphetamine (11% vs. 4%, p < .01), and phencyclidine (8% vs. 4%, p = .02). More men than women tested positive for methadone (11% vs. 6%, p = .05) and marijuana (22% vs. 15%, p = .03). Craving for opioids was significantly higher among women (p < .01). Men evidenced higher alcohol (p < .01) and legal (p = .04) ASI composite scores, whereas women had higher drug (p < .01), employment (p < .01), family (p < .01), medical (p < .01), and psychiatric (p < .01) ASI composite scores. Women endorsed significantly more current and past medical problems.

CONCLUSIONS

Important gender differences in the clinical profiles of opioid-dependent individuals were observed with regard to substance use severity, craving, medical conditions, and impairment in associated areas of functioning. The findings enhance understanding of the characteristics of treatment-seeking men and women with opioid dependence, and may be useful in improving identification, prevention, and treatment efforts for this challenging and growing population.

Mesenchymal stem cells (MSCs) exhibit immune-suppressive properties, follow a pattern of multilineage differentiation, and exhibit transdifferentiation potential. Ease in expansion from adult bone marrow, as well as its separation from ethical issues, makes MSCs appealing for clinical application. MSCs treated with retinoic acid resulted in synaptic transmission, based on immunostaining of synaptophysin and electrophysiological studies. In situ hybridization indicated that the neurotransmitter gene preprotachykinin-I was expressed in these cells. However, translation of this gene only occurred after stimulation with interleukin (IL)-1 alpha. This effect was blunted by costimulation with IL-1 receptor antagonist. This study reports on the ability of MSCs to be transdifferentiated into neurons with functional synapses with the potential to become polarized towards producing specific neurotransmitters.

Agonists at serotonin 1D (5-HT1D) receptors relieve migraine headache but are not clinically used as general analgesics. One possible explanation for this difference is that 5-HT1D receptors are preferentially expressed by cranial afferents of the trigeminal system. We compared the distribution of 5-HT1D receptor-immunoreactive (5-HT1D-IR) peripheral afferents within the trigeminal ganglion (TRG) and lumbar dorsal root ganglion (DRG) of the rat. We also examined the neurochemical identity of 5-HT1D-IR neurons with markers of primary afferent nociceptors, peripherin, isolectin B4, and substance P, and markers of myelinated afferents, N52 and SSEA3. We observed a striking similarity in the size, distribution, and neurochemical identity of 5-HT1D-IR neurons in TRG and lumbar DRG afferents. Furthermore, the vast majority of 5-HT1D-IR neurons are unmyelinated peptidergic afferents that distribute peripherally, including the dura, cornea, and the sciatic nerve. In the central projections of these afferents within the trigeminal nucleus caudalis and the spinal cord dorsal horn, 5-HT1D-IR fibers are concentrated in laminas I and outer II; a few axons penetrate to lamina V. At the ultrastructural level, 5-HT1D receptors in the spinal cord dorsal horn are localized exclusively within dense core vesicles of synaptic terminals. We observed scattered 5-HT1D-IR neurons in the nodose ganglia, and there was sparse terminal immunoreactivity in the solitary nucleus. The visceral efferents of the superior cervical ganglia did not contain 5-HT1D immunoreactivity. Our finding, that 5-HT1D receptors are distributed in nociceptors throughout the body, raises the possibility that triptans can regulate not only headache-associated pain but also nociceptive responses in extracranial tissues.

The substance P content, glutamic acid decarboxylase and choline acetyltransferase activities and the level of [3H]diprenorphine binding were measured in various regions of the lumbar spinal cord of rats after unilateral section of the sciatic nerve or after dorsal rhizotomy. Sciatic nerve section produced a 75--80% depletion of substance P in the dorsal horn but did not change the substance P content of the ventral horn. The onset of substance P depletion occurred within 7 days and was maintained for 2 months. The substance P content of the dorsal root ganglia and both the peripheral and central branches of primary sensory neurons was also reduced after sciatic nerve section. Glutamic acid decarboxylase and choline acetyltransferase activity were unchanged; however, a small decrease in opiate receptor binding occurred 1 month after nerve section. Dorsal rhizotomy produced an 80% depletion of substance P in the dorsal horn. In addition, the substance P content of the ventral horn was significantly reduced. Glutamic acid decarboxylase activity in the dorsal horn was unaffected by dorsal rhizotomy whereas opiate receptor binding was reduced by 40%. From these studies it appears that peripheral nerve injury results in the degeneration of primary sensory neurons which contain and release substance P as neurotransmitter.

Much interest has recently centred on the properties of peptides that modulate the excitability of nerve cells. Such compounds include the undecapeptide substance P, which is particularly well established as an excitatory neurotransmitter, and we examine here its effects on magnocellular cholinergic neurones taken from the medial and ventral aspects of the globus pallidus of newborn rats and grown in dissociated culture. These neurones have previously been shown to respond to substance PSubstance P depolarizes these cultured neurones by reducing an inwardly rectifying potassium conductances; this conductance has been found in several neuronal types and has similar properties to those of certain other cells. As discussed below, modulation of inward (or anomalous) rectification by substance P implies a self-reinforcing element to the depolarization caused by the peptide.

BACKGROUND

Patients with hypercholesterolemia have a reduced response to endothelium-dependent vasodilators. However, the regulatory function of the endothelium on vascular tone is mediated through the release of several vasoactive substances; therefore, a reduced response to endothelium-dependent agents does not identify which of the factors released by the endothelium is involved in this abnormality.

RESULTS

To investigate the role of nitric oxide in the endothelium-dependent vasodilation in hypercholesterolemia, we studied the effect of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of endothelial nitric oxide synthesis, on basal vascular tone and on the responses to acetylcholine, an endothelium-dependent vasodilator, and to sodium nitroprusside, a direct smooth muscle dilator. The study included 33 hypercholesterolemic patients (17 men; 51 +/- 8 years; plasma cholesterol,>> or = 240 mg/dL) and 23 normal controls (12 men; 48 +/- 7 years; plasma cholesterol, < 210 mg/dL). Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by strain-gauge plethysmography. Basal blood flow and vascular resistance were similar in hypercholesterolemic patients and normal controls (3.1 +/- 1 versus 2.6 +/- 0.8 mL/min per 100 mL and 32.1 +/- 13 versus 36.1 +/- 12 mm Hg/mL-1.min-1.100 mL-1, respectively). The reduction in basal blood flow and increase in vascular resistance produced by L-NMMA were not significantly different between the two groups. L-NMMA markedly blunted the response to acetylcholine in normals (maximum flow decreased from 16.4 +/- 8 to 7.0 +/- 3; P < .005); however, the arginine analogue did not significantly modify the response to acetylcholine in the hypercholesterolemic patients (maximum flow, 11.1 +/- 8 versus 10.0 +/- 8). L-NMMA did not modify the vasodilator response to sodium nitroprusside in either controls or patients.

CONCLUSIONS

These findings indicate that hypercholesterolemic patients have a defect in the bioactivity of nitric oxide that may explain their impaired endothelium-dependent vascular relaxation.

Vascular endothelial cells produce nitric oxide (NO), which is a potent vasodilator substance and has been proposed as having antiatherosclerotic property. Vascular endothelial cells also produce endothelin-1 (ET-1), which is a potent vasoconstrictor peptide and has potent proliferating activity on vascular smooth muscle cells. Therefore, ET-1 has been implicated in the progression of atheromatous vascular disease. Because exercise training has been reported to produce an alteration in the function of vascular endothelial cells in animals, we hypothesized that exercise training influences the production of NO and ET-1 in humans. The purpose of the present study was to examine whether chronic exercise could influence the plasma levels of NO (measured as the stable end product of NO, i.e., nitrite/nitrate [NOx]) and ET-1 in humans. Eight healthy young subjects (20.3 +/- 0.5 yr old) participated in the study and exercised by cycling on a leg ergometer (70% VO2max for 1 hour, 3-4 days/week) for 8 weeks. Venous plasma concentrations of NOx and ET-1 were measured before and after (immediately before the end of 8-week exercise training) the exercise training, and also after the 4th and 8th week after the cessation of training. The VO2max significantly increased after exercise training. After the exercise training, the plasma concentration of NOx significantly increased (30.69 +/- 3.20 vs. 48.64 +/- 8.16 micromol/L, p < 0.05), and the plasma concentration of ET-1 significantly decreased (1.65 +/- 0.14 vs. 1.23 +/- 0.12 pg/mL, p < 0.05). The increase in NOx level and the decrease in ET-1 level lasted to the 4th week after the cessation of exercise training and these levels (levels of NOx and ET-1) returned to the basal levels (the levels before the exercise training) in the 8th week after the cessation of exercise training. There was a significant negative correlation between plasma NOx concentration and plasma ET-1 concentration. The present study suggests that chronic exercise causes an increase in production of NO and a decrease in production of ET-1 in humans, which may produce beneficial effects (i.e., vasodilative and antiatherosclerotic) on the cardiovascular system.

The effect of motivational interviewing on outpatient treatment adherence among psychiatric and dually diagnosed inpatients was investigated. Subjects were 121 psychiatric inpatients, 93 (77%) of whom had concomitant substance abuse/dependence disorders, who were randomly assigned to: a) standard treatment (ST), including pharmacotherapy, individual and group psychotherapy, activities therapy, milieu treatment, and discharge planning; or b) ST plus motivational interviewing (ST+MI), which involved 15 minutes of feedback on the results of a motivational assessment early in the hospitalization, and a 1-hour motivational interview just before discharge. Interviewers utilized motivational techniques described in Miller and Rollnick (1991), such as reflective listening, discussion of treatment obstacles, and elicitation of motivational statements. Results indicated that the proportion of patients who attended their first outpatient appointment was significantly higher for the ST+MI group (47%) than for the ST group (21%; chi2 = 8.87, df = 1, p<.01) overall, and for dually diagnosed patients (42% for ST+MI vs. 16% for ST only; chi2 = 7.68, df = 1, p<.01). Therefore, brief motivational interventions show promise in improving outpatient treatment adherence among psychiatric and dually diagnosed patients.

Nicotine dependence is highly prevalent among drug- and alcohol-dependent patients. A multisite clinical trial of smoking cessation (SC) treatment was performed at outpatient community-based substance abuse rehabilitation programs affiliated with the National Drug Abuse Treatment, Clinical Trials Network. Cigarette smokers (N=225) from five methadone maintenance programs and two drug and alcohol dependence treatment programs were randomly assigned in a 2:1 ratio to receive either (1) SC treatment as an adjunct to substance abuse treatment-as-usual (TAU) or (2) substance abuse TAU. Smoking cessation treatment consisted of 1 week of group counseling before the target quit date and 8 weeks of group counseling plus transdermal nicotine patch treatment (21 mg/day for Weeks 1-6 and 14 mg/day for Weeks 7 and 8) after the target quit date. Smoking abstinence rates in SC, 10%-11% during treatment and 5%-6% at the 13- and 26-week follow-up visits, were significantly better than those in TAU during treatment (p< .01). In addition, SC was associated with significantly greater reductions as compared with TAU in cigarettes smoked per day (75% reduction, p< .001), exhaled carbon monoxide levels (p< .001), cigarette craving (p< .05), and nicotine withdrawal (p< .05). Smoking cessation did not differ from TAU on rates of retention in substance abuse treatment, abstinence from primary substance of abuse, and craving for primary substance of abuse. Compliance with SC treatment, moderate at best, was positively associated with smoking abstinence rates. Smoking cessation treatment resulted in significant reductions in daily smoking and modest smoking abstinence rates without having an adverse impact on substance abuse rehabilitation when given concurrently with outpatient substance abuse treatment. Substance abuse treatment programs should not hesitate to implement SC for established patients.

To explicate the nature of the relationship between depressive symptoms and substance use, the authors conducted research that incorporated both individual and group approaches and utilized longitudinal data across development. Multiple-group latent growth curve models were used to assess specific dimensions (cross-sectional and longitudinal correlation, within-individual change, and movement off developmental trajectories) of the relationship between depressive symptoms and substance use during adolescence and how this relationship differs by gender. Annual survey data from 8th through 11th grade were provided by 441 girls and 510 boys in the Raising Healthy Children project (E. C. Brown, R. F. Catalano, C. B. Fleming, K. P. Haggerty, & R. D. Abbott, 2005). Levels of depressive symptoms and substance use in early adolescence were positively associated for alcohol, marijuana, and cigarette use for girls, but only for marijuana use for boys. Individual changes in depressive symptoms and substance use across adolescence were positively associated for each type of substance use. Evidence was also found for positive association between episodic expressions of depressive symptoms and alcohol use that fell outside developmental trajectories. Predictive relationships across constructs were not found, with the exception of higher level of depressive symptoms in early adolescence predicting less increase in alcohol use.

BACKGROUND

Many dispensing errors made in hospital pharmacies can harm patients. Some hospitals are investing in bar code technology to reduce these errors, but data about its efficacy are limited.

OBJECTIVE

To evaluate whether implementation of bar code technology reduced dispensing errors and potential adverse drug events (ADEs).

METHODS

Before-and-after study using direct observations.

METHODS

Hospital pharmacy at a 735-bed tertiary care academic medical center.

METHODS

A bar code-assisted dispensing system was implemented in 3 configurations. In 2 configurations, all doses were scanned once during the dispensing process. In the third configuration, only 1 dose was scanned if several doses of the same medication were being dispensed.

METHODS

Target dispensing errors, defined as dispensing errors that bar code technology was designed to address, and target potential ADEs, defined as target dispensing errors that can harm patients.

RESULTS

In the pre- and post-bar code implementation periods, the authors observed 115,164 and 253,984 dispensed medication doses, respectively. Overall, the rates of target potential ADEs and all potential ADEs decreased by 74% and 63%, respectively. Of the 3 configurations of bar code technology studied, the 2 configurations that required staff to scan all doses had a 93% to 96% relative reduction in the incidence of target dispensing errors (P < 0.001) and 86% to 97% relative reduction in the incidence of potential ADEs (P < 0.001). However, the configuration that did not require scanning of every dose had only a 60% relative reduction in the incidence of target dispensing errors (P < 0.001) and an increased (by 2.4-fold) incidence of target potential ADEs (P = 0.014). There were several potentially life-threatening ADEs involving intravenous dopamine and intravenous heparin in that configuration.

CONCLUSIONS

The authors used surrogate outcomes; did not mask assessors to the purpose of study; and excluded the controlled substance fill process (a process with low error rates at baseline) from the study, which may bias the combined decrease in error rates toward a larger magnitude.

CONCLUSIONS

The overall rates of dispensing errors and potential ADEs substantially decreased after implementing bar code technology. However, the technology should be configured to scan every dose during the dispensing process.

BACKGROUND

Response inhibition abnormalities contribute to several maladaptive behaviors commonly observed during adolescence, including heavy drinking.

OBJECTIVE

The present study aimed to determine whether abnormalities in brain response during response inhibition predate or follow adolescents' transition into heavy drinking, which is pivotal in identifying the neural antecedents and consequences of adolescent alcohol use.

METHODS

Longitudinal functional magnetic resonance imaging (fMRI) acquired during a response inhibition task was collected on adolescents before the onset of heavy drinking and then again on the same scanner approximately 3 years later. Adolescents who transitioned into heavy drinking (n = 20) were matched to continuously nondrinking adolescents (n = 20) on baseline and follow-up demographic and developmental variables.

RESULTS

During no-go relative to go trials, participants showed responses common to inhibitory circuitry: frontal (e.g., pre-supplementary motor area), temporal, and parietal regions. A repeated measures analysis of covariance revealed that adolescents who later transitioned into heavy drinking showed less fMRI response contrast at baseline than continuous nondrinkers in frontal, parietal, subcortical, and cerebellar regions (p < 0.01, clusters >756 μl), then increased activation after the onset of heavy drinking in frontal, parietal, and cerebellar areas.

CONCLUSIONS

Future heavy drinkers showed less activation of inhibitory circuitry before the onset of heavy drinking. After transitioning into heavy drinking, they showed more activation during response inhibition than nondrinking controls. These results contribute to the growing literature suggesting that neural vulnerabilities exist prior to the onset of substance use, and the initiation of heavy drinking may lead to additional alterations in brain functioning.

Obesity is a risk factor for stroke and neurodegenerative disease. Excess body fat has been linked to impaired glucose metabolism, insulin resistance, and impulsivity and may be a precursor to decline in attention and executive cognitive function. Here, we investigated the effects of high BMI on regional cerebral blood flow (rCBF) using single photon emission computed tomography (SPECT) imaging in healthy subjects. A total of 16 adult men and 20 adult women were recruited from the community between January 2003 and July 2009 as part of a healthy brain study (HBS) conducted at the Amen Clinics, a private medical facility. Participants in the study were screened to exclude medical, neurological, and psychiatric conditions, including substance abuse. Subjects were categorized as normal or overweight according to BMI. Using a two sample t-test, we determined the effects of BMI on rCBF in normal vs. overweight subjects. Subjects were matched for age and gender. Statistical parametric mapping (SPM) revealed a higher BMI in healthy individuals that is associated with decreased rCBF in Broadmann areas 8, 9, 10, 11, 32, and 44, brain regions involved in attention, reasoning, and executive function (P < 0.05, corrected for multiple comparisons). We found that an elevated BMI is associated with decreased rCBF in the prefrontal cortex of a healthy cohort. These results indicate that elevated BMI may be a risk factor for decreased prefrontal cortex function and potentially impaired executive function.

Complex regional pain syndrome (CRPS) is characterized by a variety of clinical features including spontaneous pain and hyperalgesia. Increased neuropeptide release from peripheral nociceptors has been suggested as a possible pathophysiologic mechanism triggering the combination of trophic changes, edema, vasodilatation and pain. In order to verify the increased neuropeptide release in CRPS, electrically induced neurogenic vasodilatation and protein extravasation were evaluated in patients and controls. We performed a prospective study on 10 patients with acute and untreated CRPS and 10 matched healthy controls. Neurogenic inflammation was elicited by strong transcutaneous electrical stimulation via intradermal microdialysis capillaries which simultaneously enabled measurement of protein extravasation. Laser-Doppler scanning was used to assess axon reflex vasodilatation. Axon reflex vasodilatation was significantly increased in CRPS patients (438 +/- 68% of baseline vs. 306 +/- 52%; P < 0.05) and transcutaneous electrical stimulation provoked protein extravasation only in the patients (before, 0.28 +/- 0.03 mg/ml; during stimulation, 0.34 +/- 0.04 mg/ml), whereas protein concentration steadily declined during stimulation in the healthy controls (before, 0.23 +/- 0.04 mg/ml; during stimulation, 0.18 +/- 0.04; P < 0.001). The time course of electrically induced protein extravasation in the patients resembled the one observed following application of exogenous substance P (SP). We conclude that neurogenic inflammation is facilitated in CRPS. Our results suggest an increased releasability of neuropeptides in CRPS.

The urothelium is a multilayered epithelium that serves as a barrier between the urinary tract and blood, preventing the exchange of water and toxic substances. It consists of superficial cells specialized for synthesis and transport of uroplakins that assemble into a tough apical plaque, one or more layers of intermediate cells, and keratin 5-expressing basal cells (K5-BCs), which are considered to be progenitors in the urothelium and other specialized epithelia. Fate mapping, however, reveals that intermediate cells rather than K5-BCs are progenitors in the adult regenerating urothelium, that P cells, a transient population, are progenitors in the embryo, and that retinoids are critical in P cells and intermediate cells, respectively, for their specification during development and regeneration. These observations have important implications for tissue engineering and repair and, ultimately, may lead to treatments that prevent loss of the urothelial barrier, a major cause of voiding dysfunction and bladder pain syndrome.