There is shared genetic risk for dependence on multiple substances, and the nicotinic receptor gene cluster on chromosome 15 harbors multiple polymorphisms that associate to this risk. Here, we report the results of an association study with 21 SNPs genotyped across the CHRNA5, CHRNA3, and CHRNB4 loci on chromosome 15q25.1. The sample consists of a discovery set (N=1858) of European-American and African-American (AA) families, ascertained on the basis of a sibling pair with cocaine and/or opioid dependence, and a case-control replication sample (N=3388) collected for association studies of alcohol, cocaine, and opioid dependence. We tested the SNPs for association with lifetime cocaine, opioid, nicotine, and alcohol dependence. We replicated several previous findings, including associations between rs16969968 and nicotine dependence (P=0.002) and cocaine dependence (P=0.02), with opposite risk alleles for each substance. We observed these associations in AAs, which is a novel finding. The strongest association signal in either sample was between rs684513 in CHRNA5 and cocaine dependence (OR=1.43, P=0.0004) in the AA replication set. We also observed two SNPs associated with alcohol dependence, that is, rs615470 in CHRNA5 (OR=0.77, P=0.0006) and rs578776 (OR=0.78, P=0.001). The associations between CD and rs684513, AD and rs615470, and AD and rs578776 remained significant after a permutation-based correction for multiple testing. These data reinforce the importance of variation in the chromosome 15 nicotinic receptor subunit gene cluster for risk of dependence on multiple substances, although the direction of the effects may vary across substances.

1. This study characterizes the K(+) channel(s) underlying charybdotoxin-sensitive hyperpolarization of porcine coronary artery endothelium. 2. Two forms of current-voltage (I/V) relationship were evident in whole-cell patch-clamp recordings of freshly-isolated endothelial cells. In both cell types, iberiotoxin (100 nM) inhibited a current active only at potentials over +50 mV. In the presence of iberiotoxin, charybdotoxin (100 nM) produced a large inhibition in 38% of cells and altered the form of the I/V relationship. In the remaining cells, charybdotoxin also inhibited a current but did not alter the form. 3. Single-channel, outside-out patch recordings revealed a 17.1+/-0.4 pS conductance. Pipette solutions containing 100, 250 and 500 nM free Ca(2+) demonstrated that the open probability was increased by Ca(2+). This channel was blocked by charybdotoxin but not by iberiotoxin or apamin. 4. Hyperpolarizations of intact endothelium elicited by substance P (100 nM; 26.1+/-0.7 mV) were reduced by apamin (100 nM; 17.0+/-1.8 mV) whereas those to 1-ethyl-2-benzimidazolinone (1-EBIO, 600 microM, 21.0+/-0.3 mV) were unaffected (21.7+/-0.8 mV). Substance P, bradykinin (100 nM) and 1-EBIO evoked charybdotoxin-sensitive, iberiotoxin-insensitive whole-cell perforated-patch currents. 5 A porcine homologue of the intermediate-conductance Ca(2+)-activated K(+) channel (IK1) was identified in endothelial cells. 6. In conclusion, porcine coronary artery endothelial cells express an intermediate-conductance Ca(2+)-activated K(+) channel and the IK1 gene product. This channel is opened by activation of the EDHF pathway and likely mediates the charybdotoxin-sensitive component of the EDHF response.

Although substance P (SP) has been implicated as a mediator of neurogenic inflammation in the small intestine, little information is available regarding the role of SP in the pathogenesis of chronic ulcerative colitis. In this study, our aim was to investigate whether the intraperitoneal administration of a nonpeptide neurokinin-1 (NK-1) antagonist, CP-96345, which antagonizes the binding of SP to its NK-1 receptor, results in the attenuation of colonic inflammation induced in rats by 5% dextran sodium sulfate (DSS) in drinking water for 10 days compared with an inactive enantiomer, CP-96344. Disease activity was assessed daily for 10 days, after which colonic tissue damage was scored and myeloperoxidase activity and colon and urinary 8-isoprostanes were measured. Animals receiving DSS exhibited marked physical signs of colitis by day 5 compared with controls. Chronic administration of the NK-1 antagonist significantly reduced the disease activity index, mucosal myeloperoxidase activity, colonic tissue damage score, and mucosal and urinary levels of 8-isoprostanes compared with inactive enantiomer- or vehicle-injected (saline) animals receiving DSS alone. These data indicate that the administration of an NK-1 antagonist can attenuate colonic inflammation and oxidative stress and suggest a novel therapeutic approach in the treatment of chronic ulcerative colitis.

Current understanding of basal ganglia function emphasizes their involvement in the focal, context-dependent release of motor and cognitive circuits in the brainstem and frontal lobes. How such selective action can arise despite the existence of massively convergent inputs from the cerebral cortex is unknown. However, anatomical work has suggested that specificity could be achieved in corticostriatal circuits by modular patterns of convergent and divergent cortical inputs to striatal projection neurons. To test for such modular activation of striatal neurons, we electrically microstimulated physiologically identified sites in the primary somatosensory (SI) and primary motor (MI) cortex of the squirrel monkey. We compared the efferent fiber distributions anterogradely traced from these sites to the distributions of striatal neurons activated by microstimulation to express Fos- and Jun B-like immediate-early gene proteins. We show that the microstimulation of sensorimotor cortex induces Fos and Jun B expression in localized cell clusters in the putamen and that these clusters match the anatomical input fiber clusters (matrisomes). The modular activation of striatal neurons by sensorimotor cortex seems likely. Unexpectedly, >75% of the Fos-positive nuclei in densely labeled cell clusters were in enkephalin-immunoreactive neurons. This expression pattern suggests that the primate sensorimotor cortex exerts a differential influence on the enkephalinergic (indirect pathway) as opposed to the substance P/dynorphin (direct pathway) projection neurons of the putamen. The densely labeled clusters of Fos-labeled enkephalinergic neurons occurred within larger zones containing sparsely distributed Fos-labeled parvalbumin neurons. Moreover, when the cortical stimulation induced expression of Fos-like protein only in sparsely distributed neurons, almost every putamenal neuron expressing Fos was a parvalbumin-containing (GABAergic) interneuron. These patterns suggest a model in which the primate sensorimotor cortex can target parvalbumin-containing inhibitory interneurons, which in turn depress the remaining neuronal activity within and around matrisomes in a feed-forward manner until sufficient coherent cortical input can overcome the inhibition to influence selectively enkephalinergic projection neurons in the activated matrisomes. Tuning of cortical input by striatal interneurons thus may be an important mechanism by which broader anatomical connections are dynamically adjusted to achieve selective flow of information through the basal ganglia.

The neuropeptide substance P, the venom peptide mastoparan and the synthetic polyamine compound 48/80 activate rat peritoneal mast cells, leading to rapid histamine release by exocytosis. Although these effects are inhibited by pertussis toxin and involve a transient increase in IPsubstance P on rat peritoneal mast cells, this mechanism being mimicked by mastoparan and 48/80, and possibly by other cationic amphiphilic peptides such as kinins. These compounds might be of help in defining the interaction between membrane receptors and G proteins.

The localization of calcitonin gene-related peptide (CGRP) and substance P (SP) in the rat trigeminal ganglion was examined by means of the indirect immunofluorescent method. About 40% of neurons in the ganglion contained CGRP-like immunoreactivity (CGRPI), while about 20% of neurons showed SP-like immunoreactivity (SPI). In serial sections, nearly all the SPI neurons contained CGRPI.

This paper describes the amino acid sequence of the rat substance P receptor and its comparison with that of the rat substance K receptor on the basis of molecular cloning and sequence analysis. From a rat brain cDNA library constructed with an RNA expression vector, we identified a cDNA mixture containing a functional substance P receptor cDNA by examining electrophysiologically a receptor expression following injection of the mRNAs synthesized in vitro into Xenopus oocytes. A receptor cDNA clone was then isolated by cross-hybridization with the bovine substance K receptor cDNA. The clone was confirmed by selective binding of substance P to the cloned receptor expressed in mammalian COS cells. The deduced amino acid sequence (407 amino acid residues) possesses seven putative membrane spanning domains and shows a sequence similarity to the members of G-protein-coupled receptors. The rat substance P and substance K receptors are very similar in both size and amino acid sequences, particularly in the putative transmembrane regions and the first and second cytoplasmic loops. This similarity is in marked contrast to the sequence divergence in the amino- and carboxyl-terminal regions and the third cytoplasmic loop. The observed sequence similarity and divergence would thus contribute to the expression of similar but pharmacologically distinguishable activities of the two tachykinin receptors.

BACKGROUND

Studies in Europe have suggested that injectable diacetylmorphine, the active ingredient in heroin, can be an effective adjunctive treatment for chronic, relapsing opioid dependence.

METHODS

In an open-label, phase 3, randomized, controlled trial in Canada, we compared injectable diacetylmorphine with oral methadone maintenance therapy in patients with opioid dependence that was refractory to treatment. Long-term users of injectable heroin who had not benefited from at least two previous attempts at treatment for addiction (including at least one methadone treatment) were randomly assigned to receive methadone (111 patients) or diacetylmorphine (115 patients). The primary outcomes, assessed at 12 months, were retention in addiction treatment or drug-free status and a reduction in illicit-drug use or other illegal activity according to the European Addiction Severity Index.

RESULTS

The primary outcomes were determined in 95.2% of the participants. On the basis of an intention-to-treat analysis, the rate of retention in addiction treatment in the diacetylmorphine group was 87.8%, as compared with 54.1% in the methadone group (rate ratio for retention, 1.62; 95% confidence interval [CI], 1.35 to 1.95; P<0.001). The reduction in rates of illicit-drug use or other illegal activity was 67.0% in the diacetylmorphine group and 47.7% in the methadone group (rate ratio, 1.40; 95% CI, 1.11 to 1.77; P=0.004). The most common serious adverse events associated with diacetylmorphine injections were overdoses (in 10 patients) and seizures (in 6 patients).

CONCLUSIONS

Injectable diacetylmorphine was more effective than oral methadone. Because of a risk of overdoses and seizures, diacetylmorphine maintenance therapy should be delivered in settings where prompt medical intervention is available. (ClinicalTrials.gov number, NCT00175357.)

Although research on body dysmorphic disorder (BDD) has increased in recent years, this disorder's comorbidity has received little empirical attention. Further work in this area is needed, as it appears that most patients with BDD have at least one comorbid disorder. This study examined axis I comorbidity and clinical correlates of comorbidity in 293 patients with DSM-IV BDD, 175 of whom participated in a phenomenology study and 118 of whom participated in treatment studies of BDD. Subjects were evaluated with the Structured Clinical Interview for DSM-III-R (SCID-P) and a semistructured instrument to obtain information on clinical correlates. Comorbidity was common, with a mean of more than two lifetime comorbid axis I disorders in both the phenomenology and treatment groups. In both groups, the most common lifetime comorbid axis I disorders were major depression, social phobia, obsessive compulsive disorder (OCD), and substance use disorders. Social phobia usually began before onset of BDD, whereas depression and substance use disorders typically developed after onset of BDD. A greater number of comorbid disorders was associated with greater functional impairment and morbidity in a number of domains. Thus, axis I comorbidity is common in BDD patients and associated with significant functional impairment.

BACKGROUND

The localization of substance P in brain-stem regions associated with vomiting, and the results of studies in ferrets, led us to postulate that a neurokinin-1-receptor antagonist would be an antiemetic in patients receiving anticancer chemotherapy.

METHODS

In a multicenter, double-blind, placebo-controlled trial involving 159 patients who had not previously received cisplatin, we evaluated the prevention of acute emesis (occurring within 24 hours) and delayed emesis (on days 2 to 5) after a single dose of cisplatin therapy (70 mg or more per square meter of body-surface area). Before receiving cisplatin, all the patients received granisetron (10 microg per kilogram of body weight intravenously) and dexamethasone (20 mg orally). The patients were randomly assigned to one of three treatments in addition to granisetron and dexamethasone: 400 mg of an oral trisubstituted morpholine acetal (also known as L-754,030) before cisplatin and 300 mg on days 2 to 5 (group 1), 400 mg of L-754,030 before cisplatin and placebo on days 2 to 5 (group 2), or placebo before cisplatin and placebo on days 2 to 5 (group 3). Additional medication was available at any time to treat occurrences of vomiting or nausea.

RESULTS

In the acute-emesis phase, 93 percent of the patients in groups 1 and 2 combined and 67 percent of those in group 3 had no vomiting (P<0.001). In the delayed-emesis phase, 82 percent of the patients in group 1, 78 percent of those in group 2, and 33 percent of those in group 3 had no vomiting (P<0.001 for the comparison between group 1 or 2 and group 3). The median nausea score in the delayed-emesis phase was significantly lower in group 1 than in group 3 (P=0.003). No serious adverse events were attributed to L-754,030.

CONCLUSIONS

The neurokinin-1-receptor antagonist L-754,030 prevents delayed emesis after treatment with cisplatin. Moreover, combining L-754,030 with granisetron plus dexamethasone improves the prevention of acute emesis.

Although psychopathy is frequently regarded as qualitatively distinct from other conditions, relatively little research has examined whether psychopaths represent a distinct class of individuals. Using a sample of 876 prison inmates and court-ordered substance abuse patients who were administered the Psychopathy Checklist-Revised (R. D. Hare, 2003), the authors examined the latent structure of psychopathy using several taxometric procedures developed by Meehl and colleagues (P. E. Meehl & L. J. Yonce, 1994; N. G. Waller & P. E. Meehl, 1998). The results across these procedures offer no compelling support for the contention that psychopathy is a taxonic construct and contradict previous reports that psychopathy is underpinned by a latent taxon. The authors discuss the theoretical, public policy, and practice-level implications of these findings.

BACKGROUND

The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been identified in the human intervertebral disc (IVD) and have been implicated in the mechanisms associated with nerve ingrowth and nociception in degeneration of the IVD. The aim of the current study was to investigate an association between neurotrophin expression in the IVD and the severity of disc degeneration, including the effect of disc-related proinflammatory cytokines on neurotrophin and neuropeptide expression in cells derived from the human IVD.

METHODS

Immunohistochemical analysis was performed to examine the expression of NGF, BDNF and their high-affinity receptors Trk-A and Trk-B in human IVD samples, divided into three categories: non-degenerate, moderate degeneration and severe degeneration. In order to study the effect of disc-related cytokines on neurotrophin/neuropeptide gene expression, nucleus pulposus cells derived from non-degenerate and degenerate IVD samples were seeded in alginate and were stimulated with either IL-1beta or TNFalpha for 48 hours. RNA was extracted, cDNA was synthesised and quantitative real-time PCR was performed to examine the expression of NGF, BDNF and substance P.

RESULTS

Immunohistochemistry showed expression of NGF and BDNF in the native chondrocyte-like cells in all regions of the IVD and in all grades of degeneration. Interestingly only BDNF significantly increased with the severity of degeneration (P < 0.05). Similar expression was observed for Trk-A and Trk-B, although no association with disease severity was demonstrated. In cultured human nucleus pulposus cells, stimulation with IL-1beta led to significant increases in NGF and BDNF gene expression (P < 0.05). Treatment with TNFalpha was associated with an upregulation of substance P expression only.

CONCLUSIONS

Our findings show that both the annulus fibrosus and nucleus pulposus cells of the IVD express the neurotrophins NGF and BDNF, factors that may influence and enhance innervation and pain in the degenerate IVD. Expression of Trk-A and Trk-B by cells of the nondegenerate and degenerate IVD suggests an autocrine role for neurotrophins in regulation of disc cell biology. Furthermore, modulation of neurotrophin expression by IL-1beta and modulation of substance P expression by TNFalpha, coupled with their increased expression in the degenerate IVD, highlights novel roles for these cytokines in regulating nerve ingrowth in the degenerate IVD and associated back pain.

In situ hybridization experiments were performed in rat brain sections from normal and 6-hydroxydopamine-treated rats in order to map and identify the neurons expressing the D1 receptor gene in the striatum and the substantia nigra. Procedures of combined in situ hybridization, allowing the simultaneous detection of two mRNAs in the same section or in adjacent sections, were used to characterize the phenotypes of the neurons expressing the D1 receptor gene. D1 receptor mRNA was found in neurons all over the caudate-putamen, the accumbens nucleus, and the olfactory tubercle but not in the substantia nigra. In the caudate-putamen and accumbens nucleus, most of the neurons containing D1 receptor mRNA were characterized as medium-sized substance P neurons and distinct from those containing D2 receptor mRNA. Nevertheless, 15-20% of the substance P neurons did not contain D1 receptor mRNA. The neurons containing preproenkephalin A mRNA did not contain D1 receptor mRNA but contained D2 receptor mRNA. A small number of cholinergic and somatostatinergic neurons exhibited a weak reaction for D1 receptor mRNA. These results demonstrate that dopamine acts on efferent striatal neurons through expression of distinct receptors--namely, D1 and D2 in separate cell populations (substance P and preproenkephalin A neurons, respectively)--and can also act on nonprojecting neurons through D1 receptor expression.

OBJECTIVE

We examined the direct and indirect impact of minority stress on mental health and substance use among sexual minority women.

METHODS

A combination of snowball and targeted sampling strategies was used to recruit lesbian and bisexual women (N = 1,381) for a cross-sectional, online survey. Participants (M age = 33.54 years; 74% White) completed a questionnaire assessing gender expression, minority stressors (i.e., victimization, internalized homophobia, and concealment), social-psychological resources (i.e., social support, spirituality), and health-related outcomes. We used structural equation modeling to test associations among these factors, with gender expression as an antecedent and social-psychological resources as a mediator between minority stress and health.

RESULTS

The final model demonstrated acceptable fit, χ²(79) = 414.00, p < .05, confirmatory fit index = .93, Tucker-Lewis index = .91, standardized root-mean-square residual = .05, root-mean-square error of approximation = .06, accounting for significant portions of the variance in mental health problems (56%) and substance use (14%), as well as the mediator social-psychological resources (24%). Beyond indirect effects of minority stress on health outcomes, direct links emerged between victimization and substance use and between internalized homophobia and substance use.

CONCLUSIONS

Findings indicate a significant impact of minority stressors and social-psychological resources on mental health and substance use among sexual minority women. The results improve understanding of the distinct role of various minority stressors and their mechanisms on health outcomes. Health care professionals should assess for minority stress and coping resources and refer for evidence-based psychosocial treatments.

BACKGROUND

Substance use remains high among Ethiopian youth and young adolescents particularly in high schools and colleges. The use of alcohol, khat and tobacco by college and university students can be harmful; leading to decreased academic performance, increased risk of contracting HIV and other sexually transmitted diseases. However, the magnitude of substance use and the factors associated with it has not been investigated among medical students in the country. This study was conducted to determine the prevalence of substance use and identify factors that influenced the behavior among undergraduate medical students of Addis Ababa University in Ethiopia.

METHODS

A cross-sectional study using a pre-tested structured self-administered quantitative questionnaire was conducted in June 2009 among 622 medical students (Year I to Internship program) at the School of Medicine. The data were entered into Epi Info version 6.04d and analyzed using SPSS version 15 software program. Descriptive statistics were used for data summarization and presentation. Differences in proportions were compared for significance using Chi Square test, with significance level set at p < 0.05. Multivariate logistic regression analyses were used to assess the magnitude of associations between substance use and socio-demographic and behavioral correlates.

RESULTS

In the last 12 months, alcohol was consumed by 22% (25% males vs. 14% females, p = 0.002) and khat use was reported by 7% (9% males vs. 1.5% females, p < 0.001) of the students. About 9% of the respondents (10.6% males vs. 4.6% females, p = 0.014) reported ever use of cigarette smoking, and 1.8% were found to be current smokers. Using multiple logistic regression models, being male was strongly associated with alcohol use in the last 12 months (adjusted OR = 2.14, 95% CI = 1.22-3.76). Students whose friends currently consume alcohol were more likely to consume alcohol (adjusted OR = 2.47, 95% CI = 1.50-4.08) and whose friends' use tobacco more likely to smoke (adjusted OR = 3.89, 95% CI = 1.83-8.30). Khat use within the past 12 months was strongly and positively associated with alcohol consumption (adjusted OR = 15.11, 95% CI = 4.24-53.91). Similarly, ever use of cigarette was also significantly associated with alcohol consumption (adjusted OR = 8.65, 95% CI = 3.48-21.50).

CONCLUSIONS

Concordant use of alcohol, khat and tobacco is observed and exposure to friends' use of substances is often implicated. Alcohol consumption or khat use has been significantly associated with tobacco use. While the findings of this study suggest that substance use among the medical students was not alarming, but its trend increased among students from Year I to Internship program. The university must be vigilant in monitoring and educating the students about the consequences of substance use.

OBJECTIVE

The influence of enteric glia on the regulation of intestinal functions is unknown. Our aim was to determine the phenotype of enteric neurones in a model of glia alterations and the putative changes in intestinal motility and permeability.

METHODS

Transgenic mice expressing haemagglutinin (HA) in glia were used. Glia disruption was induced by injection of activated HA specific CD8+ T cells. Control mice consisted of non-transgenic littermates injected with activated HA specific CD8+ T cells. Immunohistochemical staining for choline acetyltransferase (ChAT), substance P (SP), vasoactive intestinal peptide (VIP), and nitric oxide synthase (NOS) was performed on jejunal submucosal plexus (SMP) and myenteric plexus (MP). Neurally induced jejunal muscle activity was characterised in vitro. Gastrointestinal transit and paracellular permeability were measured using fluorescein isothiocyanate-dextran markers.

RESULTS

CD3 positive T cells infiltrates were observed in the MP of transgenic mice. In the SMP, the proportions of VIP and SP positive neurones decreased in transgenic mice compared with control mice. ChAT remained unchanged. In the MP, the proportions of ChAT and NOS positive neurones increased and decreased, respectively, in transgenic mice. In contrast, VIP and SP remained unchanged. Neurally mediated jejunal relaxation was lower in transgenic mice than in controls. This relaxation was reduced by NG-nitro-L-arginine methyl ester in control mice but not in transgenic mice. Gastrointestinal transit was delayed and intestinal permeability increased in transgenic mice compared with control mice.

CONCLUSIONS

Glia disruption induces changes in the neurochemical coding of enteric neurones, which may partly be responsible for dysfunctions in intestinal motility and permeability.

In rats with unilateral lesions of the nigrostriatal dopamine pathway with 6-hydroxydopamine, the motor stimulating effects of levodopa, an indirect dopamine receptor agonist, evidenced by contraversive rotations, become enhanced upon repeated intermittent administration. However, the mechanisms of this behavioral sensitization are essentially unknown. We show that development of sensitization is accompanied by a progressive appearance of D3 receptor mRNA and binding sites, visualized by in situ hybridization and 7-[3H] hydroxy-N,N-di-n-propyl-2-aminotetralin autoradiography, respectively, occurring in the denervated caudate putamen, a brain area from which this receptor subtype is normally absent. Development and decay of these two processes occur with closely parallel time courses, whereas there were no marked changes in D1 or D2 receptor mRNAs. D3 receptor induction by levodopa is mediated by repeated D1 receptor stimulation, since it is prevented by the antagonist SCH 33390 and mimicked by the agonist SKF 38393, but not by two D2 receptor agonists. The enhanced behavioral response to levodopa is mediated by the newly synthesized D3 receptor, since it is antagonized by nafadotride, a preferential D3 receptor antagonist, in low dosage, which has no such effect before D3 receptor induction. D3 receptor induction and behavioral sensitization are also accompanied by a sustained enhancement of prodynorphin mRNA level and a progressively decreasing expression of the preprotachykinin gene. We propose that imbalance between dynorphin and substance P release from the same striatonigral motor efferent pathway, related to D3 receptor induction, is responsible for behavioral sensitization.

Progressive pulmonary insufficiency is the major cause of morbidity and mortality in patients with the inherited disease cystic fibrosis. The basic defect involves a disturbed ion transport across cells, but it is not known how this leads to the airways becoming highly susceptible to recurrent respiratory tract infection with S. aureus, H. influenzae and P. aeruginosa as the dominating pathogens. P. aeruginosa is not a primary pathogen in CF and some degree of lung damage generally has taken place before colonization begins at approximately 10 years of age. Cross-infection occurs and the incidence of P. aeruginosa infection can be reduced by interrupting person-to-person spread. P. aeruginosa infection is a chronic infection that is never permanently eradicated. However, intensive antipseudomonal chemotherapy has contributed to improved survival rates. 90% of patients remain alive more than 10 years after onset of chronic P. aeruginosa and, on an average, they can maintain an almost unchanged lung function during that period. Diagnosis of chronic infection rests on bacteriological examination and demonstration of a specific antibody response. Immunological assays to detect an early antibody response were developed. It is characteristic, but not specific for CF, that chronic lung infection is caused by alginate producing mucoid P. aeruginosa. Alginate biosynthesis is under complex genetic control and possibly regulated by environmental factors. Alginate was purified from mucoid P. aeruginosa and characterized and it was shown to be immunologically heterogenous. It is generally assumed that the infection begins with strains that are nonmucoid, but serological analysis show that these strains probably also produce the mucoid substance, alginate, in vivo. Patients infected with mucoid strains demonstrate a significantly higher antibody response to all P. aeruginosa antigens and have a lower lung function when compared to patients infected with nonmucoid strains. Despite the pronounced humoral antibody response efficient immune clearance of P. aeruginosa does not occur. Mucoid P. aeruginosa are organisms that are deficient in most of the classical virulence factors. In vivo it grows in a protected biofilm as mucoid microcolonies, where bacteria are enmeshed in a loosely bound, highly hydrated extracellular matrix of alginate. Purified alginate was shown to inhibit chemotaxis of neutrophil leukocytes and unable to activate complement. A deficient SIgA antibody response to alginate has been observed in bronchial secretions and it was hypothesized to be associated with the epithelial transport defect.(ABSTRACT TRUNCATED AT 400 WORDS)

The extracellular signal-regulated kinase (Erk) cascades are suggested to contribute to excitatory synaptic plasticity in the CNS, including the spinal cord dorsal horn. However, many of their upstream signaling pathways remain to be investigated. Here, we demonstrate that glutamate and substance P (SP), two principal mediators of sensory information between primary afferent fibers and the spinal cord, activate Erk in dorsal horn neurons of both adult rat and mouse spinal cord. In genetic knock-out mice of calcium calmodulin-stimulated adenylyl cyclase subtypes 1 (AC1) and 8 (AC8), activation of Erk in dorsal horn neurons were significantly reduced or blocked, either after peripheral tissue inflammation or by glutamate or SP in spinal cord slices. Our studies suggest that AC1 and AC8 act upstream from Erk activation in spinal dorsal horn neurons and the calcium-AC1/AC8-dependent Erk signaling pathways may contribute to spinal sensitization, an underlying mechanism for the development of persistent pain after injury.

Immunohistochemical techniques were used to examine the presence and co-localisation of a range of putative neurotransmitters and other neuronal markers in the myenteric plexus of the small and large intestine of the mouse. Distinct sub-populations of myenteric neurons were identified, based on the combinations of substances they contained and the distribution of their fibres. In the small intestine, there were two major classes of circular muscle motor neurons; one class was characterised by the presence of nitric oxide synthase, vasoactive intestinal peptide plus neuropeptide Y (NOS/VIP/NPY), and the second class contained calretinin plus substance P (CalR/SP). There were seven classes of neurons that innervated myenteric ganglia; these contained nos, vip, nos/vip, npy, calr/calbindin (calb), sp or 5-ht. In the large intestine, there were five major classes of motor neurons that contained nos, nos/vip, gaba, sp, or calr/sp, and seven major classes of neurons that innervated myenteric ganglia and contained nos, vip, calr/calb, calr, sp, gaba or 5-ht. Although some aspects of the patterns of co-localisation are similar to those in other species, this study re-inforces recent analyses that indicate significant species differences in neurochemical patterns in the enteric neurons of different species.

We aimed to assess the effect of ovariectomy on cartilage turnover and degradation, to evaluate whether ovariectomized (OVX) rats could form an experimental model of postmenopausal osteoarthritis. The effect of ovariectomy on cartilage was studied using two cohorts of female Sprague-Dawley rats, aged 5 and 7 months. In a third cohort, the effect of exogenous estrogen and a selective estrogen receptor modulator was analyzed. Knee joints were assessed by histological analysis of the articular cartilage after 9 weeks. Cartilage turnover was measured in urine by an immunoassay specific for collagen type II degradation products (CTX-II), and bone resorption was quantified in serum using an assay for bone collagen type I fragments (CTX-I). Surface erosion in the cartilage of the knee was more severe in OVX rats than in sham-operated animals, particularly in the 7-month-old cohort (P = 0.008). Ovariectomy also significant increased CTX-I and CTX-II. Both the absolute levels of CTX-II and the relative changes from baseline seen at week 4 correlated strongly with the severity of cartilage surface erosion at termination (r = 0.74, P < 0.01). Both estrogen and the selective estrogen receptor modulator inhibited the ovariectomy-induced acceleration of cartilage and bone turnover and significantly suppressed cartilage degradation and erosion seen in vehicle-treated OVX rats. The study indicates that estrogen deficiency accelerates cartilage turnover and increases cartilage surface erosion. OVX rats provide a useful experimental model for the evaluation of the chondroprotective effects of estrogens and estrogen-like substances and the model may be an in vivo representation of osteoarthritis in postmenopausal women.

BACKGROUND

Gender is increasingly being studied for risk and protective factors underlying substance abuse and addiction.

OBJECTIVE

The aim of this study was to assess gender differences in rates of substance abuse and dependence among drug users.

METHODS

A national population sample was examined, focusing on 2 age groups (youths, aged 12-17 years, and young adults, aged 18-25 years) and several commonly abused substances (alcohol, marijuana, and nonmedical prescription medication use). Combined annual data from the National Survey on Drug Use and Health (NSDUH), aggregated from 2002-2005, were used for gender comparisons of rates of substance use, as well as abuse and dependence, among users.

RESULTS

Overall rates of substance use were significantly higher for males than for females (P < 0.01 for all substances except sedatives and tranquilizers); however, patterns of use, abuse, or dependence among users differed by age group and drug. Interestingly, patterns for youths differed from the overall population and from young adults. Girls exceeded boys in their use of alcohol (P < 0.01) and their nonmedical use of psychotherapeutics (ie, prescription-type pain relievers, stimulants, tranquilizers, sedatives) (P < 0.01); among users, girls were significantly more likely to be dependent on the latter (P < 0.01). Boys reported significantly greater use and abuse of and dependence on marijuana (P < 0.01). In the young adults, the proportion of female users reporting dependence on cocaine or psychotherapeutics was significantly higher than for male users (P < 0.01), who nonetheless reported significantly greater use of these drugs (P < 0.01). Among users, males generally exceeded females in meeting abuse criteria (P < 0.01 for marijuana among 12- to 17-year-olds and for alcohol, marijuana, and psychotherapeutics among 18- to 25-year-olds), with some exceptions mainly in the youngest cohort.

CONCLUSIONS

In this national population sample of youths and young adults, these findings suggest that gender, age, and substance of abuse may all play a role in the observed patterns of drug use, abuse, and dependence. Understanding the reasons for these differences and continuing to evaluate these patterns over time could help in the development of targeted and more effective prevention and treatment interventions.

Inflammatory bowel disease (IBD) is a chronic, relapsing condition involving complex interactions between genes and the environment. The mechanisms triggering the initial attack and relapses, however, are not well understood. In the past several years the enteric nervous system (ENS) has been implicated in the pathophysiology of IBD. Both the ENS and the central nervous system (CNS) can amplify or modulate aspects of intestinal inflammation through secretion of neuropeptides that serve as a link between the ENS and CNS. Neuropeptides are defined as any peptide released from the nervous system that serves as an intercellular signaling molecule. Neuropeptides thought to play a potentially key role in IBD include substance P, corticotropin-releasing hormone, neurotensin, vasoactive intestinal peptide, mu-opioid receptor agonists, and galanin. This review focuses on the role of these neuropeptides in the pathophysiology of IBD and discusses the cell types and mechanisms involved in this process. The available evidence that neuropeptide blockade may be considered a therapeutic approach in both Crohn's disease and ulcerative colitis will also be discussed.