Mechanism of nitric oxide regulation of vascular tone in the mesenteric arteries of the cane toad, Bufo marinus

Nitric oxide control of large systemic blood vessels of the cane toad, Bufo marinus is provided by nitrergic nerves. However, the involvement of nitrergic nerves in the regulation of small blood vessels has yet to be determined. This study investigated the nitric oxide (NO) control of the mesenteric arteries (MA) of B. marinus. Immunohistochemistry and NADPH-diaphorase histochemistry demonstrated a dense plexus of nitrergic nerves in the MA of B. marinus. MAs (~ 500–700µm in diameter) were mounted in a myograph and placed under an initial tension equivalent to their normal diameter. MAs were pre-constricted with the thromboxane A2 mimetic, U46619, prior to the addition of putative, vasodilatory chemicals. Acetylcholine caused a vasodilation that was endothelium-independent, because removal of the endothelium had no effect on the dilation. The response to acetylcholine was blocked by the NOS inhibitor, L-NNA, demonstrating that the effect was NO-dependent. Interestingly, nicotine also caused a dilation that was not affected by removal of the endothelium, but was significantly inhibited by L-NNA and the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP(8–37). These findings indicate that the MA of B. marinus are controlled by NO released from nitrergic nerves. In addition, a component of the response to applied nicotine appears to be mediated CGRP, which is probably released from sensory nerves.

Vasodilator mechanisms in the dorsal aorta of the giant shovelnose ray, Rhinobatus typus (Rajiformes; Rhinobatidae)

This study investigated the nature of previous termvasodilator mechanismsnext term in the dorsal aorta of the giant shovelnose ray, Rhinobatus typus. Anatomical techniques found no evidence for an endothelial nitric oxide synthase, but neural nitric oxide synthase was found to be present in the perivascular nerve fibres of the dorsal aorta and other arteries and veins using both NADPH-diaphorase staining and immunohistochemistry with a specific neural NOS antibody. Arteries and veins both contained large nNOS-positive nerve trunks from which smaller nNOS-positive bundles branched and formed a plexus in the vessel wall. Single, varicose nNOS-positive nerve fibres were present in both arteries and veins. Within the large bundles of both arteries and veins, groups of nNOS-positive cell bodies forming microganglia were observed. Double-labelling immunohistochemistry using an antibody to tyrosine hydroxylase showed that nearly all the NOS nerves were not sympathetic. Acetylcholine always caused constriction of isolated rings of the dorsal aorta and the nitric oxide donor, sodium nitroprusside, did not mediate any dilation. Addition of nicotine (3×10−4 M) to preconstricted rings caused a vasodilation that was not affected by the nitric oxide synthase inhibitor, Image -NNA (10−4 M), nor the soluble guanylyl cyclase inhibitor, ODQ (10−5 M). This nicotine-mediated vasodilation was, therefore, not due to the synthesis and release of NO. Disruption of the endothelium significantly reduced or eliminated the nicotine-mediated vasodilation. In addition, indomethacin (10−5 M), an inhibitor of cyclooxygenases, significantly increased the time period to maximal dilation and reduced, but did not completely inhibit the nicotine-mediated vasodilation. These data support the hypothesis that a prostaglandin is released from the vascular endothelium of a batoid ray, as has been described previously in other groups of fishes. The function of the nitrergic innervation of the blood vessels is not known because nitric oxide does not appear to regulate vascular tone.

Research indepedence matters for practitioners and researchers in the addictions

As governments, industry bodies, and other interest groups become more adept at influencing the conduct and dissemination of research, it is increasingly important that the alcohol and other drug (AOD) sector maintains and protects the integrity of its evidence base. This commentary discusses the level and type of influence being exerted on the research process by different interest groups within the field. It explores the impact and influence of funding bodies, other interest groups, and social systems on addiction and recovery using relevant examples to identify questions for practitioners and researchers to consider when encountering interested parties in their day-to-day practice. Ultimately, it is service users and clinicians at the "front line" of recovery who have the most to lose from research findings that have been unduly influenced. The best protection against bias in these forms is to practice critical self-reflection and to keep openly and honestly debating those things that we find most challenging.

The treatment of opiate dependency

The portfolio examines use of opiate antagonist medication (naltrexone hydrochloride) as a safe and effective treatment for opiate dependence. The program incorporates evidence-based assessment, treatment planning and after-care counselling. Detoxification using naltrexone is highly effective. Use of naltrexone predicts long-term abstinence and better health and social outcomes. Naltrexone implants improve compliance and outcomes.

Groin injecting in injectable opioid treatment service users in South London

Femoral (or groin) injecting is an emerging public health challenge to all drug-related services within the UK. Recent work in the area has proposed that groin injecting in the UK has moved from being a ‘risk boundary’ to an ‘acceptable behaviour’. This article uses data from 10 in-depth qualitative interviews with service users from a supervised injectable opiate treatment service in South London to report on pathways to, and reasons for, groin injecting. Our findings indicate that even though groin injecting constitutes a risk boundary for some injectors, the practice is no longer heavily stigmatised and is perceived by some to be an acceptable risk. Narratives also pointed to the importance of peers in the initiation of groin injecting. Interviewees described the groin as a site of ‘last resort’ in contrast to ‘convenience’ groin injectors described in some previous research. We conclude that it might be helpful to distinguish between convenience and last resort groin injectors and support the call for innovative interventions which aim to reduce modelling of groin injection and which promote social norms supportive of using peripheral injecting sites.

The importance of family management, closeness with father and family structure in early adolescent alcohol use

Aims To examine the importance of family management, family structure and father–adolescent relationships on early adolescent alcohol use.

Design Cross-sectional data was collected across 30 randomly selected Australian communities stratified to represent a range of socio-economic and regional variation.

Setting Data were collected during school time from adolescents attending a broad range of schools.

Participants The sample consisted of a combined 8256 students (aged 10–14 years).

Measurements Students completed a web-based survey as part of the Healthy Neighbourhoods project.

Findings Family management—which included practices such as parental monitoring and family rules about alcohol use—had the strongest and most consistent relationship with alcohol use in early adolescence. Adolescents reporting higher family management were less likely to have drunk alcohol in their life-time, less likely to drink alcohol in the preceding 30 days and less likely to have had an alcohol binge. Adolescents reporting emotionally close relationships with their fathers were less likely to have drunk alcohol in their life-time and less likely to have had an alcohol binge in the preceding fortnight.

Conclusions Findings indicate that family management practices may contribute to alcohol abstinence in adolescents. Furthermore, emotionally close father–adolescent relationships may also foster abstinence; however, fathers’ drinking behaviours need to be considered.

The self-reported personal wellbeing of a sample of Australian injecting drug users

Aims To examine the self-reported personal wellbeing of a sample of Australian injecting drug users (IDU) using a standardized instrument and determine the key correlates of variations in self-reported personal wellbeing.

Design, setting and participants Cross-sectional survey of 881 Australian IDU.

Measurements Self-reported personal wellbeing collected using the Personal Wellbeing Index (PWI).

Findings IDU scored significantly lower than the general Australian population on the PWI and all subscales. Lower PWI scores were associated with a range of socio-demographic, drug use and other health and social characteristics. Across all PWI subscales, lower personal wellbeing scores were associated with unemployment, past 6-month mental health problems and more frequent injecting (all P < 0.05).

Conclusions The PWI is sufficiently sensitive to distinguish between IDU and the general population, and to identify key correlates of PWI among IDU. Some domains canvassed within the scale, such as health, standard of living and life achievements, are well within the scope of current intervention strategies, such as pharmacotherapy maintenance treatment and housing and employment support services. This suggests that the PWI could be useful in clinical settings by allowing structured identification of the areas of a person's life to be addressed as a part of a treatment regimen. In order to inform targeted prevention and intervention efforts, longitudinal studies of PWI and its correlates among IDU are required.

Altered fast- and slow-twitch muscle fibre characteristics in female mice with a (S248F) knock-in mutation of the brain neuronal nicotinic acetylcholine receptor

We generated a mouse line with a missense mutation (S248F) in the gene (CHRNA4) encoding the α4 subunit of neuronal nicotinic acetylcholine receptor (nAChR). Mutant mice demonstrate brief nicotine induced dystonia that resembles the clinical events seen in patients with the same mutation. Drug-induced dystonia is more pronounced in female mice, thus our aim was to determine if the S248F mutation changed the properties of fast- and slow-twitch muscle fibres from female mutant mice. Reverse transcriptase-PCR confirmed CHRNA4 gene expression in the brain but not skeletal muscles in normal and mutant mice. Ca²⁺ and Sr²⁺ force activation curves were obtained using skinned muscle fibres prepared from slow-twitch (soleus) and fast-twitch (EDL) muscles. Two significant results were found: (1) the (pCa₅₀ - pSr₅₀) value from EDL fibres was smaller in mutant mice than in wild type (1.01 vs. 1.30), (2) the percentage force produced at pSr 5.5 was larger in mutants than in wild type (5.76 vs. 0.24%). Both results indicate a shift to slow-twitch characteristics in the mutant. This conclusion is supported by the identification of the myosin heavy chain (MHC) isoforms. Mutant EDL fibres expressed MHC I (usually only found in slow-twitch fibres) as well as MHC IIa. Despite the lack of spontaneous dystonic events, our findings suggest that mutant mice may be having subclinical events or the mutation results in a chronic alteration to muscle neural input.

Mechanisms of nitric oxide-mediated neurogenic,vasodilation in mesenteric resistance arteries of toad, Bufo marinus

This study determined the role of nitric oxide (NO) in neurogenic vasodilation in mesenteric resistance arteries of the toad Bufo marinus. NO synthase (NOS) was anatomically demonstrated in perivascular nerves, but not in the endothelium. ACh and nicotine caused TTX-sensitive neurogenic vasodilation of mesenteric arteries. The ACh-induced vasodilation was endothelium-independent and was mediated by the NO/soluble guanylyl cyclase signaling pathway, inasmuch as the vasodilation was blocked by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and the NOS inhibitors N^ω- nitro-L-arginine methyl ester and N^ω-nitro-L-arginine. Furthermore, the ACh-induced vasodilation was significantly decreased by the more selective neural NOS inhibitor N⁵-(1-imino-3-butenyl)-L-ornithine. The nicotine-induced vasodilation was endothelium-independent and mediated by NO and calcitonin gene-related peptide (CGRP), inasmuch as pretreatment of mesenteric arteries with a combination of N^ω-nitro-L-arginine and the CGRP receptor antagonist CGRP-(8–37) blocked the vasodilation. Clotrimazole significantly decreased the ACh-induced response, providing evidence that a component of the NO vasodilation involved Ca^2+-activated K⁺ or voltage-gated K⁺ channels. These data show that NO control of mesenteric resistance arteries of toad is provided by nitrergic nerves, rather than the endothelium, and implicate NO as a potentially important regulator of gut blood flow and peripheral blood pressure.

RCT of a client-centred, caseworker-delivered smoking cessation intervention for a socially disadvantaged population

Background: Disadvantaged groups are an important target for smoking cessation intervention. Smoking rates are markedly higher among severely socially disadvantaged groups such as indigenous people, the homeless, people with a mental illness or drug and alcohol addiction, and the unemployed than in the general population. This proposal aims to evaluate the efficacy of a client-centred, caseworker delivered cessation support intervention at increasing validated self reported smoking cessation rates in a socially disadvantaged population.
Methods/Design: A block randomised controlled trial will be conducted. The setting will be a non-government organisation, Community Care Centre located in New South Wales, Australia which provides emergency relief and counselling services to predominantly government income assistance recipients. Eligible clients identified as smokers during a baseline touch screen computer survey will be recruited and randomised by a trained research assistant located in the waiting area. Allocation to intervention or control groups will be determined by time periods with clients randomised in one-week blocks. Intervention group clients will receive an intensive client centred smoking cessation intervention offered by the caseworker over two face-to-face and two telephone contacts. There will be two primary outcome measures obtained at one, six, and 12 month follow-up: 1) 24-hour expired air CO validated self-reported smoking cessation and 2) 7-day self-reported smoking cessation. Continuous abstinence will also be measured at six and 12 months follow up.
Discussion: This study will generate new knowledge in an area where the current information regarding the most effective smoking cessation approaches with disadvantaged groups is limited.

Processes of task performance as measured by the assessment of motor and process skills (AMPS): a predictor of work-related outcomes for adults with schizophrenia?

Objective: To determine whether the processes of task performance as measured by the Assessment of Motor and Process Skills (AMPS) would discriminate between the employment levels of adults with schizophrenia. Participants: Twenty adults with schizophrenia who were engaged either in competitive employment, supported employment, prevocational training, or nonvocational activities, participated in this exploratory study. Methods: Each participant completed the AMPS, the Positive and Negative Syndrome Scale (PANSS), the Addiction Severity Index (ASI), and theWorker Role Interview (WRI) to gather data about their occupational performance, symptoms, drug / alcohol use, and psychosocial / environmental factors that might influence their work related outcomes. Results: Analysis revealed a moderate correlation between the level of employment and the global scores of the process skills scale in the AMPS. Conclusions: This should be seen as preliminary evidence that beyond the basic cognitive functions, processes of task performance may also be a predictor of work related outcomes for this population. The results also highlighted the importance of considering personal causation and worker roles when assessing the work capacities of these clients. Finally, findings supported the four levels of employment used in this study, which appeared to form a continuum from nonvocational activities, prevocational training, supported employment, through to competitive employment.

Nail-biting stuff? The effect of N-acetyl cysteine on nail-biting

N-acetyl cysteine (NAC) is a widely available nutraceutical with a variety of actions. As a precursor of cysteine and glutathione, it has antioxidant properties that may impact on mood and contribute to an effect on impulsivity and obsessive behaviour. Via its additional effect on glutamate via the cystine-glutamate exchange system, NAC has been shown to mediate impulsivity in preclinical models of addiction, reduce craving, and cue extinction. Further, by boosting glutathione, NAC acts as a potent antioxidant and has been shown in two positive, large-scale randomized placebo-controlled trials to affect negative symptoms in schizophrenia and depression in bipolar disorder. We describe three cases in which its actions specifically on nail-biting and associated anxiety may offer a potential treatment. The spontaneous findings are reported as part of an ongoing treatment trial examining the utility of NAC in bipolar disorder. Its actions, if robustly replicated, also point to potential treatment targets in glutathione or glutamate pathways in the brain.

N-acetylcysteine in psychiatry - current therapeutic evidence and potential mechanisms of action

There is an expanding field of research investigating the benefits of alternatives to current pharmacological therapies in psychiatry. N-acetylcysteine (NAC) is emerging as a useful agent in the treatment of psychiatric disorders. Like many therapies, the clinical origins of NAC are far removed from its current use in psychiatry. Whereas the mechanisms of NAC are only beginning to be understood, it is likely that NAC is exerting benefits beyond being a precursor to the antioxidant, glutathione, modulating glutamatergic, neurotropic and inflammatory pathways. This review outlines the current literature regarding the use of NAC in disorders including addiction, compulsive and grooming disorders, schizophrenia and bipolar disorder. N-acetylcysteine has shown promising results in populations with these disorders, including those in whom treatment efficacy has previously been limited. The therapeutic potential of this acetylated amino acid is beginning to emerge in the field of psychiatric research.

Identifying depression and anxiety disorders in people presenting for substance use treatment

Objective: To identify the type and proportion of depressive and related mental health disorders in a group of individuals seeking outpatient treatment at an alcohol and other drug (AOD) service.
Design, setting and participants: A cross-sectional study using diagnostic interviews with 95 participants (56 men, 39 women) seeking treatment from an AOD service.
Main outcome measures: Mental health and substance disorders were measured using the Composite International Diagnostic Interview, Posttraumatic Stress Disorder Checklist, Beck Depression Inventory, and State–Trait Anxiety Inventory (Trait Version).
Results: This was a complex group with addiction, mental health and physical health conditions; 76% had a depressive disorder and 71% had an anxiety disorder. Most were diagnosed with at least two mental health disorders and 25% were diagnosed with four or more different disorders. Alcohol and cannabis use were the most commonly diagnosed AOD disorders. Further, those diagnosed with a drug use disorder reported significantly higher levels of depression compared with those with an alcohol-only disorder. Finally, 60% of the sample reported chronic health conditions, with over one third taking medication for a physical condition on a regular basis.
Conclusions: Primary care providers such as general practitioners are likely to be increasingly called on to assess, treat and/or coordinate care of patients with AOD disorders. We show that this group will likely present to their GP with more than one MJA 2011; 195: S60–S63 mental health disorder in addition to acute and chronic physical health conditions.