BACKGROUND

Meeting global health challenges requires effective behaviour change interventions (BCIs). This depends on advancing the science of behaviour change which, in turn, depends on accurate intervention reporting. Current reporting often lacks detail, preventing accurate replication and implementation. Recent developments have specified intervention content into behaviour change techniques (BCTs) - the 'active ingredients', for example goal-setting, self-monitoring of behaviour. BCTs are 'the smallest components compatible with retaining the postulated active ingredients, i.e. the proposed mechanisms of change. They can be used alone or in combination with other BCTs' (Michie S, Johnston M. Theories and techniques of behaviour change: developing a cumulative science of behaviour change. Health Psychol Rev 2012;6:1-6). Domain-specific taxonomies of BCTs have been developed, for example healthy eating and physical activity, smoking cessation and alcohol consumption. We need to build on these to develop an internationally shared language for specifying and developing interventions. This technology can be used for synthesising evidence, implementing effective interventions and testing theory. It has enormous potential added value for science and global health.

OBJECTIVE

(1) To develop a method of specifying content of BCIs in terms of component BCTs; (2) to lay a foundation for a comprehensive methodology applicable to different types of complex interventions; (3) to develop resources to support application of the taxonomy; and (4) to achieve multidisciplinary and international acceptance for future development.

METHODS

Four hundred participants (systematic reviewers, researchers, practitioners, policy-makers) from 12 countries engaged in investigating, designing and/or delivering BCIs. Development of the taxonomy involved a Delphi procedure, an iterative process of revisions and consultation with 41 international experts; hierarchical structure of the list was developed using inductive 'bottom-up' and theory-driven 'top-down' open-sort procedures (n = 36); training in use of the taxonomy (1-day workshops and distance group tutorials) (n = 161) was evaluated by changes in intercoder reliability and validity (agreement with expert consensus); evaluating the taxonomy for coding interventions was assessed by reliability (intercoder; test-retest) and validity (n = 40 trained coders); and evaluating the taxonomy for writing descriptions was assessed by reliability (intercoder; test-retest) and by experimentally testing its value (n = 190).

RESULTS

Ninety-three distinct, non-overlapping BCTs with clear labels and definitions formed Behaviour Change Technique Taxonomy version 1 (BCTTv1). BCTs clustered into 16 groupings using a 'bottom-up' open-sort procedure; there was overlap between these and groupings produced by a theory-driven, 'top-down' procedure. Both training methods improved validity (both p < 0.05), doubled the proportion of coders achieving competence and improved confidence in identifying BCTs in workshops (both p < 0.001) but did not improve intercoder reliability. Good intercoder reliability was observed for 80 of the 93 BCTs. Good within-coder agreement was observed after 1 month (p < 0.001). Validity was good for 14 of 15 BCTs in the descriptions. The usefulness of BCTTv1 to report descriptions of observed interventions had mixed results.

CONCLUSIONS

The developed taxonomy (BCTTv1) provides a methodology for identifying content of complex BCIs and a foundation for international cross-disciplinary collaboration for developing more effective interventions to improve health. Further work is needed to examine its usefulness for reporting interventions.

BACKGROUND

This project was funded by the Medical Research Council Ref: G0901474/1. Funding also came from the Peninsula Collaboration for Leadership in Applied Health Research and Care.

This paper analysed the literature published in the last 15 years regarding the onset of pancreatic fistula after pancreaticoduodenectony carried out for tumours in the periampullary region, in the head of the pancreas and in the distal common bile duct. Out of 8370 pancreatic resections we were able to go by only 2684 cases, which showed the type of treatment used in the remaining stump, the rates of leakage and relative mortality. The data collected were analysed statistically using the Cochran test and or the chi 2, evaluating the possible significant difference relative to the various methods of reconstruction. The onset of pancreatic fistrula was found to be statistically more frequent after ligation of the stump than after pancreatico-jejunal anastomosis (p = 0.001). Comparing the pancreatico-jejunal end-to-side anastomosis, to pancreatico-jejunal end-to-end and wirsung-jejunal end-to-side anastomosis the first one had shown a significantly higher rate only for leakage (respectively p = 0.008 and p = 0.010). The occlusion of the wirsung duct with biological substances showed better results compared to ligation (p = 0.001) only as regards onset of the fistula, while the comparison between the occlusion and the three types of anastomosis did not show any statistically difference, except for the pancreatico-jejunal end-to-side anastomosis, in which it was significant only as regards leakage (p = 0.009). The statistical analysis between pancreatico-gastrostomy and pancreatico-jejunal anastomoses indicated that the first technique had a lower morbidity rate than pancreatico-jejunal end-to-side (p = 0.001), pancreatico-jejunal end-to-end (p = 0.010) and wirsung-jejunal end-to-side (p = 0.011). We analysed and compared the results obtained before and after 1975, in order to discover whether was an improvement in the prevnetion or in the treatment of such a complication and its consequences. Furthermore, we tried to establish whether the transanastomotic drainage, the site of the neoplasm, the texture of pancreatic parenchyma and the patient's age could in any way influence the onset and course of the fistula.

BACKGROUND

Maternal hypothyroidism during pregnancy can cause adverse effects in the fetus. Scientific evidence has shown that probable thyroid-like function of some phthalates in vitro and in vivo, and phthalates exposure, can begin in utero. This study investigated the association between phthalate exposure and thyroid hormones in pregnant women.

METHODS

Serum and spot urine samples were collected from 76 Taiwanese pregnant women at second trimester. Thyroid hormones, including thyroid-stimulating hormone (TSH), triiodothyronine (T(3)), thyroxine (T(4)) and free T(4) (FT(4)) were analysed in serum samples, and five urinary phthalate monoesters, including mono butyl phthalate (MBP), monoethyl phthalate (MEP) and mono ethylhexyl phthalate (MEHP), were measured.

RESULTS

Urinary MBP, MEP and MEHP, the median levels of which were 81.8, 27.7 and 20.6 ng/ml, respectively, were the predominant substances in the urinary phthalate monoesters. Significant mild negative correlations were found between T(4) and urinary MBP (R = -0.248, P < 0.05), and between FT(4) and urinary MBP (R = -0.368, P < 0.05). After adjusting for age, BMI and gestation, urinary MBP levels showed negative associations with FT(4) and T(4) (FT(4): beta = -0.110, P < 0.001; T(4): beta=-0.112, P = 0.003).

CONCLUSIONS

Exposure to di-n-butyl phthalate (DBP) may affect thyroid activity in pregnant women, but how DBP affects thyroid function is unclear. Further studies are needed to elucidate the mechanism of action and to investigate whether any other factors related to DBP exposure alter the thyroid function.

In addition to the classical neurotransmitters, acetylcholine and noradrenaline, a wide number of peptides with neurotransmitter activity have been identified in the past few years. Among them, the tachykinins substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) appear to act as mediators of nonadrenergic, noncholinergic (NANC) excitatory neurotransmission. Tachykinins interact with specific membrane proteins, belonging to the family of G protein-coupling cell membrane receptors. Until now, three tachykinin receptors termed NK1 (NK1R), NK2 (NK2R) and NK3 (NK3R) have been cloned in different species. A large amount of reports suggests that these peptides are involved in nociception and neuroimmunomodulation, and in the development of different diseases such as bronchial asthma, inflammatory bowel syndrome and psychiatric disorders. Tachykinin receptor antagonists are therefore promising, therapeutically relevant agents. However, and in spite of extensive research, the obtention of selective antagonists of tachykinin receptors have revealed very difficult. An understanding of how ligands interact with their receptors is essential to permit a rational design of compounds acting selectively at the tachykinin receptor level. The major aim of the present article is to review the structure-activity data that exist for tachykinins and their receptors, with the purpose of getting insight into basic structural requirements that determine ligand/receptor interaction.

The intake of a Western diet with a high amount of red meat is associated with a high risk for colon cancer. We hypothesize that heme, the iron carrier of red meat, is involved in diet-induced colonic epithelial damage, resulting in increased epithelial proliferation. Rats were fed purified control diets, or purified diets supplemented with 1.3 micromol/g of hemin (ferriheme), protoporphyrin IX, ferric citrate, or bilirubin (n = 8/group) for 14 days. Feces were collected for biochemical analyses. Fecal cytotoxicity was determined from the degree of lysis of erythrocytes by fecal water. Colonic epithelial proliferation was measured in vivo using [3H]thymidine incorporation into colonic mucosa. The colonic epithelial proliferation in heme-fed rats was significantly increased compared to control rats [55.2 +/- 5.8 versus 32.6 +/- 6.3 dpm/microg DNA (mean +/- SE); P < 0.05]. The fecal water of the heme group was highly cytotoxic compared to the controls (90 +/- 2% versus 2 +/- 1%; P < 0.001), although the concentrations of cytotoxic bile acids and fatty acids were significantly lower. Organic iron was significantly increased compared to the controls (257 +/- 26 versus 80 +/- 21, microM; P < 0.001). Spectrophotometric analyses suggest that this organic iron is heme-associated. Thiobarbituric acid-reactive substances were greatly increased in the fecal water of heme-fed rats compared to the controls (177 +/- 12 versus 59 +/- 7 microM; P < 0.05). Heme itself could not account for the increased cytotoxicity because the addition of heme to the fecal water of the control group, which was equimolar to the organic iron content of the fecal water of the heme group, did not influence the cytotoxicity. Hence, an additional heme-induced cytotoxic factor is involved, which may be modulated by the generation of luminal-reactive oxygen species. Protoporphyrin IX, ferric citrate, and bilirubin did not increase proliferation and cytotoxicity. In conclusion, dietary heme leads to the formation of an unknown, highly cytotoxic factor in the colonic lumen. This suggests that, in heme-fed rats, colonic mucosa is damaged by the intestinal contents. This results in a compensatory hyperproliferation of the epithelium, which supposedly increases the risk for colon cancer.

BACKGROUND

The US Public Health Service and the International AIDS Society-USA recently published recommendations for antiretroviral therapy (ART) for persons infected with human immunodeficiency virus (HIV); however, anecdotal evidence suggests that HIV-infected injection drug users (IDUs) may not be receiving optimal care as defined by the recommendations.

OBJECTIVE

To assess ART use in HIV-infected IDUs.

METHODS

A cross-sectional survey of self-reported ART use between July 1996 and June 1997 in IDUs.

METHODS

A community-based clinic affiliated with Johns Hopkins University, Baltimore, Md.

METHODS

A total of 404 HIV-infected IDUs with CD4+ cell counts less than 0.50 x 10(9)/L recruited into a longitudinal study in 1988 and 1989.

METHODS

Self-reported ART use was assessed: no current therapy, monotherapy, or combination therapy with or without a protease inhibitor.

RESULTS

One half (199/404 [49%]) of patients reported no recent ART. A total of 14% (58/404) had monotherapy, 23% (90/404) were receiving combination therapy without a protease inhibitor, and 14% (57/404) had triple-combination therapy with a protease inhibitor. A multivariate analysis of factors associated with ART showed that care continuity and recent HIV-related outpatient visit (odds ratio [OR], 4.30; 95% confidence interval [CI], 2.36-7.81 and OR, 2.84; 95% CI, 1.66-4.88, respectively), CD4+ cell count of less than 0.20 x 10(9) (OR, 2.41; 95% CI, 1.51-3.84), no current drug use and being in drug treatment (OR, 2.16; 95% CI, 1.34-3.47; OR, 2.12; 95% CI, 1.23-3.66, respectively), and unemployment (OR, 2.31; 95% CI, 1.21-4.40) were associated with reporting ART use. In other analysis, less likely to receive protease inhibitors were current drug injectors (OR, 0.5; 95% CI, 0.3-1.0) and those recently incarcerated (OR, 0.2; 95% CI, 0.03-0.9), but patients with acquired immunodeficiency syndrome were more likely to receive protease inhibitors (OR, 2.0; 95% CI, 0.9-4.6). Protease inhibitor use doubled (P<.01) from July and December 1996 to January and June 1997 (7.7% and 14.8%, respectively).

CONCLUSIONS

Those IDUs infected with HIV who were not receiving ART tended to be active drug users without clinical disease who have less contact with health care providers. Although we do not have information on clinical judgment regarding treatment decisions or whether persons were prescribed therapy not taken, the proportion of subjects reporting receiving ART suggests that strategies for improving treatment in this population are indicated. Expanding simultaneous treatment services for HIV infection and substance abuse would enhance the response to these related epidemics.

Several neurotransmitters act through G-protein-coupled receptors to evoke a 'slow' excitation of neurons. These include peptides, such as substance P and neurotensin, as well as acetylcholine and noradrenaline. Unlike the fast (approximately millisecond) ionotropic actions of small-molecule neurotransmitters, the slow excitation is not well understood at the molecular level, but can be mainly attributed to suppressing K(+) currents and/or activating a non-selective cation channel. The molecular identity of this cation channel has yet to be determined; similarly, how the channel is activated and its relative contribution to neuronal excitability induced by the neuropeptides are unknown. Here we show that, in the mouse hippocampal and ventral tegmental area neurons, substance P and neurotensin activate a channel complex containing NALCN and a large previously unknown protein UNC-80. The activation by substance P through TACR1 (a G-protein-coupled receptor for substance P) occurs by means of a unique mechanism: it does not require G-protein activation but is dependent on Src family kinases. These findings identify NALCN as the cation channel activated by substance P receptor, and suggest that UNC-80 and Src family kinases, rather than a G protein, are involved in the coupling from receptor to channel.

There is compelling evidence that excessive exposure to manganese (Mn) produces neurotoxicity, especially in the basal ganglia, resulting in a dystonic Parkinsonian disorder. Several experimental or clinical observations suggest that Mn neurotoxicity could involve impairment of energy metabolism. We examined the neurotoxic effects of Mn following local intrastriatal injection. Three hours after the injection of 2 mumol of MnCl2 into rat striatum, ATP levels were reduced to 51% of the control side and lactate level were increased by 97%, indicating an impairment of oxidative metabolism. Neurochemical analysis of the striata 1 week after Mn injection showed changes consistent with a N-methyl-D-aspartate (NMDA) excitotoxic lesion. Dopamine, gamma-aminobutyric acid, and substance P concentrations showed dose-dependent significant decreases, but concentrations of somatostatin-like immunoreactivity and neuropeptide Y-like immunoreactivity were unchanged. The lesions were blocked by prior removal of the cortico-striatal glutamatergic input or by treatment with the noncompetitive NMDA antagonist MK-801. These findings indicate that Mn neurotoxicity involves a NMDA receptor-mediated process similar to that we have previously found with two characterized mitochondrial toxins, aminooxyacetic acid, and 1-methyl-4-phenylpyridinium. Our results show that Mn may produce neuronal degeneration by an indirect excitotoxic process secondary to its ability to impair oxidative energy metabolism.

Silymarin, the active principle of the milk thistle Silybum marianum, protects experimental animals against various hepatotoxic substances. To determine the effect of silymarin on the outcome of patients with cirrhosis, a double blind, prospective, randomized study was performed in 170 patients with cirrhosis. 87 patients (alcoholic 46, non-alcoholic 41; 61 male, 26 female; Child A, 47; B, 37; C, 3; mean age 57) received 140 mg silymarin three times daily. 83 patients (alcoholic 45, non-alcoholic 38; 62 male, 21 female; Child A, 42; B, 32; C, 9: mean age 58) received a placebo. Non-compliant patients and patients who failed to come to a control were considered as 'drop outs' and were withdrawn from the study. All patients received the same treatment until the last patient entered had finished 2-years of treatment. The mean observation period was 41 months. There were 10 drop outs in the placebo group and 14 in the treatment group. In the placebo group, 37 (+2 drop outs) patients had died, and in 31 of these, death was related to liver disease. In the treatment group, 24 (+4 drop outs) had died, and in 18 of these, death was related to liver disease. The 4-year survival rate was 58 +/- 9% (S.E.) in silymarin-treated patients and 39 +/- 9% in the placebo group (P = 0.036). Analysis of subgroups indicated that treatment was effective in patients with alcoholic cirrhosis (P = 0.01) and in patients initially rated 'Child A' (P = 0.03). No side effects of drug treatment were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Carbachol, phenylephrine and substance P were each capable of producing a transient release of K (86 Rb) from rat parotid slices in the absence of extracellular Ca. 2. Each of the agonists was also capable of producing "cross-receptor inactivation"; that is, if a transient response was elicited by any one of the agonists then no transient response could be obtained by either of the other two. 3. Removal of carbachol from muscarinic receptors with atropine did not reverse the cross-receptor inactivation of the substance P response unless Ca was added with substance P or unless Ca was present when atropine was added. 4. It is concluded that the K release response in the parotid gland is mediated by receptor-controlled Ca influx sites. These influx sites also bind Ca at a location inaccessible to EGTA and release the bound Ca upon receptor activation. 5. It is also conlcuded that all three receptors (muscarinic, alpha-adrenergic, and peptide) appear to regulate the same Ca influx sites.

Evidence is reviewed concerning the brain areas and neurotransmitters involved in aggressive behavior in the cat and rodent. In the cat, two distinct neural circuits involving the hypothalamus and PAG subserve two different kinds of aggression: defensive rage and predatory (quiet-biting) attack. The roles played by the neurotransmitters serotonin, GABA, glutamate, opioids, cholecystokinin, substance P, norepinephrine, dopamine, and acetylcholine in the modulation and expression of aggression are discussed. For the rat, a single area, largely coincident with the intermediate hypothalamic area, is crucial for the expression of attack; variations in the rat attack response in natural settings are due largely to environmental variables. Experimental evidence emphasizing the roles of serotonin and GABA in modulating hypothalamically evoked attack in the rat is discussed. It is concluded that significant progress has been made concerning our knowledge of the circuitry underlying the neural basis of aggression. Although new and important insights have been made concerning neurotransmitter regulation of aggressive behavior, wide gaps in our knowledge remain.

Many neuropeptides regulate feeding and arousal; the ventral tegmental area (VTA) is likely to be one site where they act. We used whole-cell patch-clamp and single-unit extracellular recordings to examine the effects of such neuropeptides on the activity of VTA neurons. Substance P (SP; 300 nM) increased the firing rate of the majority of VTA dopaminergic and gamma-aminobutyric acid (GABA)ergic neurons, and induced oscillations in two dopaminergic cells. Corticotropin-releasing factor (CRF; 200 nM) excited the majority of VTA cells directly, whereas neuropeptide Y (NPY; 300 nM) directly inhibited a subset of dopaminergic and GABAergic cells. Consecutive application of several neuropeptides revealed that all the neurons were excited by at least one of the excitatory neuropeptides SP, CRF or/and orexins. Alpha-melanocyte-stimulating hormone had no effect on dopaminergic cells (at concentrations of 500 nM and 1 microM) and affected only a small proportion of GABAergic neurons. Ghrelin (500 nM), agouti-related peptide (1 microM); cocaine and amphetamine-related transcript (500 nM) and leptin (500 nM and 1 microM) did not modulate the firing rate and membrane potential of VTA neurons. Single-cell reverse transcription polymerase chain reaction analysis showed that all NPY receptors were present in VTA neurons, and all but one cell expressed NPY and/or at least one NPY receptor. CRF was expressed in 70% of dopaminergic VTA cells; the expression of CRF receptor 2 was more abundant than that of receptor 1. These findings suggest a link between the ability of neuropeptides to promote arousal and their action on VTA neurons.

Occupational exposures were investigated in a multicenter case-control study of clinically and histologically diagnosed idiopathic pulmonary fibrosis (IPF), a chronic diffuse interstitial lung disease of unknown etiology. Results are based on 248 cases, aged 20-75 years, diagnosed at 16 referral centers between January 1989 and July 1993. There were 491 controls ascertained by random digit dialing and matched to cases on sex, age, and geographic region. Data were collected using a standard telephone questionnaire. Occupational factors were based on a detailed history of jobs lasting 6 months or more and job activity, hobby, and specific substance checklists. Several occupational factors, adjusted for age and smoking in conditional multivariate logistic regression analyses, were significantly associated with IPF: farming (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.5); livestock (OR = 2.7, 95% CI: 1.3, 5.5); hairdressing (OR = 4.4, 95% CI: 1.2, 16.3); metal dust (OR = 2.0, 95% CI: 1.0, 4.0); raising birds (OR = 4.7, 95% CI: 1.6, 14.1); stone cutting/polishing (OR = 3.9, 95% CI: 1.2, 12.7); and vegetable dust/animal dust (OR = 4.7, 95% CI: 2.1, 10.4). Interaction was detected between smoking and exposure to livestock (p = 0.06) and farming (p = 0.08). Results confirm previous studies showing increased risk associated with dusty environments.

We previously found a relative sparing of somatostatin and neuropeptide Y neurons 1 week after producing striatal lesions with NMDA receptor agonists. These results are similar to postmortem findings in Huntington's disease (HD), though in this illness there are two- to threefold increases in striatal somatostatin and neuropeptide Y concentrations, which may be due to striatal atrophy. In the present study, we examined the effects of striatal excitotoxin lesions at 6 months and 1 yr, because these lesions exhibit striatal shrinkage and atrophy similar to that occurring in HD striatum. At 6 months and 1 yr, lesions with the NMDA receptor agonist quinolinic acid (QA) resulted in significant increases (up to twofold) in concentrations of somatostatin and neuropeptide Y immunoreactivity, while concentrations of GABA, substance P immunoreactivity, and ChAT activity were significantly reduced. In contrast, somatostatin and neuropeptide Y concentrations did not increase 6 months after kainic acid (KA) or alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) lesions. At both 6 months and 1 yr, QA lesions showed striking sparing of NADPH-diaphorase neurons as compared with both AMPA and KA lesions, neither of which showed preferential sparing of these neurons. Long-term QA lesions also resulted in significant increases in concentrations of both 5-HT and 5-hydroxyindoleacetic acid (HIAA), similar to findings in HD. Chronic QA lesions therefore closely resemble the neurochemical features of HD, because they result in increases in somatostatin and neuropeptide Y and in 5-HT and HIAA. These findings strengthen the possibility that an NMDA receptor-mediated excitotoxic process could play a role in the pathogenesis of HD.

1. The effects of the specific inhibitor of nitric oxide (NO) formation, NG-monomethyl-L-arginine (L-NMMA), on resting systemic arterial blood pressure (BP) and on the actions of both endothelium-dependent and endothelium-independent vasodilators were investigated in the anaesthetized, normotensive rat. 2. Intravenous administration of L-NMMA (12.5-50 mg kg-1; 47-188 mumol kg-1) but not its enantiomer, D-NMMA, induced a dose-related increase in BP, which was reversed by the intravenous administration of L-arginine (150-600 mumol kg-1), but not D-arginine. 3. The vasodepressor responses to intravenous administration of the endothelium-dependent vasodilators, acetylcholine, bradykinin and substance P were significantly inhibited by L-NMMA (94 and 188 mumol kg-1 i.v.), but not by D-NMMA. 4. The inhibition by L-NMMA of these vasodepressor responses was reversed by administration of L-arginine, but not D-arginine. 5. Endothelin (ET-1) induced dose-related vasodepressor responses following bolus intravenous administration, which were significantly inhibited by L-NMMA but not by D-NMMA. This inhibition was reversed by administration of L-arginine. 6. The vasodepressor effects of the endothelium-independent vasodilators, glyceryl trinitrate or prostacyclin, were not significantly inhibited by L-NMMA. 7. These findings with L-NMMA suggest that resting blood pressure in the rat is modulated by endogenous NO biosynthesis and that endothelium-dependent vasodilators act through the formation of endogenous NO to exert their actions in vivo.

BACKGROUND

The transient receptor potential ankyrin 1 (TRPA1) channel, localized to airway sensory nerves, has been proposed to mediate airway inflammation evoked by allergen and cigarette smoke (CS) in rodents, via a neurogenic mechanism. However the limited clinical evidence for the role of neurogenic inflammation in asthma or chronic obstructive pulmonary disease raises an alternative possibility that airway inflammation is promoted by non-neuronal TRPA1.

RESULTS

By using Real-Time PCR and calcium imaging, we found that cultured human airway cells, including fibroblasts, epithelial and smooth muscle cells express functional TRPA1 channels. By using immunohistochemistry, TRPA1 staining was observed in airway epithelial and smooth muscle cells in sections taken from human airways and lung, and from airways and lung of wild-type, but not TRPA1-deficient mice. In cultured human airway epithelial and smooth muscle cells and fibroblasts, acrolein and CS extract evoked IL-8 release, a response selectively reduced by TRPA1 antagonists. Capsaicin, agonist of the transient receptor potential vanilloid 1 (TRPV1), a channel co-expressed with TRPA1 by airway sensory nerves, and acrolein or CS (TRPA1 agonists), or the neuropeptide substance P (SP), which is released from sensory nerve terminals by capsaicin, acrolein or CS), produced neurogenic inflammation in mouse airways. However, only acrolein and CS, but not capsaicin or SP, released the keratinocyte chemoattractant (CXCL-1/KC, IL-8 analogue) in bronchoalveolar lavage (BAL) fluid of wild-type mice. This effect of TRPA1 agonists was attenuated by TRPA1 antagonism or in TRPA1-deficient mice, but not by pharmacological ablation of sensory nerves.

CONCLUSIONS

Our results demonstrate that, although either TRPV1 or TRPA1 activation causes airway neurogenic inflammation, solely TRPA1 activation orchestrates an additional inflammatory response which is not neurogenic. This finding suggests that non-neuronal TRPA1 in the airways is functional and potentially capable of contributing to inflammatory airway diseases.

Simultaneous polysubstance use (SPU) is a common phenomenon, yet little is known about how various substances are used with one another. In the present study 149 drug-using university students completed structured interviews about their use of various substances. For each substance ever used, participants provided details about the type, order and amount of all substances co-administered during its most recent administration. Alcohol, tobacco and cannabis were frequently co-administered with each other and with all other substances. Chi-squared tests revealed that when alcohol was used in combination with any of cannabis, psilocybin, MDMA, cocaine, amphetamine, methylphenidate (ps < 0.01) or LSD (p < 0.05) its initial use preceded the administration of the other substance. Paired samples t-tests revealed that when alcohol was used with cocaine (p < 0.01) or methylphenidate (p < 0.05) it was ingested in greater quantities than when used in their absence. Patterns of cannabis use were not systematically related to other substances administered. Finally, using one-sample t-tests, tobacco use was demonstrated to be increased relative to 'sober' smoking rates when used with alcohol, cannabis, psilocybin, MDMA, cocaine, amphetamine (ps < 0.001), LSD (p < 0.01) or methylphenidate (p < 0.05). Results suggest that many substances are routinely used in a SPU context and that the pattern in which a substance is used may be related to other substances co-administered.

Combined neuroanatomical techniques were used to examine the organization of the striatal projection to the substantia nigra in the rat. Both double anterograde axonal tracing methods (Phaseolus vulgaris leuco-agglutinin (PHA-L) and 3H-amino acid tract tracing) and double fluorescent retrograde axonal transport tracing methods were used to examine the relationship among striatal neurons projecting to separate areas of the substantia nigra. Additionally, the distributions of retrogradely labeled striatonigral projection neurons were charted relative to the neurochemically distinct striatal "patch" compartment, identified by substance P- or leu-enkephalin-like immunoreactivity, and the complementary "matrix" compartment, identified by somatostatin-like immunoreactive fibers. These studies show two distinct types of organization in the striatonigral projections. One type is topographic in that the mediolateral relationships among these striatal efferent neurons are roughly maintained by their termination patterns in the substantia nigra, while the dorsoventral relationships are inverted. Projections from any part of the striatum, however, are distributed throughout the rostrocaudal axis of the substantia nigra. Despite their general topographic organization, the variable and dispersed nature of such projections from individual striatal loci results in partial overlap of afferent fields from separate striatal areas. The second type of organization is nontopographic and provides a different system for convergence of inputs from separated striatal areas that is superimposed on the rough topographic system. In this other projection system the mediolateral and dorsoventral relationships typical of the topographically ordered system are not maintained and are sometimes reversed. For example, PHA-L injected into the dorsal striatum labels a topographic (inverted relationship) projection to the ventral substantia nigra pars reticulata but also a smaller and separate projection to the dorsal pars reticulata and adjacent pars compacta. Retrograde tracer deposits in the pars compacta label neurons in the ventral striatum (the inverted relationship) but also clusters of neurons in the dorsal striatum. These clusters are in the neurochemically defined patch compartment whereas neurons in the matrix are labeled by injections into the pars reticulata. The dendrites of both retrogradely filled patch and matrix neurons are confined to the compartment containing their cell bodies, suggesting a restriction that would functionally segregate extrinsic striatal afferents shown in other studies to be confined to either patches or matrix.(ABSTRACT TRUNCATED AT 400 WORDS)

There is experimental evidence that volatile substances in human breath can reflect presence of neoplasma. Volatile aldehydes were determined in exhaled breath of 12 lung cancer patients, 12 smokers and 12 healthy volunteers. Alveolar breath samples were collected under control of expired CO(2). Reactive aldehydes were transformed into stable oximes by means of on-fiber-derivatization (SPME-OFD). Aldehyde concentrations in the ppt and ppb level were determined by means of gas chromatography-mass spectrometry (GC-MS). Exhaled concentrations were corrected for inspired values. Exhaled C(1)-C(10) aldehydes could be detected in all healthy volunteers, smokers and lung cancer patients. Concentrations ranged from 7 pmol/l (161 pptV) for butanal to 71 nmol/l (1,582 ppbV) for formaldehyde. Highest inspired concentrations were found for formaldehyde and acetaldehyde (0-55 nmol/l and 0-13 nmol/l, respectively). Acetaldehyde, propanal, butanal, heptanal and decanal concentrations showed no significant differences for cancer patients, smokers and healthy volunteers. Exhaled pentanal, hexanal, octanal and nonanal concentrations were significantly higher in lung cancer patients than in smokers and healthy controls (p(pentanal) = 0.001; p(hexanal) = 0.006; p(octanal) = 0.014; p(nonanal) = 0.025). Sensitivity and specificity of this method were comparable to the diagnostic certitude of conventional serum markers and CT imaging. Lung cancer patients could be identified by means of exhaled pentanal, hexanal, octanal and nonanal concentrations. Exhaled aldehydes reflect aspects of oxidative stress and tumor-specific tissue composition and metabolism. Noninvasive recognition of lung malignancies may be realized if analytical skills, biochemical knowledge and medical expertise are combined into a joint effort.

BACKGROUND

High prevalence estimates in epidemiological surveys have led to concerns that the DSM system is overly inclusive and that mild cases should be excluded from future DSM editions.

OBJECTIVE

To demonstrate that the DSM-III-R disorders in the baseline National Comorbidity Survey (NCS) can be placed on a severity gradient that has a dose-response relationship with outcomes assessed a decade later in the NCS follow-up survey (NCS-2) and that no inflection point exists at the mild severity level.

METHODS

The NCS was a nationally representative household survey of DSM-III-R disorders in the 3-year time span 1990-1992. The NCS-2 is a follow-up survey of 4375 NCS respondents (76.6% conditional response rate) reinterviewed in 2000 through 2002. The NCS-2 outcomes include hospitalization for mental health or substance disorders, work disability due to these disorders, suicide attempts, and serious mental illness.

RESULTS

Twelve-month NCS/DSM-III-R disorders were disaggregated into 3.2% severe, 3.2% serious, 8.7% moderate, and 16.0% mild case categories. All 4 case categories were associated with statistically significantly (P<.05, 2-sided tests) elevated risk of the NCS-2 outcomes compared with baseline noncases, with odds ratios of any outcome ranging monotonically from 2.4 (95% confidence interval, 1.6-3.4) to 15.1 (95% confidence interval, 10.0-22.9) for mild to severe cases. Odds ratios comparing mild to moderate cases were generally nonsignificant.

CONCLUSIONS

There is a graded relationship between mental illness severity and later clinical outcomes. Retention of mild cases in the DSM is important to represent the fact that mental disorders (like physical disorders) vary in severity. Decisions about treating mild cases should be based on cost-effectiveness not current severity. Cost-effectiveness analysis should include recognition that treatment of mild cases might prevent a substantial proportion of future serious cases.

Recent studies have suggested that inflammation may play an important role in the characteristic bronchial hyperresponsiveness and symptoms of chronic asthma. The mechanisms by which inflammatory cells, mediators, and nerves interact to produce the features of asthma are still uncertain, however. Although mast cells play an important role in the immediate response to allergen (and probably exercise), pharmacologic evidence argues against a critical role in the late response or bronchial hyperresponsiveness in which other cells, such as macrophages and eosinophils, may play a more important role. Many mediators have been implicated in asthma, but only PAF causes a prolonged increase in bronchial responsiveness. PAF attracts eosinophils into tissues and potently activates these cells, which may lead to epithelial damage, a key feature of asthmatic airways. PAF is also a potent inducer of microvascular leakage in airways, which may result in submucosal edema and plasma exudation into the airway lumen in the future. PAF antagonists will reveal whether PAF plays an important role in the eosinophilic inflammation of asthma. Neural mechanisms may also make an important contribution. Inflammatory mediators may influence neurotransmitter release from airway nerves, and neurotransmitters may be proinflammatory. Neural control is complex and cholinergic, adrenergic, and NANC mechanisms may contribute to bronchial hyperresponsiveness. Many neuropeptides, which may be the transmitters of NANC nerves, have been identified in airways. Neuropeptides in airway sensory nerves, such as substance P, have potent proinflammatory effects and, if these are released by an axon reflex, may amplify the inflammatory response in asthma. Since asthma may be chronic eosinophilic bronchitis, it is logical that the primary treatment should involve drugs that suppress this inflammatory response. At present, corticosteroids appear to be the most effective therapy; they have potent effects against eosinophils and macrophages (but not on mast cells) and reduce bronchial hyperresponsiveness and symptoms. By contrast, bronchodilators, such as beta-agonists, although they reduce symptoms, do not reduce the chronic inflammatory response or bronchial hyperresponsiveness and may mask the underlying inflammation. New therapies should be directed toward controlling eosinophil infiltration and activation in airways.

The hydrolysis of [Leu]enkephalin and substance P by purified pig kidney endopeptidase (EC 3.4.24.11) and synaptic membranes prepared from pig caudate nuclei has been compared. The hydrolysis of an enkephalin analogue (Tyr-D-Ala-Gly-Phe-Leu) at the Gly-Phe bond was completely inhibited by phosphoramidon. The IC50 concentration (8 nM) was similar to that reported for [Leu]enkephalin hydrolysis by the purified endopeptidase [Fulcher, I. S., Matsas, R., Turner, A. J. & Kenny, A. J. (1982) Biochem. J. 203, 519-522]. Seven peptides were produced when substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2) was hydrolyzed by the kidney endopeptidase. These were formed by cleavage at bonds Gln-Phe (positions 6 and 7), Phe-Phe (positions 7 and 8), and Gly-Leu (positions 9 and 10). Synaptic membranes generated peptides with the same HPLC retention times and hydrolysis of substance P by either preparation was inhibited completely by 10 microM phosphoramidon. The most susceptible bond appeared to be Gly-Leu (positions 9 and 10). A specific polyclonal antibody raised in rabbits to purified pig endopeptidase inhibited the hydrolysis of [Leu]enkephalin and substance P by detergent-solubilized kidney microvilli or synaptic membranes; the titration curves were essentially identical. We conclude that the endopeptidase, which we suggest should be designated "endopeptidase-24.11," is present in caudate synaptic membranes and could play an important role in the hydrolysis of neuropeptides.

The organization of neurons in the rat central nucleus of the amygdala (CNA) has been examined by using Nissl stain and immunocytochemical and retrograde tracing techniques. Four main subdivisions were identified on the basis of quantitative analyses of Nissl-stained material: medial (CM), lateral (CL), lateral capsular (CLC), and ventral (CV). An intermediate subdivision (CI), previously described by McDonald ('82), was apparent only in animals that had HRP-WGA injected into the bed nucleus of the stria terminalis. Large populations of neurotensin-, corticotropin-releasing factor (CRF)-, and enkephalin-immunoreactive neurons were present within the lateral divisions (mainly CL), although they were also seen within CM. Somatostatin-immunoreactive neurons were distributed mainly within CL and CM. Within CL, neurotensin- and enkephalin-immunoreactive neurons were more numerous laterally whereas CRF- and somatostatin-immunoreactive neurons were more numerous medially. Substance P-immunoreactive neurons were almost exclusively confined to CM. Only a few cholecystokinin- and vasoactive-polypeptide-immunoreactive neurons were seen in the CNA, and they were observed within CL, CV, and CM. The majority of neurons projecting to the dorsal medulla, hypothalamus, and ventral tegmental area were located within CM, although a significant number of cells were also seen within CL. Efferent projections to the bed nucleus of the stria terminalis were found to arise from neurons located within all subdivisions of the CNA. Thus, the distributional patterns of peptidergic and efferent neurons were not confined to individual cytoarchitectonically- defined subdivisions of the CNA. Rather, the results suggest overlapping medial to the lateral trends. Comparisons with the results of previous studies indicate that peptidergic and afferent terminal distribution patterns are more restricted to individual cytoarchitectonically defined subregions of the CNA. These observations suggest that the detailed cytoarchitecture of the CNA more likely reflects the functional integration of afferents rather than the organization of the CNA output neurons.