The tachykinins comprise a family of closely related peptides that participate in the regulation of diverse biological processes. The tachykinin peptides substance P, neurokinin A, neurokinin A(3-10), neuropeptide K, and neuropeptide gamma are produced from a single preprotachykinin gene as a result of differential RNA splicing and differential posttranslational processing. Another tachykinin, neurokinin B, is produced from a separate preprotachykinin gene. These preprotachykinin mRNAs and peptide products are differentially distributed throughout the nervous system. Three distinct G protein-coupled tachykinin receptors exist for these tachykinin peptides. The three receptors interact differentially with the tachykinin peptides and are uniquely distributed throughout the nervous system. The NK-1 receptor preferentially interacts with substance P, the NK-2 receptor prefers neurokinin A, neuropeptide K, and neuropeptide gamma, and the NK-3 receptor interacts best with neurokinin B. Examples of the roles of tachykinin peptidergic neuronal systems are taken from the spinal cord sensory system and the nigrostriatal extrapyramidal motor system. Analysis of the functional significance of multiple tachykinin peptide systems, receptor-second messenger coupling mechanisms, and developmental and regulatory mechanisms underlying peptide mRNA and receptor expression represent areas of current and future investigation.

Injection of capsaicin into the skin results in pain, primary heat and mechanical hyperalgesia, and secondary mechanical allodynia and hyperalgesia. Sensory receptors in the area of secondary mechanical allodynia and hyperalgesia are unaffected, and so the sensory changes must be due to central actions of the initial intense nociceptive discharge that follows the capsaicin injection. Central sensitization of the responses of spinothalamic tract neurons lasts several hours, but can be prevented by spinal cord administration of non-NMDA and NMDA glutamate receptor antagonists or NK1 substance P receptor antagonists. The long-lasting increase in excitability of spinothalamic tract cells depends on the activation of several second messenger cascades (PKC, PKA, and NO/PKG signal transduction pathways). The excitability change also depends on activation of calcium/calmodulin-dependent kinase II, which is consistent with the proposal that this central sensitization response is a form of long-term potentiation.

OBJECTIVE

This study implemented and evaluated procedures to help clinicians make effective referrals to 12-step self-help groups (SHGs).

METHODS

In this randomized controlled trial, individuals with substance use disorders (SUDs) entering a new outpatient treatment episode (N=345; 96% had previous SUD treatment) were randomly assigned to a standard referral or an intensive referral-to-self-help condition and provided self-reports of 12-step group attendance and involvement and substance use at baseline and at six-month and one-year follow-ups (93%). In standard referral, patients received a schedule for local 12-step SHG meetings and were encouraged to attend. Intensive referral had the key elements of counselors linking patients to 12-step volunteers and using 12-step journals to check on meeting attendance.

RESULTS

Compared with patients who received standard referral, patients who received intensive referral were more likely to attend and be involved with 12-step groups during both the first and second six-month follow-up periods, and improved more on alcohol and drug use outcomes over the year. Specifically, during both follow-up periods, patients in intensive referral were more likely to attend at least one meeting per week (70% versus 61%, p=.049) and had higher SHG involvement (mean=4.9 versus 3.7, p=.021) and abstinence rates (51% versus 41%, p=.048). Twelve-step involvement mediated the association between referral condition and alcohol and drug outcomes, and was associated with better outcomes above and beyond group attendance.

CONCLUSIONS

The intensive referral intervention was associated with improved 12-step group attendance and involvement and substance use outcomes. To most benefit patients, SUD treatment providers should focus 12-step referral procedures on encouraging broad 12-step group involvement, such as reading 12-step literature, doing service at meetings, and gaining self-identity as a SHG member.

Alterations in serotonin (5-hydroxytriptamine, 5-HT), norepinephrine, and gamma-aminobutyric acid have been linked to the pathophysiology of anxiety and depression, and medications that modulate these neurotransmitters are widely used to treat mood disorders. Recently, the neuropeptide substance P (SP) and its receptor, the neurokinin 1 receptor (NK1R), have been proposed as possible targets for new antidepressant and anxiolytic therapies. However, animal and human studies have so far failed to provide a clear consensus on the role of SP in the modulation of emotional states. Here we show that both genetic disruption and acute pharmacological blockade of the NK1R in mice result in a marked reduction of anxiety and stress-related responses. These behavioral changes are paralleled by an increase in the firing rate of 5-HT neurons in the dorsal raphe nucleus, a major source of serotonergic input to the forebrain. NK1R disruption also results in a selective desensitization of 5-HT1A inhibitory autoreceptors, which resembles the effect of sustained antidepressant treatment. Together these results indicate that the SP system powerfully modulates anxiety and suggest that this effect is at least in part mediated by changes in the 5-HT system.

Extracellular proteases of three cornea-virulent strains of Pseudomonas aeruginosa were isolated by sequential ammonium sulfate precipitation, Ultrogel AcA 54 gel filtration, and flat-bed isoelectric focusing. The purity of the preparations was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis , thin-layer isoelectric focusing in polyacrylamide gel, immunodiffusion and immunoelectrophoretic procedures, and tests for the presence of other known pseudomonal products. Light and electron microscopic examination of rabbit corneal lesions observed 4 to 6 h after the intracorneal injection of submicrogram amounts of the proteases revealed: (i) degeneration and necrosis of epithelium, endothelium, and keratocytes, (ii) infiltration, degeneration, and necrosis of polymorphonuclear leukocytes, (iii) loss of the characteristic weblike pattern, colloidal iron staining, and ruthenium red staining of the stromal proteoglycan ground substance, (iv) dispersal of strucutrally normal appearing collagen fibrils, ground substance, (iv) dispersal of structurally normal appearing collagen fibrils, and (v) accumulation of plasma proteins and fibrin in the necrotic corneas. These structural alterations are very similar to those observed previously during experimental P. aeruginosa keratitis, and this similarity supports the idea that pseudomonal proteases are responsible, at least in part, for the rapid and extensive liquefaction necrosis characteristic of pseudomonal-induced keratitis. In addition, the results support the idea that pseudomonal proteases elicit severe corneal damage by causing the loss of the corneal proteoglycan ground substance, thus resulting in dispersal of undamaged collagen fibrils, weakening of the corneal stroma, and subsequent descemetocele formation and corneal perforation by the anterior chamber pressure.

OBJECTIVE

Behavioral economic theory suggests that a reduction in substance use is most likely when there is an increase in rewarding substance-free activities. The goal of this randomized controlled clinical trial was to evaluate the incremental efficacy of a novel behavioral economic supplement (Substance-Free Activity Session [SFAS]) to a standard alcohol brief motivational interviewing (BMI) session for heavy-drinking college students.

METHODS

Participants were 82 first-year college students (50% female; 81.7% White/European American; M age = 18.5 years, SD = 0.71) who reported 2 or more past-month heavy drinking episodes. After completing a baseline assessment and an individual alcohol-focused BMI, participants were randomized to either the SFAS or to a Relaxation Training (RT) control session. The SFAS was delivered in an MI style and attempted to increase the salience of delayed academic and career rewards and the patterns of behavior leading to those rewards.

RESULTS

The combination of an alcohol BMI plus the SFAS was associated with significantly greater reductions in alcohol problems compared with an alcohol BMI plus RT at the 1-month and 6-month follow-up assessments (p = .015, ηp² = .07), an effect that was partially mediated by increases in protective behavioral strategies. BMI + SFAS was also associated with greater reductions in heavy drinking among participants who at baseline reported low levels of substance-free reinforcement or symptoms of depression.

CONCLUSIONS

These results are consistent with behavioral economic theory and suggest that a single session focused on increasing engagement in alternatives to drinking can enhance the effects of brief alcohol interventions.

Moderate daily exercise is known to be beneficial to health, reducing risks of a number of age-related disorders. Molecular mechanisms that bring about these effects are not clear. In contrast, it has been claimed that some types of prolonged physical exertion are detrimental to health because active oxygen species are generated excessively by enhanced oxygen consumption. Using two age groups of rats, young (4 week) and middle aged (14 months), we investigated the effects of long-term swimming training on the oxidative status of phospholipids, proteins, and DNA. The concentration of thiobarbituric acid reactive substances and 4-hydroxynonenal protein adducts did not differ in the gastrocnemius muscle between exercised and nonexercised animals in the two age groups. The extent of carbonylation in a protein of molecular weight around 29 KDa and the amount of 8-hydroxydeoxyguanosine in nuclear DNA were smaller (p<.05) in the exercised rats than in the sedentary animals. Activities of DT-diaphorase (C1: 29.3+/-1.9; C2: 36.1+/-2.6; E1: 27.2+/-1.3; C2: 33.4+/-2.9 nmol/mg protein) and proteasome, a major proteolytic enzyme for oxidatively modified proteins were significantly higher in the exercised animals of both age groups (p<.05). The adaptive response against oxidative stress induced by moderate endurance exercise constitutes a beneficial effect of exercise.

Genetic variation at the locus encoding the brain derived neurotrophic factor (BDNF) has been implicated in some neuropsychiatric disorders such as Alzheimer's disease (AD), affective disorders (AFDs), schizophrenia, and substance dependence. We therefore performed a mutation scan of the BDNF gene to identify novel gene variants and examined the association between BDNF variants and several neuropsychiatric phenotypes in European American (EA) subjects and controls. Using denaturing high performance liquid chromatography (dHPLC), we identified a novel variant (G-712A) in the putative promoter region. This variant and two previously reported BDNF SNPs (C270T and Val66Met) were genotyped in 295 patients with AD, 108 with AFDs, 96 with posttraumatic stress disorder (PTSD), 84 with schizophrenia, 327 with alcohol and/or drug dependence, and 250 normal control subjects. No association was found between these three BDNF gene variants and AD, AFDs, PTSD, or schizophrenia. However, there was a nominally higher frequency of the G-712A G-allele and the G/G genotype in subjects with substance dependence than in controls (Allele: chi(2) = 4.080, df = 1, P = 0.043; Genotype: chi(2) = 7.225, df = 2, P = 0.027). Although after correction for multiple testing, the findings are not considered significant (threshold P-value was set at 0.020 by the program SNPSpD), logistic regression analyses confirmed the modest association between SNP G-712A and substance dependence, when the sex and age of subjects were taken into consideration. The negative results for AFDs, PTSD, and schizophrenia could be due to the low statistical power. Further study with larger samples is warranted.

This paper reviews and provides new data on the relationship of the peptide content in rat dorsal root ganglion (DRG) neurons to a) the neurofilament content of the soma and b) the conduction velocities of the fibres. The latter involved intracellular recordings made in vitro followed by dye injection and immunocytochemistry. Because neurofilament-poor DRG neurones have C-fibres, and A-fibre neurones are neurofilament rich, the soma neurofilament content of peptide containing neurones allowed predictions to be made about their conduction velocity ranges. Substance P-like immunoreactive (SP-LI) neurones were mostly small, neurofilament poor, but a few (15%) were neurofilament rich. From conduction velocity measurements, about half the C-fibre neurones studied and 10% of A delta-neurones but no A alpha/beta-neurones showed SP-LI. CGRP-LI neurones were also mainly neurofilament poor neurones, but 32% were neurofilament rich, including small, medium, and large neurones. Fibres of CGRP-LI neurones conducted in the C, A delta or A alpha/beta ranges. Neurones with somatostatin-LI (SOM-LI) were all neurofilament poor; preliminary data is consistent with SOM-LI neurones having C-fibres.

The existence of a third tachykinin receptor (SP-N) in the mammalian nervous system was demonstrated by development of highly selective agonists. Systematic N-methylation of individual peptide bonds in the C-terminal hexapeptide of substance P gave rise to agonists which specifically act on different receptor subtypes. The most selective analog of this series, succinyl-[Asp6,Me-Phe8]SPP-N receptor at a concentration of 0.5 nM. At least 60,000-fold higher concentrations of this peptide are required to stimulate the other two tachykinin receptors (SP-P and SP-E). The action of selective SP-N agonists in the guinea pig ileum is antagonized by opioid peptides, suggesting a functional counteraction between opiate and SP-N receptors. These results indicate that the tachykinin receptors are distinct entities which may mediate different physiological functions.

The gene product of the steel locus of the mouse represents a growth factor for murine mast cells and a ligand for the c-kit proto-oncogene receptor, a member of the tyrosine kinase receptor class of oncogenes (for review, see O. N. Witte. 1990. Cell 63:5). We have studied the effect of the human recombinant c-kit receptor ligand stem cell factor (rhSCF) on the release of inflammatory mediators from human skin mast cells and peripheral blood basophils and compared its activity to that of rhIL-3, rhSCF (1 ng/ml to 1 microgram/ml) activated the release of histamine and PGD2 from mast cells isolated from human skin. Analysis by digital video microscopy indicated that purified human skin mast cells (84 +/- 5% pure) responded to rhSCF (0.1 to 1 microgram/ml) challenge with a rapid, sustained rise in intracellular Ca2+ levels that was accompanied by secretion of histamine. A brief preincubation (10 min) of mast cells with rhSCF (0.1 pg/ml to 1 ng/ml) significantly enhanced (100 +/- 35%) the release of histamine induced by anti-IgE (3 micrograms/ml), but was much less effective on IgE-mediated release of PGD2. In contrast, a short term incubation with rhSCF did not potentiate the secretion of histamine activated by substance P (5 microM). A 24-h incubation of mast cells with rhSCF did not affect the release of mediators induced by anti-IgE (3 micrograms/ml), probably due to receptor desensitization, rhSCF (1 ng/ml to 3 micrograms/ml) neither caused release of histamine or leukotriene C4 (LTC4) release from leukocytes of 14 donors, nor induced a rise in intracellular Ca2+ levels in purified (greater than 70%) basophils. Brief preincubation (10 min) of leukocytes with rhSCF (1 ng/ml to 3 micrograms/ml) caused an enhancement (69 +/- 11%) of anti-IgE-induced release of histamine that was significant at concentrations as low as 3 ng/ml (p less than 0.05), whereas it appeared less effective in potentiating IgE-mediated LTC4 release. In contrast, a prolonged incubation (24 h) with rhSCF (0.1 pg/ml to 100 ng/ml) did not enhance the release of histamine or LTC4 induced by anti-IgE (0.1 microgram/ml), whereas rhIL-3 (3 ng/ml) significantly potentiated the release of both mediators.(ABSTRACT TRUNCATED AT 400 WORDS)

In a companion paper (Ju and Swanson; J. Comp. Neurol. 280:587-602, '89) we described a parcellation scheme for the bed nuclei of the stria terminalis (BST) that was based on cytoarchitectonic criteria. In the work reported here, antisera to the neuropeptides corticotropin-releasing hormone, neurotensin, galanin, substance P, and cholecystokinin were used to determine the extent to which immunostained neuronal cell bodies and presumed terminal fields are correlated with this cytoarchitectonic scheme in the adult male rat. The results confirm the validity of the cytoarchitectonic parcellation and provide additional chemoarchitectonic criteria for determining the (as yet still somewhat arbitrarily defined) border between the BST and the ventrally adjacent preoptic region, for distinguishing between the anterior and posterior divisions of the BST, and for identifying and distinguishing between the particular cell groups or nuclei within each division. The projections of each neuropeptide-containing cell group in various parts of the BST remain to be determined, as do the precise origins of the localized immunoreactive terminal fields identified here.

Mechanical forces influence chondrocyte metabolism and are critically important for maintenance of normal cartilage structure and integrity. In cells of the musculoskeletal system and mechanoresponsive cells in other tissues, integrins seem to be involved in the mechanotransduction process. Integrin activity is important in the early cellular responses to mechanical stimulation, regulating activation of a number of intracellularcascades that induce changes in gene expression and tissue remodeling. In normal human articular chondrocytes, integrin activation, consequent to mechanical stimulation in vitro, results in tyrosine phosphorylation of regulatory proteins and subsequent secretion of autocrine and paracrine acting soluble mediators including substance P and interleukin 4. Significant differences in signaling events and cellular responses are seen when normal and osteoarthritic chondrocytes are mechanically stimulated. These differences may relate to differences in integrin expression and function. Improved comprehension of how integrins mediate chondrocyte responses to mechanical stimulation, and how cross talk between integrin signaling, extracellular matrix, and autocrine/paracrine signaling molecules regulate mechanotransduction and cellular reactions are necessary for further understanding of how load influences cartilage structure.

OBJECTIVE

Despite ample evidence of excess cardiovascular mortality in bipolar disorder (BD), few studies have demonstrated increased prevalence of cardiovascular disease (CVD) and/or hypertension (HTN) in BD. We therefore examined this topic in a representative epidemiologic sample.

METHODS

The 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions was used to determine whether prevalence of physician-diagnosed CVD and HTN is elevated among subjects with lifetime bipolar I disorder (BD-I), and whether CVD and HTN are prevalent at earlier ages among subjects with BD-I.

RESULTS

The age-, race-, and sex-adjusted prevalence of CVD was significantly greater among subjects with BD-I versus controls [odds ratio (OR) = 4.95, 95% confidence interval (CI): 4.27-5.75] and versus subjects with major depressive disorder [(MDD); OR =1.80, 95% CI: 1.52-2.14], as was the prevalence of HTN (OR = 2.38, 95% CI: 2.16-2.62 versus controls, OR = 1.44, 95% CI: 1.30-1.61 versus MDD; p < 0.0001 for all). Controlling additionally for marital status, education, income, obesity, smoking, anxiety disorders, and substance use disorders did not substantially alter these findings. The mean age of BD-I subjects with CVD and HTN was 14 and 13 years younger, respectively, than controls with CVD and HTN.

CONCLUSIONS

Adults with BD-I are at increased risk of CVD and HTN, prevalent over a decade earlier than non-BD adults. Strategies are needed to prevent excessive and premature cardiovascular burden in BD-I.

OBJECTIVE

To analyze oxidative stress in primary open-angle glaucoma (POAG).

METHODS

A case-control study including 90 eyes of 90 patients who needed antiglaucomatous surgery in the course of POAG (glaucoma group, n=50) and from patients who were operated of nonpathologic cataracts (cataract group, n=40). Free radical formation via lipid peroxidation by malondialdehyde-thiobarbituric acid reactive substances (MDA-TBARS) test and total antioxidant status in the aqueous humor samples of both groups were determined. Statistical analyses were carried out in relation to MDA-TBARS and total antioxidant status and their correlations with glaucoma risk factors.

RESULTS

Significantly higher MDA-TBARS were detected in the POAG with respect to the comparative group of cataract subjects (P<0.001). Antioxidant activity was significantly lower in the POAG than in the cataract group (P<0.001).

CONCLUSIONS

Aqueous humor samples may be used for determining oxidative and antioxidant status in pathologic processes. Glaucomatous eyes had a significant increase in oxidative status and decreased antioxidant activity in the aqueous humor than the cataract eyes. Oxidative stress may play a pathogenical role in the POAG.

The distribution of nitric oxide synthase (NOS) immunoreactivity was investigated in the guinea-pig small intestine. There were many immunoreactive nerve cell bodies in the myenteric plexus but very few in submucous ganglia. NOS immunoreactivity was not found in non-neuronal cells except for rare mucosal endocrine cells. Abundant immunoreactive nerve fibres in both myenteric and submucous ganglia, and in the circular muscle, arose from myenteric nerve cells whose axons projected anally along the intestine. NOS immunoreactivity coexisted with VIP-immunoreactivity, but not with substance P immunoreactivity. We conclude that nitric oxide synthase is located in a sub-population of enteric neurons, amongst which are inhibitory motor neurons that supply the circular muscle layer.

BACKGROUND

The mechanism of the hemodynamic effect of insulin in the skeletal muscle circulation has not been fully elucidated. The purpose of this study was to assess whether the hemodynamic response to insulin involves the concurrent release of endothelin (ET-1) and nitric oxide (NO), 2 substances with opposing vasoactive properties.

RESULTS

Bioactivity of ET-1 and NO was assessed without insulin and during insulin infusion in the forearm circulation of healthy subjects by use of blockers of ET-1 receptors and by NO synthesis inhibition. In the absence of hyperinsulinemia, ET-1 receptor blockade did not result in any significant change in forearm blood flow from baseline (P=0.29). Intra-arterial insulin administration did not significantly modify forearm blood flow (P=0. 88). However, in the presence of hyperinsulinemia, ET-1 receptor antagonism was associated with a significant vasodilator response (P<0.001). In the presence of ET-1 receptor blockade, the vasoconstrictor response to NO inhibition by N(G)-monomethyl-L-arginine was significantly higher after insulin infusion than in the absence of hyperinsulinemia (P=0.006).

CONCLUSIONS

These findings suggest that in the skeletal muscle circulation, insulin stimulates both ET-1 and NO activity. An imbalance between the release of these 2 substances may be involved in the pathophysiology of hypertension and atherosclerosis in insulin-resistant states associated with endothelial dysfunction.

Cardiac adiposity defined as increased epicardial adipose tissue and massive deposits of fat within the atrial septum (lipomatous hypertrophy) is seen in overweight persons and is associated with coronary artery disease (CAD), atrial arrhythmias, and increased risk of left ventricular free wall rupture after acute myocardial infarction. Unlike subcutaneous fat, epicardial fat is metabollically active and produces hormones, cytokines, and other vasoactive substances that work systemically or locally to alter vascular endothelial function and may be implicated in the pathogenesis of CAD. The aim of the study was to assess the feasibility of measuring epicardial fat volume (EFV) and identify its clinical correlates using (64-slice) multislice computed tomography (MSCT). A protocol was devised to measure EFV using MSCT in 151 adults (age 26 to 83 years, mean 51 +/- 12; 55% men). Cross-sectional tomographic cardiac slices (2.5-mm thick) from base to apex (range 28 to 40 per heart) were traced semiautomatically using an off-line workstation, and EFV was measured by assigning Hounsfield units ranging from -30 to -250 to fat. Coronary computed tomographic angiography was performed using a standard protocol. EFV ranged from 25 to 274 ml (mean 121 +/- 47), corresponding to 2.4% to 30.5% (mean 15 +/- 5%) of total cardiac volume and correlated with age, atrial septum thickness, body weight, and body mass index. Coronary calcium score was significantly higher in patients with EFV >100 ml (67 +/- 155 vs 216 +/- 639; p = 0.03), and a higher percentage of patients with increased EFV had CAD (46% vs 31%; p <0.05) or metabolic syndrome (44% vs 29%; p <0.05). In conclusion, quantification of EFV was feasible using MSCT. Large deposits of fat around the heart and within the atrial septum were associated with obesity, coronary calcium, metabolic syndrome, and CAD. Measurement of EFV may provide another useful noninvasive indicator of heightened risk of CAD in addition to calcium score and coronary angiography.

BACKGROUND

Patients with complex health needs are increasingly the focus of health system redesign.

OBJECTIVE

To characterize complex patients, as defined by their primary care physicians (PCPs), and to compare this definition with other commonly used algorithms.

METHODS

Cohort study.

METHODS

1 hospital-based practice, 4 community health centers, and 7 private practices in a primary care network in the United States.

METHODS

40 physicians who reviewed a random sample of 120 of their own patients.

METHODS

After excluding patients for whom they were not directly responsible, PCPs indicated which of their patients they considered complex. These patients were characterized, independent predictors of complexity were identified, and PCP-defined complexity was compared with 3 comorbidity-based methods (Charlson score, Higashi score, and a proprietary Centers for Medicare & Medicaid Services algorithm).

RESULTS

Physicians identified 1126 of their 4302 eligible patients (26.2%) as complex and assigned a mean of 2.2 domains of complexity per patient (median, 2.0 [interquartile range, 1 to 3]). Mental health and substance use were identified as major issues in younger complex patients, whereas medical decision making and care coordination predominated in older patients (P<0.001 for trends by decade). Major independent predictors of PCP-defined complexity (P<0.001) included age (probability of complexity increased from 14.8% to 19.8% with age increasing from 55 to 65 years), poorly controlled diabetes (from 12.7% to 47.6% if hemoglobin A1c level≥9%), use of antipsychotics (from 12.7% to 31.8%), alcohol-related diagnoses (from 12.9% to 27.4%), and inadequate insurance (from 12.5% to 19.2%). Classification agreement for complex patients ranged from 26.2% to 56.0% when PCP assignment was compared with each of the other methods.

CONCLUSIONS

Results may not be generalizable to other primary care settings.

CONCLUSIONS

Primary care physicians identified approximately one quarter of their patients as complex. Medical, social, and behavioral factors all contributed to PCP-defined complexity. Physician-defined complexity had only modest agreement with 3 comorbidity-based algorithms.

BACKGROUND

Partners Community Healthcare, Inc.

OBJECTIVE

To examine the safety and efficacy of modafinil (200 mg/day) compared to placebo in the treatment of methamphetamine dependence and to examine predictors of post-treatment outcome.

METHODS

Eighty methamphetamine-dependent subjects in Sydney, Australia were allocated randomly to modafinil (200 mg/day) (n = 38) or placebo (n = 42) under double-blind conditions for 10 weeks with a further 12 weeks post-treatment follow-up.

METHODS

Comprehensive drug use data (urine specimens and self-report) and other health and psychosocial data were collected weekly during treatment and research interviews at baseline, week 10 and week 22.

RESULTS

Treatment retention and medication adherence were equivalent between groups. There were no differences in methamphetamine abstinence, craving or severity of dependence. Medication-compliant subjects tended to provide more methamphetamine-negative urine samples over the 10-week treatment period (P = 0.07). Outcomes were better for methamphetamine-dependent subjects with no other substance dependence and those who accessed counselling. There were statistically significant reductions in systolic blood pressure (P = 0.03) and weight gain (P = 0.05) in modafinil-compliant subjects compared to placebo. There were no medication-related serious adverse events. Adverse events were generally mild and consistent with known pharmacological effects.

CONCLUSIONS

Modafinil demonstrated promise in reducing methamphetamine use in selected methamphetamine-dependent patients. The study findings support definitive trials of modafinil in larger multi-site trials.

Experiments on the sensitization of guinea pigs with simple chemical compounds are described. Positive effects were obtained by the administration of small quantities, namely fractions of milligrams, with 1:2:4 chlorodinitrobenzene, p-nitrosodimethylaniline, 1:2:4 trinitrobenzene, picryl chloride, four dichlorodinitrobenzenes, and a number of other aromatic compounds. Several substances chemically similar to those enumerated gave negative results. The first named compound is known to produce hypersensitiveness in human beings, a large number of cases having been observed in factory workers. The mechanism of these effects is discussed.

BACKGROUND

Strong relationships between exposure to childhood traumatic stressors and smoking behaviours inspire the question whether these adverse childhood experiences (ACEs) are associated with an increased risk of lung cancer during adulthood.

METHODS

Baseline survey data on health behaviours, health status and exposure to adverse childhood experiences (ACEs) were collected from 17,337 adults during 1995-1997. ACEs included abuse (emotional, physical, sexual), witnessing domestic violence, parental separation or divorce, or growing up in a household where members with mentally ill, substance abusers, or sent to prison. We used the ACE score (an integer count of the 8 categories of ACEs) as a measure of cumulative exposure to traumatic stress during childhood. Two methods of case ascertainment were used to identify incident lung cancer through 2005 follow-up: 1) hospital discharge records and 2) mortality records obtained from the National Death Index.

RESULTS

The ACE score showed a graded relationship to smoking behaviors. We identified 64 cases of lung cancer through hospital discharge records (age-standardized risk = 201 x 100,000(-1) population) and 111 cases of lung cancer through mortality records (age-standardized mortality rate = 31.1 x 100,000(-1) person-years). The ACE score also showed a graded relationship to the incidence of lung cancer for cases identified through hospital discharge (P = 0.0004), mortality (P = 0.025), and both methods combined (P = 0.001). Compared to persons without ACEs, the risk of lung cancer for those with>>or= 6 ACEs was increased approximately 3-fold (hospital records: RR = 3.18, 95%CI = 0.71-14.15; mortality records: RR = 3.55, 95%CI = 1.25-10.09; hospital or mortality records: RR = 2.70, 95%CI = 0.94-7.72). After a priori consideration of a causal pathway (i.e., ACEs ->> smoking ->> lung cancer), risk ratios were attenuated toward the null, although not completely. For lung cancer identified through hospital or mortality records, persons with>>or= 6 ACEs were roughly 13 years younger on average at presentation than those without ACEs.

CONCLUSIONS

Adverse childhood experiences may be associated with an increased risk of lung cancer, particularly premature death from lung cancer. The increase in risk may only be partly explained by smoking suggesting other possible mechanisms by which ACEs may contribute to the occurrence of lung cancer.

There is great evidence in recent years that oxygen free radicals play an important role in the pathophysiology of schizophrenia. The present study was performed to assess the changes in plasma nitric oxide (NO) and thiobarbituric acid-reactive substances (TBARS) levels, and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and xanthine oxidase (XO) activities in schizophrenic patients compared to age- and sex-matched normal controls. A hundred patients with schizophrenia and 51 healthy volunteers were included in the study. XO, SOD, and GSH-Px activities as well as NO and TBARS levels were estimated by standard biochemical techniques in the plasma of normal healthy controls and schizophrenia patients. In schizophrenia, increased plasma XO activity (P < .0001) and NO levels (P < .0001), decreased SOD activity (P < .0001), and unchanged GSH-Px activity were detected compared to control group. Plasma TBARS levels were increased in schizophrenic patients (P < .01), especially in the residual subtype. TBARS levels in nonsmoker schizophrenic patients were found to be higher than nonsmoker controls. Although TBARS levels in both patients and controls were found to be higher in smokers as compared to nonsmokers, it was not statistically significant. No effects of duration of the illness, gender, and low and high dose of daily neuroleptic treatment equivalent to chlorpromazine on oxidant and antioxidant parameters were observed. Because the dose and the duration of treatment with drugs have no influence on the results, it can be interpreted that the findings are more likely to be related mainly to the underlying disease. These findings indicated a possible role of increased oxidative stress and diminished enzymatic antioxidants, both of which may be relevant to the pathophysiology of schizophrenia. On the other hand, increased NO production by nitric oxide synthetases (NOSs) suggests a possible role of NO in the pathophysiological process of schizophrenia. These findings may also suggest some clues for the new treatment strategies with antioxidants and NO synthase (NOS) inhibitors in schizophrenia.

1. Isometric tension was recorded in isolated rings of aorta, carotid, coronary and mesenteric arteries taken from endothelial nitric oxide synthase knockout mice (eNOS(-/-) mice) and the corresponding wild-type strain (eNOS(+/+) mice). The membrane potential of smooth muscle cells was measured in coronary arteries with intracellular microelectrodes. 2. In the isolated aorta, carotid and coronary arteries from the eNOS(+/+) mice, acetylcholine induced an endothelium-dependent relaxation which was inhibited by N(omega)-L-nitro-arginine. In contrast, in the mesenteric arteries, the inhibition of the cholinergic relaxation required the combination of N(omega)-L-nitro-arginine and indomethacin. 3. The isolated aorta, carotid and coronary arteries from the eNOS(-/-) mice did not relax in response to acetylcholine. However, acetylcholine produced an indomethacin-sensitive relaxation in the mesenteric artery from eNOS(-/-) mice. 4. The resting membrane potential of smooth muscle cells from isolated coronary arteries was significantly less negative in the eNOS(-/-) mice (-64.8 +/- 1.8 mV, n = 20 and -58.4 +/- 1.9 mV, n = 17, for eNOS(+/+) and eNOS(-/-) mice, respectively). In both strains, acetylcholine, bradykinin and substance P did not induce endothelium-dependent hyperpolarizations whereas cromakalim consistently produced hyperpolarizations (- 7.9 +/- 1.1 mV, n = 8 and -13.8 +/- 2.6 mV, n = 4, for eNOS(+/+) and eNOS(-/-) mice, respectively). 5. These findings demonstrate that in the blood vessels studied: (1) in the eNOS(+/+) mice, the endothelium-dependent relaxations to acetylcholine involve either NO or the combination of NO plus a product of cyclo-oxygenase but not EDHF; (2) in the eNOS(-/-) mice, NO-dependent responses and EDHF-like responses were not observed. In the mesenteric arteries acetylcholine releases a cyclo-oxygenase derivative.