The development of a novel manual method designed to measure serum glycosylprotein as an index of diabetic control is described. The method relies on the ability of ketoamines (fructosamines) to act as reducing agents in alkaline solution. Conditions are described for a simple colorimetric procedure which permits assay of both a synthetic fructosamine and purified albumin while severely limiting the contribution of interfering substances. Applied to whole sera, the measurement is linear with volume of serum assayed. It allows clear discrimination of normal and diabetic populations (p less than 0.001), and is significantly correlated with fasting blood glucose concentration (r = 0.72) and with a thiobarbituric acid procedure for measuring glycosylprotein-derived hydroxymethylfurfural (r = 0.58). The method is rapid (at least 12 samples per hour) and demands only simple equipment.

BACKGROUND

One potential site of convergence of the nicotine and alcohol actions is the family of the neuronal nicotinic acetylcholine receptors. Our study examines the genetic association between variations in the genomic region containing the CHRNA5, A3, and B4 gene cluster (A5A3B4) and several phenotypes of alcohol and tobacco use in an ethnically diverse young adult sample. Significant results were then replicated in a separate adult population-representative sample.

METHODS

In a selected sample, nine single nucleotide polymorphisms (SNPs) were tested for association with various nicotine and alcohol phenotypes, including age of initiation and measures of frequency, quantity, and subjective responses to the substances. Analysis was conducted with the statistical genetics program WHAP in the full sample (1075 subjects) including ethnicities as covariates and within each ethnic group sub-sample. Replication of the significant results in a separate population-based sample was carried out with the PBAT statistical genetics program.

RESULTS

Two linked SNPs (rs8023462 and rs1948) located in a conserved region of the A5A3B4 gene cluster significantly predicted early age of initiation for tobacco with a hazard ratio (HR) of 1.35 (95% confidence interval [CI]1.08-1.70) for the CC genotype of rs8023462 and a HR of 1.29 (95% CI 1.01-1.63) for the TT genotype of rs1948 [corrected]. These findings were then replicated in a separate population-representative sample, showing rs1948 and rs8023462 to be associated with age of initiation for both tobacco and alcohol use (p < .01 and p < .001).

CONCLUSIONS

Variations in A5A3B4 genes might influence behaviors that promote early age of experimentation with drugs.

Uptake of glucose, fructose, and the nonmetabolizable analog 6-deoxyglucose was measured in wild-type Saccharomyces cerevisiae and two mutant strains, one (hxk1 hxk2) lacking both hexokinase A(P-I) and B(P-II) but containing glucokinase (and hence able to grow on glucose but not fructose) and the other (hxk1 hxk2 glk) also lacking glucokinase (and not able to grow on glucose either). Uptake of the nonmetabolized substances (i.e., 6-deoxyglucose in all three strains, fructose in the two mutants, and glucose in the triple mutant) reached a plateau at or below the external concentration. The kinetic characteristics of uptake were determined from 5-sec incubations by plotting velocity (V) vs. velocity/substrate concentration (V/S) curves. According to such plots, in the wild-type strain uptake had two components, "high affinity uptake" with Km values of ca. 1 mM for glucose and 6 mM for fructose and "low affinity uptake" with Km values of ca. 20 and 50 mM, respectively. The double kinase mutant showed both components for glucose but only the high Km component for fructose, while the triple kinase mutant showed only high Km uptake for both glucose and fructose. Genetic analysis showed that only in strains lacking both hexokinases (hxk1 hxk2) was the low Km system for fructose absent. Low Km uptake was restored to the triple mutant by introduction of the cloned wild-type genes: HXK1 or HXK2, for fructose uptake, and HXK1, HXK2, or GLK1, for glucose uptake. A phosphoglucose isomerase mutant had both low and high Km uptake for glucose. These results indicate the presence of two types of uptake mechanism for glucose and fructose in yeast, the functioning of one of which, the low Km system, is influenced by the cognate kinases.

OBJECTIVE

To measure, and seek clinical correlates with, levels of substance P (SP) in the cerebrospinal fluid (CSF) of fibromyalgia syndrome (FMS) patients.

METHODS

CSF from 32 FMS patients and 30 normal control subjects was tested for SP by radioimmunoassay. Clinical measures included tender point examination and standardized questionnaires.

RESULTS

CSF SP levels were 3-fold higher in FMS patients than in normal controls (P < 0.001), but they correlated only weakly with tenderness found on examination.

CONCLUSIONS

SP is significantly elevated in FMS CSF, but other abnormalities must exist in FMS to more fully explain the symptoms.

The tachykinins, exemplified by substance P, are one of the most intensively studied neuropeptide families. They comprise a series of structurally related peptides that derive from alternate processing of three Tac genes and are expressed throughout the nervous and immune systems. Tachykinins interact with three neurokinin G protein-coupled receptors. The signaling, trafficking, and regulation of neurokinin receptors have also been topics of intense study. Tachykinins participate in important physiological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems, including inflammation, nociception, smooth muscle contractility, epithelial secretion, and proliferation. They contribute to multiple diseases processes, including acute and chronic inflammation and pain, fibrosis, affective and addictive disorders, functional disorders of the intestine and urinary bladder, infection, and cancer. Neurokinin receptor antagonists are selective, potent, and show efficacy in models of disease. In clinical trials there is a singular success: neurokinin 1 receptor antagonists to treat nausea and vomiting. New information about the involvement of tachykinins in infection, fibrosis, and pruritus justifies further trials. A deeper understanding of disease mechanisms is required for the development of more predictive experimental models, and for the design and interpretation of clinical trials. Knowledge of neurokinin receptor structure, and the development of targeting strategies to disrupt disease-relevant subcellular signaling of neurokinin receptors, may refine the next generation of neurokinin receptor antagonists.

Individual neostriatal-matrix spiny neurons were stained intracellularly with biocytin after intracellular recording in vivo, and their axons were traced into the globus pallidus (GP), entopeduncular nucleus (EP), and/or substantia nigra (SN). The locations of the neurons within the matrix compartment of the neostriatum (NS) were established by immunocytochemical counterstaining of sections containing the cell bodies using antibodies for calbindin-D28K. This allowed nearly complete visualization of the axonal projections of single NS neurons. On the basis of their intrastriatal axonal arborizations, matrix spiny neurons could be divided into 2 types. One type, which was the more common, had local axonal arborizations restricted to the region of the dendritic field, often with axon collaterals arborizing within the dendritic field of the cells of origin. A second, less common, cell type in the matrix had local axon collaterals distributed widely in the NS. Among matrix neurons with restricted local collateral fields, 3 subtypes could be distinguished on the basis of their efferent axonal projections. Type I cells projected only to the GP. Type IIa cells projected to the GP, EP, and SN pars reticulata. Type IIb cells projected to the GP and SN but not to the EP. The shapes and densities of the GP arborizations varied in the 3 cell types, with the cells projecting only to the GP (type I) projecting more heavily and filling a larger volume there than type II cells. The dendrites and intrastriatal axon collaterals of 3 subtypes were similar in morphology. The class of matrix spiny neurons with intrastriatal axon collaterals distributed widely in the NS were observed to project to the GP. Projections beyond the GP were not identified for this cell type, but could not be ruled out. Somatodendritic morphologies of neurons did not differ according to the projection site. These results demonstrate that NS matrix spiny cells are more heterogeneous in their efferent projection patterns than previously suspected on the basis of retrograde axonal tracing and immunocytochemical studies. As predicted by those previous studies, there is a class of matrix neurons that projects only to the GP. Presumably, these cells contain enkephalin. Cells projecting to the SN and EP, and so presumably containing substance P, give off a small projection to the GP, as well, and differ in their collateralization patterns within the 3 major target nuclei.

The authors investigated whether substance use and self-reported racial discrimination were associated in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Smoking status, alcohol consumption, and lifetime use of marijuana, amphetamines, and opiates were ascertained in 2000-2001, 15 years after baseline (1985-1986). Most of the 1,507 African Americans reported having experienced racial discrimination, 79.5% at year 7 and 74.6% at year 15, compared with 29.7% and 23.7% among the 1,813 Whites. Compared with African Americans experiencing no discrimination, African Americans reporting any discrimination had more education and income, while the opposite was true for Whites (all p < 0.001). African Americans experiencing racial discrimination in at least three of seven domains in both years had 1.87 (95% confidence interval (CI): 1.18, 2.96) and 2.12 (95% CI: 1.42, 3.17) higher odds of reporting current tobacco use and having any alcohol in the past year than did their counterparts experiencing no discrimination. With control for income and education, African Americans reporting discrimination in three or more domains in both years had 3.31 (95% CI: 1.90, 5.74) higher odds of using marijuana 100 or more times in their lifetime, relative to African Americans reporting no discrimination. These associations were similarly positive in Whites but not significant. Substance use may be an unhealthy coping response to perceived unfair treatment for some individuals, regardless of their race/ethnicity.

BACKGROUND

Lead, mercury, and arsenic have been detected in a substantial proportion of Indian-manufactured traditional Ayurvedic medicines. Metals may be present due to the practice of rasa shastra (combining herbs with metals, minerals, and gems). Whether toxic metals are present in both US- and Indian-manufactured Ayurvedic medicines is unknown.

OBJECTIVE

To determine the prevalence of Ayurvedic medicines available via the Internet containing detectable lead, mercury, or arsenic and to compare the prevalence of toxic metals in US- vs Indian-manufactured medicines and between rasa shastra and non-rasa shastra medicines.

METHODS

A search using 5 Internet search engines and the search terms Ayurveda and Ayurvedic medicine identified 25 Web sites offering traditional Ayurvedic herbs, formulas, or ingredients commonly used in Ayurveda, indicated for oral use, and available for sale. From 673 identified products, 230 Ayurvedic medicines were randomly selected for purchase in August-October 2005. Country of manufacturer/Web site supplier, rasa shastra status, and claims of Good Manufacturing Practices were recorded. Metal concentrations were measured using x-ray fluorescence spectroscopy.

METHODS

Prevalence of medicines with detectable toxic metals in the entire sample and stratified by country of manufacture and rasa shastra status.

RESULTS

One hundred ninety-three of the 230 requested medicines were received and analyzed. The prevalence of metal-containing products was 20.7% (95% confidence interval [CI], 15.2%-27.1%). The prevalence of metals in US-manufactured products was 21.7% (95% CI, 14.6%-30.4%) compared with 19.5% (95% CI, 11.3%-30.1%) in Indian products (P = .86). Rasa shastra compared with non-rasa shastra medicines had a greater prevalence of metals (40.6% vs 17.1%; P = .007) and higher median concentrations of lead (11.5 microg/g vs 7.0 microg/g; P = .03) and mercury (20,800 microg/g vs 34.5 microg/g; P = .04). Among the metal-containing products, 95% were sold by US Web sites and 75% claimed Good Manufacturing Practices. All metal-containing products exceeded 1 or more standards for acceptable daily intake of toxic metals.

CONCLUSIONS

One-fifth of both US-manufactured and Indian-manufactured Ayurvedic medicines purchased via the Internet contain detectable lead, mercury, or arsenic.

BACKGROUND

Methadone hydrochloride treatment is the most common pharmacological intervention for opioid dependence, and recent interest has focused on expanding methadone treatment availability beyond traditional specially licensed clinics. However, despite recommendations regarding effective dosing of methadone, controlled clinical trials of higher-dose methadone have not been conducted.

OBJECTIVE

To compare the relative clinical efficacy of moderate- vs high-dose methadone in the treatment of opioid dependence.

METHODS

A 40-week randomized, double-blind clinical trial starting in June 1992 and ending in October 1995.

METHODS

Outpatient substance abuse treatment research clinic at the Johns Hopkins University Bayview Campus, Baltimore, Md.

METHODS

One hundred ninety-two eligible clinic patients.

METHODS

Daily oral methadone hydrochloride in the dose range of 40 to 50 mg (n = 97) or 80 to 100 mg (n = 95), with concurrent substance abuse counseling.

METHODS

Opioid-positive urinalysis results and retention in treatment.

RESULTS

By intent-to-treat analysis through week 30 patients in the high-dose group had significantly lower rates of opioid-positive urine samples compared with patients in the moderate-dose group (53.0% [95% confidence interval [CI], 46.9%-59.2%] vs 61.9% [95% CI, 55.9%-68.0%]; P = .047. These differences persisted during withdrawal from methadone. Through day 210 no significant difference was evident between dose groups in treatment retention (high-dose group mean retention, 159 days; moderate-dose group mean retention, 157 days). Nineteen (33%) of 57 patients in the high-dose group and 11 (20%) of 54 patients in the moderate-dose group completed detoxification.

CONCLUSIONS

Both moderate- and high-dose methadone treatment resulted in decreased illicit opioid use during methadone maintenance and detoxification. The high-dose group had significantly greater decreases in illicit opioid use.

BACKGROUND

Childhood sexual abuse (CSA) is a worldwide problem. Although most studies on the long-term consequences of CSA have focused on women, sexual abuse of both boys and girls is common. Thus, a comparison of the long-term effects of CSA by gender of the victim will provide perspective on the need for future research, prevention activities, and treatment of survivors.

METHODS

A retrospective cohort study was conducted from 1995 to 1997 among 17,337 adult HMO members in San Diego, California. Participants completed a survey about abuse or household dysfunction during childhood, and multiple other health-related issues. Multivariate logistic regression was used to examine the relationships between severity of CSA (intercourse vs no intercourse) and long-term health and social problems (substance use and abuse, mental illness, and current problems with marriage and family) by gender of victim. Models controlled for exposure to other forms of adverse childhood experiences that co-occur with CSA. Among men, the relationship between the gender of the CSA perpetrator to the outcomes was also examined.

RESULTS

Contact CSA was reported by 16% of males and 25% of females. Men reported female perpetration of CSA nearly 40% of the time, and women reported female perpetration of CSA 6% of the time. CSA significantly increased the risk of the outcomes. The magnitude of the increase was similar for men and women. For example, compared to reporting no sexual abuse, a history of suicide attempt was more than twice as likely among both men and women who experienced CSA (p<0.05). Compared with those who did not report CSA, men and women exposed to CSA were at a 40% increased risk of marrying an alcoholic, and a 40% to 50% increased risk of reporting current problems with their marriage (p<0.05).

CONCLUSIONS

In this cohort of adult HMO members, experiencing CSA was common among both men and women. The long-term impact of CSA on multiple health and social problems was similar for both men and women. These findings strongly indicate that boys and girls are vulnerable to this form of childhood maltreatment; the similarity in the likelihood for multiple behavioral, mental, and social outcomes among men and women suggests the need to identify and treat all adults affected by CSA.

The effects of alcohol abuse on HIV disease <em>p</em>rogression have not been definitively established. A <em>p</em>ros<em>p</em>ective, 30-month, longitudinal study of 231 HIV(+) adults included history of alcohol and illicit drug use, adherence to antiretroviral thera<em>p</em>y (ART), CD4(+) cell count, and HIV viral load every 6 months. Frequent alcohol users (two or more drinks daily) were 2.91 times (95% CI: 1.23-6.85, <em>p</em> = 0.015) more likely to <em>p</em>resent a decline of CD4 to <or=200 cells/microl, inde<em>p</em>endent of baseline CD4(+) cell count and HIV viral load, antiretroviral use over time, time since HIV diagnosis, age, and gender. Frequent alcohol users who were not on ART also increased their risk for CD4 cell decline to <or=200 cells/mm(3) (HR = 7.76: 95% CI: 1.2-49.2, <em>p</em> = 0.03). Combined frequent alcohol use with crack-cocaine showed a significant risk of CD4(+) cell decline (HR = 3.57: 95% CI: 1.24-10.31, <em>p</em> = 0.018). Frequent alcohol intake was associated with higher viral load over time (beta = 0.259, <em>p</em> = 0.038). This significance was maintained in those receiving ART (beta = 0.384, <em>p</em> = 0.0457), but not in those without ART. Frequent alcohol intake and the combination of frequent alcohol and crack-cocaine accelerate HIV disease <em>p</em>rogression. The effect of alcohol on CD4(+) cell decline a<em>p</em><em>p</em>ears to be inde<em>p</em>endent of ART, through a direct action on CD4 cells, although alcohol and <em>substance</em> abuse may lead to unmeasured behaviors that <em>p</em>romote HIV disease <em>p</em>rogression. The effect of alcohol abuse on viral load, however, a<em>p</em><em>p</em>ears to be through reduced adherence to ART.

Topical capsaicin formulations are used for pain management. Safety and modest efficacy of low-concentration capsaicin formulations, which require repeated daily self-administration, are supported by meta-analyses of numerous studies. A high-concentration capsaicin 8% patch (Qutenza™) was recently approved in the EU and USA. A single 60-min application in patients with neuropathic pain produced effective pain relief for up to 12 weeks. Advantages of the high-concentration capsaicin patch include longer duration of effect, patient compliance, and low risk for systemic effects or drug-drug interactions. The mechanism of action of topical capsaicin has been ascribed to depletion of substance P. However, experimental and clinical studies show that depletion of substance P from nociceptors is only a correlate of capsaicin treatment and has little, if any, causative role in pain relief. Rather, topical capsaicin acts in the skin to attenuate cutaneous hypersensitivity and reduce pain by a process best described as 'defunctionalization' of nociceptor fibres. Defunctionalization is due to a number of effects that include temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fibre terminals. Peripheral neuropathic hypersensitivity is mediated by diverse mechanisms, including altered expression of the capsaicin receptor TRPV1 or other key ion channels in affected or intact adjacent peripheral nociceptive nerve fibres, aberrant re-innervation, and collateral sprouting, all of which are defunctionalized by topical capsaicin. Evidence suggests that the utility of topical capsaicin may extend beyond painful peripheral neuropathies.

This article provides a brief overview of the history of substance P from its discovery in the 1930s to the present day. The development of substance P receptor agonists and antagonists, and more recently the employment of transgenic mice, provide a framework to explore the functional role of substance P. Chronic inflammation and pain are associated with a number of diseases, and it has been proposed that substance P, released from primary afferent nerve endings play a role in these conditions. Recent developments with substance P antagonists have demonstrated the importance of substance P in several models of disease that span from asthma to chronic bronchitis; from cystitis, inflammatory bowel disease to migraine; emesis, depression, pain and seizures. Advancements in the knowledge of the role of substance P, its agonists and antagonists could provide clinical solutions for a variety of chronic inflammatory conditions.

RDC8 has been recently cloned and characterized as an adenosine A2 receptor. This receptor is expressed exclusively by medium-sized neurons of the striatum as demonstrated by in situ hybridization. We have now studied the relationship of this receptor with three major components of the rat caudate-putamen: enkephalin, substance P, and choline acetyltransferase. Our results demonstrate that the adenosine A2 receptor is expressed exclusively by the enkephalinergic striatal subpopulation but not by the substance P-containing or cholinergic neurons.

BACKGROUND

Within street-based sex work and substance-using populations, there is growing evidence to support the role of place, both physical setting and social meanings attached to place, in mediating the effectiveness and reach of health and harm reduction services.

METHODS

Social mapping was used to explore how health service and syringe availability may be impacted at the geographic level by avoidance of physical settings due to violence and policing among women in street-level sex work. Through a community-based research partnership and extensive peer-led outreach over a 6-month period, women were invited to participate in interview-questionnaires and mapping of their community, working conditions, and access to resources. Results were compiled used ArcGIS software and GIS street maps. In secondary analysis, logistic regression was used to model the geographic association (using likelihood ratio and significance at p<0.05) and stratified models were run to assess differential patterns of avoidance based on age, ethnicity and drug use.

RESULTS

The findings reveal a significant geographic relationship between a heavily concentrated core area of health and syringe availability and avoidance of physical settings due to violence and policing by 198 women in street-level sex work in Vancouver, Canada. Of particular concern, this correlation is significantly elevated among younger and Aboriginal women, active injection drug users, and daily crack cocaine smokers, suggesting significant environmental-structural barriers to interventions among these vulnerable populations.

CONCLUSIONS

The resultant displacement of sex work to primarily industrial settings and side streets pushes women further from health and social supports and reduces access to safer injection and drug use paraphernalia. This study offers important evidence for environmental-structural level prevention and safer environment interventions, supported by legal reforms, that facilitate safer sex work environments, including spatial programming, peer-based prevention, outreach and mobile resources, and peer-supervised safer sex work settings.

OBJECTIVE

To develop a brief alcohol and other drug (AOD) screening test for adolescents.

METHODS

A 9-item test was constructed by combining and modifying items from several AOD assessments, and administered concurrently with the Personal Involvement With Chemicals Scale (PICS), the criterion standard.

METHODS

A hospital-based adolescent clinic.

METHODS

Fourteen- to 18-year-old patients consecutively arriving for routine medical care who were known to have used AOD.

METHODS

Internal consistency of the 9 items was calculated using the Cronbach alpha. The relationship between the brief screen and PICS raw score was determined by stepwise linear regression analysis. The PICS T score has been shown to correctly classify substance abuse treatment need as no treatment (T<35), brief office intervention (T = 35-40), outpatient or short-term treatment (T = 41-54), and inpatient or long-term treatment (T> or =55). Sensitivity and specificity rates for predicting a PICS T score of 55 or higher were calculated from 2 x 2 tables.

RESULTS

Ninety-nine adolescents were tested (70.7% female, 36.4% black, 32.3% white, 19.2% Hispanic, mean age, 16.3 years). The 9 items had good internal consistency (Cronbach alpha = .79). Stepwise linear regression analysis identified 6 items whose total combined score was highly correlated with PICS (Pearson r = 0.84, P<.01). This model correctly classified 86% of subjects according to the PICS criteria. Two or more yes answers had a sensitivity of 92.3% and specificity of 82.1% for intensive AOD treatment need. The 6 items were arranged into a mnemonic (CRAFFT).

CONCLUSIONS

Further research must confirm the test's psychometric properties in a general clinic population. However, CRAFFT seems promising as a brief AOD screening test.

OBJECTIVE

To quantify the overall effectiveness of computer-delivered interventions for alcohol and tobacco use.

METHODS

Meta-analysis of 42 effect sizes from randomized controlled trials, based on the responses of 10 632 individuals.

RESULTS

The weighted average effect size (d) was 0.20, P < 0.001. While lower effect sizes were associated with studies addressing tobacco use (d = 0.14) this may well reflect differences in the types of outcome measure used. Effect sizes did not vary significantly as a function of treatment location, inclusion of entertaining elements, provision of normative feedback, availability of a discussion feature, number of treatment sessions, emphasis on relapse prevention, level of therapist involvement or follow-up period.

CONCLUSIONS

Findings of the meta-analysis suggest that minimal contact computer-delivered treatments that can be accessed via the internet may represent a cost-effective means of treating uncomplicated substance use and related problems.

We have previously described a subpopulation of patients with septic shock who had a reversible depression of radionuclide-determined left ventricular ejection fraction (EF). To investigate the mechanism of this myocardial depression, an in vitro model of mammalian myocardial cell performance was established employing primary spontaneously beating rat myocardial cells. The contraction of a single cardiac cell was quantitated by recording the changes in area occupied by the cell during contraction and relaxation. In 20 septic shock patients during the acute phase, the mean left ventricular EF was decreased (mean = 0.33, normal mean = 0.50), and serum obtained during this acute phase induced a mean (+/- standard error of the mean) 33 +/- 4% decrease in extent and 25 +/- 4% decrease in velocity of myocardial cell shortening during contraction (P less than 0.001). In contrast, serum obtained from 11 of these same patients before shock (n = 2) or after recovery (n = 9) of the left ventricular EF (mean = 0.50) showed a return toward normal in extent and velocity of shortening (P less than 0.001). Sera from 17 critically ill nonseptic patients, from 10 patients with structural heart disease as a cause for a depressed EF, and from 12 healthy laboratory personnel, induced no significant changes in in vitro myocardial cell performance. In 20 patients during the acute phase of septic shock, the decreased EF in vivo demonstrated a significant correlation (r = +0.52, P less than 0.01) with a decrease in the extent of myocardial cell shortening in vitro. The quantitative and temporal correlation between the decreased left ventricular EF and this serum myocardial depressant substance argues for a pathophysiologic role for this depressant substance in producing the reversible cardiomyopathy seen during septic shock in humans.

BACKGROUND

The 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) has been found to moderate several categories of emotional response after stressful life events. Previous studies generally focused on its effect on depressive symptoms; little is known about its moderation of the development of posttraumatic stress disorder (PTSD).

OBJECTIVE

To examine the effects of childhood adversity, adult traumatic events, 5-HTTLPR genotypes, and gene x environment interactions on the etiology of PTSD.

METHODS

A cross-sectional study in which participants in several studies investigating the genetics of substance dependence were also screened for lifetime PTSD. The triallelic system of 5-HTTLPR was genotyped. Logistic regression modeling was used in the analyses.

METHODS

General community.

METHODS

Five hundred eighty-two European American and 670 African American individuals who reported experiences of childhood adversity, adult traumatic events, or both. Main Outcome Measure Diagnosis of PTSD, defined by DSM-IV diagnostic criteria and assessed through the Semi-Structured Assessment for Drug Dependence and Alcoholism interview.

RESULTS

Childhood adversity and adult traumatic events both predicted PTSD. Although the 5-HTTLPR genotype alone did not predict the onset of PTSD, it interacted with adult traumatic events and childhood adversity to increase the risk for PTSD, especially for those with high rates of both types of trauma exposure (European American: odds ratio [OR], 2.86; 95% confidence interval [CI], 1.50-5.45; P = .002; African American: OR, 1.88; 95% CI, 1.04-3.40; P = .04; pooled: OR, 2.31; 95% CI, 1.50-3.56; P < .001).

CONCLUSIONS

Participants who had both childhood adversity and adult traumatic events were more likely to develop lifetime PTSD compared with those who experienced either type of adverse event. The risk was increased in individuals with 1 or 2 copies of the S' (S) allele compared with the L' (L) homozygotes. Our study provides additional direct evidence that PTSD is influenced by the interactive effect of environmental and genetic factors.

OBJECTIVE

To address the putative association between attention-deficit hyperactivity disorder (ADHD) and prenatal exposure to maternal cigarette smoking, drugs of abuse, and alcohol attending to potential confounding by familial ADHD, maternal depression, conduct disorder, and indicators of social adversity in the environment.

METHODS

A retrospective, hospital-based, case-control study was conducted with 280 ADHD cases and 242 non-ADHD controls of both genders. The case and control children and their relatives were systematically assessed with structured diagnostic interviews. Logistic regression analysis was used to determine the adjusted effect of prenatal exposure to substance use and ADHD.

RESULTS

ADHD cases were 2.1 times (95% confidence interval = 1.1-4.1;p = .02) more likely to have been exposed to cigarettes and 2.5 times (95% confidence interval = 1.1-5.5; p = .03) more likely to have been exposed to alcohol in utero than were the non-ADHD control subjects. Adjustment by familial psychopathology, Rutter's indicators of social adversity, and comorbid conduct disorder did not account for the effect of prenatal exposure to alcohol or the products of cigarettes.

CONCLUSIONS

ADHD may be an additional deleterious outcome associated with prenatal exposure to alcohol independently of the association between prenatal exposure to nicotine and smoke products and other familial risk factors for the disorder.

A study was undertaken to examine the effects of the heavy metals copper, lead, and zinc on biofilm and planktonic Pseudomonas aeruginosa. A rotating-disk biofilm reactor was used to generate biofilm and free-swimming cultures to test their relative levels of resistance to heavy metals. It was determined that biofilms were anywhere from 2 to 600 times more resistant to heavy metal stress than free-swimming cells. When planktonic cells at different stages of growth were examined, it was found that logarithmically growing cells were more resistant to copper and lead stress than stationary-phase cells. However, biofilms were observed to be more resistant to heavy metals than either stationary-phase or logarithmically growing planktonic cells. Microscopy was used to evaluate the effect of copper stress on a mature P. aeruginosa biofilm. The exterior of the biofilm was preferentially killed after exposure to elevated concentrations of copper, and the majority of living cells were near the substratum. A potential explanation for this is that the extracellular polymeric substances that encase a biofilm may be responsible for protecting cells from heavy metal stress by binding the heavy metals and retarding their diffusion within the biofilm.

Angiogenesis and microvascular remodeling are known features of chronic inflammatory diseases such as asthma and chronic bronchitis, but the mechanisms and consequences of the changes are just beginning to be elucidated. In a model of chronic airway inflammation produced by Mycoplasma pulmonis infection of the airways of mice or rats, angiogenesis and microvascular remodeling create vessels that mediate leukocyte influx and leak plasma proteins into the airway mucosa. These vascular changes are driven by the immune response to the organisms. Plasma leakage results from gaps between endothelial cells, as well as from increased vascular surface area and probably other changes in the newly formed and remodeled blood vessels. Treatment with long-acting beta2 agonists can reduce but not eliminate the plasma occurring after infection. In addition to the elevated baseline leakage, the remodeled vessels in the airway mucosa are abnormally sensitive to substance P, but not to platelet-activating factor or serotonin, suggesting that the infection leads to a selective upregulation of NK1 receptors on the vasculature. The formation of new vessels and the remodeling of existing vessels are likely to be induced by multiple growth factors, including vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang1). VEGF increases vascular permeability, but Ang1 has the opposite effect. This feature is consistent with evidence that VEGF and Ang1 play complementary and coordinated roles in vascular growth and remodeling and have powerful effects on vascular function. Regulation of vascular permeability by VEGF and Ang1 may be their most rapid and potent actions in the adult, as these effects can occur independent of their effects on angiogenesis and vascular remodeling. The ability of Ang1 to block plasma leakage without producing angiogenesis may be therapeutically advantageous. Furthermore, because VEGF and Ang1 have additive effects in promoting angiogenesis but opposite effects on vascular permeability, they could be used together to avoid the formation of leaky vessels in therapeutic angiogenesis. Finally, the elucidation of the protective effect of Ang1 on blood vessel leakiness to plasma proteins raises the possibility of a new strategy for reducing airway edema in inflammatory airway diseases such as asthma and chronic bronchitis.

BACKGROUND

Diabetes is one of the commonest chronic medical conditions, affecting around 347 million adults worldwide. Structured patient education programmes reduce the risk of diabetes-related complications four-fold. Internet-based self-management programmes have been shown to be effective for a number of long-term conditions, but it is unclear what are the essential or effective components of such programmes. If computer-based self-management interventions improve outcomes in type 2 diabetes, they could potentially provide a cost-effective option for reducing the burdens placed on patients and healthcare systems by this long-term condition.

OBJECTIVE

To assess the effects on health status and health-related quality of life of computer-based diabetes self-management interventions for adults with type 2 diabetes mellitus.

METHODS

We searched six electronic bibliographic databases for published articles and conference proceedings and three online databases for theses (all up to November 2011). Reference lists of relevant reports and reviews were also screened.

METHODS

Randomised controlled trials of computer-based self-management interventions for adults with type 2 diabetes, i.e. computer-based software applications that respond to user input and aim to generate tailored content to improve one or more self-management domains through feedback, tailored advice, reinforcement and rewards, patient decision support, goal setting or reminders.

METHODS

Two review authors independently screened the abstracts and extracted data. A taxonomy for behaviour change techniques was used to describe the active ingredients of the intervention.

RESULTS

We identified 16 randomised controlled trials with 3578 participants that fitted our inclusion criteria. These studies included a wide spectrum of interventions covering clinic-based brief interventions, Internet-based interventions that could be used from home and mobile phone-based interventions. The mean age of participants was between 46 to 67 years old and mean time since diagnosis was 6 to 13 years. The duration of the interventions varied between 1 to 12 months. There were three reported deaths out of 3578 participants.Computer-based diabetes self-management interventions currently have limited effectiveness. They appear to have small benefits on glycaemic control (pooled effect on glycosylated haemoglobin A1c (HbA1c): -2.3 mmol/mol or -0.2% (95% confidence interval (CI) -0.4 to -0.1; P = 0.009; 2637 participants; 11 trials). The effect size on HbA1c was larger in the mobile phone subgroup (subgroup analysis: mean difference in HbA1c -5.5 mmol/mol or -0.5% (95% CI -0.7 to -0.3); P < 0.00001; 280 participants; three trials). Current interventions do not show adequate evidence for improving depression, health-related quality of life or weight. Four (out of 10) interventions showed beneficial effects on lipid profile.One participant withdrew because of anxiety but there were no other documented adverse effects. Two studies provided limited cost-effectiveness data - with one study suggesting costs per patient of less than $140 (in 1997) or 105 EURO and another study showed no change in health behaviour and resource utilisation.

CONCLUSIONS

Computer-based diabetes self-management interventions to manage type 2 diabetes appear to have a small beneficial effect on blood glucose control and the effect was larger in the mobile phone subgroup. There is no evidence to show benefits in other biological outcomes or any cognitive, behavioural or emotional outcomes.

BACKGROUND

Normal adult articular cartilage is thought to be avascular and aneural.

OBJECTIVE

To describe neurovascular structures at the osteochondral junction and in osteophytes in tibiofemoral osteoarthritis (OA) displaying a range of severity of cartilage changes.

METHODS

Articular surfaces were obtained from 40 patients at total knee joint replacement surgery for tibiofemoral OA (TKR) and seven patients post mortem (PM). Antibodies directed against CD34 (vascular endothelium), protein gene product 9.5 (pan-neuronal marker), substance P and calcitonin gene-related peptide (sensory nerves) and C-flanking peptide of neuropeptide Y (sympathetic nerves) were used to localise blood vessels and nerves by immunohistochemistry. Severity of OA cartilage changes was graded histologically.

RESULTS

TKR and PM samples displayed a range of OA cartilage changes including tidemark breaching by vascular channels. Sympathetic and sensory nerves were both present within vascular channels in the articular cartilage, in both mild and severe OA. Perivascular and free nerve fibres, and nerve trunks were observed within the subchondral bone marrow and within the marrow cavities of osteophytes. Sensory and sympathetic nerves displayed similar distributions in each region studied.

CONCLUSIONS

Vascularisation and the associated innervation of articular cartilage may contribute to tibiofemoral pain in OA across a wide range of structural disease severity.