Hoping to get more insight into a role of vascular endothelial growth factor (VEGF), a putative substance involved in the development of preeclampsia, we measured concentrations of soluble VEGF receptor-1 (sVEGFR-1), a natural antagonist of VEGF, in serum from women with (n = 31) and without (n = 52) preeclampsia. The concentrations of sVEGFR-1 in serum from women with preeclampsia (median 7791 pg/mL) were>> 6-fold higher than those from control (1132 pg/mL, p < 0.0001). The levels of sVEGFR-1 decreased markedly after delivery in both groups. Serum sVEGFR-1 levels of non-preeclamptic women were positively correlated with gestational age (r = 0.570, p < 0.0001), whereas those of preeclamptic women exhibited no correlation with gestational age (r = -0.130, p = 0.476). These findings may point to an involvement of sVEGFR-1 in the pathophysiology of preeclampsia possibly by antagonizing of VEGF effects on the formation of placental vasculature and maternal endothelial cell function.

The ability to taste phenylthiocarbamide (PTC) is a classic phenotype that has long been known to vary in human populations. This phenotype is of genetic, epidemiologic, and evolutionary interest because the ability to taste PTC is correlated with the ability to taste other bitter substances, many of which are toxic. Thus, variation in PTC perception may reflect variation in dietary preferences throughout human history and could correlate with susceptibility to diet-related diseases in modern populations. To test R. A. Fisher's long-standing hypothesis that variability in PTC perception has been maintained by balancing natural selection, we examined patterns of DNA sequence variation in the recently identified PTC gene, which accounts for up to 85% of phenotypic variance in the trait. We analyzed the entire coding region of PTC (1,002 bp) in a sample of 330 chromosomes collected from African (n=62), Asian (n=138), European (n=110), and North American (n=20) populations by use of new statistical tests for natural selection that take into account the potentially confounding effects of human population growth. Two intermediate-frequency haplotypes corresponding to "taster" and "nontaster" phenotypes were found. These haplotypes had similar frequencies across Africa, Asia, and Europe. Genetic differentiation between the continental population samples was low (FST=0.056) in comparison with estimates based on other genes. In addition, Tajima's D and Fu and Li's D and F statistics demonstrated a significant deviation from neutrality because of an excess of intermediate-frequency variants when human population growth was taken into account (P<.01). These results combine to suggest that balancing natural selection has acted to maintain "taster" and "nontaster" alleles at the PTC locus in humans.

Calcitonin gene-related peptide (CGRP) and/or substance P (SP) immunoreactivity as well as isolectin B(4) (IB(4)) binding are commonly used to define peptidergic and non-peptidergic nociceptor populations, respectively. Although this demarcation is well supported in the mouse, there is accumulating evidence to suggest it is not so in the rat. Hence, this investigation was undertaken to evaluate and quantify the colocalization of the neuropeptides CGRP and SP with IB(4) binding sites and the transient receptor potential vanilloid subfamily type 1 (TRPV1) channel and to compare this colocalization between trigeminal (TG) and dorsal root ganglia (DRG) in adult rats. These findings illustrate that there is a substantial overlap ( approximately 45% in the DRG and approximately 30% in the TG) between peptidergic neurons (ie, CGRP- and SP-expressing) and neurons that bind IB(4) in rat sensory ganglia. However, there were also significant differences in the colocalization of these markers between the DRG and TG. For instance, in the DRG, significantly more CGRP-immunoreactive neurons also expressed IB(4) binding sites (44.5%) compared with the TG (27.5%). In contrast, significantly fewer CGRP-immunoreactive neurons in the DRG colocalized TRPV1 immunoreactivity (49.2%) compared with the TG (70%). Moreover, we directly assessed the colocalization of CGRP and IB(4) in the TG of rats and mice using a CGRP antibody that recognizes this peptide in both species. Thus, whereas only an approximately 10% overlap was observed in TG neurons of mouse, significantly greater overlap (approximately 35%) was observed in those of rat.

CONCLUSIONS

These data indicate that in adult rat sensory ganglia, there is not a clear distinction between the peptidergic and non-peptidergic nociceptor subclasses as a function of IB(4) binding. Furthermore, there are significant differences between the TG and DRG in the degree to which commonly utilized nociceptive neuronal markers are co-expressed. Taken together, the present findings dictate prudence when extrapolating experimental conclusions about the neurochemical classification of neurons between sensory ganglia or between species, including humans.

BACKGROUND

Although guideline-concordant depression treatment is clearly effective, treatment often falls short of evidence-based recommendations. Organized depression care programs significantly improve treatment quality, but employer purchasers have been slow to adopt these programs based on lack of evidence for cost-effectiveness from their perspective.

OBJECTIVE

To evaluate the effects of a depression outreach-treatment program on workplace outcomes, a concern to employers.

METHODS

A randomized controlled trial involving 604 employees covered by a managed behavioral health plan were identified in a 2-stage screening process as having significant depression. Patient treatment allocation was concealed and assessment of depression severity and work performance at months 6 and 12 was blinded. Employees with lifetime bipolar disorder, substance disorder, recent mental health specialty care, or suicidality were excluded.

METHODS

A telephonic outreach and care management program encouraged workers to enter outpatient treatment (psychotherapy and/or antidepressant medication), monitored treatment quality continuity, and attempted to improve treatment by giving recommendations to providers. Participants reluctant to enter treatment were offered a structured telephone cognitive behavioral psychotherapy.

METHODS

Depression severity (Quick Inventory of Depressive Symptomatology, QIDS) and work performance (World Health Organization Health and Productivity Questionnaire [HPQ], a validated self-report instrument assessing job retention, time missed from work, work performance, and critical workplace incidents).

RESULTS

Combining data across 6- and 12-month assessments, the intervention group had significantly lower QIDS self-report scores (relative odds of recovery, 1.4; 95% confidence interval, 1.1-2.0; P = .009), significantly higher job retention (relative odds, 1.7; 95% confidence interval, 1.1-3.3; P = .02), and significantly more hours worked among the intervention (beta=2.0; P=.02; equivalent to an annualized effect of 2 weeks of work) than the usual care groups that were employed.

CONCLUSIONS

A systematic program to identify depression and promote effective treatment significantly improves not only clinical outcomes but also workplace outcomes. The financial value of the latter to employers in terms of recovered hiring, training, and salary costs suggests that many employers would experience a positive return on investment from outreach and enhanced treatment of depressed workers.

BACKGROUND

clinicaltrials.gov Identifier: NCT00057590.

BACKGROUND

Despite clinicopathological evidence that Parkinson's disease (PD) may begin in peripheral tissues, identification of premotor Parkinson's disease is not yet possible. Alpha-synuclein aggregation underlies Parkinson's disease pathology, and its presence in peripheral tissues may be a reliable disease biomarker.

OBJECTIVE

We sought evidence of alpha-synuclein pathology in colonic tissues before the development of characteristic Parkinson's disease motor symptoms.

METHODS

Old colon biopsy samples were available for three subjects with PD. Biopsies were obtained 2-5 years before PD onset. We performed immunohistochemistry studies for the presence of alpha-synuclein and Substance P in these samples.

RESULTS

All subjects showed immunostaining for alpha-synuclein (two, five and two years before first motor Parkinson's disease symptom). No similar alpha-synuclein immunostaining was seen in 23 healthy controls. Staining of samples for substance P suggested colocalization of alpha-synuclein and substance P in perikarya and neurites.

CONCLUSIONS

This is the first demonstration of alpha-synuclein in colon tissue prior to onset of PD. Additional study is required to determine whether colonic mucosal biopsy may be a biomarker of premotor PD.

Following peripheral axotomy, long-lasting changes in the expression of neuropeptides and their receptors in primary sensory neurons are observed. These changes involve the downregulation of the excitatory peptides substance P and calcitonin gene-related peptide and the upregulation of the inhibitory peptides neuropeptide tyrosine and galanin, resulting in a reduction of transmission in the dorsal horn. The changes observed are thought to represent adaptive responses to limit the consequences of peripheral nerve damage to the organism as a whole and to promote survival and recovery of the individual neuron.

Taste buds contain a variety of morphological and histochemical types of elongate cells. Serotonin, neuron-specific enolase (NSE), ubiquitin carboxyl terminal hydrolase (PGP 9.5), and neural cell adhesion molecule (N-CAM) all have been described as being present in the morphologically defined Type III taste cells in rats. In order to determine whether these substances coexist in a single cell, we undertook immunohistochemical and ultrastructural analysis of taste buds in rats. Double-label studies show that PGP 9.5 and NSE always colocalize. In contrast, PGP 9.5 and serotonin seldom colocalize. Further, whereas the serotonin-immunoreactive cells are always slender and elongate, the PGP 9.5/NSE population comprise two morphological types--one slender, the other broader and pyriform. Although gustducin-immunoreactive taste cells appear similar in overall shape to the pyriform PGP 9.5/NSE population, gustducin never colocalizes with PGP 9.5 or NSE. The serotonin-immunoreactive taste cells have an invaginated nucleus, synaptic contacts with nerve fibers, and taper apically to a single, large microvillus. These are all characteristics of Type III taste cells described previously in rabbits (Murray [1973] Ultrastructure of Sensory Organs I. Amsterdam: North Holland. p 1-81). PGP 9.5-immunoreactive taste cells exhibit two morphological varieties. One type is similar to the serotonin-immunoreactive population, containing an invaginated nucleus, synapses with nerve fibers, and a single large microvillus. The other type of PGP 9.5-immunoreactive taste cell has a large round nucleus and the apical end of the cell tapers to a tuft of short microvilli, which are characteristics of Type II taste cells. Thus, in rats, some Type III cells accumulate serotonin but do not express PGP 9.5, whereas others express PGP 9.5 but do not accumulate amines. Similarly, Type II taste cells come in at least two varieties: those immunoreactive for gustducin and those immunoreactive for PGP 9.5.

There has been little exploration of major biologic regulators of cerebral development in autism. In archived neonatal blood of children with autistic spectrum disorders (n = 69), mental retardation without autism (n = 60), or cerebral palsy (CP, n = 63) and of control children (n = 54), we used recycling immunoaffinity chromatography to measure the neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP), and the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4/5 (NT4/5). Neonatal concentrations of VIP, CGRP, BDNF, and NT4/5 were higher (ANOVA, all p values < 0.0001 by Scheffe test for pairwise differences) in children in the autistic spectrum and in those with mental retardation without autism than in control children. In 99% of children with autism and 97% with mental retardation, levels of at least one of these substances exceeded those of all control children. Concentrations were similar in subgroups of the autistic spectrum (core syndrome with or without mental retardation, other autistic spectrum disorders with or without mental retardation) and in the presence or absence of a history of regression. Among children with mental retardation, concentrations did not differ by severity or known cause (n = 11, including 4 with Down syndrome). Concentrations of measured substances were similar in children with CP as compared with control subjects. SP, PACAP, NGF, and NT3 were not different by diagnostic group. No measured analyte distinguished children with autism from children with mental retardation alone. In autism and in a heterogeneous group of disorders of cognitive function, overexpression of certain neuropeptides and neurotrophins was observed in peripheral blood drawn in the first days of life.

BACKGROUND

Previous research based on problem-behavior theory has found that early age of onset of substance use is associated with engaging in multiple health risk behaviors among high school students. It is unknown whether these relationships begin during early adolescence.

OBJECTIVE

To examine the relationships between early age of onset of cigarette, alcohol, marijuana, and cocaine use and engaging in multiple risk behaviors among middle school students.

METHODS

A modified version of the Centers for Disease Control and Prevention Youth Risk Behavior Survey was administered to 2227 sixth through eighth grade students attending 53 randomly selected middle schools in North Carolina. A Health Risk Behavior Scale was constructed from 16 behaviors, including indicators of violence and weapon carrying; current substance use; nonuse of helmets when biking, in-line skating or skateboarding; not wearing a seat belt; riding with a driver who had been drinking; and suicide plans. Among this sample of middle school students, the scale had a mean (SD) of 4.1 (2.7) (range=O-15), and had a high internal reliability coefficient (alpha(=0.74). The independent variables included first time use of cigarettes, alcohol, marijuana, and cocaine at age 11 years or earlier; actual age of onset of each substance; race and ethnicity; family composition; sex; school grade; academic ranking; and older age for school grade. These data were analyzed with analysis of variance, Spearman r, and multiple linear regression.

RESULTS

All the independent variables were found to be associated (P<.005) with the Health Risk Behavior Scale during the bivariate analyses. When each of these significant variables were entered into a multiple regression model, having smoked at age 11 years or younger accounted for 21.9% of the variation in the Health Risk Behavior Scale. Male sex, early marijuana or cocaine use, older age, lower academic rank, white race, and living in a 1-parent family explained an additional 19.1% of variation in the model (adjusted R2=0.41, P<.001). When the actual ages of onset of the use of substances were analyzed, in order of magnitude; age of onset of smoking; male sex; age of onset of alcohol and marijuana use; age; lower academic ranking; age of onset of cocaine use; white race; and lower academic rating accounted for 52.8% (P<.001) of the variation in the Health Risk Behavior Scale.

CONCLUSIONS

Even when considering sociodemographic factors, early age of onset of cigarette use was the strongest correlate of the number of health risk behaviors in which these young adolescents had engaged. Early onset of use of other substances was also associated with a clustering of health risk behaviors among this sample of middle school students. The findings suggest that screening for early experimentation with tobacco and other substance use will help identify young adolescents at increased risk for engaging in multiple health risk behaviors.

BACKGROUND

Problems inhibiting non-adaptive behaviors have been linked to an increased risk for substance use and other risk taking behaviors in adolescence. This study examines the hypothesis that abnormalities in neural activation during inhibition in early adolescence may predict subsequent substance involvement.

METHODS

Thirty eight adolescents from local area middle schools, ages 12-14, with very limited histories of substance use, underwent functional magnetic resonance imaging (fMRI) as they performed a go/no-go task of response inhibition and response selection. Adolescents and their parents were then followed annually with interviews covering substance use and other behaviors. Based on follow-up data, youth were classified as transitioning to heavy use of alcohol (TU; n=21), or as healthy controls (CON; n=17).

RESULTS

At baseline, prior to the onset of use, youth who later transitioned into heavy use of alcohol showed significantly less activation than those who went on to remain non to minimal users throughout adolescence. Activation reductions in TU at baseline were seen on no-go trials in 12 brain regions, including right inferior frontal gyrus, left dorsal and medial frontal areas, bilateral motor cortex, cingulate gyrus, left putamen, bilateral middle temporal gyri, and bilateral inferior parietal lobules (corrected p<.01, each cluster ≥32 contiguous voxels).

CONCLUSIONS

These results support the hypothesis that less neural activity during response inhibition demands predicts future involvement with problem behaviors such as alcohol and other substance use.

BACKGROUND

Current research on the etiology of cigarette smoking has largely focused on the identification of psychosocial predictors of tobacco onset. Few data are available on the predictors of different stages of smoking among adolescents. The present study examines the psychosocial predictors of different stages of smoking, including trial, experimental, and regular use, among high school students.

METHODS

The predictor variables were measured when the students were in the 7th grade. Logistic regression was used to predict different smoking stages at grade 12.

RESULTS

The results show that four domains of psychosocial variables, including social and interpersonal factors, attitudinal and belief factors, intrapersonal factors, and use of other substances, predicted one or more stages of smoking. The important correlates of transition from trial to experimental use (all P value <0.001) included friends' smoking and approval, cigarette offers by friends, smoking intentions, school grade, and alcohol and marijuana use. The significant predictors of the transition from experimental to regular use included only parental smoking (P < 0.01) and family conflicts (P < 0.05). We found some gender differences in these predictors.

CONCLUSIONS

Psychosocial predictors may differ by different stages of smoking.

Septic shock is a life-threatening condition that results from exposure to bacterial endotoxin. It is manifested by cardiovascular collapse and mediated by the release of cytokines such as tumor necrosis factor. Some of these cytokines cause the release of vasoactive substances. In the present study, administration of 40 microgram/kg of bacterial endotoxin to dogs caused a 33% decrease in peripheral vascular resistance and a 54% fall in mean arterial blood pressure within 30 to 90 minutes. Vascular resistance and systemic arterial pressure returned to normal within 1.5 minutes after intravenous administration of NG-methyl-L-arginine (20 mg/kg), a potent and selective inhibitor of nitric oxide synthesis. L-Arginine reversed the effect of L-NMA and restored the endotoxin-induced hypotension. Although NG-methyl-L-arginine injection increased blood pressure in control dogs, the hypertensive effect was much greater in endotoxemic dogs (24.8 +/- 2.7 mmHg vs 47.8 +/- 6.8 mmHg, p = 0.01, n = 4). NG-Methyl-L-arginine caused only a modest increase in blood pressure in dogs made hypotensive by continuous intravenous infusion of nitroglycerin (17.1 +/- 5.0 mm Hg, n = 3). These findings suggest that nitric oxide overproduction is an important contributor to endotoxic shock. Moreover, our findings demonstrate for the first time, the utility of nitric oxide synthesis inhibitors in endotoxic shock and suggest that such inhibitors may be of therapeutic value in the treatment of septic shock.

Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs (NSAIDs) in the periphery is commonly accepted as the primary mechanism by which these agents produce a selective attenuation of pain (analgesia). NSAIDs are now shown to exert a direct spinal action by blocking the excessive sensitivity to pain (hyperalgesia) induced by the activation of spinal glutamate and substance P receptors. These findings demonstrate that the analgesic effects of NSAIDs can be dissociated from their anti-inflammatory actions. Spinal prostanoids are thus critical for the augmented processing of pain information at the spinal level.

The breathing motor pattern in mammals originates in brainstem networks. Whether pacemaker neurons play an obligatory role remains a key unanswered question. We performed whole-cell recordings in the preBotzinger Complex in slice preparations from neonatal rodents and tested for pacemaker activity. We observed persistent Na+ current (I(NaP))-mediated bursting in approximately 5% of inspiratory neurons in postnatal day 0 (PPPPP)-mediated bursting was voltage dependent and blocked by 20 mum riluzole (RIL). We found Ca2+ current (I(Ca))-dependent bursting in 7.5% of inspiratory neurons in PPPPPPsubstance P restarts it. We conclude that I(NaP) and I(CAN) enhance neuronal excitability and promote rhythmogenesis, even if their magnitude is insufficient to support bursting-pacemaker activity in individual neurons. When I(NaP) and I(CAN) are removed pharmacologically, the rhythm can be maintained by boosting neural excitability, which is inconsistent with a pacemaker-essential mechanism of respiratory rhythmogenesis by the preBotzinger complex.

The expression of short-chain fatty acid receptors GPR41/FFAR3 and GPR43/ free fatty acid receptor 2 (FFAR2) was studied in the gastrointestinal tract of transgenic monomeric red fluorescent protein (mRFP) reporter mice. In the stomach free fatty acid receptor 3 (FFAR3)-mRFP was expressed in a subpopulation of ghrelin and gastrin cells. In contrast, strong expression of FFAR3-mRFP was observed in all cholecystokinin, glucose-dependent insulinotropic peptide (GIP), and secretin cells of the proximal small intestine and in all glucagon-like peptide-1 (GLP-1), peptide YY, and neurotensin cells of the distal small intestine. Throughout the colon and rectum, FFAR3-mRFP was strongly expressed in the large population of peptide YY and GLP-1 cells and in the neurotensin cells of the proximal colon. A gradient of expression of FFAR3-mRFP was observed in the somatostatin cells from less than 5% in the stomach to more than 95% in the rectum. Substance P-containing enterochromaffin cells displayed a similar gradient of FFAR3-mRFP expression throughout the small intestine. Surprisingly, FFAR3-mRFP was also expressed in the neuronal cells of the submucosal and myenteric ganglia. Quantitative PCR analysis of fluorescence-activated cell sorting (FACS) purified FFAR3-mRFP positive cells confirmed the coexpression with the various peptide hormones as well as key neuronal marker proteins. The FFAR2-mRFP reporter was strongly expressed in a large population of leukocytes in the lamina propria of in particular the small intestine but surprisingly only weakly in a subpopulation of enteroendocrine cells. Nevertheless, synthetic ligands specific for either FFAR3 or FFAR2 each released GLP-1 from colonic crypt cultures and the FFAR2 agonist mobilized intracellular Ca²⁺ in FFAR2 positive enteroendocrine cells. It is concluded that FFAR3-mRFP serves as a useful marker for the majority of enteroendocrine cells of the small and large intestine and that FFAR3 and FFAR2 both act as sensors for short-chain fatty acids in enteroendocrine cells, whereas FFAR3 apparently has this role alone in enteric neurons and FFAR2 in enteric leukocytes.

OBJECTIVE

To provide an evidence-based practice guideline on the pharmacological management of alcohol withdrawal.

METHODS

English-language articles published before July 1, 1995, identified through MEDLINE search on "substance withdrawal--ethyl alcohol" and review of references from identified articles.

METHODS

Articles with original data on human subjects.

METHODS

Structured review to determine study design, sample size, interventions used, and outcomes of withdrawal severity, delirium, seizures, completion of withdrawal, entry into rehabilitation, adverse effects, and costs. Data from prospective controlled trials with methodologically sound end points corresponding to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were abstracted by 2 independent reviewers and underwent meta-analysis.

RESULTS

Benzodiazepines reduce withdrawal severity, reduce incidence of delirium (-4.9 cases per 100 patients; 95% confidence interval, -9.0 to -0.7; P=.04), and reduce seizures (-7.7 seizures per 100 patients; 95% confidence interval, -12.0 to -3.5; P=.003). Individualizing therapy with withdrawal scales results in administration of significantly less medication and shorter treatment (P<.001). beta-Blockers, clonidine, and carbamazepine ameliorate withdrawal severity, but evidence is inadequate to determine their effect on delirium and seizures. Phenothiazines ameliorate withdrawal but are less effective than benzodiazepines in reducing delirium (P=.002) or seizures (P<.001).

CONCLUSIONS

Benzodiazepines are suitable agents for alcohol withdrawal, with choice among different agents guided by duration of action, rapidity of onset, and cost. Dosage should be individualized, based on withdrawal severity measured by withdrawal scales, comorbid illness, and history of withdrawal seizures. beta-Blockers, clonidine, carbamazepine, and neuroleptics may be used as adjunctive therapy but are not recommended as monotherapy.

METHODS

Herniated lumbar disc specimens were obtained from patients undergoing surgical discectomy for persistent radiculopathy and cultured in vitro to determine whether various biochemical agents were being produced.

OBJECTIVE

Our hypothesis is that biochemical mediators of inflammation and tissue degradation play a role in intervertebral disc degeneration and in the pathophysiology of radiculopathy.

BACKGROUND

Low back pain with or without radiculopathy is a significant clinical problem, but the etiology of low back pain and the exact pathophysiology of radiculopathy remain elusive. The biochemical events that occur with intervertebral disc degeneration and, in particular, the role of biochemical mediators of inflammation and tissue degradation have received sparse attention in the literature. There is some preliminary evidence that inflammatory mediators may have an important role in the pathophysiology of radiculopathy.

METHODS

Eighteen herniated lumbar discs were obtained from 15 patients undergoing disc surgery. The specimens were cultured and incubated for 72 hours, and the media were collected subsequently for biochemical analysis. Biochemical assays for matrix metalloproteinases, nitric oxide, prostaglandin E2, and a variety of cytokines were performed. As a control group, eight lumbar disc specimens were obtained from four patients undergoing anterior surgery for scoliosis and traumatic burst fractures, and similar biochemical analyses were performed.

RESULTS

The culture media from the herniated lumbar discs showed increased levels of matrix metalloproteinase activity compared with the control discs. Similarly, the levels of nitric oxide, prostaglandin E2, and interleukin-6 were significantly higher in the herniated discs compared with the control discs. Interleukin 1 alpha, interleukin-1 beta, tumor necrosis factor-alpha, interleukin-1 receptor antagonist protein, and substance P were not detected in the culture media of either the herniated or control discs.

CONCLUSIONS

Herniated lumbar discs were making spontaneously increased amounts of matrix metalloproteinases, nitric oxide, prostaglandin E2, and interleukin-6. These products may be involved intimately in the biochemistry of disc degeneration and the pathophysiology of radiculopathy. Their exact roles certainly need further investigation, but their mere presence implicates biochemical processes in intervertebral disc degeneration.

The <em>P</em>2X3 receptor subunit, a member of the <em>P</em>2X family of AT<em>P</em>-gated ion channels, is almost exclusively localized in sensory neurons. In the present study, we sought to gain insight into the role of <em>P</em>2X3 and <em>P</em>2X3-containing neurons in sensory transmission, using immunohistochemical approaches. In rat dorsal root ganglia (DRG), <em>P</em>2X3-immunoreactivity (-ir) was observed in small- and medium-sized neurons. Approximately 40% of DRG neuronal profiles in normal rats contained <em>P</em>2X3-ir. In rats that had received neonatal capsaicin treatment, the number of <em>P</em>2X3-positive neurons was decreased by approximately 70%. Analysis of the colocalization of <em>P</em>2X3-ir with cytochemical markers of DRG neurons indicated that approximately 94% of the <em>P</em>2X3-positive neuronal profiles were labelled by isolectin B4 from Bandeiraea simplicifolia, while only 3% contained <em>substance</em> <em>P</em>-ir, and 7% contained somatostatin-ir. In dorsal horn of rat spinal cord, <em>P</em>2X3-ir was observed in the inner portion of lamina II and was reduced subsequent to dorsal rhizotomy, as well as subsequent to neonatal capsaicin treatment. Finally, <em>P</em>2X3-ir accumulated proximal to the site of sciatic nerve ligation, and was seen in nerve fibres in skin and corneal epithelium. In summary, our results suggest that <em>P</em>2X3 is expressed by a functionally heterogeneous population of BSI-B4-binding sensory neurons, and is transported into both central and peripheral processes of these neurons.

BACKGROUND

Declining serum concentrations of 25-hydroxyvitamin D seen in the fall and winter as distance increases from the equator may be a factor in the seasonal increased prevalence of influenza and other viral infections. This study was done to determine if serum 25-hydroxyvitamin D concentrations correlated with the incidence of acute viral respiratory tract infections.

RESULTS

In this prospective cohort study serial monthly concentrations of 25-hydroxyvitamin D were measured over the fall and winter 2009-2010 in 198 healthy adults, blinded to the nature of the substance being measured. The participants were evaluated for the development of any acute respiratory tract infections by investigators blinded to the 25-hydroxyvitamin D concentrations. The incidence of infection in participants with different concentrations of vitamin D was determined. One hundred ninety-five (98.5%) of the enrolled participants completed the study. Light skin pigmentation, lean body mass, and supplementation with vitamin D were found to correlate with higher concentrations of 25-hydroxyvitamin D. Concentrations of 38 ng/ml or more were associated with a significant (p<0.0001) two-fold reduction in the risk of developing acute respiratory tract infections and with a marked reduction in the percentages of days ill.

CONCLUSIONS

Maintenance of a 25-hydroxyvitamin D serum concentration of 38 ng/ml or higher should significantly reduce the incidence of acute viral respiratory tract infections and the burden of illness caused thereby, at least during the fall and winter in temperate zones. The findings of the present study provide direction for and call for future interventional studies examining the efficacy of vitamin D supplementation in reducing the incidence and severity of specific viral infections, including influenza, in the general population and in subpopulations with lower 25-hydroxyvitamin D concentrations, such as pregnant women, dark skinned individuals, and the obese.

OBJECTIVE

Both bullies and victims of bullying are at risk for psychiatric problems in childhood, but it is unclear if this elevated risk extends into early adulthood.

OBJECTIVE

To test whether bullying and/or being bullied in childhood predicts psychiatric problems and suicidality in young adulthood after accounting for childhood psychiatric problems and family hardships.

METHODS

Prospective, population-based study.

METHODS

Community sample from 11 counties in Western North Carolina.

METHODS

A total of 1420 participants who had being bullied and bullying assessed 4 to 6 times between the ages of 9 and 16 years. Participants were categorized as bullies only, victims only, bullies and victims (hereafter referred to as bullies/victims), or neither.

METHODS

Psychiatric outcomes, which included depression, anxiety, antisocial personality disorder, substance use disorders, and suicidality (including recurrent thoughts of death, suicidal ideation, or a suicide attempt), were assessed in young adulthood (19, 21, and 24-26 years) by use of structured diagnostic interviews. RESULTS Victims and bullies/victims had elevated rates of young adult psychiatric disorders, but also elevated rates of childhood psychiatric disorders and family hardships. After controlling for childhood psychiatric problems or family hardships, we found that victims continued to have a higher prevalence of agoraphobia (odds ratio [OR], 4.6 [95% CI, 1.7-12.5]; P < .01), generalized anxiety (OR, 2.7 [95% CI, 1.1-6.3]; P < .001), and panic disorder (OR, 3.1 [95% CI, 1.5-6.5]; P < .01) and that bullies/victims were at increased risk of young adult depression (OR, 4.8 [95% CI, 1.2-19.4]; P < .05), panic disorder (OR, 14.5 [95% CI, 5.7-36.6]; P < .001), agoraphobia (females only; OR, 26.7 [95% CI, 4.3-52.5]; P < .001), and suicidality (males only; OR, 18.5 [95% CI, 6.2-55.1]; P < .001). Bullies were at risk for antisocial personality disorder only (OR, 4.1 [95% CI, 1.1-15.8]; P < .04).

CONCLUSIONS

The effects of being bullied are direct, pleiotropic, and long-lasting, with the worst effects for those who are both victims and bullies.

The present article provides a brief overview of various aspects on neuropeptides, emphasizing their multitude and their wide distribution in both the peripheral and central nervous system. Interestingly, neuropeptides are also expressed in various types of glial cells under normal and experimental conditions. The recent identification of, often multiple, receptor subtypes for each peptide, as well as the development of peptide antagonists, have provided an experimental framework to explore functional roles of neuropeptides. A characteristic of neuropeptides is the plasticity in their expression, reflecting the fact that release has to be compensated by de novo synthesis at the cell body level. In several systems peptides can be expressed at very low levels normally but are upregulated in response to, for example, nerve injury. The fact that neuropeptides virtually always coexist with one or more classic transmitters suggests that they are involved in modulatory processes and probably in many other types of functions, for example exerting trophic effects. Recent studies employing transgene technology have provided some information on their functional role, although compensatory mechanisms in all probability could disguise even a well defined action. It has been recognized that both 'old' and newly discovered peptides may be involved in the regulation of food intake. Recently the first disease-related mutation in a peptidergic system has been identified, and clinical efficacy of a substance P antagonist for treatment of depression has been reported. Taken together it seems that peptides may play a role particularly when the nervous system is stressed, challenged or afflicted by disease, and that peptidergic systems may, therefore, be targets for novel therapeutic strategies.

BACKGROUND

Tobacco dependence is the leading cause of preventable death and disabilities worldwide and nicotine is the main substance responsible for the addiction to tobacco. A vaccine against nicotine was tested in a 6-month randomized, double blind phase II smoking cessation study in 341 smokers with a subsequent 6-month follow-up period.

RESULTS

229 subjects were randomized to receive five intramuscular injections of the nicotine vaccine and 112 to receive placebo at monthly intervals. All subjects received individual behavioral smoking cessation counseling. The vaccine was safe, generally well tolerated and highly immunogenic, inducing a 100% antibody responder rate after the first injection. Point prevalence of abstinence at month 2 showed a statistically significant difference between subjects treated with Nicotine-Qbeta (47.2%) and placebo (35.1%) (P = 0.036), but continuous abstinence between months 2 and 6 was not significantly different. However, in subgroup analysis of the per-protocol population, the third of subjects with highest antibody levels showed higher continuous abstinence from month 2 until month 6 (56.6%) than placebo treated participants (31.3%) (OR 2.9; P = 0.004) while medium and low antibody levels did not increase abstinence rates. After 12 month, the difference in continuous abstinence rate between subjects on placebo and those with high antibody response was maintained (difference 20.2%, P = 0.012).

CONCLUSIONS

Whereas Nicotine-Qbeta did not significantly increase continuous abstinence rates in the intention-to-treat population, subgroup analyses of the per-protocol population suggest that such a vaccination against nicotine can significantly increase continuous abstinence rates in smokers when sufficiently high antibody levels are achieved. Immunotherapy might open a new avenue to the treatment of nicotine addiction.

BACKGROUND

Swiss Medical Registry 2003DR2327; ClinicalTrials.gov NCT00369616.

Exercise studies have suggested that the presence of carbohydrate in the human mouth activates regions of the brain that can enhance exercise performance but direct evidence of such a mechanism is limited. The first aim of the present study was to observe how rinsing the mouth with solutions containing glucose and maltodextrin, disguised with artificial sweetener, would affect exercise performance. The second aim was to use functional magnetic resonance imaging (fMRI) to identify the brain regions activated by these substances. In Study 1A, eight endurance-trained cyclists (VO2max 60.8 +/- 4.1 ml kg(-1) min(-1)) completed a cycle time trial (total work = 914 +/- 29 kJ) significantly faster when rinsing their mouths with a 6.4% glucose solution compared with a placebo containing saccharin (60.4 +/- 3.7 and 61.6 +/- 3.8 min, respectively, P = 0.007). The corresponding fMRI study (Study 1B) revealed that oral exposure to glucose activated reward-related brain regions, including the anterior cingulate cortex and striatum, which were unresponsive to saccharin. In Study 2A, eight endurance-trained cyclists (VO2max 57.8 +/- 3.2 ml kg(-1) min(-1)) tested the effect of rinsing with a 6.4% maltodextrin solution on exercise performance, showing it to significantly reduce the time to complete the cycle time trial (total work = 837 +/- 68 kJ) compared to an artificially sweetened placebo (62.6 +/- 4.7 and 64.6 +/- 4.9 min, respectively, P = 0.012). The second neuroimaging study (Study 2B) compared the cortical response to oral maltodextrin and glucose, revealing a similar pattern of brain activation in response to the two carbohydrate solutions, including areas of the insula/frontal operculum, orbitofrontal cortex and striatum. The results suggest that the improvement in exercise performance that is observed when carbohydrate is present in the mouth may be due to the activation of brain regions believed to be involved in reward and motor control. The findings also suggest that there may be a class of so far unidentified oral receptors that respond to carbohydrate independently of those for sweetness.