OBJECTIVE

Maternal infection, particularly bacterial vaginosis (BV) in pregnancy, is one of the leading causes of adverse perinatal outcomes. The determinants of individual differences in susceptibility, or vulnerability, to maternal infections are poorly understood. This study examines whether chronic maternal stress predisposes women to infection during pregnancy, and if so, whether the effects of chronic stress on infection are independent of other established risk factors.

METHODS

We conducted a cross-sectional, clinical prevalence study of chronic maternal stress and BV status in a sample of 454 pregnant women at 14.3+/-0.3 weeks gestation (+/-SEM). BV was diagnosed by Gram-stain of vaginal fluid samples; chronic maternal stress was assessed using the Cohen Perceived Stress Scale. Other established risk factors for BV, including maternal age, race/ethnicity, marital status, SES, and behaviors related to feminine hygiene, sexual practices, and substance use, were measured using a structured interview.

RESULTS

Of the 454 women enrolled in this study, 224 (49%) were BV positive (Nugent score 7-10), 64 (14%) had intermediate vaginal flora (Nugent score 4-6), and 166 (37%) were BV negative (Nugent score 0-3). BV+ women had significantly higher chronic stress levels than BV- women (24.6+/-0.5 vs. 22.2+/-0.6 units (+/-SEM), respectively; t = 3.19; p < .01). Maternal sociodemographic variables (African-American race/ethnicity) and behavioral characteristics (vaginal douching, number of lifetime sexual partners, and use of illicit drugs) also were significantly associated with the presence of BV. After controlling for the effects of these variables, using a multivariable logistic regression model, chronic maternal stress remained a significant and independent predictor of BV status. Women in the moderate-stress group (third quartile) and high-stress (fourth quartile) group were 2.3 times (95% CI = 1.2-4.3) and 2.2 times (95% CI = 1.1-4.2) more likely to be BV+ than women in the low-stress group (bottom quartile).

CONCLUSIONS

High levels of chronic stress during pregnancy are associated with bacterial vaginosis. The effect of chronic maternal stress is independent of the effects of other established sociodemographic and behavioral risk factors for BV.

Contingency management (CM) based interventions that reinforce adherence to prescribed medications have shown promise in a variety of disadvantaged populations. Fifty-six participants with histories of illicit substance use who were prescribed antiretroviral medication but evidenced suboptimal adherence during a baseline assessment were randomly assigned to 16 weeks of weekly CM-based counseling or supportive counseling, followed by 16 additional weeks of data collection and adherence feedback to providers. The CM intervention involved review of data generated by electronic pill-bottle caps that record bottle opening (MEMS) and brief substance abuse counseling. CM participants were reinforced for MEMS-measured adherence with drawings from a bowl for prizes and bonus drawings for consecutive weeks of perfect adherence. Potential total earnings averaged $800. Mean MEMS-measured adherence to the reinforced medication increased from 61% at baseline to 76% during the 16-week treatment phase and was significantly increased relative to the supportive counseling group (p = 0.01). Furthermore, mean log-transformed viral load was significantly lower in the CM group. However, by the end of the 16-week follow-up phase, differences between groups in adherence and viral load were no longer significantly different. Proportions of positive urine toxicology tests did not differ significantly between the two groups at any phase. A brief CM-based intervention was associated with significantly higher adherence and lower viral loads. Future studies should evaluate methods to extend effects for longer term benefits.

The preprotachykinin-A gene-derived peptides substance P and neurokinin (NK) A are expressed in distinct neural pathways of the mammalian gut. When released from intrinsic enteric or extrinsic primary afferent neurons, tachykinins have the potential to influence both nerve and muscle by way of interaction with three different types of tachykinin receptor, termed NK1, NK2 and NK3 receptors. Most prominent among the effects of tachykinins is their excitatory action on gastrointestinal motor activity, which is seen in virtually all regions and layers of the mammalian gut. This action depends not only on a direct activation of the muscle through NK1 and/or NK2 receptors, but also on stimulation of excitatory enteric motor pathways through NK3 and/or NK1 receptors. In addition, tachykinins can inhibit motor activity by stimulating either inhibitory neuronal pathways or interrupting excitatory relays. A synopsis of the available data indicates that endogenous substance P and NKA interact with other enteric transmitters in the physiological control of gastrointestinal motor activity. Derangement of the regulatory roles of tachykinins may be a factor in the gastrointestinal dysmotility associated with infection, inflammation, stress and pain. In a therapeutic perspective, it would seem conceivable, therefore, that tachykinin agonists and antagonists are adjuncts to the treatment of motor disorders that involve pathological disturbances of the gastrointestinal tachykinin system.

OBJECTIVE

To identify and characterise nerve fibres and inflammatory alterations in painful Achilles tendinosis and thus gain evidence about the origin of pain in Achilles tendinosis.

METHODS

The composition of 10 tendon samples from patients with a prior history of painful Achilles tendinosis and 10 samples from patients with spontaneously ruptured tendons but no previous pain was compared by immunohistochemistry and conventional histology.

RESULTS

The presence of granulation tissue was shown in 8/10 cases of Achilles tendinosis. Nociceptive substance P (SP) positive nerve fibres were significantly increased, and an inflammatory infiltration comprising B and T lymphocytes was found. Additionally, small foci with iron positive haemosiderophages, indicating prior microtraumatic events, were found in 6/10 samples. None of the spontaneously ruptured tendons contained granulation tissue or haemosiderophages. Inflammatory infiltration in these patients consisted almost exclusively of granulocytes and SP positive nerve fibres were decreased. The density of sympathetic nerve fibres did not differ in the two conditions.

CONCLUSIONS

Achilles tendinosis is associated with the presence of granulation tissue, haemosiderophages, and SP positive nerve fibres, which may transmit the clinically pertinent pain. Achilles tendinosis may be caused by repeated microtraumata with ensuing organisation that is accompanied by sprouting of nociceptive SP positive nerve fibres.

BACKGROUND

Gastric carcinogenesis is a multifactorial, multistep process, in which chronic inflammation plays a major role.

OBJECTIVE

In order to ascertain whether free radical mediated oxidative DNA damage is involved in such a process, concentrations of 8-hydroxydeoxyguanosine (8OHdG), a mutagenic/carcinogenic adduct, and thiobarbituric acid reactive substances (TBARS), as an indirect measure of free radical mediated damage, were determined in biopsy specimens from patients undergoing endoscopy.

METHODS

Eighty eight patients were divided into histological subgroups as follows: 27 with chronic non-atrophic gastritis, 41 with atrophic gastritis, six with gastric cancer, and 14 unaffected controls.

METHODS

Intestinal metaplasia, Helicobacter pylori infection, and disease activity were semiquantitatively scored. 8OHdG concentrations were assessed by HPLC with electrochemical detection, and TBARS concentrations were fluorimetrically assayed.

RESULTS

8OHdG concentrations (mean number of adducts/10(5) dG residues) were significantly higher in chronic atrophic gastritis (p = 0.0009). Significantly higher concentrations were also detected in the presence of severe disease activity (p = 0.02), intestinal metaplasia (p = 0.035), and H pylori infection (p = 0.001). TBARS concentrations were also higher in atrophic gastritis, though not significantly so. In a multiple logistic regression analysis, 8OHdG concentrations correlated best with the presence and severity of H pylori infection (r = 0.53, p = 0.002).

CONCLUSIONS

Chronic gastritis is characterised by the accumulation of oxidative DNA damage with mutagenic and carcinogenic potential. H pylori infection is the major determinant for DNA adduct formation.

Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT(3)) antagonist and a corticosteroid. The neurokinin-1 (NK(1)) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT(3) antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK(1) antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT(3) antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK(1) antagonist occurred within the first 8-12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT(3) antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8-12 h following cisplatin-based chemotherapy, after which time substance P acting at NK(1) receptors becomes the dominant mediator of vomiting

The 5-HT3 receptor is a pentameric ligand-gated cation channel which is found in the central and peripheral nervous system and on extraneuronal locations like lymphocytes, monocytes and fetal tissue. Five monomer subtypes, the 5-HT(3A-E) subunits, have been identified which show differences in the amino-terminal and the transmembrane region. The functional relevance of different receptor compositions is not yet clarified. 5-HT3 receptors are located predominantly in CNS regions that are involved in the integration of the vomiting reflex, pain processing, the reward system and anxiety control. The preferential localization on nerve endings is consistent with a physiological role of 5-HT3 receptors in the control of neurotransmitter release such as dopamine, cholecystokinin, glutamate, acetylcholine, GABA, substance P, or serotonin itself. 5-HT3-receptor agonists cause unpleasant effects like nausea and anxiety, and no clinical use has been considered. In contrast, the introduction of 5-HT3-receptor antagonists for chemotherapy-induced vomiting was extremely successful. After development of other gastrointestinal indications like postoperative vomiting and diarrhea-predominant irritable bowel syndrome recent research focuses on rheumatological indications such as fibromyalgia, rheumatoid arthritis and tendinopathies. Positive effects have also been observed for pain syndromes such as chronic neuropathic pain and migraine. These effects seem to be related to substance P-mediated inflammation and hyperalgesia. Furthermore, antiinflammatory and immunomodulatory properties have been observed for 5-HT3-receptor antagonists which might explain promising findings in systemic sclerosis and other immunological conditions. For all of these innovative indications the optimal dosing schedule is a crucial issue, since a bell-shaped dose-response curve has been observed repeatedly for 5-HT3-receptor antagonists, particularly in CNS effects.

BACKGROUND

Evidence-based practices designed for large urban clinics are not necessarily portable into smaller isolated clinics. Implementing practice-based collaborative care for depression in smaller primary care clinics presents unique challenges because it is often not feasible to employ on-site psychiatrists.

OBJECTIVE

The purpose of the Telemedicine Enhanced Antidepressant Management (TEAM) study was to evaluate a telemedicine-based collaborative care model adapted for small clinics without on-site psychiatrists.

METHODS

Matched sites were randomized to the intervention or usual care.

METHODS

Small VA Community-based outpatient clinics with no on-site psychiatrists, but access to telepsychiatrists. In 2003-2004, 395 primary care patients with PHQ9 depression severity scores>> or = 12 were enrolled, and followed for 12 months. Patients with serious mental illness and current substance dependence were excluded.

METHODS

Medication adherence, treatment response, remission, health status, health-related quality of life, and treatment satisfaction.

RESULTS

The sample comprised mostly elderly, white, males with substantial physical and behavioral health comorbidity. At baseline, subjects had moderate depression severity (Hopkins Symptom Checklist, SCL-20 = 1.8), 3.7 prior depression episodes, and 67% had received prior depression treatment. Multivariate analyses indicated that intervention patients were more likely to be adherent at both 6 (odds ratio [OR] = 2.1, p = .04) and 12 months (OR = 2.7, p = .01). Intervention patients were more likely to respond by 6 months (OR = 2.0, p = .02), and remit by 12 months (OR = 2.4, p = .02). Intervention patients reported larger gains in mental health status and health-related quality of life, and reported higher satisfaction.

CONCLUSIONS

Collaborative care can be successfully adapted for primary care clinics without on-site psychiatrists using telemedicine technologies.

Peptides released in the spinal cord from the central terminals of nociceptors contribute to the persistent hyperalgesia that defines the clinical experience of chronic pain. Using substance P (SP) and calcitonin gene-related peptide (CGRP) as examples, this review addresses the multiple mechanisms through which peptidergic neurotransmission contributes to the development and maintenance of chronic pain. Activation of CGRP receptors on terminals of primary afferent neurons facilitates transmitter release and receptors on spinal neurons increases glutamate activation of AMPA receptors. Both effects are mediated by cAMP-dependent mechanisms. Substance P activates neurokinin receptors (3 subtypes) which couple to phospholipase C and the generation of the intracellular messengers whose downstream effects include depolarizing the membrane and facilitating the function of AMPA and NMDA receptors. Activation of neurokinin-1 receptors also increases the synthesis of prostaglandins whereas activation of neurokinin-3 receptors increases the synthesis of nitric oxide. Both products act as retrograde messengers across synapses and facilitate nociceptive signaling in the spinal cord. Whereas these cellular effects of CGRP and SP at the level of the spinal cord contribute to the development of increased synaptic strength between nociceptors and spinal neurons in the pathway for pain, the different intracellular signaling pathways also activate different transcription factors. The activated transcription factors initiate changes in the expression of genes that contribute to long-term changes in the excitability of spinal and maintain hyperalgesia.

BACKGROUND

We report a genome-wide association study (GWAS) of two populations, African-American and European-American (AA, EA) for opioid dependence (OD) in three sets of subjects, to identify pathways, genes, and alleles important in OD risk.

METHODS

The design employed three phases (on the basis of separate sample collections). Phase 1 included our discovery GWAS dataset consisting of 5697 subjects (58% AA) diagnosed with opioid and/or other substance dependence and control subjects. Subjects were genotyped with the Illumina OmniQuad microarray, yielding 890,000 single nucleotide polymorphisms (SNPs) suitable for analysis. Additional genotypes were imputed with the 1000 Genomes reference panel. Top-ranked findings were further evaluated in Phase 2 by incorporating information from the publicly available Study of Addiction: Genetics and Environment dataset, with GWAS data from 4063 subjects (32% AA). In Phase 3, the most significant SNPs from Phase 2 were genotyped in 2549 independent subjects (32% AA). Analyses were performed with case-control and ordinal trait designs.

RESULTS

Most significant results emerged from the AA subgroup. Genome-wide-significant associations (p < 5.0 × 10(-8)) were observed with SNPs from multiple loci-KCNG2*rs62103177 was most significant after combining results from datasets in every phase of the study. The most compelling results were obtained with genes involved in potassium signaling pathways (e.g., KCNC1 and KCNG2). Pathway analysis also implicated genes involved in calcium signaling and long-term potentiation.

CONCLUSIONS

This is the first study to identify risk variants for OD with GWAS. Our results strongly implicate risk pathways and provide insights into novel therapeutic and prevention strategies and might biologically bridge OD and other non-substance dependence psychiatric traits where similar pathways have been implicated.

<AbstractText>Co-occurring mental health or <em>p</em>sychiatric conditions are common in autism, im<em>p</em>airing quality of life. Re<em>p</em>orted <em>p</em>revalences of co-occurring mental health or <em>p</em>sychiatric conditions in <em>p</em>eo<em>p</em>le with autism range widely. Im<em>p</em>roved <em>p</em>revalence estimates and identification of moderators are needed to enhance recognition and care, and to guide future research.</AbstractText><AbstractText>In this systematic review and meta-analysis, we searched MEDLINE, Embase, PsycINFO, Sco<em>p</em>us, Web of Science, and grey literature for <em>p</em>ublications between Jan 1, 1993, and Feb 1, 2019, in English or French, that re<em>p</em>orted original research using an observational design on the <em>p</em>revalence of co-occurring mental health conditions in <em>p</em>eo<em>p</em>le with autism and re<em>p</em>orted confirmed clinical diagnoses of the co-occurring conditions and autism using DSM or ICD criteria. For co-occurring mental health conditions re<em>p</em>orted with at least 15 data<em>p</em>oints (studies), we assessed risk of bias and we determined <em>p</em>ooled estimates of <em>p</em>revalence for different co-occurring conditions in autism using random-effects models, and descri<em>p</em>tively com<em>p</em>ared these with <em>p</em>revalence estimates for the general <em>p</em>o<em>p</em>ulation from the literature (<em>p</em>ost hoc). We investigated heterogeneity in <em>p</em>revalence estimates using random-effects meta-regression models. This systematic review is registered with PROSPERO, CRD42018103176.</AbstractText>(<em>p</em>)<div><b>FINDINGS</b></div>Of 9746 unique studies identified, 432 were selected for full-text review. 100 studies were eligible for inclusion in our qualitative synthesis, of which 96 were included in our meta-analyses. 11 categories of co-occurring conditions were investigated, of which eight conditions were included in the meta-analyses and three were descri<em>p</em>tively synthesised (ie, trauma and stressor-related disorders, <em>substance</em>-related and addictive disorders, and gender dys<em>p</em>horia). From our meta-analyses, we found overall <em>p</em>ooled <em>p</em>revalence estimates of 28% (95% CI 25-32) for attention-deficit hy<em>p</em>eractivity disorder; 20% (17-23) for anxiety disorders; 13% (9-17) for slee<em>p</em>-wake disorders; 12% (10-15) for disru<em>p</em>tive, im<em>p</em>ulse-control, and conduct disorders; 11% (9-13) for de<em>p</em>ressive disorders; 9% (7-10) for obsessive-com<em>p</em>ulsive disorder; 5% (3-6) for bi<em>p</em>olar disorders; and 4% (3-5) for schizo<em>p</em>hrenia s<em>p</em>ectrum disorders. Estimates in clinical sam<em>p</em>le-based studies were higher than in <em>p</em>o<em>p</em>ulation-based and registry-based studies, and these estimates were mostly higher than those in the general <em>p</em>o<em>p</em>ulation (<em>p</em>ost hoc). Age, gender, intellectual functioning, and country of study were associated with heterogeneity in <em>p</em>revalence estimates, yet remaining heterogeneity not ex<em>p</em>lained was still substantial (all I<su<em>p</em>)2</su<em>p</em>) >95%).</<em>p</em>)<AbstractText>Co-occurring mental health conditions are more <em>p</em>revalent in the autism <em>p</em>o<em>p</em>ulation than in the general <em>p</em>o<em>p</em>ulation. Careful assessment of mental health is an essential com<em>p</em>onent of care for all <em>p</em>eo<em>p</em>le on the autism s<em>p</em>ectrum and should be integrated into clinical <em>p</em>ractice.</AbstractText><AbstractText>Academic Scholars Awards, De<em>p</em>artment of Psychiatry, University of Toronto; O'Brien Scholars Program, Slaight Family Child and Youth Mental Health Innovation Fund, and The Catherine and Maxwell Meighen Foundation via the Centre for Addiction and Mental Health Foundation.</AbstractText>

The presence of a population of nerve fibers containing immunoreactive calcitonin gene-related peptide (CGRP) has been demonstrated around cerebral arteries of the cat with immunocytochemistry and radioimmunoassay. CGRP immunoreactivity in the feline cerebral vasculature, as characterized by high-performance liquid chromatography, is similar to authentic rat CGRP. Numerous perikarya containing CGRP are present in the trigeminal ganglia, and surgical lesions of the trigeminal ganglia significantly reduce the levels of CGRP in the cerebral vasculature, suggesting that this cranial nerve is the principal origin of these cerebrovascular nerve fibers. As demonstrated by sequential immunocytochemistry, CGRP coexists with substance P both in the trigeminal ganglion and nerve fibers around cerebral blood vessels. The presence of CGRP in the cerebrovascular trigeminal innervation provides further versatility and complexity for this sensory afferent system putatively involved in the transmission of intracranial pain.

We have deleted cDNA sequences encoding portions of the amino- and carboxy-terminal end of a human type I epidermal keratin K14, and examined the molecular consequences of forcing the expression of these mutants in simple epithelial and squamous cell carcinoma lines. To follow the expression of our mutant products in transfected cells, we have tagged the 3' end of the K14 coding sequence with a sequence encoding an antigenic domain of the neuropeptide substance P. Using DNA transfection and immunohistochemistry (with an antibody against substance P), we have defined the limits of K14 sequence necessary to incorporate into a keratin filament network in vivo without disrupting its architecture. We have also uncovered major differences in the behavior of carboxy- and amino-terminal alpha-helical mutants which do perturb the cytoskeletal network of IFs: whereas carboxy terminal mutants give rise to aggregates of keratin in the cytoplasm, amino-terminal mutants tend to produce aggregates of keratins which seem to localize at the nuclear surface. An examination of the phenotypes generated by the carboxy and amino-terminal mutants and the behavior of cells at late times after transfection suggests a model whereby initiation of filament assembly occurs at discrete sites on the nuclear envelope and filaments grow from the nucleus toward the cytoplasm.

Patch-clamp techniques were used to examine the effect of substance P on acetylcholine-induced current in bovine chromaffin cells. Cells had been enzymatically isolated and kept in short-term culture. Experiments were performed at 22 degrees C. Under whole-cell voltage-clamp conditions substance P alone (2-10 microM) did not induce ionic currents. Acetylcholine (ACh, 20 microM) at -60 mV induced an inward current that desensitized in the continued presence of ACh. The time course of desensitization was somewhat variable from cell to cell. In most cases it could be fitted by a single exponential with time constant of 8-10 s. Substance P (2-50 microM) applied simultaneously with ACh induced what appeared to be an acceleration of the desensitization process. The time course in the presence of 10 microM-substance P (20 microM-ACh) was best fitted by the sum of two exponentials with time constants of 0.6 s and 5 s respectively. The effect was reversible. The recovery of ACh-induced current from desensitization was not affected by substance P. The time constant for recovery was approximately 7 s in the presence or absence of substance P. Single-channel records showed that the conductance of individual channels was not changed by substance P. The mean open time of single channels was shortened by substance P both at high (20 microM) and at low (0.5 microM) concentrations of ACh. The inverse mean open time varied linearly with substance P concentration. Single-channel responses appeared in bursts and clusters after almost complete desensitization at 20 microM-ACh, as was previously observed in frog skeletal muscle. Substance P dramatically reduced ACh current by increasing interburst intervals while decreasing burst duration and the number of openings per burst. We conclude that substance P inhibits ACh-induced depolarization of chromaffin cells either by increasing the rate of desensitization or by inducing channel blockade, which indirectly enhances desensitization. Possible models of desensitization in the absence and presence of substance P are discussed.

BACKGROUND

Postoperative pain after total knee arthroplasty (TKA) can be difficult to manage and may delay recovery. Recent studies have suggested that periarticular infiltration with local anesthetics may improve outcome.

METHODS

80 patients undergoing TKA under spinal anesthesia were randomized to receive continuous femoral nerve block (group F) or peri- and intraarticular infiltration and injection (group I). Group I received a solution of 300 mg ropivacaine, 30 mg ketorolac, and 0.5 mg epinephrine by infiltration of the knee at the end of surgery, and 2 postoperative injections of these substances through an intraarticular catheter.

RESULTS

More patients in group I than in group F could walk < 3 m on the first postoperative day (29/39 vs. 7/37, p < 0.001). Group I also had significantly lower pain scores during activity and lower consumption of opioids on the first postoperative day. No differences between groups were seen regarding side effects or length of stay.

CONCLUSIONS

Peri- and intraarticular application of analgesics by infiltration and bolus injections can improve early analgesia and mobilization for patients undergoing TKA. Further studies of optimal drugs, dosage, and duration of this treatment are warranted.

A meta-analysis was conducted on studies reporting data on associations between candidate genes and human personality. Studies reporting data for psychiatric populations (including organic disease and substance abuse) were excluded. A total of 46 studies contributed to the analysis. Pooled data using a fixed-effects model suggested significant associations between the 5HTT LPR, DRD4 c>t, DRD4 length, DRD2 A1/A2, DRD3 A1/A2 polymorphisms and personality traits. A multivariate analysis using a mixed-effects model and including age, sex and predominant ethnicity as covariates was applied to the analyses of 5HTT LPR and DRD4 length polymorphism data. Only the association between the 5HTT LPR polymorphism and avoidance traits remained significant (P=0.038). However, sensitivity analyses excluding data from studies reporting allele frequencies not in Hardy-Weinberg equilibrium and unpublished data resulted in this association no longer being significant. Implications for the design of future association studies of human personality are discussed, including the likely sample sizes that will be required to achieve sufficient power and the potential role of moderating variables such as sex.

1. The present study addressed the hypothesis that jugular and nodose vagal ganglia contain the somata of functionally and anatomically distinct airway afferent fibres. 2. Anatomical investigations were performed by injecting guinea-pig airways with the neuronal tracer Fast Blue. The animals were killed 7 days later, and the ganglia were removed and immunostained with antisera against substance P (SP) and neurofilament protein (NF). In the nodose ganglion, NF-immunoreactive neurones accounted for about 98% of the Fast Blue-labelled cells while in the jugular ganglion they accounted for approximately 48%. SP and NF immunoreactivity was never (n = 100) observed in the same cell suggesting that the antisera labelled distinct populations. 3. Electrophysiological investigations were performed using an in vitro guinea-pig tracheal and bronchial preparation with intact afferent vagal pathways, including nodose and jugular ganglia. Action potentials arriving from single airway afferent nerve endings were monitored extracellularly using a glass microelectrode positioned near neuronal cell bodies in either ganglion. 4. The nodose ganglion contained the somata of mainly fast-conducting tracheal A delta fibres whereas the jugular ganglion contained equal numbers of C fibre and A delta fibre tracheal afferent somata. The nodose A delta neurones adapted rapidly to mechanical stimulation, had relatively low mechanical thresholds, were not activated by capsaicin and adapted rapidly to a hyperosmotic stimulus. By contrast, jugular A delta and C fibres adapted slowly to mechanical stimulation, were often activated by capsaicin, had higher mechanical thresholds and displayed a slow adaptation to a hyperosmotic stimulus. 5. The anatomical, physiological and pharmacological data provide evidence to support the contention that the vagal ganglionic source of the fibre supplying the airways ultimately dictates its neurochemical and physiological phenotype.

Neurogenic inflammatory responses have recently been linked to both acute and chronic pathological conditions in the urinary tract. Neurogenic inflammation encompasses a series of vascular and non-vascular inflammatory responses, triggered by the activation of primary sensory neurons and the subsequent release of inflammatory neuropeptides, including substance P and calcitonin gene-related peptide. The reduction of neurogenic inflammatory responses may be key in the mode of action of the adrenergic alpha(1)-adrenoceptor antagonists used to treat lower urinary tract symptoms (LUTS). Indeed, the alpha(1)-adrenoceptor antagonist alfuzosin inhibits expression of the oncogene c-fos- a marker of nociceptive pathway activation - evoked by cyclophosphamide in rats. Capsaicin ameliorates urinary bladder symptoms through its stimulatory action on the transient receptor potential vanilloid 1 (TRPV1) calcium channel, resulting in desensitization of bladder sensory nerve terminals. Involvement of the TRP cation channel, subfamily A, member 1 (TRPA1) has also been reported in models of neurogenic inflammation and nociception promoted by the cyclophosphamide metabolite, acrolein. Blockade by alfuzosin demonstrates the beneficial effects of alpha(1)-adrenoceptor antagonists on neurogenic inflammation via the transient receptor potential family of ionic channels. Consequently, these drugs may have an important role in reducing LUTS.

A correlation was made between the effects of synthetic substance P (ssP) on spinal dorsal horn neurones and the responses of these neurones to natural peripheral stimulation. It was found that ssP caused excitation only of those units which were excited by noxious radiant heat applied to the skin. ssP also caused a small facilitation of the excitatory response to this noxious stimulus and, in two cases, led to a response to noxious heat of units which had previously been unaffected by this stimulus. The ratio of ssP sensitive to insensitive units was highest in the deeper parts of the dorsal horn. Excitation by ssP showed a positive correlation to excitation by bradykinin. These results suggest that substance P may be involved in excitatory spinal processes and that its actions may be associated specifically with nociception.

The effects of Red Bull Energy Drink, which includes taurine, glucuronolactone, and caffeine amongst the ingredients, were examined over 3 studies in a total of 36 volunteers. Assessments included psychomotor performance (reaction time, concentration, memory), subjective alertness and physical endurance. When compared with control drinks, Red Bull Energy Drink significantly (P < 0.05) improved aerobic endurance (maintaining 65-75% max. heart rate) and anaerobic performance (maintaining max. speed) on cycle ergometers. Significant improvements in mental performance included choice reaction time, concentration (number cancellation) and memory (immediate recall), which reflected increased subjective alertness. These consistent and wide ranging improvements in performance are interpreted as reflecting the effects of the combination of ingredients.

This review explains symptoms and nature of neuropeptide signaling and its importance for clinical symptoms of CRPS. Neurogenic inflammation regularly accompanies excitation of primary afferent nociceptors. It has two major components-plasma extravasation and vasodilatation. The most important mediators are the calcitonin gene-related peptide (CGRP) and substance P (SP). After peripheral trauma immune reaction (e.g. cytokines) and the attempts of the tissue to regenerate (e.g. growth factors) sensitize nociceptors and amplify neurogenic inflammation. This cascade of events has been demonstrated in rat models of CRPS. Clinical findings in these animals strongly resemble clinical findings in CRPS, and can be prevented by anti-cytokine and anti-neuropeptide treatment. In CRPS patients, there is meanwhile also plenty of evidence that neurogenic inflammation contributes to clinical presentation. Increased cytokine production was demonstrated, as well as facilitated neurogenic inflammation. Very recently even "non-inflammatory" signs of CRPS (hyperhidrosis, cold skin) have been linked to neuropeptide signaling. Surprisingly, there was even moderately increased neurogenic inflammation in unaffected body regions. This favors the possibility that CRPS patients share genetic similarities. The future search for genetic commonalities will help us to further unravel the "mystery" CRPS.

Abnormalities in the gamma-aminobutyric acid (GABA) neurotransmitter system have been noted in subjects with mood and anxiety disorders. Glutamic acid decarboxylase (GAD) enzymes synthesize GABA from glutamate, and, thus, are reasonable candidate susceptibility genes for these conditions. In this study, we examined the GAD1 and GAD2 genes for their association with genetic risk across a range of internalizing disorders. We used multivariate structural equation modeling to identify common genetic risk factors for major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia and neuroticism (N) in a sample of 9270 adult subjects from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each twin pair for whom DNA was available was selected as a case or control based on scoring at the extremes of the genetic factor extracted from the analysis. The resulting sample of 589 cases and 539 controls was entered into a two-stage association study in which candidate loci were screened in stage 1, the positive results of which were tested for replication in stage 2. Several of the six single-nucleotide polymorphisms tested in the GAD1 region demonstrated significant association in both stages, and a combined analysis in all 1128 subjects indicated that they formed a common high-risk haplotype that was significantly over-represented in cases (P=0.003) with effect size OR=1.23. Out of 14 GAD2 markers screened in stage 1, only one met the threshold criteria for follow-up in stage 2. This marker, plus three others that formed significant haplotype combinations in stage 1, did not replicate their association with the phenotype in stage 2. Subject to confirmation in an independent sample, our study suggests that variations in the GAD1 gene may contribute to individual differences in N and impact susceptibility across a range of anxiety disorders and major depression.

Protection by ischemic preconditioning is lost in cardiomyocytes and hearts of heterozygous connexin 43 deficient (Cx43+/-) mice. Because connexin 43 (Cx43) is localized in cardiomyocyte mitochondria and mitochondrial Cx43 content is increased with ischemic preconditioning, we now tried to identify a functional defect at the level of the mitochondria in Cx43+/- mice by use of diazoxide and menadione. Diazoxide stimulates the mitochondrial formation of reactive oxygen species (ROS) and menadione generates superoxide at multiple intracellular sites; both substances elicit cardioprotection through increased ROS formation. ROS formation in response to the potassium ionophore valinomycin was also measured for comparison. Menadione (2 micromol/L) and valinomycin (10 nmol/L) induced similar ROS formation in wild-type (WT) and Cx43+/- cardiomyocytes. In contrast, diazoxide (200 micromol/L) increased ROS formation by 43+/-10% versus vehicle in WT, but only by 18+/-4% in Cx43+/- cardiomyoctes (P<0.05). Two hour-simulated ischemia and oxygenated, hypo-osmolar reperfusion reduced viability as compared with normoxia (WT: 7+/-1% versus 39+/-2%, (Cx43+/-): 8+/-1% versus 40+/-3%, P<0.01). Although menadione protected WT and Cx43+/- cardiomyocytes, diazoxide increased viability (17+/-2%, P<0.01) in WT, but not in Cx43+/- (9+/-1%). Menadione (37 microg/kg i.v.) before 30 minutes coronary occlusion and 2 hour reperfusion reduced infarct size in WT and Cx43+/- mice (24+/-4% versus 24+/-5%). In contrast, diazoxide (5 mg/kg i.v.) reduced infarct size in WT (35+/-4% versus 55+/-3% of area at risk, P<0.01), but not in Cx43+/- mice (56+/-2% versus 54+/-3%). Cardiomyocytes of Cx43+/- mice have a specific functional deficit in ROS formation in response to diazoxide and accordingly less protection.

OBJECTIVE

It has been suggested that migraine is caused by neural dysfunction without involvement of vasodilatation. Because dismissal of vascular mechanisms seemed premature, we examined diameter of extra- and intracranial vessels in migraine without aura patients.

METHODS

A novel high-resolution direct magnetic resonance angiography imaging technique was used to measure arterial circumference of the extracranial middle meningeal artery (MMA) and the intracranial middle cerebral artery (MCA). Data were obtained at baseline, during migraine attack, and after treatment with the migraine abortive drug sumatriptan (a 5-hydroxytryptamine agonist).

RESULTS

We found dilatation of both MMA and MCA during migraine attack (p = 0.001). Sumatriptan administration caused amelioration of headache (p < 0.001) and contraction of MMA (p < 0.001), but MCA remained unchanged (p = 0.16). Exploratory analysis revealed that in migraine attacks with half-sided headache, there was only dilatation on the headache side of MMA of 12.49% (95% confidence interval [CI], 4.16-20.83%) and of MCA of 12.88% (95% CI, 3.49-22.27%) and no dilatation on the non headache side of MMA (95% CI, -4.27 to 11.53%) and MCA (95% CI, -6.7 to 14.28%). In double-sided headache we found bilateral vasodilatation of both MMA and MCA (p < 0.001).

CONCLUSIONS

These data show that migraine without aura is associated with dilatation of extra- and intracerebral arteries and that the headache location is associated with the location of the vasodilatation. Furthermore, contraction of extracerebral and not intracerebral arteries is associated with amelioration of headache. Collectively, these data suggest that vasodilatation and perivascular release of vasoactive substances is an integral mechanism of migraine pathophysiology.