BACKGROUND

Placebo treatment can significantly influence subjective symptoms. However, it is widely believed that response to placebo requires concealment or deception. We tested whether open-label placebo (non-deceptive and non-concealed administration) is superior to a no-treatment control with matched patient-provider interactions in the treatment of irritable bowel syndrome (IBS).

METHODS

Two-group, randomized, controlled three week trial (August 2009-April 2010) conducted at a single academic center, involving 80 primarily female (70%) patients, mean age 47 ± 18 with IBS diagnosed by Rome III criteria and with a score ≥ 150 on the IBS Symptom Severity Scale (IBS-SSS). Patients were randomized to either open-label placebo pills presented as "placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes" or no-treatment controls with the same quality of interaction with providers. The primary outcome was IBS Global Improvement Scale (IBS-GIS). Secondary measures were IBS Symptom Severity Scale (IBS-SSS), IBS Adequate Relief (IBS-AR) and IBS Quality of Life (IBS-QoL).

RESULTS

Open-label placebo produced significantly higher mean (±SD) global improvement scores (IBS-GIS) at both 11-day midpoint (5.2 ± 1.0 vs. 4.0 ± 1.1, p<.001) and at 21-day endpoint (5.0 ± 1.5 vs. 3.9 ± 1.3, p = .002). Significant results were also observed at both time points for reduced symptom severity (IBS-SSS, p = .008 and p = .03) and adequate relief (IBS-AR, p = .02 and p = .03); and a trend favoring open-label placebo was observed for quality of life (IBS-QoL) at the 21-day endpoint (p = .08).

CONCLUSIONS

Placebos administered without deception may be an effective treatment for IBS. Further research is warranted in IBS, and perhaps other conditions, to elucidate whether physicians can benefit patients using placebos consistent with informed consent.

BACKGROUND

ClinicalTrials.gov NCT01010191.

OBJECTIVE

Obstructive sleep apnea syndrome (OSA) is associated with an increased rate of cardiovascular morbidity, which has been suggested to be related to oxidative stress. The present study investigated the concentration of lipid peroxidation biomarkers in patients with OSA in comparison with nonapneic controls and the effects of treatment with nasal continuous positive airway pressure (nCPAP) on these biomarkers.

METHODS

In Experiment 1, morning plasma levels of the oxidative-stress biomarkers, thiobarbituric reactive substances (TBARS) and peroxides (PD), and of the antioxidant protective enzyme paraxonase-1 (PON1), were measured in OSA patients with and without cardiovascular disease (CVD) and in nonapneic controls after an overnight fasting. The concentrations of the biomarkers were compared between patients and controls and were correlated with respiratory disturbance index (RDI). In Experiment 2, TBARS and PD were measured at hourly intervals during sleep in sleep-apnea patients before and after nCPAP treatment as well as in controls.

METHODS

In the first experiment, 114 consecutive patients with sleep apnea, 55 without (+OSA/-CVD) and 59 with CVD (+OSA/+CVD), and 30 nonapneic controls were investigated. Nine patients and 6 controls participated in Experiment 2. Five of the patients were also studied 9.3 +/- 3.9 months after nCPAP treatment.

RESULTS

Morning levels of TBARS and PD were found to be significantly higher in both groups of OSA patients than in controls. The PON1 was lower in +OSA/+CVD patients than in controls and +OSA/-CVD patients, but the difference between the 2 OSA groups bordered on statistical significance. The concentrations of TBARS and PD were significantly positively correlated with RDI (.43, P < .0001 and .36, P < .0002, respectively), while a negative correlation was found between RDI and PON1 activity (-.24, P < .01). Stepwise regression analysis revealed that RDI was an independent significant predictor of all 3 lipid-peroxidation biomarkers. In the second experiment, nocturnal levels of TBARS and PD were significantly higher in sleep-apnea patients than in controls and were significantly lowered by nCPAP treatment.

CONCLUSIONS

These results support the existence of an increased state of oxidative stress in OSA and its possible involvement in cardiovascular morbidity.

The vanilloid receptor-1 (VR1, now TRPV1) was the founding member of a subgroup of cation channels within the TRP family. The TRPV subgroup contains six mammalian members, which all function as Ca2+ entry channels gated by a variety of physical and chemical stimuli. TRPV4, which displays 45% sequence identity with TRPV1, is characterized by a surprising gating promiscuity: it is activated by hypotonic cell swelling, heat, synthetic 4alpha-phorbols, and several endogenous substances including arachidonic acid (AA), the endocannabinoids anandamide and 2-AG, and cytochrome P-450 metabolites of AA, such as epoxyeicosatrienoic acids. This review summarizes data on TRPV4 as a paradigm of gating diversity in this subfamily of Ca2+ entry channels.

BACKGROUND

Vitamin D receptors are present in many tissues. Hypovitaminosis D is considered to be a risk factor for atherosclerosis.

OBJECTIVE

This study explores the effects of vitamin D replacement on insulin sensitivity, endothelial function, inflammation, oxidative stress, and leptin in vitamin D-deficient subjects.

METHODS

Twenty-three asymptomatic vitamin D-deficient subjects with 25-hydroxyvitamin D [25(OH)D] levels below 25 nmol/liter were compared with a control group that had a mean 25(OH)D level of 75 nmol/liter. The vitamin D-deficient group received 300,000 IU im monthly for 3 months. The following parameters were evaluated before and after treatment: vitamin D metabolites, leptin, endothelial function by brachial artery flow mediated dilatation (FMD), insulin sensitivity index based on oral glucose tolerance test, and lipid peroxidation as measures of thiobarbituric acid reactive substances (TBARS).

RESULTS

FMD measurements were significantly lower in 25(OH)D-deficient subjects than controls (P = 0.001) and improved after replacement therapy (P = 0.002). Posttreatment values of TBARS were significantly lower than pretreatment levels (P < 0.001). A positive correlation between FMD and 25(OH)D (r = 0.45; P = 0.001) and a negative correlation between FMD and TBARS (r = -0.28; P < 0.05) were observed. There was a significant increase in leptin levels after therapy, and the leptin levels were positively correlated with 25(OH)D levels (r = 0.45; P < 0.05).

CONCLUSIONS

This study shows that 25(OH)D deficiency is associated with endothelial dysfunction and increased lipid peroxidation. Replacement of vitamin D has favorable effects on endothelial function. Vitamin D deficiency can be seen as an independent risk factor of atherosclerosis. Hypovitaminosis D-associated endothelial dysfunction may predispose to higher rates of cardiovascular disease in the winter.

Nonsteroid anti-inflammatory drugs (NSAIDs) are major drugs against inflammation and pain. They are well known inhibitors of cyclooxygenases (COXs). However, many studies indicate that they may also act on other targets. Acidosis is observed in inflammatory conditions such as chronic joint inflammation, in tumors and after ischemia, and greatly contributes to pain and hyperalgesia. Administration of NSAIDs reduces low-pH-induced pain. The acid sensitivity of nociceptors is associated with activation of H(+)-gated ion channels. Several of these, cloned recently, correspond to the acid-sensing ion channels (ASICs) and others to the vanilloid receptor family. This paper shows (1) that ASIC mRNAs are present in many small sensory neurons along with substance P and isolectin B4 and that, in case of inflammation, ASIC1a appears in some larger Abeta fibers, (2) that NSAIDs prevent the large increase of ASIC expression in sensory neurons induced by inflammation, and (3) that NSAIDs such as aspirin, diclofenac, and flurbiprofen directly inhibit ASIC currents on sensory neurons and when cloned ASICs are heterologously expressed. These results suggest that the combined capacity to block COXs and inhibit both inflammation-induced expression and activity of ASICs present in nociceptors is an important factor in the action of NSAIDs against pain.

OBJECTIVE

To investigate the biochemical milieu of the upper trapezius muscle in subjects with active, latent, or absent myofascial trigger points (MTPs) and to contrast this with that of the noninvolved gastrocnemius muscle.

METHODS

We used a microanalytic technique, including needle insertions at standardized locations in subjects identified as active (having neck pain and MTP), latent (no neck pain but with MTP), or normal (no neck pain, no MTP). We followed a predetermined sampling schedule; first in the trapezius muscle and then in normal gastrocnemius muscle, to measure pH, bradykinin, substance P, calcitonin gene-related peptide, tumor necrosis factor alpha, interleukin 1beta (IL-1beta), IL-6, IL-8, serotonin, and norepinephrine, using immunocapillary electrophoresis and capillary electrochromatography. Pressure algometry was obtained. We compared analyte concentrations among groups with 2-way repeated-measures analysis of variance.

METHODS

A biomedical research facility.

METHODS

Nine healthy volunteer subjects.

METHODS

Not applicable.

METHODS

Preselected analyte concentrations.

RESULTS

Within the trapezius muscle, concentrations for all analytes were higher in active subjects than in latent or normal subjects (P<.002); pH was lower (P<.03). At needle insertion, analyte concentrations in the trapezius for the active group were always higher (pH not different) than concentrations in the gastrocnemius muscle. At all times within the gastrocnemius, the active group had higher concentrations of all analytes than did subjects in the latent and normal groups (P<.05); pH was lower (P<.01).

CONCLUSIONS

We have shown the feasibility of continuous, in vivo recovery of small molecules from soft tissue without harmful effects. Subjects with active MTPs in the trapezius muscle have a biochemical milieu of selected inflammatory mediators, neuropeptides, cytokines, and catecholamines different from subjects with latent or absent MTPs in their trapezius. These concentrations also differ quantitatively from a remote, uninvolved site in the gastrocnemius muscle. The milieu of the gastrocnemius in subjects with active MTPs in the trapezius differs from subjects without active MTPs.

BACKGROUND

This study updated and expanded upon Harris and Barraclough's empirical review [Harris, E.C., Barraclough, B., 1997. Suicide as an outcome for mental disorders. A meta-analysis, Br. J. Psychiatry 170, 205-228] of retrospective and prospective cohort studies of alcohol and drug use disorders and suicide.

METHODS

Studies presenting data on alcohol and drug use disorders and suicide originally identified by Harris and Barraclough were used in this study. To find additional studies, (1) the location of English language reports on MEDLINE (1994-2002) were identified with the search terms 'substance-disorders' with 'mortality' and 'follow-up', (2) read throughs were conducted of four prominent alcohol and drug specialty journals from 1966 through 2002, and (3) the reference sections of studies that met criteria were searched for additional reports. This strategy yielded 42 new studies meeting eligibility criteria.

RESULTS

The estimated standardized mortality ratios (SMR; 95% confidence interval) for suicide were as follows: alcohol use disorder (979; 95% CI 898-1065; p < 0.001), opioid use disorder (1351; 95% CI 1047-1715; p < 0.001), intravenous drug use (1373; 95% CI 1029-1796; p < 0.001), mixed drug use (1685; 95% CI 1473-1920; p < 0.001), heavy drinking (351; 95% CI 251-478; p < 0.001). SMR estimates stratified by sex were also calculated.

CONCLUSIONS

Additional studies on the association of suicide and mixed drug use, heavy drinking, and alcohol use disorders in women augmented the findings of Harris and Barraclough, along with a novel estimate for intravenous drug use, a byproduct of intensive research on HIV in the past decade. There is a large empirical literature on alcohol use disorders and suicide and a moderate literature on suicide and opioid use disorders and IV drug use. There remains limited prospective data on the association of suicide and other drug use disorders (e.g., cocaine, cannabis).

OBJECTIVE

To determine the accuracy of the CRAFFT substance abuse screening test.

METHODS

Criterion standard validation study comparing the score on the 6-item CRAFFT test with screening categories determined by a concurrently administered substance-use problem scale and a structured psychiatric diagnostic interview. Screening categories were "any problem" (ie, problem use, abuse, or dependence), "any disorder" (ie, abuse or dependence), and "dependence."

METHODS

A large, hospital-based adolescent clinic.

METHODS

Patients aged 14 to 18 years arriving for routine health care.

METHODS

The CRAFFT receiver operating characteristic curve, sensitivity, specificity, positive predictive value, and negative predictive value.

RESULTS

Of the 538 participants, 68.4% were female, and 75.8% were from racial and ethnic minority groups. Diagnostic classifications for substance use during the past 12 months were no use (49.6%), occasional use (23.6%), problem use (10.6%), abuse (9.5%), and dependence (6.7%). Classifications were strongly correlated with the CRAFFT score (Spearman rho, 0.72; P<.001). A CRAFFT score of 2 or higher was optimal for identifying any problem (sensitivity, 0.76; specificity, 0.94; positive predictive value, 0.83; and negative predictive value, 0.91), any disorder (sensitivity, 0.80; specificity, 0.86; positive predictive value, 0.53; and negative predictive value, 0.96) and dependence (sensitivity, 0.92; specificity, 0.80; positive predictive value, 0.25; and negative predictive value 0.99). Approximately one fourth of participants had a CRAFFT score of 2 or higher. Validity was not significantly affected by age, sex, or race.

CONCLUSIONS

The CRAFFT test is a valid means of screening adolescents for substance-related problems and disorders, which may be common in some general clinic populations.

BACKGROUND

Although expert opinion has asserted that there is an increased risk of violence in individuals with schizophrenia and other psychoses, there is substantial heterogeneity between studies reporting risk of violence, and uncertainty over the causes of this heterogeneity. We undertook a systematic review of studies that report on associations between violence and schizophrenia and other psychoses. In addition, we conducted a systematic review of investigations that reported on risk of homicide in individuals with schizophrenia and other psychoses.

RESULTS

Bibliographic databases and reference lists were searched from 1970 to February 2009 for studies that reported on risks of interpersonal violence and/or violent criminality in individuals with schizophrenia and other psychoses compared with general population samples. These data were meta-analysed and odds ratios (ORs) were pooled using random-effects models. Ten demographic and clinical variables were extracted from each study to test for any observed heterogeneity in the risk estimates. We identified 20 individual studies reporting data from 18,423 individuals with schizophrenia and other psychoses. In men, ORs for the comparison of violence in those with schizophrenia and other psychoses with those without mental disorders varied from 1 to 7 with substantial heterogeneity (I(2) = 86%). In women, ORs ranged from 4 to 29 with substantial heterogeneity (I(2) = 85%). The effect of comorbid substance abuse was marked with the random-effects ORs of 2.1 (95% confidence interval [CI] 1.7-2.7) without comorbidity, and an OR of 8.9 (95% CI 5.4-14.7) with comorbidity (p<0.001 on metaregression). Risk estimates of violence in individuals with substance abuse (but without psychosis) were similar to those in individuals with psychosis with substance abuse comorbidity, and higher than all studies with psychosis irrespective of comorbidity. Choice of outcome measure, whether the sample was diagnosed with schizophrenia or with nonschizophrenic psychoses, study location, or study period were not significantly associated with risk estimates on subgroup or metaregression analysis. Further research is necessary to establish whether longitudinal designs were associated with lower risk estimates. The risk for homicide was increased in individuals with psychosis (with and without comorbid substance abuse) compared with general population controls (random-effects OR = 19.5, 95% CI 14.7-25.8).

CONCLUSIONS

Schizophrenia and other psychoses are associated with violence and violent offending, particularly homicide. However, most of the excess risk appears to be mediated by substance abuse comorbidity. The risk in these patients with comorbidity is similar to that for substance abuse without psychosis. Public health strategies for violence reduction could consider focusing on the primary and secondary prevention of substance abuse. Please see later in the article for Editors' Summary.

The resurgence of tuberculosis in New York City has been largely attributed to the acquired immune deficiency syndrome (AIDS) epidemic. However, historical events predating the advent of AIDS and worsening economic and social conditions, including a rise in homelessness, have contributed significantly to the increase. We prospectively studied 224 consecutive patients with tuberculosis admitted to a large public hospital in New York over the first 9 months of 1988. Initial assessment included medical status, human immunodeficiency virus (HIV) risk factors, and detailed social information, including substance abuse history and housing status. All patients were tracked after discharge to determine compliance and cure rates. Tuberculosis patients were predominantly male (79%), with high rates of alcohol use (53%), intravenous drug and/or "crack" cocaine use (64%), and homelessness or unstable housing (68%). Half the patients had AIDS or AIDS-related complex (ARC) or were HIV antibody positive. A total of 178 patients were discharged on tuberculosis treatment, but 89% of these were lost to follow-up and failed to complete therapy. Of the 178 discharged patients, 48(27%) were readmitted within 12 months with confirmed active tuberculosis. Of these patients, 40 were discharged on treatment and at least 35 were again lost to follow-up. In a multivariate regression model noncompliance was significantly associated with the absence of AIDS or ARC (p less than 0.001), homelessness (p less than 0.005), and alcoholism (p less than 0.05). Because HIV infection and tuberculosis converge in a subpopulation with high rates of substance abuse and homelessness, the problem of ensuring treatment compliance may grow considerably in the future.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND

Current interest in the role of functional foods in weight control has focused on plant ingredients capable of interfering with the sympathoadrenal system.

OBJECTIVE

We investigated whether a green tea extract, by virtue of its high content of caffeine and catechin polyphenols, could increase 24-h energy expenditure (EE) and fat oxidation in humans.

METHODS

Twenty-four-hour EE, the respiratory quotient (RQ), and the urinary excretion of nitrogen and catecholamines were measured in a respiratory chamber in 10 healthy men. On 3 separate occasions, subjects were randomly assigned among 3 treatments: green tea extract (50 mg caffeine and 90 mg epigallocatechin gallate), caffeine (50 mg), and placebo, which they ingested at breakfast, lunch, and dinner.

RESULTS

Relative to placebo, treatment with the green tea extract resulted in a significant increase in 24-h EE (4%; P < 0.01) and a significant decrease in 24-h RQ (from 0.88 to 0.85; P < 0.001) without any change in urinary nitrogen. Twenty-four-hour urinary norepinephrine excretion was higher during treatment with the green tea extract than with the placebo (40%, P < 0.05). Treatment with caffeine in amounts equivalent to those found in the green tea extract had no effect on EE and RQ nor on urinary nitrogen or catecholamines.

CONCLUSIONS

Green tea has thermogenic properties and promotes fat oxidation beyond that explained by its caffeine content per se. The green tea extract may play a role in the control of body composition via sympathetic activation of thermogenesis, fat oxidation, or both.

A central question in prescribing opioids for chronic non-cancer pain (CNCP) is how to best balance the risk of opioid abuse and dependence with the benefits of pain relief. To achieve this balance, clinicians need an understanding of the risk factors for opioid abuse, an issue that is only partially understood. We conducted a secondary data analysis of regional VA longitudinal administrative data (years 2000-2005) for chronic users of opioids for CNCP (n=15,160) to investigate risk factors for the development of clinically recognized (i.e., diagnosed) opioid abuse or dependence among these individuals. We analyzed four broad groups of possible risk factors: (i) non-opioid substance abuse disorders, (ii) painful physical health disorders, (iii) mental health disorders, and (iv) socio-demographic factors. In adjusted models, a diagnosis of non-opioid substance abuse was the strongest predictor of opioid abuse/dependence (OR=2.34, p<0.001). Mental health disorders were moderately strong predictors (OR=1.46, p=0.005) of opioid abuse/dependence. However, the prevalence of mental health disorders was much higher than the prevalence of non-opioid substance abuse disorders (45.3% vs. 7.6%) among users of opioids for CNCP, suggesting that mental health disorders account for more of the population attributable risk for opioid abuse than does non-opioid substance abuse. Males, younger adults, and individuals with greater days supply of prescription opioids dispensed in 2002 were more likely to develop opioid abuse/dependence. Clinicians need to carefully screen for substance abuse and mental health disorders in candidates for opioid therapy and facilitate appropriate treatment of these disorders.

OBJECTIVE

Cellular changes associated with diabetic and idiopathic gastroparesis are not well described. The aim of this study was to describe histologic abnormalities in gastroparesis and compare findings in idiopathic versus diabetic gastroparesis.

METHODS

Full-thickness gastric body biopsy specimens were obtained from 40 patients with gastroparesis (20 diabetic) and matched controls. Sections were stained for H&E and trichrome and immunolabeled with antibodies against protein gene product (PGP) 9.5, neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide, substance P, and tyrosine hydroxylase to quantify nerves, S100β for glia, Kit for interstitial cells of Cajal (ICC), CD45 and CD68 for immune cells, and smoothelin for smooth muscle cells. Tissue was also examined by transmission electron microscopy.

RESULTS

Histologic abnormalities were found in 83% of patients. The most common defects were loss of ICC with remaining ICC showing injury, an abnormal immune infiltrate containing macrophages, and decreased nerve fibers. On light microscopy, no significant differences were found between diabetic and idiopathic gastroparesis with the exception of nNOS expression, which was decreased in more patients with idiopathic gastroparesis (40%) compared with diabetic patients (20%) by visual grading. On electron microscopy, a markedly increased connective tissue stroma was present in both disorders.

CONCLUSIONS

This study suggests that on full-thickness biopsy specimens, cellular abnormalities are found in the majority of patients with gastroparesis. The most common findings were loss of Kit expression, suggesting loss of ICC, and an increase in CD45 and CD68 immunoreactivity. These findings suggest that examination of tissue can lead to valuable insights into the pathophysiology of these disorders and offer hope that new therapeutic targets can be found.

OBJECTIVE

Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC).

METHODS

Eighty-nine patients with quiescent UC were recruited for this randomized, double-blind, multicenter trial of curcumin in the prevention of relapse. Forty-five patients received curcumin, 1g after breakfast and 1g after the evening meal, plus sulfasalazine (SZ) or mesalamine, and 44 patients received placebo plus SZ or mesalamine for 6 months. Clinical activity index (CAI) and endoscopic index (EI) were determined at entry, every 2 months (CAI), at the conclusion of 6-month trial, and at the end of 6-month follow-up.

RESULTS

Seven patients were protocol violators. Of 43 patients who received curcumin, 2 relapsed during 6 months of therapy (4.65%), whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P=.040). Recurrence rates evaluated on the basis of intention to treat showed significant difference between curcumin and placebo (P=.049). Furthermore, curcumin improved both CAI (P=.038) and EI (P=.0001), thus suppressing the morbidity associated with UC. A 6-month follow-up was done during which patients in both groups were on SZ or mesalamine. Eight additional patients in the curcumin group and 6 patients in the placebo group relapsed.

CONCLUSIONS

Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.

BACKGROUND

Cue reactivity studies in alcohol-dependent adults have shown atypical physiological, cognitive, and neural responses to alcohol-related stimuli that differ from the responses of light drinkers. Cue reactivity and its neural substrates are unclear in youth. We hypothesized that teens with alcohol use disorder would show greater brain response than nonabusing teens to alcohol images relative to neutral beverage images in limbic and frontal brain regions.

METHODS

We tested the hypotheses in a cross-sectional functional magnetic resonance imaging study. Adolescents aged 14 to 17 were recruited from local high schools. Teens with alcohol use disorders (n = 15) and demographically similar infrequent drinkers (n = 15) met strict exclusion criteria (no left-handedness or neurological, other psychiatric, or other substance use disorders). Diagnoses were determined by means of structured and semistructured clinical interviews. Subjects were shown pictures of alcoholic and nonalcoholic beverage advertisements during blood oxygen level-dependent functional magnetic resonance imaging. Self-reports of craving were obtained before and after cue exposure.

RESULTS

Teens with alcohol use disorders showed substantially greater brain activation to alcoholic beverage pictures than control youths, predominantly in the left anterior, limbic, and visual system areas (P<.05; cluster threshold, 515 microL). The degree of brain response to the alcohol pictures was highest in youths who consumed more drinks per month and reported greater desires to drink.

CONCLUSIONS

These results confirm previous studies by demonstrating an association between the urge to drink alcohol and blood oxygen use in areas of the brain previously linked to reward, desire, positive affect, and episodic recall. This study extends this relationship to adolescents with relatively brief drinking histories using visual alcohol stimuli, and suggests a neural basis for response to alcohol advertisements in youths with drinking problems.

Substance P receptor (SPR)-expressing spinal neurons were ablated with the selective cytotoxin substance P-saporin. Loss of these neurons resulted in a reduction of thermal hyperalgesia and mechanical allodynia associated with persistent neuropathic and inflammatory pain states. This loss appeared to be permanent. Responses to mildly painful stimuli and morphine analgesia were unaffected by this treatment. These results identify a target for treating persistent pain and suggest that the small population of SPR-expressing neurons in the dorsal horn of the spinal cord plays a pivotal role in the generation and maintenance of chronic neuropathic and inflammatory pain.

Myofascial pain associated with myofascial trigger points (MTrPs) is a common cause of nonarticular musculoskeletal pain. Although the presence of MTrPs can be determined by soft tissue palpation, little is known about the mechanisms and biochemical milieu associated with persistent muscle pain. A microanalytical system was developed to measure the in vivo biochemical milieu of muscle in near real time at the subnanogram level of concentration. The system includes a microdialysis needle capable of continuously collecting extremely small samples (approximately 0.5 microl) of physiological saline after exposure to the internal tissue milieu across a 105-microm-thick semi-permeable membrane. This membrane is positioned 200 microm from the tip of the needle and permits solutes of <75 kDa to diffuse across it. Three subjects were selected from each of three groups (total 9 subjects): normal (no neck pain, no MTrP); latent (no neck pain, MTrP present); active (neck pain, MTrP present). The microdialysis needle was inserted in a standardized location in the upper trapezius muscle. Due to the extremely small sample size collected by the microdialysis system, an established microanalytical laboratory, employing immunoaffinity capillary electrophoresis and capillary electrochromatography, performed analysis of selected analytes. Concentrations of protons, bradykinin, calcitonin gene-related peptide, substance P, tumor necrosis factor-alpha, interleukin-1beta, serotonin, and norepinephrine were found to be significantly higher in the active group than either of the other two groups (P < 0.01). pH was significantly lower in the active group than the other two groups (P < 0.03). In conclusion, the described microanalytical technique enables continuous sampling of extremely small quantities of substances directly from soft tissue, with minimal system perturbation and without harmful effects on subjects. The measured levels of analytes can be used to distinguish clinically distinct groups.

1. TRPM8 (CMR1) is a Ca(2+)-permeable channel, which can be activated by low temperatures, menthol, eucalyptol and icilin. It belongs to the transient receptor potential (TRP) family, and therefore is related to vanilloid receptor type-1 (VR1, TRPV1). We tested whether substances which are structurally related to menthol, or which produce a cooling sensation, could activate TRPM8, and compared the responses of TRPM8 and VR1 to these ligands. 2. The effects of 70 odorants and menthol-related substances on recombinant mouse TRPM8 (mTRPM8), expressed in HEK293 cells, were examined using a FLIPR assay. In all, 10 substances (linalool, geraniol, hydroxycitronellal, WS-3, WS-23, FrescolatMGA, FrescolatML, PMD38, CoolactP and Cooling Agent 10) were found to be agonists. 3. The EC(50) values of the agonists defined their relative potencies: icilin (0.2+/-0.1 microM>>FrescolatML (3.3+/-1.5 microM)>> WS-3 (3.7+/-1.7 microM)>>(-)menthol (4.1+/-1.3 microM)>>frescolatMAG (4.8+/-1.1 microM)>> cooling agent 10 (6+/-2.2 microM)>>(+)menthol (14.4+/-1.3 microM)>> PMD38 (31+/-1.1 microM)>> WS-23 (44+/-7.3 microM)>> Coolact P (66+/-20 microM)>> geraniol (5.9+/-1.6 mM)>> linalool (6.7+/-2.0 mM)>> eucalyptol (7.7+/-2.0 mM)>> hydroxycitronellal (19.6+/-2.2 mM). 4. Known VR1 antagonists (BCTC, thio-BCTC and capsazepine) were also able to block the response of TRPM8 to menthol (IC(50): 0.8+/-1.0, 3.5+/-1.1 and 18+/-1.1 microM, respectively). 5. The Ca(2+) response of hVR1-transfected HEK293 cells to the endogenous VR1 agonist N-arachidonoyl-dopamine was potentiated by low pH. In contrast, menthol- and icilin-activated TRPM8 currents were suppressed by low pH. 6. In conclusion, in the present study, we identified 10 new agonists and three antagonists of TRPM8. We found that, in contrast to VR1, TRPM8 is inhibited rather than potentiated by protons.

BACKGROUND

The prevalence of medical disorders is high among substance abuse patients, yet medical services are seldom provided in coordination with substance abuse treatment.

OBJECTIVE

To examine differences in treatment outcomes and costs between integrated and independent models of medical and substance abuse care as well as the effect of integrated care in a subgroup of patients with substance abuse-related medical conditions (SAMCs).

METHODS

Randomized controlled trial conducted between April 1997 and December 1998.

METHODS

Adult men and women (n = 592) who were admitted to a large health maintenance organization chemical dependency program in Sacramento, Calif.

METHODS

Patients were randomly assigned to receive treatment through an integrated model, in which primary health care was included within the addiction treatment program (n = 285), or an independent treatment-as-usual model, in which primary care and substance abuse treatment were provided separately (n = 307). Both programs were group based and lasted 8 weeks, with 10 months of aftercare available.

METHODS

Abstinence outcomes, treatment utilization, and costs 6 months after randomization.

RESULTS

Both groups showed improvement on all drug and alcohol measures. Overall, there were no differences in total abstinence rates between the integrated care and independent care groups (68% vs 63%, P =.18). For patients without SAMCs, there were also no differences in abstinence rates (integrated care, 66% vs independent care, 73%; P =.23) and there was a slight but nonsignificant trend of higher costs for the integrated care group ($367.96 vs $324.09, P =.19). However, patients with SAMCs (n = 341) were more likely to be abstinent in the integrated care group than the independent care group (69% vs 55%, P =.006; odds ratio [OR], 1.90; 95% confidence interval [CI], 1.22-2.97). This was true for both those with medical (OR, 3.38; 95% CI, 1.68-6.80) and psychiatric (OR, 2.10; 95% CI, 1.04-4.25) SAMCs. Patients with SAMCs had a slight but nonsignificant trend of higher costs in the integrated care group ($470.81 vs $427.95, P =.14). The incremental cost-effectiveness ratio per additional abstinent patient with an SAMC in the integrated care group was $1581.

CONCLUSIONS

Individuals with SAMCs benefit from integrated medical and substance abuse treatment, and such an approach can be cost-effective. These findings are relevant given the high prevalence and cost of medical conditions among substance abuse patients, new developments in medications for addiction, and recent legislation on parity of substance abuse with other medical benefits.

OBJECTIVE

To determine whether the pattern of brain injury in term neonatal encephalopathy is associated with distinct prenatal and perinatal factors and to determine whether the pattern of injury is associated with 30-month neurodevelopmental outcome.

METHODS

A total of 173 term newborns with neonatal encephalopathy from 2 centers underwent magnetic resonance imaging (MRI) at a median of 6 days of age (range, 1-24 days). Patterns of injury on MRI were defined on the basis of the predominant site of injury: watershed predominant, basal ganglia/thalamus predominant, and normal.

RESULTS

The watershed pattern of injury was seen in 78 newborns (45%), the basal ganglia/thalamus pattern was seen in 44 newborns (25%), and normal MRI studies were seen in 51 newborns (30%). Antenatal conditions such as maternal substance use, gestational diabetes, premature rupture of membranes, pre-eclampsia, and intra-uterine growth restriction did not differ across patterns. The basal ganglia/thalamus pattern was associated with more severe neonatal signs, including more intensive resuscitation at birth ( P = .001), more severe encephalopathy ( P = .0001), and more severe seizures ( P = .0001). The basal ganglia/thalamus pattern was associated with the most impaired motor and cognitive outcome at 30 months.

CONCLUSIONS

The patterns of brain injury in term neonatal encephalopathy are associated with different clinical presentations and neurodevelopmental outcomes. Measured prenatal risk factors did not predict the pattern of brain injury.

In asthma, damage to airway epithelium, possibly caused by eosinophil products, exposes C-fibre afferent nerve endings. Stimulation of these endings by inflammatory mediators such as bradykinin may result in an axon (local) reflex with antidromic conduction down afferent nerve collaterals and release of sensory neuropeptides such as substance P, neurokinin A, and calcitonin gene-related peptide. These peptides are potent inducers of airway smooth muscle contraction, bronchial oedema, extravasation of plasma, mucus hypersecretion, and possibly inflammatory cell infiltration and secretion. Thus, axon reflexes could account for at least some of the pathophysiology of asthma and this concept might lead to new strategies for treatment.

A rabbit endocarditis model was utilized to evaluate the virulence conferred by the conjugative plasmid pAD1 with the following strains: Enterococcus faecalis plasmid-free FA2-2 and FA2-2 containing plasmids pAD1 (hemolysin and aggregation substance positive), pAM9058 (insertional inactivation of hemolysin), and pAM944 or pAM947 (insertional inactivation of aggregation substance). All isolates were similar in ability to produce endocarditis. Mean vegetation weight was greater in animals inoculated with strains that produced aggregation substance (P < 0.01). Mortality was significantly increased in animals given FA2-2 containing pAD1 compared with those given all other strains (P < 0.01). These results suggest that the combination of hemolysin and aggregation substance is associated with increased mortality and that vegetation weight is associated with production of aggregation substance in experimental E. faecalis endocarditis.

BACKGROUND

The purported functions of medial temporal lobe structures suggest their involvement in the pathophysiology of bipolar disorder (BD). Previous reports of abnormalities in the volume of the amygdala and hippocampus in patients with BD have been inconsistent in their findings and limited to adult samples. Appreciation of whether volumetric abnormalities are early features of BD or whether the abnormalities represent neurodegenerative changes associated with illness duration is limited by the paucity of data in juvenile samples.

OBJECTIVE

To investigate amygdala and hippocampal volume in adults and adolescents with BD.

METHODS

Subjects included 36 individuals (14 adolescents and 22 adults) in outpatient treatment for BD type I at a university hospital or Veterans Affairs medical center or in the surrounding community, and 56 healthy comparison subjects (23 adolescents and 33 adults).

METHODS

Amygdala and hippocampal volumes were defined and measured on high-resolution anatomic magnetic resonance imaging scans. We used a mixed-model, repeated-measures statistical analysis to compare amygdala and hippocampal volumes across groups while covarying for total brain volume, age, and sex. Potential effects of illness features were explored, including rapid cycling, medication, alcohol or other substance dependence, duration, and mood state.

RESULTS

For both the amygdala and hippocampal regions, we found an overall significant volume reduction in the BD compared with the control group (P<.0001). Amygdala volume reductions (15.6%) were highly significant (P<.0001). We observed a nonsignificant trend (P =.054) toward reductions in hippocampal volumes of lesser magnitude (5.3%). Effects of illness features were not detected.

CONCLUSIONS

These results suggest that BD is associated with decreased volumes of medial temporal lobe structures, with greater effect sizes in the amygdala than in the hippocampus. These abnormalities are likely manifested early in the course of illness, as they affected adolescent and adult subjects similarly in this sample.

1. Peripheral inflammation is associated with the local production of neuroactive inflammatory cytokines and growth factors. These may contribute to inflammatory pain and hyperalgesia by directly or indirectly altering the function or chemical phenotype of responsive primary sensory neurones. 2. To investigate this, inflammation was produced by the intraplantar injection of complete Freund's adjuvant (CFA) in adult rats. This resulted in a significant elevation in interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF) levels in the inflamed tissue and of the peptides, substance P and calcitonin gene-related peptide (CGRP) in the L4 dorsal root ganglion 48 h post CFA injection. 3. The effects of a steroidal (dexamethasone) and a non-steroidal (indomethacin) anti-inflammatory drug on the levels of NGF and IL-1 beta in inflamed tissue were investigated and compared with alterations in behavioural hyperalgesia and neuropeptide expression in sensory neurones. 4. Systemic dexamethasone (120 micrograms kg-1 per day starting the day before the CFA injection) had no effect on the inflammatory hyperalgesia. When the dose was administered 3 times daily, a reduction in mechanical and to a lesser extent thermal sensitivity occurred. Indomethacin at 2 mg kg-1 daily (i.p.) had no effect on the hyperalgesia and a dose of 4 mg kg-1 daily was required to reduce significantly mechanical and thermal hypersensitivity. 5. The increase in NGF produced by the CFA inflammation was prevented by both dexamethasone and indomethacin, but only at the higher dose levels. Dexamethasone at the lower and higher dose regimes diminished the upregulation of IL-1 beta whereas indomethacin had an effect only at the higher dose. 6. The increase in SP and CGRP levels produced by the CFA inflammation was prevented by dexamethasone and indomethacin at the lower and higher dose regimes. 7. Intraplantar injections of IL-1 beta (0.01, 0.1 and 1 ng) produced a brief (6 h) thermal hyperalgesia and an elevation in cutaneous NGF levels which was prevented by pretreatment with human recombinant IL-1 receptor antagonist (IL-1 ra) (0.625 microgram, i.v.). The thermal hyperalgesia but not the NGF elevation produced by intraplantar IL-1 beta (1 ng) was prevented by administration of a polyclonal neutralizing anti-NGF serum. 8. IL-1 ra significantly reduced the mechanical hyperalgesia produced by CFA for 6 h after administration as well as the CFA-induced elevation in NGF levels. Anti-NGF pretreatment substantially reduced CFA-induced mechanical and thermal hyperalgesia without reducing the elevation in IL-1 beta. 9. Intraplantar NGF (0.02, 0.2 and 2 microg) injections produced a short lasting thermal and mechanical hyperalgesia but did not change IL-1beta levels in the hindpaw skin.10. Our results demonstrate that IL-1beta contributes to the upregulation of NGF during inflammation and that NGF has a major role in the production of inflammatory pain hypersensitivity.