OBJECTIVE

The aim of this study was to develop a self-diagnostic scale that could distinguish smartphone addicts based on the Korean self-diagnostic program for Internet addiction (K-scale) and the smartphone's own features. In addition, the reliability and validity of the smartphone addiction scale (SAS) was demonstrated.

METHODS

A total of 197 participants were selected from Nov. 2011 to Jan. 2012 to accomplish a set of questionnaires, including SAS, K-scale, modified Kimberly Young Internet addiction test (Y-scale), visual analogue scale (VAS), and substance dependence and abuse diagnosis of DSM-IV. There were 64 males and 133 females, with ages ranging from 18 to 53 years (M = 26.06; SD = 5.96). Factor analysis, internal-consistency test, t-test, ANOVA, and correlation analysis were conducted to verify the reliability and validity of SAS.

RESULTS

Based on the factor analysis results, the subscale "disturbance of reality testing" was removed, and six factors were left. The internal consistency and concurrent validity of SAS were verified (Cronbach's alpha = 0.967). SAS and its subscales were significantly correlated with K-scale and Y-scale. The VAS of each factor also showed a significant correlation with each subscale. In addition, differences were found in the job (p<0.05), education (p<0.05), and self-reported smartphone addiction scores (p<0.001) in SAS.

CONCLUSIONS

This study developed the first scale of the smartphone addiction aspect of the diagnostic manual. This scale was proven to be relatively reliable and valid.

BACKGROUND

Effective endogenous fibrinolysis requires rapid release of tissue plasminogen activator (tPA) from the vascular endothelium. Smoking is a known risk factor for arterial thrombosis and myocardial infarction, and it causes endothelial dysfunction. We therefore examined the effects of cigarette smoking on substance P-induced tPA release in vivo in humans.

RESULTS

Blood flow and plasma fibrinolytic factors were measured in both forearms of 12 smokers and 12 age- and sex-matched nonsmokers who received unilateral brachial artery infusions of substance P (2 to 8 pmol/min). In both smokers and nonsmokers, substance P caused dose-dependent increases in blood flow and local release of plasma tPA antigen and activity (P<0.001 for all) but had no effect on the local release of plasminogen activator inhibitor type 1. Compared with nonsmokers, increases in forearm blood flow (P=0.03) and release of tPA antigen (P=0.04) and activity (P<0.001) caused by substance P were reduced in smokers. The area under the curve for release of tPA antigen and activity decreased by 51% and 53%, respectively.

CONCLUSIONS

Cigarette smoking causes marked inhibition of substance P-induced tPA release in vivo in humans. This provides an important mechanism whereby endothelial dysfunction may increase the risk of atherothrombosis through a reduction in the acute fibrinolytic capacity.

In mammalian intestine immunoreactive Substance P is localized not only in the plexuses of Auerbach and Meissner, as could be anticipated, but also in a number of basally situated, often basigranular, endocrine cells which have been identified tentatively as enterochromaffin. The presence of a neurohormone in cells of this type confirms their close association with the nervous system, noted by Masson (1924), and suggests that their postulated origin from the nervous system (Danisch, 1924) may well be correct.

In 1991, a group of expert scientists at a Wingspread work session on endocrine-disrupting chemicals (EDCs) concluded that "Many compounds introduced into the environment by human activity are capable of disrupting the endocrine system of animals, including fish, wildlife, and humans. Endocrine disruption can be profound because of the crucial role hormones play in controlling development." Since that time, there have been numerous documented examples of adverse effects of EDCs in invertebrates, fish, wildlife, domestic animals, and humans. Hormonal systems can be disrupted by numerous different anthropogenic chemicals including antiandrogens, androgens, estrogens, AhR agonists, inhibitors of steroid hormone synthesis, antithyroid substances, and retinoid agonists. In addition, pathways and targets for endocrine disruption extend beyond the traditional estrogen/androgen/thyroid receptor-mediated reproductive and developmental systems. For example, scientists have expressed concern about the potential role of EDCs in increasing trends in early puberty in girls, obesity and type II diabetes in the United States and other populations. New concerns include complex endocrine alterations induced by mixtures of chemicals, an issue broadened due to the growing awareness that EDCs present in the environment include a variety of potent human and veterinary pharmaceutical products, personal care products, nutraceuticals and phytosterols. In this review we (1) address what have we learned about the effects of EDCs on fish, wildlife, and human health, (2) discuss representative animal studies on (anti)androgens, estrogens and 2,3,7,8-tetrachlorodibenzo-p-dioxin-like chemicals, and (3) evaluate regulatory proposals being considered for screening and testing these chemicals.

A cDNA encoding a novel multispecific organic anion transporter, OAT4, was isolated from a human kidney cDNA library. The OAT4 cDNA consisted of 2210 base pairs that encoded a 550-amino acid residue protein with 12 putative membrane-spanning domains. The amino acid sequence of OAT4 showed 38 to 44% identity to those of other members of the OAT family. Northern blot analysis revealed that OAT4 mRNA is abundantly expressed in the placenta as well as in the kidney. When expressed in Xenopus oocytes, OAT4 mediated the high affinity transport of estrone sulfate (K(m) = 1.01 microM) and dehydroepiandrosterone sulfate (K(m) = 0.63 microM) in a sodium-independent manner. OAT4 also mediated the transport of ochratoxin A. OAT4-mediated transport of estrone sulfate was inhibited by several sulfate conjugates, such as p-nitrophenyl sulfate, alpha-naphthyl sulfate, beta-estradiol sulfate, and 4-methylumbelliferyl sulfate. By contrast, glucuronide conjugates showed little or no inhibitory effect on the OAT4-mediated transport of estrone sulfate. OAT4 interacted with chemically heterogeneous anionic compounds, such as nonsteroidal anti-inflammatory drugs, diuretics, sulfobromophthalein, penicillin G, and bile salts, whereas tetraethylammonium, an organic cation, did not. OAT4 is the first member of the multispecific organic anion transporter family, which is expressed abundantly in the placenta. OAT4 might be responsible for the elimination and detoxification of harmful anionic substances from the fetus.

In 30 patients with diagnosed fibromyalgia, the CSF level of immunoreactive substance P (SP) was investigated. Compared to normal values (9.6 +/- 3.2 fmol/ml), all the patients had elevated CSF levels of SP (36.1 +/- 2.7 fmol/ml, range 16.5-79.1 fmol/ml). Anamnestic information from the patients revealed that 53.3% had Raynaud/Raynaud-like phenomenon localized in the fingers, the toes or both. Although SP levels did not differ significantly in patients with or without the Raynaud phenomenon, elevated activity may be present in the peripheral branches of SP neurons which could be responsible for the last (rubor) phase of the triphasic Raynaud's phenomenon. SP levels were significantly higher in patients who were smokers (40.1 +/- 2.7 fmol/ml, range 25.3-64.1 fmol/ml), compared to patients who were non-smokers (29.2 +/- 5.0 fmol/ml, range 16.5-79.1 fmol/ml). We propose elevated CSF levels of SP and the Raynaud phenomenon as characteristic features for fibromyalgia with potential as diagnostic markers of the disease and further that smoking might be an aggravating factor for its pathogenesis or development.

In situ hybridization histochemistry was used to show the distribution of messenger RNA for central cannabinoid CB 1 receptors in dorsal root ganglia of the rat. CB1 messenger RNA was highly expressed in neuronal subpopulations of rat dorsal root ganglia. The phenotypes of neurons that express messenger RNA for CB1 were subsequently examined by combining a 35S-labeled ribonucleotide probe for CB1 messenger RNA with digoxigenin-labeled riboprobes for preprotachykinin A (substance P precursor), alpha-calcitonin gene-related peptide and preprosomatostatin (somatostatin precursor) messenger RNAs. Qualitative examination revealed expression of CBI messenger RNA predominantly in medium-and large-sized cells distributed throughout the dorsal root ganglia. The majority of neurons expressing substance P messenger RNA were CB1 messenger RNA negative and smaller in size than the CB1 messenger RNA-positive cells. Only 13% of substance P messenger RNA-positive cells expressed CB1 messenger RNA. A similar degree of co-localization was observed with alpha-calcitonin gene-related peptide: 10% of cells expressing messenger RNA for this neuropeptide were CB1 messenger RNA positive. Co-localization of CB1 and somatostatin messenger RNAs was observed in less than 0.5% of somatostatin messenger RNA-positive cells. The data suggest that subpopulations of neurons in rat dorsal root ganglia are capable of synthesizing cannabinoid receptors and inserting them on terminals in the superficial dorsal horn. These findings provide anatomical evidence for cannabinoid modulation of primary afferent transmission. Although an anatomical basis for cannabinoid-mediated suppression of release of neurogenic peptides from nociceptive primary afferents is provided, our results demonstrate that the majority of CB messenger RNA-positive neurons in the dorsal root ganglia contain transmitters and/or neuromodulators other than the neuropeptides examined herein.

The neurotoxin, botulinum toxin type A, has been used successfully, in some patients, as an analgesic for myofascial pain syndromes, migraine, and other headache types. The toxin inhibits the release of the neurotransmitter, acetylcholine, at the neuromuscular junction thereby inhibiting striated muscle contractions. In the majority of pain syndromes where botulinum toxin type A is effective, inhibiting muscle spasms is an important component of its activity. Even so, the reduction of pain often occurs before the decrease in muscle contractions suggesting that botulinum toxin type A has a more complex mechanism of action than initially hypothesized. Current data points to an antinociceptive effect of botulinum toxin type A that is separate from its neuromuscular activity. The common biochemical mechanism, however, remains the same between botulinum toxin type A's effect on the motor nerve or the sensory nerve: enzymatic blockade of neurotransmitter release. The antinociceptive effect of the toxin was reported to block substance P release using in vitro culture systems. The current investigation evaluated the in vivo mechanism of action for the antinociceptive action of botulinum toxin type A. In these studies, botulinum toxin type A was found to block the release of glutamate. Furthermore, Fos, a product of the immediate early gene, c-fos, expressed with neuronal stimuli was prevented upon peripheral exposure to the toxin. These findings suggest that botulinum toxin type A blocks peripheral sensitization and, indirectly, reduces central sensitization. The recent hypothesis that migraine involves both peripheral and central sensitization may help explain how botulinum toxin type A inhibits migraine pain by acting on these two pathways. Further research is needed to determine whether the antinociceptive mechanism mediated by botulinum toxin type A affects the neuronal signaling pathways that are activated during migraine.

The buffered picric acid paraformaldehyde fixative originally recommended for electronmicroscopy and which has since been used occasionally for light-microscopic immunocytochemistry, has been supplemented with glutaraldehyde and used as primary fixative for the perfusion of rat brains. In the basal ganglia and preoptic area, substance P, somatostatin and leu-enkephalin immunoreactive material was localized with the unlabelled antibody enzyme method in thick sections cut from freeze-thaw treated blocks. Good penetration of the antibodies without the use of detergents and the light background of the osmium-treated sections allowed the selection for electron-microscopy of immunoreactive structures as small as individual boutons that had been identified at the light-microscopic level. It is suggested that the procedure may be useful for electron-microscopic sampling of immunoreactive structures occurring infrequently over a large area or for the electron-microscopic study of light-microscopically classified neurons.

OBJECTIVE

To determine the relation between delirium in critically ill patients and their outcomes in the short term (in the intensive care unit and in hospital) and after discharge from hospital.

METHODS

Systematic review and meta-analysis of published studies.

METHODS

PubMed, Embase, CINAHL, Cochrane Library, and PsychINFO, with no language restrictions, up to 1 January 2015.

UNASSIGNED

Reports were eligible for inclusion if they were prospective observational cohorts or clinical trials of adults in intensive care units who were assessed with a validated delirium screening or rating system, and if the association was measured between delirium and at least one of four clinical endpoints (death during admission, length of stay, duration of mechanical ventilation, and any outcome after hospital discharge). Studies were excluded if they primarily enrolled patients with a neurological disorder or patients admitted to intensive care after cardiac surgery or organ/tissue transplantation, or centered on sedation management or alcohol or substance withdrawal. Data were extracted on characteristics of studies, populations sampled, identification of delirium, and outcomes. Random effects models and meta-regression analyses were used to pool data from individual studies.

RESULTS

Delirium was identified in 5280 of 16,595 (31.8%) critically ill patients reported in 42 studies. When compared with control patients without delirium, patients with delirium had significantly higher mortality during admission (risk ratio 2.19, 94% confidence interval 1.78 to 2.70; P<0.001) as well as longer durations of mechanical ventilation and lengths of stay in the intensive care unit and in hospital (standard mean differences 1.79 (95% confidence interval 0.31 to 3.27; P<0.001), 1.38 (0.99 to 1.77; P<0.001), and 0.97 (0.61 to 1.33; P<0.001), respectively). Available studies indicated an association between delirium and cognitive impairment after discharge.

CONCLUSIONS

Nearly a third of patients admitted to an intensive care unit develop delirium, and these patients are at increased risk of dying during admission, longer stays in hospital, and cognitive impairment after discharge.

The dependence of vascular relaxation on an intact endothelium and the relationship between relaxation and cyclic GMP accumulation were determined in coronary arteries isolated from cardiac transplantation patients with or without coronary atherosclerosis. In nonatherosclerotic arteries, the endothelium-dependent agent acetylcholine produced concentration-related relaxations. In atherosclerotic arteries, endothelium-dependent relaxations were abolished with acetylcholine, partly suppressed with substance P and histamine, and completely preserved with the ionophore A23187. In these arteries, the endothelium-independent agent nitroglycerin remained fully active. Accumulation of cyclic GMP in atherosclerotic strips was suppressed with acetylcholine but unattenuated with A23187 and nitroglycerin. In aortas from rabbits with diet-induced atherosclerosis, there was likewise an impaired cholinergic relaxation and cyclic GMP accumulation in the presence of preserved responses to A23187 and nitroglycerin. The results demonstrate that impaired cholinergic responses in atherosclerotic arteries reflect a muscarinic defect and not an inability of endothelium to release endothelial factor or smooth muscle to respond to it.

BACKGROUND

Cue reactivity in alcohol dependent adults has revealed autonomic, cognitive, and neural responses to alcohol-related stimuli that differ from those of nonabusers. Cue reactivity and craving responses have not been studied in youth.

METHODS

Alcohol-dependent young women (n=8) and female light social drinkers (n=9) ages 18-24 were administered an alcohol cue reactivity task during functional magnetic resonance imaging (fMRI) to examine brain response to alcohol-related words.

RESULTS

Alcohol dependent young women demonstrated significantly more blood oxygen level dependent (BOLD) response than nonabusers during alcohol word presentation trials relative to neutral word trials in subcallosal, anterior cingulate, left prefrontal, and bilateral insular regions (P<.025). However, controls showed greater response to alcohol words in some right hemisphere cortical regions. Increased craving after cue exposure correlated with increased subcallosal cortex BOLD response to alcohol cues (r=.87) among alcohol dependent subjects.

CONCLUSIONS

This pilot study corroborates previous reports of increased limbic and frontal response to substance cues and extends these findings to young alcohol dependent women. This limbic reaction may underlie the elevated physiological response and altered cognitive reactions to alcohol stimuli that are observed in alcohol dependent individuals.

In an attempt to reveal the function sites of substance P (SP) in the central nervous system (CNS), the distribution of SP receptor (SPR) was immunocytochemically investigated in adult rat and compared with that of SP-positive fibers. SPR-like immunoreactivity (LI) was mostly localized to neuronal cell bodies and dendrites. Neurons with intense SPR-LI were distributed densely in the cortical amygdaloid nucleus, hilus of the dentate gyrus, locus ceruleus, rostral half of the ambiguus nucleus, and intermediolateral nucleus of the thoracic cord; moderately in the caudatoputamen, nucleus accumbens, olfactory tubercle, median, pontine, and magnus raphe nuclei, laminae I and III of the caudal subnucleus of the spinal trigeminal nucleus, and lamina I of the spinal cord; and sparsely in the cerebral cortex, basal nucleus of Meynert, claustrum, gigantocellular reticular nucleus, and lobules IX and X of the cerebellar vermis. Neurons with weak to moderate SPR-LI were distributed more widely throughout the CNS. The regional patterns of distribution of SPR-LI were not necessarily the same as those of SP-positive fibers. The entopedunucular nucleus, substantia nigra, and lateral part of the interpeduncular nucleus showed intense SP-LI but displayed almost no SPR-LI. Conversely, the hilus of the dentate gyrus, anterodorsal thalamic nucleus, central nucleus of the inferior colliculus, and dorsal tegmental nucleus showed intense to moderate SPR-LI but contained few axons with SP-LI. These findings confirmed the presence of the "mismatch" problem between SP and SPR localizations. However, the distribution of SPR-LI was quite consistent with that of the SP-binding activity, which has been studied via autoradiography. This indicates that the sites of SPR-LI revealed in the present study represent most, if not all, sites of SP-binding activity.

Gabapentin and pregabalin are amino acid derivatives of gamma-amino butyric acid that have anticonvulsant, analgesic, and anxiolytic-like properties in animal models. The mechanisms of these effects, however, are not well understood. To ascertain whether these drugs have effects on sensory neurons, we studied their actions on capsaicin-evoked release of the sensory neuropeptides, substance P and calcitonin gene-related peptide from rat spinal cord slices in vitro. Although release of immunoreactive peptides from non-inflamed animals was not altered by either drug, prior in vivo treatment by intraplantar injection of complete Freund's adjuvant enhanced release from spinal tissues in vitro, which was attenuated by gabapentin and pregabalin. These drugs also reduced release of immunoreactive neuropeptides in spinal tissues pretreated in vitro with the protein kinase C activator, phorbol 12,13-dibutyrate. Our results suggest that gabapentin and pregabalin modulate the release of sensory neuropeptides, but only under conditions corresponding to significant inflammation-induced sensitization of the spinal cord.

The skin offers an ideally suited, clinically relevant model for studying the crossroads between peripheral and systemic responses to stress. A 'brain-skin connection' with local neuroimmunoendocrine circuitry underlies the pathogenesis of allergic and inflammatory skin diseases, triggered or aggravated by stress. In stressed mice, corticotropin-releasing hormone, nerve growth factor, neurotensin, substance P and mast cells are recruited hierarchically to induce neurogenic skin inflammation, which inhibits hair growth. The hair follicle is both a target and a source for immunomodulatory stress mediators, and has an equivalent of the hypothalamus-pituitary-adrenal axis. Thus, the skin and its appendages enable the study of complex neuroimmunoendocrine responses that peripheral tissues launch upon stress exposure, as a basis for identifying new targets for therapeutic stress intervention.

OBJECTIVE

While HIV-associated neurocognitive disorders (HAND) remain prevalent despite combination antiretroviral therapy (CART), the clinical relevance of asymptomatic neurocognitive impairment (ANI), the most common HAND diagnosis, remains unclear. We investigated whether HIV-infected persons with ANI were more likely than those who were neurocognitively normal (NCN) to experience a decline in everyday functioning (symptomatic decline).

METHODS

A total of 347 human participants from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort were NCN (n = 226) or had ANI (n = 121) at baseline. Neurocognitive assessments occurred approximately every 6 months, with median (interquartile range) follow-up of 45.2 (28.7-63.7) months. Symptomatic decline was based on self-report (SR) or objective, performance-based (PB) problems in everyday functioning. Proportional hazards modeling was used to generate risk ratios for progression to symptomatic HAND after adjusting for baseline and time-dependent covariates, including CD4+ T-lymphocyte count (CD4), virologic suppression, CART, and mood.

RESULTS

The ANI group had a shorter time to symptomatic HAND than the NCN after adjusting for baseline predictors: adjusted risk ratios for symptomatic HAND were 2.0 (confidence interval [CI] 1.1-3.6; p = 0.02) for SR, 5.8 (CI 3.2-10.7; p < 0.0001) for PB, and 3.2 (CI 2.0-5.0; p < 0.0001) for either SR or PB. Current CD4 and depression were significant time-dependent covariates, but antiretroviral regimen, virologic suppression, and substance abuse or dependence were not.

CONCLUSIONS

This longitudinal study demonstrates that ANI conveys a 2-fold to 6-fold increase in risk for earlier development of symptomatic HAND, supporting the prognostic value of the ANI diagnosis in clinical settings. Identifying those at highest risk for symptomatic decline may offer an opportunity to modify treatment to delay progression.

OBJECTIVE

The peristaltic reflex induced by mucosal stimuli is mediated by intrinsic sensory calcitonin gene-related peptide (CGRP) neurons activated by 5-hydroxytryptamine (5-HT) released from enterochromaffin cells. The involvement of 5-HT4 receptors was examined with selective 5-HT4 agonists.

METHODS

Compartmented intestinal segments were used to measure neurotransmitter release and the mechanical components of the reflex.

RESULTS

In human jejunal and rat and guinea pig colonic segments, addition of the 5-HT4 agonist HTF 919 elicited release of CGRP only into the compartment where the 5-HT4 agonist was added; vasoactive intestinal peptide (VIP) was released only into the compartment where descending relaxation was measured, and substance P (SP) was released only into the compartment where ascending contraction was measured. The CGRP antagonist hCGRPP, VIP, and SP as well as ascending and descending responses were inhibited by selective 5-HT4 but not by selective 5-HT3 antagonists. Similar results were obtained with a different 5-HT4 agonist, R093877. However, HTF 919 was 10-30 times more potent (median effective concentration, approximately 10 nmol/L for peptide release and 5 nmol/L for mechanical responses) than R093877.

CONCLUSIONS

Selective 5-HT4 agonists applied to the mucosa in nanomolar concentrations trigger the peristaltic reflex in human, rat, and guinea pig intestine.

Large neurons in laminae III and IV of the spinal cord which express the neurokinin 1 receptor and have dendrites that enter the superficial laminae are a major target for substance P (SP)-containing (nociceptive) primary afferents. Although some of these neurons project to the thalamus, we know little about other possible projection targets. The main aim of this study was to determine whether all cells of this type are projection neurons and to provide information about brainstem sites to which they project. Injections of cholera toxin B subunit were made into four brainstem areas that receive input from the spinal cord, and the proportion of cells of this type in the L4 spinal segment that were retrogradely labelled was determined in each case. The results suggest that most of these cells (>90%) project to the contralateral lateral reticular nucleus (or to a nearby region), while many (>60%) send axons to the lateral parabrachial area and some to the dorsal part of the caudal medulla. However, few of these cells project to the periaqueductal grey matter. As lamina I neurons with the neurokinin 1 receptor appear to be important in the generation of hyperalgesia, we also examined projection neurons in this lamina and found that for each injection site the great majority possessed the receptor. These results demonstrate that dorsal horn neurons which express the neurokinin 1 receptor contribute to several ascending pathways that are thought to be important in pain mechanisms.

There has been a need for a brief assessment tool for providers who treat chronic pain patients to determine potential risk of abuse when prescribed opioids for pain. The purpose of this study was to develop and begin the validation of a self-administered screening tool (Screener and Opioid Assessment for Patients with Pain, SOAPP) for chronic pain patients considered for long-term opioid therapy. A consensus of 26 pain and addiction experts was obtained on important characteristics of chronic pain patients that predict future medication misuse using concept mapping. A 24-item SOAPP (version 1.0) was developed based on this consensus and was administered to 175 patients who were taking opioids for chronic pain. After 6 months, 95 of these patients were re-evaluated. Validation of the SOAPP was conducted by identifying those patients exhibiting aberrant drug-related behavior as determined by any of the following: a positive score on the Prescription Drug Use Questionnaire (PDUQ) interview, positive urine toxicology screen, and/or ratings by staff as to whether patients had a serious drug problem. Of the original 24 items, 14 SOAPP items appeared to predict subsequent aberrant behaviors. Coefficient alpha for these 14 items was acceptable for a short scale (0.74). Receiver operating characteristics curve analysis yielded an area under the curve of 0.881 (P<0.001), suggesting adequate sensitivity and specificity for a screening device. These reliability and predictive validity results suggest that the SOAPP is a promising step toward screening risk potential for substance misuse among persons with chronic pain.

Keratinocytes have the ability to kill pathogenic fungi and bacteria by producing antimicrobial substances. Recent studies suggest that microbial components use signaling molecules of the human Toll-like receptor (TLR) family to transduce signals in various cells. Here we provide evidence that keratinocytes express both TLR2 and TLR4 at the mRNA and protein levels, and show that TLR2 and TLR4 are present in the normal human epidermis in vivo and that their expression is regulated by microbial components. The expression of myeloid differentiation protein gene (MyD88), which is involved in the signaling pathway of many TLR, was also demonstrated in keratinocytes. LPS + IFN-gamma increased the expression of TLR2 and TLR4 50- and 5-fold respectively. Treatment of keratinocytes with Candida albicans, mannan, Mycobacterium tuberculosis or LPS with IFN-gamma resulted in the activation and nuclear translocation of NF-kappaB. Inhibition of NF-kappaB blocked the Candida-killing activity of keratinocytes, suggesting that the antimicrobial effect of keratinocytes requires NF-kappaB activation. LPS + IFN-gamma, C. albicans (4 Candida/KC), peptidoglycan (1 micro g/ml) or M. tuberculosis extract significantly increased IL-8 gene expression after 3 h of treatment (P < 0.05). The increases over the 0-h level were 15-, 8-, 10.8- and 7-fold, respectively. The microbial compound-induced increase in IL-8 gene expression could be inhibited by anti-TLR2 and anti-TLR4 neutralizing antibodies, suggesting that TLRs are involved in the pathogen-induced expression of this pro-inflammatory cytokine. Our findings stress the importance of the role of keratinocytes as a component of innate immunity.

Acupuncture has a beneficial effect when treating many diseases and painful conditions, and therefore is thought to be useful as a complementary therapy or to replace generally accepted pharmacological intervention. The attributive effect of acupuncture has been investigated in inflammatory diseases, including asthma, rhinitis, inflammatory bowel disease, rheumatoid arthritis, epicondylitis, complex regional pain syndrome type 1 and vasculitis. Large randomised trials demonstrating the immediate and sustained effect of acupuncture are missing. Mechanisms underlying the ascribed immunosuppressive actions of acupuncture are reviewed in this communication. The acupuncture-controlled release of neuropeptides from nerve endings and subsequent vasodilative and anti-inflammatory effects through calcitonine gene-related peptide is hypothesised. The complex interactions with substance P, the analgesic contribution of beta-endorphin and the balance between cell-specific pro-inflammatory and anti-inflammatory cytokines tumour necrosis factor-alpha and interleukin-10 are discussed.

The neuroendocrine system affects the immune system through the neuroendocrine humoral outflow via the pituitary, and through direct neuronal influences via the sympathetic, parasympathetic (cholinergic) and peptidergic/sensory innervation of peripheral tissues. Circulating hormones or locally released neurotransmitters and neuropeptides regulate major immune functions, such as antigen presentation, antibody production, lymphocyte activity, proliferation and traffic, and the secretion of cytokines including the selection of T helper (Th)1 or Th2 cytokine responses. During inflammation, the activation of the stress system, through induction of a Th2 shift protects the organism from systemic "overshooting" with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones, substance P, ATP and the activation of the corticotropin-releasing hormone/substance P-histamine axis may actually facilitate inflammation, through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor (TNF)-alpha and CRP production. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression and atherosclerosis. Better understanding of the neuroendocrine control of inflammation may provide critical insights into mechanisms underlying a variety of common human immune-related diseases.

BACKGROUND

Pharmaceutical opioid related deaths have increased. This study aimed to place pharmaceutical opioid overdose deaths within the context of heroin, cocaine, psychostimulants, and pharmaceutical sedative hypnotics examine demographic trends, and describe common combinations of substances involved in opioid related deaths.

METHODS

We reviewed deaths among 15-64 year olds in the US from 1999-2009 using death certificate data available through the CDC Wide-Ranging Online Data for Epidemiologic Research (WONDER) Database. We identified International Classification of Disease-10 codes describing accidental overdose deaths, including poisonings related to stimulants, pharmaceutical drugs, and heroin. We used crude and age adjusted death rates (deaths/100,000 person years [p-y] and 95% confidence interval [CI] and multivariable Poisson regression models, yielding incident rate ratios; IRRs), for analysis.

RESULTS

The age adjusted death rate related to pharmaceutical opioids increased almost 4-fold from 1999 to 2009 (1.54/100,000 p-y [95% CI 1.49-1.60] to 6.05/100,000 p-y [95% CI 5.95-6.16; p<0.001). From 1999 to 2009, pharmaceutical opioids were responsible for the highest relative increase in overdose death rates (IRR 4.22, 95% CI 3.03-5.87) followed by sedative hypnotics (IRR 3.53, 95% CI 2.11-5.90). Heroin related overdose death rates increased from 2007 to 2009 (1.05/100,000 persons [95% CI 1.00-1.09] to 1.43/100,000 persons [95% CI 1.38-1.48; p<0.001). From 2005-2009 the combination of pharmaceutical opioids and benzodiazepines was the most common cause of polysubstance overdose deaths (1.27/100,000 p-y (95% CI 1.25-1.30).

CONCLUSIONS

Strategies, such as wider implementation of naloxone, expanded access to treatment, and development of new interventions are needed to curb the pharmaceutical opioid overdose epidemic.