BACKGROUND

The introduction of Apple's iPhone provided a platform for developers to design third-party apps, which greatly expanded the functionality and utility of mobile devices for public health.

OBJECTIVE

This study provides an overview of the developers' written descriptions of health and fitness apps and appraises each app's potential for influencing behavior change.

METHODS

Data for this study came from a content analysis of health and fitness app descriptions available on iTunes during February 2011. The Health Education Curriculum Analysis Tool (HECAT) and the Precede-Proceed Model (PPM) were used as frameworks to guide the coding of 3336 paid apps.

RESULTS

Compared to apps with a cost less than US $0.99, apps exceeding US $0.99 were more likely to be scored as intending to promote health or prevent disease (92.55%, 1925/3336 vs 83.59%, 1411/3336; P<.001), to be credible or trustworthy (91.11%, 1895/3336 vs 86.14%, 1454/3349; P<.001), and more likely to be used personally or recommended to a health care client (72.93%, 1517/2644 vs 66.77%, 1127/2644; P<.001). Apps related to healthy eating, physical activity, and personal health and wellness were more common than apps for substance abuse, mental and emotional health, violence prevention and safety, and sexual and reproductive health. Reinforcing apps were less common than predisposing and enabling apps. Only 1.86% (62/3336) of apps included all 3 factors (ie, predisposing, enabling, and reinforcing).

CONCLUSIONS

Development efforts could target public health behaviors for which few apps currently exist. Furthermore, practitioners should be cautious when promoting the use of apps as it appears most provide health-related information (predisposing) or make attempts at enabling behavior, with almost none including all theoretical factors recommended for behavior change.

BACKGROUND

Universal screening for mental health problems and suicide risk is at the forefront of the national agenda for youth suicide prevention, yet no study has directly addressed the potential harm of suicide screening.

OBJECTIVE

To examine whether asking about suicidal ideation or behavior during a screening program creates distress or increases suicidal ideation among high school students generally or among high-risk students reporting depressive symptoms, substance use problems, or suicide attempts.

METHODS

A randomized controlled study conducted within the context of a 2-day screening strategy. Participants were 2342 students in 6 high schools in New York State in 2002-2004. Classes were randomized to an experimental group (n = 1172), which received the first survey with suicide questions, or to a control group (n = 1170), which did not receive suicide questions.

METHODS

Distress measured at the end of the first survey and at the beginning of the second survey 2 days after the first measured on the Profile of Mood States adolescent version (POMS-A) instrument. Suicidal ideation assessed in the second survey.

RESULTS

Experimental and control groups did not differ on distress levels immediately after the first survey (mean [SD] POMS-A score, 5.5 [9.7] in the experimental group and 5.1 [10.0] in the control group; P = .66) or 2 days later (mean [SD] POMS-A score, 4.3 [9.0] in the experimental group and 3.9 [9.4] in the control group; P = .41), nor did rates of depressive feelings differ (13.3% and 11.0%, respectively; P = .19). Students exposed to suicide questions were no more likely to report suicidal ideation after the survey than unexposed students (4.7% and 3.9%, respectively; P = .49). High-risk students (defined as those with depression symptoms, substance use problems, or any previous suicide attempt) in the experimental group were neither more suicidal nor distressed than high-risk youth in the control group; on the contrary, depressed students and previous suicide attempters in the experimental group appeared less distressed (P = .01) and suicidal (P = .02), respectively, than high-risk control students.

CONCLUSIONS

No evidence of iatrogenic effects of suicide screening emerged. Screening in high schools is a safe component of youth suicide prevention efforts.

BACKGROUND

The prevalence and correlates of alcohol use disorder (AUD) and drug use disorder (DUD) diagnoses in Iraq and Afghanistan veterans who are new users of Department of Veterans Affairs (VA) healthcare nationwide has not been evaluated.

METHODS

VA administrative data were used in retrospective cross-sectional descriptive and multivariable analyses to determine the prevalence and independent correlates of AUD and DUD in 456,502 Iraq and Afghanistan veterans who were first-time users of VA healthcare between October 15, 2001 and September 30, 2009 and followed through January 1, 2010.

RESULTS

Over 11% received substance use disorder diagnoses: AUD, DUD or both; 10% received AUD diagnoses, 5% received DUD diagnoses and 3% received both. Male sex, age < 25 years, being never married or divorced, and proxies for greater combat exposure were independently associated with AUD and DUD diagnoses. Of those with AUD, DUD or both diagnoses, 55-75% also received PTSD or depression diagnoses. AUD, DUD or both diagnoses were 3-4.5 times more likely in veterans with PTSD and depression (p < 0.001).

CONCLUSIONS

Post-deployment AUD and DUD diagnoses were more prevalent in subgroups of Iraq and Afghanistan veterans and were highly comorbid with PTSD and depression. Stigma and lack of universal screening may have reduced the number of DUD diagnoses reported. There is a need for improved screening and diagnosis of substance use disorders and increased availability of integrated treatments that simultaneously address AUD and DUD in the context of PTSD and other deployment-related mental health disorders.

BACKGROUND

Mitochondrial oxidative stress and damage play major roles in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). We hypothesized that overexpression of the mitochondrial antioxidant, peroxiredoxin-3 (Prx-3), could attenuate this deleterious process.

RESULTS

We created MI in 12- to 16-week-old, male Prx-3-transgenic mice (TG+MI, n=37) and nontransgenic wild-type mice (WT+MI, n=39) by ligating the left coronary artery. Prx-3 protein levels were 1.8 times higher in the hearts from TG than WT mice, with no significant changes in other antioxidant enzymes. At 4 weeks after MI, LV thiobarbituric acid-reactive substances in the mitochondria were significantly lower in TG+MI than in WT+MI mice (mean+/-SEM, 1.5+/-0.2 vs 2.2+/-0.2 nmol/mg protein; n=8 each, P<0.05). LV cavity dilatation and dysfunction were attenuated in TG+MI compared with WT+MI mice, with no significant differences in infarct size (56+/-1% vs 55+/-1%; n=6 each, P=NS) and aortic pressure between groups. Mean LV end-diastolic pressures and lung weights in TG+MI mice were also larger than those in WT+sham-operated mice but smaller than those in WT+MI mice. Improvement in LV function in TG+MI mice was accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis in the noninfarcted LV. Mitochondrial DNA copy number and complex enzyme activities were significantly decreased in WT+MI mice, and this decrease was also ameliorated in TG+MI mice.

CONCLUSIONS

Overexpression of Prx-3 inhibited LV remodeling and failure after MI. Therapies designed to interfere with mitochondrial oxidative stress including the antioxidant Prx-3 might be beneficial in preventing cardiac failure.

The CNS cell groups that innervate the sympathoadrenal preganglionic neurons of rats were identified by a transneuronal viral cell body labeling technique combined with neurotransmitter immunohistochemistry. Pseudorabies virus was injected into the adrenal gland. This resulted in retrograde viral infections of the ipsilateral sympathetic preganglionic neurons (T4-T13) and caused retrograde transneuronal cell body infections in 5 areas of the brain: the caudal raphe nuclei, ventromedial medulla, rostral ventrolateral medulla, A5 cell group, and paraventricular hypothalamic nucleus (PVH). In the spinal cord, the segmental distribution of virally infected neurons was the same as the retrograde cell body labeling observed following Fluoro-gold injections in the adrenal gland except there was almost a 300% increase in the number of cells labeled and a shift in cell group distribution. These results imply there are local interneurons that regulate the sympathoadrenal preganglionic neurons. In the medulla oblongata, serotonin (5-HT)-, substance P (SP)-, thyrotropin-releasing hormone-, Met-enkephalin-, and somatostatin-immunoreactive neurons of the raphe pallidus and raphe obscurus nuclei and the ventromedial medulla were infected. In the ventromedial and rostral ventrolateral medulla, immunoreactive phenylethanolamine-N-methyltransferase, SP, neuropeptide Y, somatostatin, and enkephalin neurons were infected. The A5 noradrenergic cells were labeled, as were some somatostatin-immunoreactive neurons in this area. In the were infected. The A5 noradrenergic cells were labeled, as were some somatostatin-immunoreactive neurons in this area. In the hypothalamus, tyrosine hydroxylase- and SP-immunoreactive neurons of the dorsal parvocellular PVH were infected. Only a few immunoreactive vasopressin, oxytocin, Met-enkephalin, neurotensin, and somatostatin PVH neurons were labeled.

We performed immunohistochemical analysis of specimens from three autopsied patients with Parkinson's disease, using antibodies to tyrosine hydroxylase (TH), vasoactive intestinal polypeptide (VIP), somatostatin, met-enkephalin, leu-enkephalin and substance P in an attempt to reveal the types of neurons that contain Lewy bodies (LBs) in the paravertebral and celiac sympathetic ganglia and in the enteric nervous system of the alimentary tract. In the sympathetic ganglia, almost all LB-containing neuronal cell bodies and processes were immunoreactive for TH. In the alimentary tract, however, most LBs were found in the VIP-immunoreactive (VIP-IR) neuronal cell bodies and processes. In spite of the significant presence of TH-IR neuronal cell bodies and processes in the alimentary tract, LB-containing TH-IR neuronal elements were rarely encountered. These findings indicate that in the alimentary tract, the VIP neuron system is mainly involved in the disease process of Parkinson's disease.

Despite substantial improvements in perioperative mortality, complications, and specifically the development of a pancreatic fistula, remain a common occurrence after pancreaticoduodenectomy. It was the objective of this study to evaluate the role of fibrin glue sealant as an adjunct to decrease the rate of pancreatic fistula after pancreaticoduodenectomy. One hundred twenty-five patients were randomized after pancreaticoduodenal resection only if, in the opinion of the surgeon, the pancreaticojejunal anastomosis was at high risk for development of a pancreatic anastomotic leak. After completion of the pancreaticojejunal anastomosis, the patients were randomized to topical application of fibrin glue sealant to the surface of the anastomosis or no such application. The primary postoperative end points in this study were pancreatic fistula, total complications, death, and length of hospital stay. A total of 59 patients were randomized to the fibrin glue arm, whereas 66 patients were randomized to the control arm and did not receive fibrin glue application. The pancreatic fistula rate in the fibrin glue arm of the study was 26% vs. 30% in the control group (p = not significant [NS]). The mean length of postoperative stay for all patients randomized was similar (fibrin glue = 12.2 days, control = 13.6 days) and the mean length of stay for patients in whom pancreatic fistula developed was also not different (fibrin glue = 18.9 days, control = 21.7 days). There were no differences with respect to total complications or specific complications such as postoperative bleeding, infection, or delayed gastric emptying. These data demonstrate that the topical application of fibrin glue sealant to the surface of the pancreatic anastomosis in this patient population undergoing high-risk pancreaticojejunal anastomosis did not reduce the incidence of pancreatic fistula or total complications after pancreaticodudodenectomy. There seems to be no benefit regarding the use of this substance in this setting.

Studies on cultured cells have shown that agonists induce several types of G protein-coupled receptors to undergo internalization. We have investigated this phenomenon in rat striatum, using substance P (SP)-induced internalization of the SP receptor (SPR) as our model system. Within 1 min of a unilateral striatal injection of SP in the anesthetized rat, nearly 60% of the SPR-immunoreactive neurons within the injection zone display massive internalization of the SPR--i.e., 20-200 SPR+ endosomes per cell body. Within the dendrites the SPR undergoes a striking translocation from the plasma membrane to endosomes, and these dendrites also undergo a morphological reorganization, changing from a structure of rather uniform diameter to one characterized by large, swollen varicosities connected by thin fibers. In both cell bodies and dendrites the number of SPR+ endosomes returns to baseline within 60 min of SP injection. The number of neurons displaying substantial endosomal SPR internalization is dependent on the concentration of injected SP, and the SP-induced SPR internalization is inhibited by the nonpeptide neurokinin 1 receptor antagonist RP-67,580. These data demonstrate that in the central nervous system in vivo, SP induces a rapid and widespread SPR internalization in the cell bodies and dendrites and a structural reorganization of the dendrites. These results suggest that many of the observations that have been made on the internalization and recycling of G protein-coupled receptors in in vitro transfected cell systems are applicable to similar events that occur in the mammalian central nervous system in vivo.

Panax ginseng C. A. Meyer is a perennial herb native to Korea and China and has been used as an herbal remedy in eastern Asia for thousands of years. Modern therapeutic claims refer to vitality, immune function, cancer, cardiovascular diseases, improvement of cognitive and physical performance and sexual function. A recent systematic review of randomised controlled trials found that the efficacy of ginseng root extract could not be established beyond doubt for any of these indications. In order to obtain a balanced assessment of the therapeutic value of P. ginseng it is also necessary to consider the safety profile. In view of the extremely widespread use of P. ginseng it seems important to ask whether this herbal medicine involves health risks for the consumer. This review was conducted as a systematic attempt to document and evaluate all the available safety data on P. ginseng root extracts. Systematic searches were performed in five electronic databases and the reference lists of all papers located were checked for further relevant publications. All articles containing original data on adverse events and drug interactions with P. ginseng were included. Information was also requested from 12 manufacturers of ginseng preparations, the spontaneous reporting schemes of the WHO and national drug safety bodies. No language restrictions were imposed. Data from clinical trials suggest that the incidence of adverse events with ginseng monopreparations is similar to that with placebo. The most commonly experienced adverse events are headache, sleep and gastrointestinal disorders. The possibility of more serious adverse events is indicated in isolated case reports and data from spontaneous reporting schemes; however, causality is often difficult to determine from the evidence provided. Combination products containing ginseng as one of several constituents have been associated with serious adverse events and even fatalities. Interpretation of these cases is difficult as ingredients other than P. ginseng may have caused the problems. Possible drug interactions have been reported between P. ginseng and warfarin, phenelzine and alcohol. Collectively, these data suggest that P. ginseng monopreparations are rarely associated with adverse events or drug interactions. The ones that are documented are usually mild and transient. Combined preparations are more often associated with such events but causal attribution is usually not possible.

The glycine cleavage system catalyzes the following reversible reaction: Glycine + H(4)folate + NAD(+) <=>> 5,10-methylene-H(4)folate + CO(2) + NH(3) + NADH + H(+)The glycine cleavage system is widely distributed in animals, plants and bacteria and consists of three intrinsic and one common components: those are i) P-protein, a pyridoxal phosphate-containing protein, ii) T-protein, a protein required for the tetrahydrofolate-dependent reaction, iii) H-protein, a protein that carries the aminomethyl intermediate and then hydrogen through the prosthetic lipoyl moiety, and iv) L-protein, a common lipoamide dehydrogenase. In animals and plants, the proteins form an enzyme complex loosely associating with the mitochondrial inner membrane. In the enzymatic reaction, H-protein converts P-protein, which is by itself a potential alpha-amino acid decarboxylase, to an active enzyme, and also forms a complex with T-protein. In both glycine cleavage and synthesis, aminomethyl moiety bound to lipoic acid of H-protein represents the intermediate that is degraded to or can be formed from N(5),N(10)-methylene-H(4)folate and ammonia by the action of T-protein. N(5),N(10)-Methylene-H(4)folate is used for the biosynthesis of various cellular substances such as purines, thymidylate and methionine that is the major methyl group donor through S-adenosyl-methionine. This accounts for the physiological importance of the glycine cleavage system as the most prominent pathway in serine and glycine catabolism in various vertebrates including humans. Nonketotic hyperglycinemia, a congenital metabolic disorder in human infants, results from defective glycine cleavage activity. The majority of patients with nonketotic hyperglycinemia had lesions in the P-protein gene, whereas some had mutant T-protein genes. The only patient classified into the degenerative type of nonketotic hyperglycinemia had an H-protein devoid of the prosthetic lipoyl residue. The crystallography of normal T-protein as well as biochemical characterization of recombinants of the normal and mutant T-proteins confirmed why the mutant T-proteins had lost enzyme activity. Putative mechanisms of cellular injuries including those in the central nervous system of patients with nonketotic hyperglycinemia are discussed.

Mammalian and in vitro studies have raised concerns about the toxicity of titanium dioxide nanoparticles (TiO2 NPs), but there are very limited data on ecotoxicity to aquatic life. This paper is an observational study where we aim to describe the toxicity of TiO2 NPs to the main body systems of rainbow trout. Stock solutions of dispersed TiO2 NPs were prepared by sonication without using solvents. A semi-static test system was used to expose rainbow trout to either a freshwater control, 0.1, 0.5, or 1.0 mg l(-1) TiO2 NPs for up to 14 days. Exposure to TiO2 NPs caused some gill pathologies including oedema and thickening of the lamellae. No major haematological or blood disturbances were observed in terms of red and white blood cell counts, haematocrit values, whole blood haemoglobin, and plasma Na+ or K+ concentrations. Tissue metal levels (Na+, K+, Ca2+ and Mn) were generally unaffected. However, some exposure concentration-dependent changes in tissue Cu and Zn levels were observed, especially in the brain. Exposure to TiO2 NPs caused statistically significant decreases in Na+K+-ATPase activity (ANOVA, P<0.05) in the gills and intestine, and a trend of decreasing enzyme activity in the brain (the latter was not statistically significant). Thiobarbituric acid reactive substances (TBARS) showed exposure concentration-dependent and statistically significant (ANOVA or Kruskal-Wallis test, P<0.05) increases (two-fold or more) in the gill, intestine and brain, but not the liver during exposure to TiO2 NPs compared to controls. TiO2 NP exposure caused statistically significant (ANOVA, P<0.05) increases in the total glutathione levels in the gills, but depletion of hepatic glutathione compared to controls. Total glutathione levels in the brain and intestine were unaffected. Liver cells exposed to TiO2 NPs showed minor fatty change and lipidosis, and some hepatocytes showed condensed nuclear bodies (apoptotic bodies). Fish probably ingested water containing TiO2 NPs during exposure (stress-induced drinking) which may have resulted in some areas of erosion on the intestinal epithelium. Overall we conclude that titanium dioxide nanoparticles are not a major ionoregulatory toxicant, or haemolytic, at the concentration and exposure times used. Respiratory distress is a concern and sub-lethal toxicity involves oxidative stress, organ pathologies, and the induction of anti-oxidant defences, such as glutathione.

OBJECTIVE

Epidemiologic studies have linked exposure to severe environmental stress, such as natural disasters and combat operations, to the onset of specific psychiatric disorders. Some research also suggests that these exposures may be associated with the onset of chronic diseases as well. However, these chronic disease outcome studies often have been obscured by bias and confounding.

METHODS

The medical histories of 1399 male Vietnam veterans approximately 20 years after combat exposure (mean years = 17) were analyzed by lifetime posttraumatic stress disorder (PTSD) status (lifetime PTSD = 332 cases). These men were included in a national, random in-person study of United States Army veterans of the Vietnam War (study completion rate = 65%).

RESULTS

After controlling for preservice, in-service, and postservice factors (including intelligence, race, region of birth, enlistment status, volunteer status, Army marital status, Army medical profile, hypochondriasis, age, smoking history, substance abuse, education, and income), associations were found for reported circulatory [odds ratio (OR) = 1.62, p = .007], digestive (OR = 1.47, p = .036), musculoskeletal (OR = 1.78, p = .008), endocrine-nutritional-metabolic (OR = 1.58, p = .10), nervous system (OR = 2.47, p < .001), respiratory (OR = 1.54, p = .042), and nonsexually transmitted infectious diseases (OR = 2.14, p < .004) after military service.

CONCLUSIONS

Although this study has some limitations, it suggests that there is a direct link between severe stress exposures and a broad spectrum of human diseases. In the future, medical researchers and clinicians should focus more on the medical consequences of exposure to severe environmental stress and seek to better integrate psychobiologic models of disease pathogenesis.

1. The depressant actions of Mg2+ and a range of other divalent ions on synaptic excitation and on responses produced by excitatory amino acids and other putative transmitters have been investigated in hemisected isolated spinal cords of frogs and neonatal rats. Some comparative studies were also made using the rat isolated superior cervical ganglion. 2. At concentrations above 10 microM, Mg2+ selectively antagonized N-methyl-D-aspartate (NMDA)-induced motoneurone depolarization as recorded from ventral roots of tetrodotoxin-blocked spinal cords. Depolarization evoked by quisqualate (unaffected by 20 mM-Mg2+) was resistant to the depressant action of these ions, while depolarizations evoked by other excitant amino acids were depressed to intermediate degrees. 3. Mn2+, Co2+ and Ni2+ had qualitatively similar actions to Mg2+; Mn2+ was somewhat less potent and Co2+ and Ni2+ more potent than Mg2+. The alkaline earth metal ions, Ca2+, Sr2+ and Ba2+, had very weak Mg2+-like actions. Ca2+ and Mg2+ acted additively in depressing amino acid-induced responses. 4. Mg2+ also depressed motoneurone responses evoked by noradrenaline, substance P and carbachol in the neonatal rat isolated spinal cord. However, none of these effects were as marked as the depression of NMDA-induced responses by Mg2+ in this preparation. Mg2+ did not depress motoneurone depolarization produced by 5-HT in the rat spinal cord or the depolarizing action of GABA on primary afferent terminals of the isolated frog spinal cord. 5. At concentrations producing marked depression of NMDA-induced responses, Mg2+ also depressed synaptic transmission in spinal cords in the absence of an effect on ganglionic transmission. At the same concentrations, Mn2+, Co2+ and Ni2+ depressed synaptic transmission in both preparations. 6. From the similarity in action between Mg2+ and the D-alpha-aminoadipate group of NMDA antagonists, it is suggested that the central depressant action of low concentrations of Mg2+ involves predominantly a postsynaptically mediated interference with the action of an excitatory amino acid transmitter.

BACKGROUND

In isolated mammalian cardiomyocytes, papillary muscle preparations, and ejecting hearts, nitric oxide (NO) or other cyclic GMP-elevating interventions increase diastolic cell length and reduce peak contractile performance by hastening onset of myocardial relaxation. In the present study, the effect of NO on left ventricular (LV) relaxation and diastolic distensibility was investigated in humans.

RESULTS

The NO donor substance sodium nitroprusside was infused during cardiac catheterization in the global coronary bed of the LV of patients (n = 13) investigated for chest pain who were without evidence of obstructive coronary artery or other cardiac disease. Sodium nitroprusside was infused intracoronarily at a dosage (< or = 4 micrograms/min) that was previously shown to be devoid of systemic effects when infused into the brachial artery to investigate the reactivity of the forearm vascular bed. The effect of this global intracoronary infusion of the NO donor sodium nitroprusside was assessed by sequential LV angiograms and tip-micromanometer pressure recordings. During global intracoronary nitroprusside infusion, there was a decrease in heart rate from 78 +/- 11 to 76 +/- 12 beats per minute (P < .05), in LV peak systolic pressure from 161 +/- 18 to 146 +/- 18 mm Hg (P < .001), and in time to onset of LV relaxation (interval from Q wave on the ECG to LV dP/dtmin) from 432 +/- 36 to 419 +/- 36 milliseconds (P < .01). In 7 patients in whom adequate sequential LV angiograms could be obtained, LV end-diastolic volume increased from 158 +/- 34 to 165 +/- 40 mL (P < .05), whereas LV end-diastolic pressure fell from 18 +/- 5 to 12 +/- 3 mm Hg (P < .02), and in 5 of these 7 patients, a downward shift of the diastolic LV pressure-volume relation was observed. In 5 patients, a right atrial infusion of sodium nitroprusside was performed either before (n = 2) or after the global intracoronary infusion. The decrease in LV peak systolic pressure observed during right atrial infusion was significantly smaller (P < .01) than during global intracoronary infusion.

CONCLUSIONS

The present study reveals reduced LV pressure development, an LV relaxation-hastening effect, and improved LV diastolic distensibility during global intracoronary infusion of the NO donor substance sodium nitroprusside. These effects appeared to be unrelated to systemic vasodilation or to pericardial constraint and could be explained by a direct myocardial effect of NO, probably through activation of guanylyl cyclase to increase cyclic GMP or through modification of other cellular proteins.

We used a "current signature" method to subclassify acutely dissociated dorsal root ganglion (DRG) cells into nine subgroups. Cells subclassified by current signature had uniform properties. The type 1 cell had moderate capsaicin sensitivity (25.9 pA/pF), powerful, slowly desensitizing (tau = 2,300 ms), ATP-activated current (13.3 pA/pF), and small nondesensitizing responses to acidic solutions (5.6 pA/pF). Type 1 cells expressed calcitonin gene-related peptide immunoreactivity (CGRP-IR), manifested a wide action potential (7.3 ms), long duration afterhyperpolarization (57.0 ms), and were IB4 positive. The type 2 cell exhibited large capsaicin activated currents (134.9 pA/pF) but weak nondesensitizing responses to protons (15.3 pA/pF). Currents activated by ATP and alphabeta-m-ATP (51.7 and 44.6 pA/pF, respectively) had fast desensitization kinetics (tau = 214 ms) that were distinct from all other cell types. Type 2 cells were IB4 positive but did not contain either substance P (SP) or CGRP-IR. Similar to capsaicin-sensitive nociceptors in vivo, the afterhyperpolarization of the type 2 cell was prolonged (54.7 ms). The type 3 cell expressed, amiloride-sensitive, rapidly desensitizing (tau = 683 ms) proton-activated currents (127.0 pA/pF), and was insensitive to ATP or capsaicin. The type 3 cell was IB4 negative and contained neither CGRP nor SP-IR. The afterhyperpolarization (17.5 ms) suggested nonnociceptive function. The type 4 cell had powerful ATP-activated currents (17.4 pA/pF) with slow desensitization kinetics (tau = 2, 813 ms). The afterhyperpolarization was prolonged (46.5 ms), suggesting that this cell type might belong to a capsaicin-insensitive nociceptor population. The type 4 cell did not contain peptides. The type 7 cell manifested amiloride-sensitive, proton-activated currents (45.8 pA/pF) with very fast desensitization kinetics (tau = 255 ms) and was further distinct from the type 3 cell by virtue of a nondesensitizing amiloride-insensitive component (6.0 pA/pF). Capsaicin and ATP sensitivity were relatively weak (4.3 and 2.9 pA/pF, respectively). Type 7 cells were IB4 positive and contained both SP and CGRP-IR. They exhibited an exceptionally long afterhyperpolarization (110 ms) that was suggestive of a silent (mechanically insensitive) nociceptor. We concluded that presorting of DRG cells by current signatures separated them into internally homogenous subpopulations that were distinct from other subclassified cell types.

BACKGROUND

Attention deficit hyperactivity disorder (ADHD) is a common mental disorder associated with factors that are likely to increase mortality, such as oppositional defiant disorder or conduct disorder, criminality, accidents, and substance misuse. However, whether ADHD itself is associated with increased mortality remains unknown. We aimed to assess ADHD-related mortality in a large cohort of Danish individuals.

METHODS

By use of the Danish national registers, we followed up 1·92 million individuals, including 32,061 with ADHD, from their first birthday through to 2013. We estimated mortality rate ratios (MRRs), adjusted for calendar year, age, sex, family history of psychiatric disorders, maternal and paternal age, and parental educational and employment status, by Poisson regression, to compare individuals with and without ADHD.

RESULTS

During follow-up (24·9 million person-years), 5580 cohort members died. The mortality rate per 10,000 person-years was 5·85 among individuals with ADHD compared with 2·21 in those without (corresponding to a fully adjusted MRR of 2·07, 95% CI 1·70-2·50; p<0·0001). Accidents were the most common cause of death. Compared with individuals without ADHD, the fully adjusted MRR for individuals diagnosed with ADHD at ages younger than 6 years was 1·86 (95% CI 0·93-3·27), and it was 1·58 (1·21-2·03) for those aged 6-17 years, and 4·25 (3·05-5·78) for those aged 18 years or older. After exclusion of individuals with oppositional defiant disorder, conduct disorder, and substance use disorder, ADHD remained associated with increased mortality (fully adjusted MRR 1·50, 1·11-1·98), and was higher in girls and women (2·85, 1·56-4·71) than in boys and men (1·27, 0·89-1·76).

CONCLUSIONS

ADHD was associated with significantly increased mortality rates. People diagnosed with ADHD in adulthood had a higher MRR than did those diagnosed in childhood and adolescence. Comorbid oppositional defiant disorder, conduct disorder, and substance use disorder increased the MRR even further. However, when adjusted for these comorbidities, ADHD remained associated with excess mortality, with higher MRRs in girls and women with ADHD than in boys and men with ADHD. The excess mortality in ADHD was mainly driven by deaths from unnatural causes, especially accidents.

BACKGROUND

This study was supported by a grant from the Lundbeck Foundation.

A novel mammalian neuropeptide, the tachykinin substance K, is specified by a discrete genomic segment. Alternative RNA splicing generates two distinct mRNAs encoding the neuropeptide substance P alone or with substance K from a single preprotachykinin gene. Relative amounts of the mRNAs vary in different tissues, suggesting that the substance K-encoding sequence is regulated in a tissue-specific manner.

OBJECTIVE

To study the association between hepatitis C virus (HCV) infection and essential mixed cryoglobulinemia.

METHODS

Wards and clinics of the Ospedali Riuniti di Bergamo and Ospedale di Treviglio e Caravaggio, Italy.

METHODS

Fifty-one patients with essential mixed cryoglobulinemia associated with glomerulonephritis and 45 controls with noncryoglobulinemic glomerulopathies.

METHODS

Antibodies to hepatitis C virus (anti-HCV) in sera from patients with essential mixed cryoglobulinemia and from controls, using two enzyme-linked immunosorbent assays (c100 ELISA and c22/c200 ELISA) and a recombinant immunoblot assay (4-RIBA); cryoprecipitate anti-HCV before and after use of dithiothreitol, a substance able to destroy IgM antibodies with rheumatoid factor activity, in patients with essential mixed cryoglobulinemia; serum HCV RNA by polymerase chain reaction in patients with essential mixed cryoglobulinemia.

RESULTS

In patients with essential mixed cryoglobulinemia, the c22/c200 ELISA detected anti-HCV in 98% of serum samples (95% CI, 90% to 100%), whereas the rate of reactivity remained at 2% (CI, 0% to 12%) in the control group (P less than 0.0001). These results were confirmed by the 4-RIBA in 66% of patients with essential mixed cryoglobulinemia. The study of cryoprecipitate by c100 ELISA showed anti-HCV in 41% (Cl, 28% to 56%) of patients. After dithiothreitol, the rate of reactivity increased to 94% (CI, 84% to 99%; P less than 0.0001 by the McNemar paired chi-square test), suggesting that the elimination of rheumatoid factor leads to unmasking of anti-HCV in cryoprecipitate. Polymerase chain reaction detected HCV RNA in 13 of 16 sera from patients with essential mixed cryoglobulinemia.

CONCLUSIONS

The extremely high prevalence of anti-HCV in serum and cryoprecipitate along with the frequently associated serum HCV RNA suggests a close relation between essential mixed cryoglobulinemia and chronic HCV infection.

Serotonin activates respiration and enhances the stimulatory effect of CO2 on breathing. The present study tests whether the mechanism involves the retrotrapezoid nucleus (RTN), a group of medullary glutamatergic neurons activated by extracellular brain pH and presumed to regulate breathing. We show that the RTN is innervated by both medullary and pontine raphe and receives inputs from thyrotropin-releasing hormone (TRH) and substance P-expressing neurons. Coexistence of serotonin and substance P in terminals within RTN confirmed that lower medullary serotonergic neurons innervate RTN. In vivo, unilateral injection of serotonin into RTN stimulated inspiratory motor activity, and pH-sensitive RTN neurons were activated by iontophoretic application of serotonin or substance P. In brain slices, pH-sensitive RTN neurons were activated by serotonin, substance P, and TRH. The effect of serotonin in slices was ketanserin sensitive and persisted in the presence of glutamate, GABA, glycine, and purinergic ionotropic receptor antagonists. Serotonin and pH had approximately additive effects on the discharge rate of RTN neurons, both in slices and in vivo. In slices, serotonin produced an inward current with little effect on conductance and had no effect on the pH-induced current. We conclude that (1) RTN receives input from multiple raphe nuclei, (2) serotonin, substance P, and TRH activate RTN chemoreceptors, and (3) excitatory effects of serotonin and pH are mediated by distinct ionic conductances. Thus, RTN neurons presumably contribute to the respiratory stimulation caused by serotonergic neurons, but serotonin seems without effect on the cellular mechanism by which RTN neurons detect pH.

Risk of opioid dependence is genetically influenced. We recruited a sample of 393 small nuclear families (including 250 full-sib and 46 half-sib pairs), each with at least one individual with opioid dependence. Subjects underwent a detailed evaluation of substance dependence-related traits. As planned a priori to reduce heterogeneity, we used cluster analytic methods to identify opioid dependence-related symptom clusters, which were shown to be heritable. We then completed a genomewide linkage scan (with 409 markers) for the opioid-dependence diagnosis and for the two cluster-defined phenotypes represented by >250 families: the heavy-opioid-use cluster and the non-opioid-use cluster. Further exploratory analyses were completed for the other cluster-defined phenotypes. The statistically strongest results were seen with the cluster-defined traits. For the heavy-opioid-use cluster, we observed a LOD score of 3.06 on chromosome 17 (empirical pointwise P = .0002) for European American (EA) and African American (AA) subjects combined, and, for the non-opioid-use cluster, we observed a LOD score of 3.46 elsewhere on chromosome 17 (empirical pointwise P = .00002, uncorrected for multiple traits studied) for EA subjects only. We also identified a possible linkage (LOD score 2.43) of opioid dependence with chromosome 2 markers for the AA subjects. These results are an initial step in identifying genes for opioid dependence on the basis of a genomewide investigation (i.e., a study not conditioned on prior physiological candidate-gene hypotheses).

Historically, mast cells were known as a key cell type involved in type I hypersensitivity. Until last two decades, this cell type was recognized to be widely involved in a number of non-allergic diseases including inflammatory bowel disease (IBD). Markedly increased numbers of mast cells were observed in the mucosa of the ileum and colon of patients with IBD, which was accompanied by great changes of the content in mast cells such as dramatically increased expression of TNFalpha, IL-16 and substance P. The evidence of mast cell degranulation was found in the wall of intestine from patients with IBD with immunohistochemistry technique. The highly elevated histamine and tryptase levels were detected in mucosa of patients with IBD, strongly suggesting that mast cell degranulation is involved in the pathogenesis of IBD. However, little is known of the actions of histamine, tryptase, chymase and carboxypeptidase in IBD. Over the last decade, heparin has been used to treat IBD in clinical practice. The low molecular weight heparin (LMWH) was effective as adjuvant therapy, and the patients showed good clinical and laboratory response with no serious adverse effects. The roles of PGD2, LTC4, PAF and mast cell cytokines in IBD were also discussed. Recently, a series of experiments with dispersed colon mast cells suggested there should be at least two pathways in man for mast cells to amplify their own activation-degranulation signals in an autocrine or paracrine manner. The hypothesis is that mast cell secretogogues induce mast cell degranulation, release histamine, then stimulate the adjacent mast cells or positively feedback to further stimulate its host mast cells through H1 receptor. Whereas released tryptase acts similarly to histamine, but activates mast cells through its receptor PAR-2. The connections between current anti-IBD therapies or potential therapies for IBD with mast cells were discussed, implicating further that mast cell is a key cell type that is involved in the pathogenesis of IBD. In conclusion, while pathogenesis of IBD remains unclear, the key role of mast cells in this group of diseases demonstrated in the current review implicates strongly that IBD is a mast cell associated disease. Therefore, close attentions should be paid to the role of mast cells in IBD.

BACKGROUND

An early clinical trial suggested that the substance P (neurokinin(1) receptor) antagonist, aprepitant, might provide a unique mechanism of antidepressant activity. Phase III trials were conducted to confirm these findings.

METHODS

Five 8-week, randomized, double-blind, parallel-groups, placebo-controlled, multicenter trials in outpatients with Major Depressive Disorder were performed. Aprepitant 160 mg and placebo were included in all trials. Aprepitant 80 mg and paroxetine 20 mg (active comparator) were included in three trials. Approximately 150 patients were enrolled per treatment group in each trial. The primary end point was the mean change-from-baseline of the first 17 items of the Hamilton Rating Scale for Depression (HAM-D(17)) score at 8 weeks. A positron emission tomography (PET) study was also performed in normal subjects to determine the relationship between neurokinin(1) receptor occupancy and aprepitant plasma concentrations in dosing regimens relevant to the trials.

RESULTS

No statistically significant differences from placebo on the HAM-D(17) were observed at week 8 for either dose of aprepitant in any of the trials, whereas paroxetine 20 mg was significantly (p <or= .05) more effective than placebo at week 8 in each of the three trials in which it was included. Results from the <em>P</em>ET study indicated that the aprepitant dosing regimens provided continuously high levels of neurokinin(1) receptor blockade over 8 weeks.

CONCLUSIONS

Because the methodology employed confirmed the antidepressant efficacy of paroxetine, the absence of an effect for aprepitant indicates that it was not an effective treatment for depression. The concept of neurokinin(1) receptor antagonism as an antidepressant mechanism was not supported.

By light microscopic immunocytochemistry it has been previously shown that approximately equal to 70% of the neurons in rat dorsal root ganglia are labeled with an antiserum for glutamate conjugated to hemocyanin; the smaller among these neurons are also positive for substance P. By using a postembedding ImmunoGold method and electron microscopy, it is shown here that synaptic terminals in the superficial laminae of the spinal cord of rats selectively stain for the same glutamate antiserum. Immunolabeling is in small dome-shaped and in large scalloped synaptic terminals. Scalloped terminals are of two types. One type consists of dark terminals with many agranular vesicles of different size and a few large granular vesicles; these are probably endings of unmyelinated and small myelinated primary afferent fibers. The other type consists of light terminals with small agranular vesicles homogeneous in size with neurofilaments and many mitochondria; these are probably endings of larger myelinated primary afferent fibers. By means of double-labeling electron microscopic immunocytochemistry with colloidal gold particles of two different sizes, it is also shown here that substance P is present in only the dark type of glutamate-labeled scalloped terminals. The primary afferent origin of the terminals labeled by the antisera for glutamate and for substance P is demonstrated by a triple-labeling strategy: immunocytochemistry for both antisera on sections from rats in which dorsal rhizotomy or dorsal root ganglion injection of horseradish peroxidase conjugated to wheat germ agglutinin was performed. It is proposed that glutamate is the neurotransmitter in primary afferents mediating input from different peripheral receptor classes, including nociceptors. Effects of glutamate and substance P on spinal dorsal horn neurons may result from co-release of these two mediators from the same dorsal root afferent terminal.

The masking of antigens by aldehyde-containing fixatives or by paraffin embedding procedures is a problem for immunohistochemical studies. Enzymatic digestion, formic acid treatment, microwave heating and autoclave heating have been used to deal with this problem, with microwave heating-based antigen retrieval having become widely used as the method of choice. Microwave heating, however, has the shortcoming that it is difficult to precisely control the heating temperature and it is difficult to apply this method of heating to free-floating sections without damaging the sections. We describe here a simple, reliable and sensitive antigen retrieval method that uses water-bath heating. By this method, the temperature can be precisely controlled to yield effective antigen retrieval with minimal tissue damage in free-floating or paraffin-embedded slide-mounted sections. We found that the best results were obtained with a 30 min incubation in a 10-50 mM sodium citrate solution (pH 8.5-9.0) preheated to and maintained at 80 degrees C in a water-bath, followed by 30 min incubation in 0.3-3% nonfat dry milk to reduce nonspecfic staining. This method is highly effective for both 40 microm free floating sections, slide-mounted cryostat sections and paraffin-embedded slide-mounted sections, and it works well for tissue from diverse species (human, rat, mouse, pigeon, and zebra finch) and for diverse antigens (e.g. enkephalin, substance P, huntingtin, GluR1, GFAP, and ubiquitin). This method was also found to enhance immunolabeling in glutaraldehyde-fixed tissue that had been prepared for ultrastructural examination, without having a deleterious effect on the ultrastructure.