Background Epicutaneous allergen administration using a patch may be an alternative to subcutaneous or sublingual immunotherapy. Objective To optimize treatment dose and to demonstrate the efficacy ...and safety of epicutaneous immunotherapy. Methods This monocentric, placebo-controlled, double-blind trial included 132 patients with grass pollen–induced rhinoconjunctivitis. In February 2008, patients were randomly allocated to receive placebo or 3 different doses of allergen. Before and during the pollen season 2008, patients received 6 weekly patches. Efficacy was assessed 4 to 5 months later (n = 110) and during the pollen season of the treatment-free follow-up year in 2009 (n = 93). The primary outcome was patient-reported changes in hay fever symptoms assessed by a visual analog scale. Secondary outcome measures were weekly visual analog scale symptom scores during pollen season, use of rescue medication, changes in conjunctival and skin reactivity, as well as safety. Results Hay fever symptoms during the pollen season were reduced by more than 30% in 2008 and by 24% in 2009 in the high-dose group as compared with that in the placebo group, and the alleviation of symptoms in the follow-up year was dependent on the treatment dose. Higher allergen doses were associated with drug-related adverse events (AEs), predominantly manifested by pruritus, erythema, wheal, or eczema. Eleven systemic AEs of grades 1 to 2 required treatment and led to study exclusion. The dropout rate due to AEs was 8.3%. No drug-related serious AE was recorded. Conclusion Epicutaneous immunotherapy is safe and efficacious in a dose-dependent manner after 6 patches only.
The classical serotonergic psychedelics LSD, psilocybin, mescaline are not known to cause brain damage and are regarded as non-addictive. Clinical studies do not suggest that psychedelics cause ...long-term mental health problems. Psychedelics have been used in the Americas for thousands of years. Over 30 million people currently living in the US have used LSD, psilocybin, or mescaline.
To evaluate the association between the lifetime use of psychedelics and current mental health in the adult population.
Data drawn from years 2001 to 2004 of the National Survey on Drug Use and Health consisted of 130,152 respondents, randomly selected to be representative of the adult population in the United States. Standardized screening measures for past year mental health included serious psychological distress (K6 scale), mental health treatment (inpatient, outpatient, medication, needed but did not receive), symptoms of eight psychiatric disorders (panic disorder, major depressive episode, mania, social phobia, general anxiety disorder, agoraphobia, posttraumatic stress disorder, and non-affective psychosis), and seven specific symptoms of non-affective psychosis. We calculated weighted odds ratios by multivariate logistic regression controlling for a range of sociodemographic variables, use of illicit drugs, risk taking behavior, and exposure to traumatic events.
21,967 respondents (13.4% weighted) reported lifetime psychedelic use. There were no significant associations between lifetime use of any psychedelics, lifetime use of specific psychedelics (LSD, psilocybin, mescaline, peyote), or past year use of LSD and increased rate of any of the mental health outcomes. Rather, in several cases psychedelic use was associated with lower rate of mental health problems.
We did not find use of psychedelics to be an independent risk factor for mental health problems.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A recent large population study of 130,000 adults in the United States failed to find evidence for a link between psychedelic use (lysergic acid diethylamide, psilocybin or mescaline) and mental ...health problems. Using a new data set consisting of 135,095 randomly selected United States adults, including 19,299 psychedelic users, we examine the associations between psychedelic use and mental health. After adjusting for sociodemographics, other drug use and childhood depression, we found no significant associations between lifetime use of psychedelics and increased likelihood of past year serious psychological distress, mental health treatment, suicidal thoughts, suicidal plans and suicide attempt, depression and anxiety. We failed to find evidence that psychedelic use is an independent risk factor for mental health problems. Psychedelics are not known to harm the brain or other body organs or to cause addiction or compulsive use; serious adverse events involving psychedelics are extremely rare. Overall, it is difficult to see how prohibition of psychedelics can be justified as a public health measure.
Assessments of lysergic acid diethylamide (LSD) in the treatment of alcoholism have not been based on quantitative meta-analysis. Hence, we performed a meta-analysis of randomized controlled trials ...in order to evaluate the clinical efficacy of LSD in the treatment of alcoholism. Two reviewers independently extracted the data, pooling the effects using odds ratios (ORs) by a generic inverse variance, random effects model. We identified six eligible trials, including 536 participants. There was evidence for a beneficial effect of LSD on alcohol misuse (OR, 1.96; 95% CI, 1.36–2.84; p = 0.0003). Between-trial heterogeneity for the treatment effects was negligible (I2 = 0%). Secondary outcomes, risk of bias and limitations are discussed. A single dose of LSD, in the context of various alcoholism treatment programs, is associated with a decrease in alcohol misuse.
...if a large amount of allergen penetrates beyond the nonvascularized epidermis toward the dermal vasculature, systemic allergic reactions are frequent, as observed in 6 patients after abrasion. ...Because end points were efficacy and immunological changes, no power calculations were done for the present retrospective analysis.\n Statistical analysis Because this study is retrospective analysis of a clinical trial determining the safety and efficacy of allergen EPIT by comparing it to placebo EPIT (ClinicalTrials.govNCT00777374), sample size calculation was powered to show the clinical efficacy of allergen EPIT compared with that of placebo EPIT.
...it should not be forgotten that these "invalid" injections are followed by "valid" maintenance doses that are administered with a minimum 4-week interval in accordance with the Centers for Disease ...Control and Prevention guidelines. ...pulsatile antigen kinetics, such as achieved by our monthly injections, tend to induce a TH1-polarized immune response, whereas prolonged antigen exposure produced by frequent injections tends to induce a TH2-polarized response.
FBPs are components of the SCF protein E3 ubiquitin ligase and can specifically bind to substrates and thereby regulate multiple tumor behaviors. However, the role of FBPs, FBXO25 in particular, in ...cutaneous squamous cell carcinoma (cSCC) has not been explored yet. In this study, we found FBXO25 to be highly expressed in cSCC in mice and in vitro, whereas it was significantly less expressed in normal keratinocytes. Stable silencing of FBXO25 in SCC13 cells led to reduced tumor growth, and the knockdown of FBXO25 was accompanied by downregulation of cyclin D1. Correspondingly, stable overexpression of cyclin D1 in FBXO25-deficient SCC13 tumors increased tumor growth, supporting the hypothesis that FBXO25 promotes cSCC growth and metastasis through cyclin D1. Moreover, we found FBXO25 and cyclin D1 interaction to be facilitated through the repressor (Oct-1) of cyclin D1. Our data indicate that Oct-1 interacts directly with FBXO25 and undergoes downregulation, consequently stabilizing cyclin D1 and promoting tumor growth and metastasis.
Background Subcutaneous allergen-specific immunotherapy frequently causes allergic side effects and requires 30 to 80 injections over 3 to 5 years. Objective We sought to improve immunotherapy by ...using intralymphatic allergen administration (intralymphatic immunotherapy ILIT) and by targeting allergen to the MHC class II pathway. Methods Recombinant major cat dander allergen Fel d 1 was fused to a translocation sequence (TAT) and to part of the human invariant chain, generating a modular antigen transporter (MAT) vaccine (MAT–Fel d 1). In a randomized double-blind trial ILIT with MAT–Fel d 1 in alum was compared with ILIT with placebo (saline in alum) in allergic patients ( ClinicalTrials.gov NCT00718679 ). Results ILIT with MAT–Fel d 1 elicited no adverse events. After 3 placebo injections within 2 months, nasal tolerance increased less than 3-fold, whereas 3 intralymphatic injections with MAT–Fel d 1 increased nasal tolerance 74-fold ( P < .001 vs placebo). ILIT with MAT–Fel d 1 stimulated regulatory T-cell responses ( P = .026 vs placebo) and increased cat dander–specific IgG4 levels by 5.66-fold ( P = .003). The IgG4 response positively correlated with IL-10 production ( P < .001). Conclusion In a first-in-human clinical study ILIT with MAT–Fel d 1 was safe and induced allergen tolerance after 3 injections.
Background Antihistamines are considered safe and used worldwide against allergy, pruritus, nausea, and cough and as sleeping aids. Nonetheless, a growing number of reports suggest that ...antihistamines also have immunoregulatory functions. Objective We examined the extent and by what potential mechanisms histamine-1-receptor (H1R) antagonists exert immune suppressive effects. Methods Immune suppression by antihistamines and immunosuppressants was tested in mice infected with Listeria monocytogenes . Potential modes of action were studied in vitro by using murine and human cells. We also tested whether injection of clemastine in healthy volunteers affected the activation of peripheral macrophages and monocytes. Finally, therapeutic application of clemastine-mediated immune suppression was tested in a murine model of sepsis. Results Clemastine and desloratadine strongly reduced innate responses to Listeria monocytogenes in mice as did dexamethasone. The immune suppression was MyD88 independent and characterized by inhibition of the mitogen-activated protein kinase–extracellular signal-regulated kinase signaling pathway, leading to overall impaired innate immunity with reduced TNF-α and IL-6 production. Surprisingly, the observed effects were H1R independent as demonstrated in H1R-deficient mice. Moreover, in a double-blind placebo-controlled clinical trial, 1 intravenous administration of clemastine reduced the TNF-α secretion potential of peripheral blood macrophages and monocytes. This inhibition could be exploited to treat sepsis in mice. Conclusions The safety profile of antihistamines may need to be revisited. However, antihistamine-mediated immune suppression may also be exploited and find applications in the treatment of inflammatory diseases.
The gastric lamina propria of mice that have been experimentally infected with the pathobiont Helicobacter pylori hosts a dense network of myeloid cells that includes BATF3-dependent CD103+ dendritic ...cells (DCs). We show here that CD103+ DCs are strictly required for gastric Th1 responses to H. pylori and for H. pylori infection control. A similar dependence of type 1 immunity on CD103+ DCs is observed in a Mycobacterium bovis BCG infection model, and in a syngeneic colon cancer model. Strikingly, we find that not only the expansion and/or recruitment of Th1 cells, but also of peripherally induced, neuropilin-negative regulatory T-cells to sites of infection requires BATF3-dependent DCs. A shared feature of the examined models is the strongly reduced production of the chemokines and CXCR3 ligands CXCL9, 10 and 11 in BATF3-deficient mice. The results implicate BATF3-dependent DCs in the recruitment of CXCR3+ effector and regulatory T-cells to target tissues and in their local expansion.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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