Clear Dose-dependent Relationship Research Articles

The antioxidant, anti-inflammatory and analgesic activity effect of ethyl acetate extract from the flowers of Syringa pubescens Turcz

Ethnopharmacological relevanceSyringa Pubescens Turcz. (SP), a member of the Oleaceae family, is a species of plant known as Syringa. Flowers, as the medicinal part, are commonly used in the treatment of hepatitis and tonsillitis.Aim of the study: The research was the first to assess the antioxidant and anti-inflammatory potential of different parts of SP flowers (SPF) in vitro. The most promising fraction was ethyl acetate fraction of SP flower (SPFEA). The antioxidant, anti-inflammatory and analgesic activities of SPFEA were further studied, and the chemical components were identified. MethodsHPLC was used to identify the major components in various fraction of SPF. DPPH and ABTS + radical scavenging assays as well as FRAP test and β-carotene bleaching test were employed to assess the antioxidant potential of SPF fraction in vitro. The inhibitory effect on NO production in LPS-treated RAW264.7 cells and heat-induced protein denaturation test were used to evaluate the anti-inflammatory potential of SPF fraction. Further analysis of the biological activity of SPFEA was performed. Acute toxicity test was conducted to assess the toxicity of SPFEA. The anti-inflammatory effect was assessed by utilizing xylene induced ear edema model, carrageenan-induced foot edema model and peritonitis model in vivo. The analgesic effect of SPFEA was evaluated using hot plate test, tail immersion test, formaldehyde test as well as acetic acid-induced abdominal writhing pain experiment in vivo. In carrageenan induced foot edema model, ELISA kits were employed to measure levels of inflammation factors (NO, TNF-α, IL-6, COX-2, IL-1β) in foot tissue as well as MDA, CAT, SOD, GSH-PX levels in liver tissue. ResultsHPLC results showed that there were significant differences in bioactive substances among different fractions of SPF, and SPFEA was rich in bioacitve components. Compared with other fractions of SPF, SPFEA exhibited better antioxidant and anti-inflammatory abilities. The 3000 mg/kg SPFEA group in mice had no obvious side effects. The xylene-induced ear edema model, carrageenan-induced foot edema and peritonitis models demonstrated that the SPFEA had significant anti-inflammatory effect. Moreover, inflammation factors including NO, TNF-α, IL-6, COX-2, IL-1β were significantly reduced in SPFEA groups in foot tissue induced by carrageenan. Additionally, SPFEA effectively decreased liver tissue oxidative stress levels (MDA, SOD, GSH-PX and CAT). The bioactivities of SPFEA demonstrated a clear dose-dependent relationship. The results of the hot plate test, tail immersion test, formaldehyde test and acetic acid-induced abdominal writhing pain experiments indicated the SPFEA possessed an excellent analgesic effect, and this effect was in dose-dependent manner. ConclusionThe study provides a scientific foundation for understanding the pharmacological action of SPFEA. It has been indicated that SPFEA has excellent antioxidant, analgesic and anti-inflammatory effects.

Dose-Exposure-Response Relationships of Biomarkers and Efficacy Measures with Iptacopan, a Complement Factor B Inhibitor, in Patients (pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH) with or without Concomitant Anti-C5 Therapy

Background: Standard of care treatment for pts with PNH targets C5 in the complement pathway; however, residual intravascular hemolysis (IVH) and emerging C3-mediated extravascular hemolysis (EVH) can still occur. In two Phase II trials (X2201 [NCT03439839] and X2204 [NCT03896152]), the oral, selective, reversible complement factor B inhibitor iptacopan provided hematologic benefit in pts with PNH who had active hemolysis, both as add-on therapy in anti-C5-treated pts and monotherapy in anti-C5-naïve pts (Risitano et al. Lancet Haematol 2021; Jang et al. Blood Adv 2022). Using data from these two studies, this integrated analysis aimed to evaluate dose-exposure-response relationships of biomarkers and efficacy measures to support dose selection for iptacopan. Methods: X2201 and X2204 were open-label studies that enrolled pts with PNH who had active hemolysis, despite treatment with anti-C5 therapy, or in the absence of prior anti-C5 therapy, respectively. In X2201, pts with lactate dehydrogenase (LDH) ≥1.5 x upper limit of normal (ULN) received iptacopan 200 mg twice daily (bid; Cohort 1) and pts with LDH ≥1.25 x ULN and hemoglobin (Hb) <10.5 g/dL received iptacopan 50 mg bid (Cohort 2). Pts in Cohort 2 could have their dose increased to 200 mg bid if hemolysis persisted. Both cohorts received iptacopan as add-on therapy to eculizumab; eculizumab treatment could be adjusted or withdrawn after 26 weeks (wks) at the investigator's discretion. In X2204, pts with LDH ≥1.5 x ULN and Hb <10.5 g/dL who were naïve to anti-C5 treatment were randomized to receive iptacopan 25 mg bid for 4 wks followed by iptacopan 100 mg bid for 8 wks (Cohort 1), or iptacopan 50 mg bid for 4 wks followed by iptacopan 200 mg bid for 8 wks (Cohort 2). To quantify the exposure-response relationship, trough concentrations of iptacopan (Ctrough) were correlated with LDH, Hb, factor Bb fragments, Wieslab® alternative complement pathway activity assay data, C3 fragment deposition on red blood cells (RBCs) and PNH RBC clone size using sigmoid maximum effect (Emax) models. Analyses were performed after pts had received iptacopan at the same dose for 4 wks. Results: A total of 29 pts with PNH were enrolled (X2201, N=16; X2204, N=13). The pharmacokinetic parameters of iptacopan were in line with previous reports in these two studies (Risitano et al. Lancet Haematol 2021; Jang et al.Blood Adv 2022) and were similar between the two study populations. In the dose range 25-200 mg bid, increases in dose resulted in a less than proportional increase in exposure, probably because of on-target binding to the highly abundant plasma factor B. Age and sex did not significantly impact exposure; the impact of ethnicity was not assessed because it was confounded by the study populations (15/16 pts in X2201 were Caucasian; all pts in X2204 were Asian). When assessing LDH, Hb, factor Bb fragments and Wieslab® assay data, 95% of the maximum response was reached with Ctrough >700 ng/mL, >650 ng/mL, >500 ng/mL and >750 ng/mL (EC95), respectively. C3 deposition was only informative in X2201; in X2204, C3 deposition was negligible at baseline and throughout the study because the pts were anti-C5-naïve. Complete abrogation of C3 deposition was reached at all dose levels in X2201 (Ctrough >600 ng/mL). PNH RBC cell clone size increased in both studies, but no clear dose-dependent relationship was observed. Accounting for interpatient variability in exposure, iptacopan 200 mg bid was identified as the optimum regimen to achieve Ctrough >750 ng/mL in most pts. Conclusions: Results from this pooled dose-exposure-response analysis of the X2201 and X2204 studies indicate that iptacopan 200 mg bid is the optimum dose to achieve Ctrough >750 ng/mL and consequently to provide maximal disease control via alternative complement pathway inhibition. The dose-exposure-response relationship was similar between pts regardless of whether they had a partial response to C5 inhibition (X2201) or were anti-C5-naïve (X2204), supporting the use of iptacopan 200 mg bid in both populations. Based on clinical efficacy and safety data from these two studies (Risitano et al. Lancet Haematol 2021; Jang et al. Blood Adv 2022) and supported by data from this integrated dose-exposure-response analysis, two ongoing Phase III trials are investigating iptacopan monotherapy at a dose of 200 mg bid in anti-C5 treated (APPLY-PNH; NCT04558918) and anti-C5-naïve (APPOINT-PNH; NCT04820530) pts with PNH.

Developmental exposure to the brominated flame retardant DE-71 reduces serum thyroid hormones in rats without hypothalamic-pituitary-thyroid axis activation or neurobehavioral changes in offspring

Polybrominated diphenyl ethers (PBDEs) are legacy flame retardants for which human exposure remains ubiquitous. This is of concern since these chemicals can perturb development and cause adverse health effects. For instance, DE-71, a technical mixture of PBDEs, can induce liver toxicity as well as reproductive and developmental toxicity. DE-71 can also disrupt the thyroid hormone (TH) system which may induce developmental neurotoxicity indirectly. However, in developmental toxicity studies, it remains unclear how DE-71 exposure affects the offspring's thyroid hormone system and if this dose-dependently relates to neurodevelopmental effects. To address this, we performed a rat toxicity study by exposing pregnant dams to DE-71 at 0, 40 or 60 mg/kg/day during perinatal development from gestational day 7 to postnatal day 16. We assessed the TH system in both dams and their offspring, as well as potential hearing and neurodevelopmental effects in prepubertal and adult offspring. DE-71 significantly reduced serum T4 and T3 levels in both dams and offspring without a concomitant upregulation of TSH, thus inducing a hypothyroxinemia-like effect. No discernible effects were observed on the offspring's brain function when assessed in motor activity boxes and in the Morris water maze, or on offspring hearing function. Our results, together with a thorough review of the literature, suggest that DE-71 does not elicit a clear dose-dependent relationship between low serum thyroxine (T4) and effects on the rat brain in standard behavioral assays. However, low serum TH levels are in themselves believed to be detrimental to human brain development, thus we propose that we lack assays to identify developmental neurotoxicity caused by chemicals disrupting the TH system through various mechanisms.

Spanish Satureja montana L. hydrolate: Ecotoxicological study in soil and water non-target organisms

Despite the current popularity of herbal and flower hydrolates and the multiple applications found in the food, wood, pharmaceutical, pesticide, perfume, cosmetic, and aromatherapy industries, the effect of hydrolates in the environment is poorly known. This study evaluates the ecotoxicity of the Satureja montana L. hydrolate on water and soil bioindicators and also on the fluvial periphyton mesocosms for a more ecological point of view. The acute toxicity of the fresh water invertebrate Daphnia magna, the bacteria Vibrio fisheri, and the earthworm Eisenia fetida, was quantified as well as the phytotoxic effect on the plant Allium cepa L. Communities of river periphyton were used to study the impact of the hydrolate on the freshwater ecosystems. The taxonomic study of these communities revealed a rich diversity of diatoms. The hydrolate of S. montana showed a high ecotoxicity at very low percentages of hydrolate in all organisms tested and in the periphyton communities. The LC50 varies from 0.05% to 4.25%, with a clear dose-dependent relationship. The effect of the hydrolate in decreasing order was: A.cepa > D. magna > V. fisheri > periphyton > E. fetida. The strong phytotoxic effect on A. cepa allows exploring possible uses of the hydrolate as a bio-herbicide. The Gas Chromatography Mass Spectrometry (GC-MS) characterisation of the hydrolate reveals 1 alcohol and 6 terpenes. Carvacrol (89.03%) and thymol (6.66%) are the volatile compounds found in the highest proportion, products that have multiple biological properties and known synergistic effects, which could explain the high bioactivity of the hydrolate. Our study suggests that S. montana hydrolate could impact different trophic levels of the river ecosystems and can affect the soil functions affecting earthworms due its powerful bioactivity on a wide range of non-target organisms even in complex communities such as the fluvial periphyton. Therefore, although hydrolates can become a good alternative to synthetic products, the use of these products is not free of environmental risks and their release to the environment should be evaluated.

Cytotoxicity and genotoxicity of Hevea brasiliensis latex C-serum DCS sub-fraction as anticancer agents

Dialysed latex C-serum supernatant (DCS) sub-fraction from the rubber tree (Hevea brasiliensis) was reported to exert significant anti-proliferative effect on specific cancer cell lines, especially in human triple negative breast cancer (MDA-MB-231) and human liver carcinoma (HepG2) cells. In the present study, two human non-cancer origin cell lines, MCF-10A (human breast epithelial cells) and HDFa (human adult dermal fibroblast cells), showed least susceptibility when treated with DCS sub-fraction at concentration range 0–100 µg/mL using 2,5-diphenyl tetrazolium bromide (MTT) assay. Genotoxicity of DCS sub-fraction was assessed through Ames test, in vitro mouse lymphoma assay, and in vitro micronucleus assay. All genotoxicity experiments were tested with the presence and absence of S9 mixture as metabolic activation system. Ames test results showed negative result of mutagenicity as no clear dose-dependent relationship was observed despite mutagenic potential was detected in frame shift-based TA98 and TA1535 Salmonella typhimurium strains. Mouse lymphoma assay produced non-linear dose-dependent effect in experiments without the presence of S9. Meanwhile, experiment with the presence of S9 resulted in an inverse effect of the dose-dependent relationship. In micronucleus assay, the dose-dependent cytotoxicity effect of DCS sub-fraction showed no correlation with the increase number of cells containing micronuclei but appeared to be time-dependent. In conclusion, DCS sub-fraction showed no significant positive results in genotoxicity assays. In vivo genotoxicity assays should be conducted to ensure the safe use of DCS sub-fraction in further exploration for biological applications.

Genotoxic Assessment of the Dry Decoction of Myracrodruon urundeuva Allemão (Anacardiaceae) Leaves in Somatic Cells of Drosophila melanogaster by the Comet and SMART Assays.

Medicinal plants are worldwide used as an efficient treatment of many diseases. Myracrodruon urundeuva Allemão (Anacardiaceae) is widely used Brazilian folk medicine to treat inflammations and infections of the female genital tract, conditions of the stomach and throat, and to heal wounds on the skin and mucous membranes. Several pharmacological properties of extracts and compounds isolated from M. urundeuva are found in the literature, corroborating its uses as antiulcer and gastroprotective, anti-inflammatory and analgesic, as well as antimicrobial. Despite these many uses in traditional herbal medicine, there are few reports of its toxic-genetic effect. This work aimed to investigate the genotoxic and mutagenic potential in vivo of the dry decoction of M. urundeuva leaves on somatic cells of Drosophila melanogaster, through the Comet assay and somatic mutation and recombination test (SMART). Six concentrations (0.5, 1.0, 2.0, 4.0, 8.0, and 16.0 mg/mL) were studied after feeding individuals for 24 hr in culture medium hydrated with extracts of M. urundeuva. In the Comet assay, all concentrations showed a genotoxic effect significantly higher than the negative control group, treated with distilled water. The two highest concentrations were also superior to the positive control group, treated with cyclophosphamide (1 mg/mL). In the SMART, there was a mutagenic effect at all concentrations tested, with a clear dose-dependent relationship. Both recombination and mutation account for these mutagenic effects. The set of results indicate that the dry decoction of M. urundeuva leaves is genotoxic and mutagenic for D. melanogaster under the experimental conditions of this study. Environ. Mol. Mutagen. 61:329-337, 2020. © 2019 Wiley Periodicals, Inc.

Antipsychotic drugs and risk of newly diagnosed tuberculosis in schizophrenia.

Patients with schizophrenia have a higher incidence of tuberculosis than do people in the general population. Information is limited regarding the association between antipsychotic agents and the risk of tuberculosis in patients with schizophrenia. This exploratory study assessed the risk of tuberculosis among patients with schizophrenia on antipsychotic therapy. Among a nationwide schizophrenia cohort derived from the National Health Insurance Research Database in Taiwan (n = 32 399), we identified 284 patients who had developed newly diagnosed tuberculosis after their first psychiatric admission. Ten or fewer matched controls were selected randomly from the cohort for each patient based on risk-set sampling. We categorized exposure to antipsychotic medications by type and defined daily dose. Using multivariate methods, we explored individual antipsychotic agents for the risk of tuberculosis and employed a propensity-scoring method in sensitivity analyses to validate any associations. Among the antipsychotic agents studied and after adjustment for covariates, current use of clozapine was the only antipsychotic agent associated with a 63% increased risk of tuberculosis (adjusted risk ratio = 1.63, P = 0.014). In addition, the association did not show a clear dose-dependent relationship. Clozapine combined with other antipsychotic agents showed a potential synergistic risk for tuberculosis (adjusted risk ratio = 2.30, P = 0.044). This exploratory study suggests the potential risk of clozapine on the risk of tuberculosis, especially for those on clozapine in combination with other antipsychotics. Future studies are needed to verify the association.

Antipsychotic Medications and Risk of Acute Coronary Syndrome in Schizophrenia: A Nested Case-Control Study.

BackgroundThis study assessed the risk of developing acute coronary syndrome requiring hospitalization in association with the use of certain antipsychotic medications in schizophrenia patients.MethodsA nationwide cohort of 31,177 inpatients with schizophrenia between the ages of 18 and 65 years whose records were enrolled in the National Health Insurance Research Database in Taiwan from 2000 to 2008 and were studied after encrypting the identifications. Cases (n = 147) were patients with subsequent acute coronary syndrome requiring hospitalization after their first psychiatric admission. Based on a nested case-control design, each case was matched with 20 controls for age, sex and the year of first psychiatric admission using risk-set sampling. The effects of antipsychotic agents on the development of acute coronary syndrome were assessed using multiple conditional logistic regression and sensitivity analyses to confirm any association.ResultsWe found that current use of aripiprazole (adjusted risk ratio [RR] = 3.68, 95% CI: 1.27–10.64, p<0.05) and chlorpromazine (adjusted RR = 2.96, 95% CI: 1.40–6.24, p<0.001) were associated with a dose-dependent increase in the risk of developing acute coronary syndrome. Although haloperidol was associated with an increased risk (adjusted RR = 2.03, 95% CI: 1.20–3.44, p<0.01), there was no clear dose-dependent relationship. These three antipsychotic agents were also associated with an increased risk in the first 30 days of use, and the risk decreased as the duration of therapy increased. Sensitivity analyses using propensity score-adjusted modeling showed that the results were similar to those of multiple regression analysis.ConclusionsPatients with schizophrenia who received aripiprazole, chlorpromazine, or haloperidol could have a potentially elevated risk of developing acute coronary syndrome, particularly at the start of therapy.

Significant Beneficial Association of High Dietary Selenium Intake with Reduced Body Fat in the CODING Study

Selenium (Se) is a trace element which plays an important role in adipocyte hypertrophy and adipogenesis. Some studies suggest that variations in serum Se may be associated with obesity. However, there are few studies examining the relationship between dietary Se and obesity, and findings are inconsistent. We aimed to investigate the association between dietary Se intake and a panel of obesity measurements with systematic control of major confounding factors. A total of 3214 subjects participated in the study. Dietary Se intake was determined from the Willett food frequency questionnaire. Body composition was measured using dual-energy X-ray absorptiometry. Obese men and women had the lowest dietary Se intake, being 24% to 31% lower than corresponding normal weight men and women, classified by both BMI and body fat percentage. Moreover, subjects with the highest dietary Se intake had the lowest BMI, waist circumference, and trunk, android, gynoid and total body fat percentages, with a clear dose-dependent inverse relationship observed in both gender groups. Furthermore, significant negative associations discovered between dietary Se intake and obesity measurements were independent of age, total dietary calorie intake, physical activity, smoking, alcohol, medication, and menopausal status. Dietary Se intake alone may account for 9%–27% of the observed variations in body fat percentage. The findings from this study strongly suggest that high dietary Se intake is associated with a beneficial body composition profile.

Evaluation of masseter muscle hypertrophy in oral submucous fibrosis patients -an ultrasonographic study.

Oral submucous fibrosis (OSMF) is a chronic insidious disease of the oral mucosa, commonly seen in South East Asia. It occurs mainly due to the habit of quid or gutkha chewing. There is a clear dose dependent relationship between gutkha chewing and development of OSMF, also due to continuous chewing for larger intervals of time unnecessary forces are exerted on the muscles mainly the masseter muscle. So, the present study was done to evaluate the thickness of masseter muscle in OSMF patients and to compare it with normal patients. The present study involved 50 subjects, 25 OSMF patients and 25 normal individuals. The thickness of masseter muscle was evaluated by ultrasonography (5-11mHz). There is a positive association between masseter muscle hypertrophy and OSMF (p-value 0.001). Thickness of masseter muscle was found to be more in OSMF patients as compared to control group and also thickness is more during contraction as compared to relaxation in both OSMF patients and normal individuals.

Association between body mass index and mortality among institutionalized elderly adults in Japan

The purpose of this study is to assess the association between body mass index (BMI) and mortality among nursing home residents in Japan. A one-year prospective cohort study was conducted with 8,510 elderly individuals across 140 nursing homes. Baseline measurements included age, sex, height, weight, BMI, activities of daily living (ADL) (Barthel Index), and degree of dementia. Information regarding dates of discharge and mortality were also obtained to calculate person-years. Cox's proportional hazards model was used to estimate hazard ratios. Mean age and BMI were 84.3 [standard deviation (SD) 8.1] years and 20.6 (SD 3.8) kg/m²), respectively. Hazard ratios of mortality adjusted for sex, age, ADL, degree of dementia, and type of home were 2.4 [95 % confidence interval (CI): 1.9-3.1] for the 1st quintile of BMI (<17.3 kg/m²), 1.7 (95 % CI: 1.3-2.3) for the 2nd quintile (17.3-19.2 kg/m²), 1.5 (95 % CI: 1.2-2.0) for the 3rd quintile (19.3-21.1 kg/m²), and 1.2 (95 % CI: 0.9-1.6) for the 4th quintile (21.2-23.5 kg/m²) (P for trend <0.001), compared with the reference 5th quintile (23.6≤ kg/m²). There was a clear inverse dose-dependent relationship between BMI and mortality. Future studies should be conducted to determine the effects of nutritional intervention on mortality in institutionalized elderly adults.

Effect of Metoprolol Versus Carvedilol on Outcomes in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy)

This study sought to compare the effects of metoprolol and carvedilol in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) study. The impact of beta-blockers in heart failure (HF) patients with devices is uninvestigated. All patients receiving either metoprolol or carvedilol in the MADIT-CRT study were identified and compared. Time-dependent Cox proportional hazard regression analyses were performed to assess differences in hospitalization for HF or death and ventricular arrhythmias. Hospitalization for HF or death occurred in 30% of the patients on metoprolol and in 23% on carvedilol. Treatment with carvedilol was associated with a significantly decreased risk of hospitalization for HF or death when compared with metoprolol (hazard ratio [HR]: 0.70, [95% confidence interval (CI): 0.57 to 0.87], p = 0.001). This reduction in risk was further attenuated in the subgroup of cardiac resynchronization therapy with implantable cardioverter-defibrillator (CRT-D) patients (HR: 0.61 [95% CI: 0.46 to 0.82], p = 0.001) and CRT-D patients with left bundle branch block (LBBB) (HR: 0.51 [95% CI: 0.35 to 0.76], p < 0.001). Ventricular arrhythmias occurred in 26% and in 22%, respectively, of the patients receiving metoprolol or carvedilol (HR: 0.80 [95% CI: 0.63 to 1.00], p = 0.050). General use of beta-blockers and adherence in this study was high, and a clear dose-dependent relationship was found in carvedilol, but not in metoprolol. In HF patients in New York Heart Association functional class I and II and with wide QRS complexes, carvedilol was associated with a 30% reduction in hospitalizations for HF or death when compared with metoprolol. A novel beneficial and synergistic effect of carvedilol was seen in patients with CRT-D and LBBB. Furthermore, we found a pronounced dose-dependent relationship in carvedilol, but not in metoprolol.

Mental health comorbidity in patients with atopic dermatitis

Recent data, primarily from Europe, suggest that children with atopic dermatitis (AD) might be at increased risk of mental health disorders. We aimed to quantify the mental health burden associated with pediatric AD in the United States. A cross-sectional study design was used analyzing data from the 2007 National Survey of Children's Health, a survey reporting on the health status of 92,642 noninstitutionalized children aged 0 to 17 years. The lifetime prevalence of various provider-diagnosed mental health conditions was calculated for those with and without a history of AD. The odds of having attention deficit hyperactivity disorder was significantly increased in children with AD compared with the odds in control subjects without AD (odds ratio, 1.87; 95% CI, 1.54-2.27), even after controlling for known confounders. The adjusted odds ratios for depression, anxiety, conduct disorder, and autism were 1.81 (95% CI, 1.33-2.46), 1.77 (95% CI, 1.36-2.29), 1.87 (95% CI, 1.46-2.39), and 3.04 (95% CI, 2.13-4.34), respectively, and these estimates were all statistically significant. A clear dose-dependent relationship was observed between the prevalence of a mental health disorder and the reported severity of the skin disease. Our data reveal a striking association between mental health disorders and AD in the US pediatric population. The severity of the skin disease alters the strength of the association. Prospective cohort studies are needed to verify these associations and to explore underlying mechanisms. Strategies to prevent AD or to aggressively treat early skin inflammation might modify the risk of mental health disorders in at-risk children.

No association between cigarette smoking and incidence of plasma cell myeloma: A meta‐analysis of 17 observational studies

Plasma cell myeloma (PCM) is a lymphoproliferative disorder characterized by the malignant growth of monoclonal plasma cells within the bone marrow. Although risk factors for the development of PCM have been identified, the etiology on the majority of patients with PCM remains unclear. Cigarette smoking has been postulated as a potential risk factor for lymphoid malignancies; however, the association with PCM is inconclusive. We have carried out a meta-analysis of observational studies to assess the relationship, if any, between cigarette smoking and PCM. A literature search through December 2011 rendered 4 prospective cohort and 13 case–control studies evaluating such association. Our categorical meta-analysis showed that there is no association between ever, current, and former smokers and PCM.This lack of association was maintained when analyzing by study design, study quality, and geographical area of report. Similarly, meta regression analysis showed no association with the number of cigarettes smoked per day. In conclusion, our meta-analysis shows that there is no relationship between cigarette smoking and an increased incidence of PCM. Future studies should focus on other potential risk factors for PCM.

Second-Generation Antipsychotic Medications and Risk of Pneumonia in Schizophrenia

This study assessed the association between second-generation antipsychotic medications and risk of pneumonia requiring hospitalization in patients with schizophrenia because the evidence is limited in the population. We enrolled a nationwide cohort of 33,024 inpatients with schizophrenia ranged in age from 18 to 65 years, who were derived from the National Health Insurance Research Database in Taiwan from 2000 to 2008. Cases (n = 1741) were defined as patients who developed pneumonia after their first psychiatric admissions. Risk set sampling was used to match each case with 4 controls by age, sex, and the year of the first admission based on nested case-control study. Antipsychotic exposure was categorized by type, duration, and daily dose, and the association between exposure and pneumonia was assessed using conditional logistic regression. We found that current use of clozapine (adjusted risk ratio = 3.18, 95% CI: 2.62-3.86, P < .001) was associated with a dose-dependent increase in the risk. Although quetiapine, olanzapine, zotepine, and risperidone were associated with increased risk, there was no clear dose-dependent relationship. Amisulpride was associated with a low risk of pneumonia. The use of clozapine combined with another drug (olanzapine, quetiapine, zotepine, risperidone, or amisulpride), as assessed separately, was associated with increased risk for pneumonia. In addition, with the exception of amisulpride, each drug was associated with increased risk for pneumonia at the beginning of treatment. Clinicians who prescribe clozapine to patients with schizophrenia should closely monitor them for pneumonia, particularly at the start of therapy and when clozapine is combined with other antipsychotics.

Efficacy of Cymelarsan® and Diminasan® against Trypanosoma equiperdum infections in mice and horses

Trypanocidal sensitivity studies were conducted to assess the efficacy of Diminazene diaceturate (Diminasan) and Bis (aminoethylthio) 4-melaminophenylarsine dihydrochloride (Cymelarsan) against Trypanosoma equiperdum (isolated from two mares with chronic cases of dourine) 713/943 and 834/940 Dodola strains in experimentally infected mice and horses. Diminasan at doses from 3.5 mg/kg to 28 mg/kg and Cymelarsan at doses of 0.25 mg/kg and 0.5 mg/kg body weight failed to cure any of the mice, indicating a clear dose dependent relationship in the mean time of relapse observed in mice. Indeed, mice treated with lower doses relapsed after a shorter time than mice treated with higher doses. However, mice treated with Cymelarsan at doses of 1.0 mg/kg and 2.0 mg/kg body weight were cured and no parasitemia was observed for 60 days. The efficacy of Cymelarsan was also tested in horses. Two groups of horses containing two animals each were infected with T. equiperdum 834/940 Dodola strain and treated with Cymelarsan at a dose rate of 0.25 mg/kg and 0.5 mg/kg, respectively. Cymelarsan at 0.25 mg/kg and 0.5 mg/kg body weight cleared parasitemia within 24 h post treatment and none of the animals were found to show relapse throughout the 320 days of observation. The sensitivity of the particular trypanosome strain to Cymelarsan was also supported by the relative improvement in the mean PCV levels of horses following treatment. A statistically significant difference (p<0.01) in the mean PCV levels of horses treated with Cymelarsan was observed between day 20 at peak parasitemia and days 40 as well as 60 of observation. The mean PCV levels of horses in the control group progressively decreased within the first 60 days of post infection. Two of the horses in the control group developed chronic form of dourine manifested by genital as well as nervous signs with progressive loss of body condition within 320 days post infection. The efficacy of Cymelarsan against the chronic form of dourine was confirmed after treatment of one of the control horses with Cymelarsan at a dose rate of 0.25 mg/kg body weight at day 282 post infection. It was noted that the treated horse improved overall body condition and clinical signs such as incoordination of hind legs, weakness and ventral oedema disappeared within 10 days of treatment. Thus, Cymelarsan was found to be quite effective in curing horses in acute as well as chronic form of dourine. The results obtained from the present study will be important for designing effective control measures against dourine.

Local effect of calcitonin gene-related peptide on human sweat gland function

The effect of local administration of calcitonin gene-related peptide (CGRP) on sweating activity was evaluated on normal human volunteers. CGRP and methacholine chloride (MCH) was dissolved in 0.1 ml of 0.9% NaCl solution to a specified concentration, and was injected intradermally at the center of a 1.3 cm2 forearm test area. The sweat rate was recorded continuously by capacitance hygrometry in a relatively cool environment (Ta, 23 degrees C). CGRP did not elicit any sweat secretion when administrated by alone, but significantly increased the sweat rate when it was administrated with MCH. The maximum enhancement of MCH-induced sweating by CGRP was observed at a concentration of 10(-5) g/ml of CGRP. There was clear dose-dependent relationship between the dose of CGRP and its enhancement. Recently, CGRP-like immunoreactivity is demonstrated to be present in cholinergic nerve terminals around the human sweat glands. These observations have strongly suggested that CGRP enhances the cholinergic sweating activity. Although the underlying mechanism is still obscure, CGRP may enhance the sweating as a consequence of vasodilation which has been known to be a major activity of CGRP. As for the evaluation of human sweat gland function, CGRP-induced peptidergic regulation should be considered as well as cholinergic regulation.

Platelet-activating factor causes goblet cell depletion in the conjunctiva

Platelet-activating factor (PAF) (1-O-hexadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) produced dose-dependent depletion of the goblet cell population associated with the conjunctival epithelium. Reductions in goblet cell numbers did not correspond to leukocyte infiltration and were consistent with a direct effect of PAF. In contrast, LTD 4 and LTE 4 did not affect the goblet cell population although they caused massive eosinophil infiltration into the conjunctival epithelium. Histamine also produced conjunctival goblet cell depletion, but this appeared secondary to eosinophil degranulation and resultant epithelial desquamation. In addition to globlet cell expulsion, PAF produced on increase in conjunctival microvascular permeability over an identical dose-range. PAF-induced leukocyte emigration was small or absent and comprised a neutrophil infiltrate which exhibited no clear dose-dependent relationship. Lyso-PAF produced effects only at the highest dose employed where pathological changes and a distinct increase in conjunctival microvascular permeability were evident. Lyso-PAF- and PAF-induced increases in conjunctival microvascular permeability were virtually abolished by the PAF antagonist CV-6209. The pronounced inhibitory activity of CV-6209 suggests that high doses of lyso-PAF may either weakly stimulate conjunctival PAF receptors or that there may be sufficient conversion of lyso-PAF to biologically active levels of PAF.

Modulation of 6-hydroxydopamine induced alteration of the postnatal development of central noradrenaline neurons

The effect of substance P and morphine on the 6-hydroxydopamine (6-OHDA) induced alteration of the postnatal development of central noradrenaline (NA) neurons in the rat has been investigated using neurochemical techniques. Neonatal administration of 6-OHDA systemically leads to permanent NA denervations of distant NA projections, while the projections close to the NA cell bodies are increased, leading to NA hyperinnervation. Intracisternal injection of substance P was found to counteract both the NA denervation and hyperinnervation induced by 6-OHDA. The effect of substance P disclosed a clear dose-dependent relationship. Morphine, on the other hand, was observed to potentiate the alterations induced by 6-OHDA, both the NA denervation and hyperinnervation. The effect of morphine was dose-dependent and could be blocked by the morphine antagonist naloxone. The present results give further support for the view that the 6-OHDA induced alteration of the postnatal development of central NA neurons is related to a “pruning effect.” The data furthermore imply that the end-result from a 6-OHDA induced degeneration of central NA neurons during ontogeny may be modulated by the functional state of the neurons.

An experimental study of the “Bennett And Kenny” reaction in guinea-pigs infected with Trypanosoma equiperdum

Trypanocidal sensitivity studies were conducted to assess the efficacy of Diminazene diaceturate (Diminasan®) and Bis (aminoethylthio) 4-melaminophenylarsine dihydrochloride (Cymelarsan®) against Trypanosoma equiperdum (isolated from two mares with chronic cases of dourine) 713/943 and 834/940 Dodola strains in experimentally infected mice and horses. Diminasan® at doses from 3.5 mg/kg to 28 mg/kg and Cymelarsan® at doses of 0.25 mg/kg and 0.5 mg/kg body weight failed to cure any of the mice, indicating a clear dose dependent relationship in the mean time of relapse observed in mice. Indeed, mice treated with lower doses relapsed after a shorter time than mice treated with higher doses. However, mice treated with Cymelarsan® at doses of 1.0 mg/kg and 2.0 mg/kg body weight were cured and no parasitemia was observed for 60 days. The efficacy of Cymelarsan® was also tested in horses. Two groups of horses containing two animals each were infected with T. equiperdum 834/940 Dodola strain and treated with Cymelarsan® at a dose rate of 0.25 mg/kg and 0.5 mg/kg, respectively. Cymelarsan® at 0.25 mg/kg and 0.5 mg/kg body weight cleared parasitemia within 24 h post treatment and none of the animals were found to show relapse throughout the 320 days of observation. The sensitivity of the particular trypanosome strain to Cymelarsan® was also supported by the relative improvement in the mean PCV levels of horses following treatment. A statistically significant difference (p < 0.01) in the mean PCV levels of horses treated with Cymelarsan® was observed between day 20 at peak parasitemia and days 40 as well as 60 of observation. The mean PCV levels of horses in the control group progressively decreased within the first 60 days of post infection. Two of the horses in the control group developed chronic form of dourine manifested by genital as well as nervous signs with progressive loss of body condition within 320 days post infection. The efficacy of Cymelarsan® against the chronic form of dourine was confirmed after treatment of one of the control horses with Cymelarsan® at a dose rate of 0.25 mg/kg body weight at day 282 post infection. It was noted that the treated horse improved overall body condition and clinical signs such as incoordination of hind legs, weakness and ventral oedema disappeared within 10 days of treatment. Thus, Cymelarsan® was found to be quite effective in curing horses in acute as well as chronic form of dourine. The results obtained from the present study will be important for designing effective control measures against dourine.