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Statement of problem: Hardness of restorative materials like glass-ionomer is an important factor in the longevity of restoration. Objectives: The aim of this study was to evaluate the microhardness of glass-ionomer modified with different materials. Materials and Methods: Sixty disk-shaped specimens were examined in six groups in this study, including conventional glass-ionomer (Shofu, Japan), zirconia-reinforced glass-ionomer (Zirconomer, Shofu, Kyoto, Japan), silver-reinforced glass-ionomer (HI-DENSE XP, Shofu, Kyoto, Japan) and mixture of these three types of glass-ionomer with 20 wt% of microhydroxyapatite (Sigma-Aldrich, St. Louis, USA). All the specimens were stored in deionized water for 24 hours. Then Vickers microhardness test was carried out and the results were analyzed by using two-way ANOVA test and paired t-test (P

Statement of Problem: Accumulation of plaque and staining due to a rough surface, and penetration of colourant agents from food and beverages in to the resin composite results in an incomplete polymerization. There is a little information on the effect of finishing and polishing techniques on the discoloration of nanohybrid and microhybrid composites when exposed to staining solutions. Objectives: To determine the degree of surface staining of nanohybrid and microhybrid composites after polishing and immersion in distilled water and two commonly used staining solutions. Materials and Methods: A nanohybrid (Ice; SDI) and microhybrid (Gradis direct; GC) composites were used. Disc-shaped specimens were prepared and treated with either a matrix finish or polished using Sof-Lex discs (3M/ ESPE) and Enhance point (Dentsply). After 24 h immersion in distilled water at 37°C the specimens were polished and colour coefficients (CIE L* a* b*) was measured by a spectrophotometer. All specimens were immersed in 37°C distilled water in an incubator for 7 days and colour coefficients were measured again. The colour change (ΔE) was calculated using the following formula: ΔE = [(Δa)2+(Δb)2+(ΔL)2] 1/2. The data were analyzed using three-way ANOVA, one-way ANOVA/Tukey HSD and Student’s t-test. Results: There was a significant interaction between resin composites, polishing systems and staining solutions (p < 0. 05). ANOVA and Tukey’s tests showed that Ice had a significantly lesser colour change than Gradia direct and matrix finish revealed the smoothest surface followed by Sof-Lex discs and Enhance point. Distilled water and cola caused no perceptible colour change (ΔE < 3.3). The effect of surface polish on staining was statistically significant (p < 0 .05). Conclusions: Sof-Lex discs in comparison to Enhance point stimulated greater staining resistance for both composites. The nanohybrid exhibited less colour change than microhybrid composite. Coffee was the only storage media that induced a perceptible colour change (ΔE > 3.3) compared to cola and distilled water.

Statement of Problem: Resin composites are a common type of tooth coloured restorative materials. These materials are brittle and their major shortcomings are sensitivity to flaws and defects, low tensile strength, and susceptibility to catastrophic failure.The role of home bleaching agents on the fracture toughness of resin composites using four-point bending test is scanty. Objectives: To compare the fracture toughness (KIc) of resin composites on a fourpoint bending test and to assess the effect of distilled water and a home bleaching agent on the resistance of the materials to fracture. Materials and Methods: seventy-two bar-shaped specimens were prepared from three materials: Rok (SDI), Estelite (Tokuyama), and Vit-l-escence (Ultradent) and divided into three groups. Two groups were assigned as “control” and conditioned in distilled water at 37oC for 24 hours or 21 days, respectively. The specimens in the third group (treatment) were stored in distilled water for 21 days and bleached using Polanight (SDI) for 2 hours daily. For each material, a total of 24 disc-shaped specimens were prepared and after each time interval loaded in a four-point bending test using a universal testing machine with a crosshead speed of 0.5 mm/m. The maximum load to specimen failure was recorded and the KIc was calculated. Results: Statistical analysis using two-way ANOVA showed a significant relationship between materials and treatment (P

Statement of Problem: Deliberating the patients' rights is one of the major human ethical and legal principles which can be investigated through the agenda of professional and medical ethics accordingly, the students of dentistry have to be educated about this issue and achieve the necessary skills in deliberating and concerning the patients' rights. Purpose: The present study aimed to investigate Shiraz dental students' awareness and attitude regarding the patients' rights as well as the principles of dental ethics in order to design methods for organizing and improving the ethics in dentistry. Materials and Method: The present descriptive-analytical study was conducted on 111 students of different departments of Shiraz Dental School. The study data were collected through a questionnaire designed based on the patients' rights charter in Iran, ADA ethical codes which are internationally acceptable in the field of dentistry, and the guidelines of the ministry of health, treatment, and medical education (No. 140588). Then, the data were entered into the SPSS statistical software and analyzed. Results: Of all participants, 21.6% were men and 78.4% were women. According to the results, 71% of the students were acquainted with the patients' rights. In addition, the patients' characteristics, including gender and nationality, were not important for 58.6% of the students. Conclusion: The study findings showed that 71% of the participants were acquainted with the patients' rights Establishment of a comprehensive, integrated charter in Iran is needed. With rapid development of medical sciences, new issues appear which necessitate taking into account the mutual rights of the physicians, people, and patients. [ABSTRACT FROM AUTHOR]

Background/aims: Non-alcoholic fatty liver disease (NAFLD), defined as the accumulation of >5% fat in the liver, is the most frequently co-exist disease with diabetics up to 70%. Current study was conducted to compare efficacy of combination therapy of empagliflozin (EMPA) or pioglitazone (PGZ) with metformin (MET) in patients with T2DM and NAFLD., Methods: In this open label, prospective clinical trial, sixty patients were randomly assigned to receive EMPA 10 mg/day or PGZ 30 mg/day in combination Metformin (at least 1500 mg) for six months. NAFLD grade and liver stiffness were defined and measured at the beginning and after 6 months. As the secondary outcomes, anthropometric characteristics, lipid profile, plasma glucose test, and liver enzymes test were measured at the baseline and endpoint., Results: The results showed that both combination therapy with EMPA+ MET or PGZ+MET significantly reversed fibrosis stage of NAFLD (P<0.05). Significant reduction in lipid profile test, and liver enzymes test were seen in both groups (P<0.05). However, the greater reduction in waist circumference was observed in EMPA groups compared to PGZ (-4.4 ± 2.39 vs -2.05±1.28, p<0.001), meanwhile weight and BMI decreased significantly only in the patients receiving EMPA (-5.78 ± 3.6 kg vs 0.93 ± 0.33 kg and -2.01± 3.19 kg/m 2 vs 0.33 ± 0.12 kg/m 2 , respectively, P<0.001)., Conclusion: combination of EMPA or PGZ with metformin equally improved liver fibrosis stage and stiffness in T2DM patients with NAFLD. The improvements of laboratory tests were observed in the both groups, while, regarding weight reduction, only the regimen containing EMPA was effective., Competing Interests: Declaration of competing interest The authors declared that no competing of interest are existed., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Epigenetic modifications, particularly histone acetylation-deacetylation and its related enzymes, such as sirtuin 1 (SIRT1) deacetylase, may have substantial roles in the pathogenesis of obesity and its associated health issues. This study aimed to evaluate global histone acetylation status and SIRT1 gene expression in children and adolescents with obesity and their association with metabolic and anthropometric parameters., Methods: This study included 60 children and adolescents, 30 with obesity and 30 normal-weight. The evaluation consisted of the analysis of global histone acetylation levels and the expression of the SIRT1 gene in peripheral blood mononuclear cells, by specific antibody and real-time PCR, respectively. Additionally, insulin, fasting plasma glucose, lipid profile and tumor necrosis factor α (TNF-α) levels were measured. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Metabolic syndrome was determined based on the diagnostic criteria established by IDF., Results: Individuals with obesity, particularly those with insulin resistance, had significantly higher histone acetylation levels compared to control group. Histone acetylation was positively correlated with obesity indices, TNF-α, insulin, and HOMA-IR. Additionally, a significant decrease in SIRT1 gene expression was found among obese individuals, which was negatively correlated with the histone acetylation level. Furthermore, SIRT1 expression levels showed a negative correlation with various anthropometric and metabolic parameters., Conclusion: Histone acetylation was enhanced in children and adolescents with obesity, potentially resulting from down-regulation of SIRT1, and could play a role in the obesity-associated metabolic abnormalities and insulin resistance. Targeting global histone acetylation modulation might be considered as an epigenetic approach for early obesity management., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Taghizadeh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Opioid receptors modulate neurochemical and behavioral responses to drugs of abuse in nonclinical models. Samidorphan (SAM) is a new molecular entity that binds with high affinity to human mu- (μ), kappa- (κ), and delta- (δ) opioid receptors and functions as a μ-opioid receptor antagonist with partial agonist activity at κ- and δ-opioid receptors. Based on its in vitro profile, we hypothesized that SAM would block key neurobiological effects of drugs of abuse. Therefore, we assessed the effects of SAM on ethanol-, oxycodone-, cocaine-, and amphetamine-induced increases in extracellular dopamine (DA ext ) in the nucleus accumbens shell (NAc-sh), and ethanol and cocaine self-administration behavior in rats. In microdialysis studies, administration of SAM alone did not result in measurable changes in NAc-sh DA ext when given across a large range of doses. However, SAM markedly decreased average and maximal increases in NAc-sh DA ext produced by each of the drugs of abuse tested. In behavioral studies, SAM attenuated fixed-ratio ethanol self-administration and progressive ratio cocaine self-administration. These results highlight the potential of SAM to counteract the neurobiological and behavioral effects of several drugs of abuse with differing mechanisms of action., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) includes a range of disorders from simple steatosis to non-alcoholic steatohepatitis. There is no proven drug treatment for NAFLD, and diet modification is considered part of the main line of treatment for this disease. The aim of this study was to investigate the efficacy of garlic supplementation in NAFLD patients. The effect of garlic powder supplementation on hepatic steatosis, liver enzymes and lipid profile was investigated in NAFLD patients. Ninety NAFLD patients were randomly assigned to take either a garlic powder supplement or a placebo for 12 weeks. The treatment group received four tablets of garlic daily (each tablet contained 400 mg garlic powder). The control group received four tablets of placebo (each placebo contained 400 mg starch). At the end of the study, hepatic steatosis was significantly reduced in the treatment group compared with the control group (P = 0·001). In addition, a significant decrease was seen in the serum concentration of alanine transaminase (P < 0·001), aspartate transaminase (P = 0·002), γ-glutamyltransferase (P = 0·003) as well as total cholesterol (P = 0·009), TAG (P < 0·001), HDL-cholesterol (P < 0·001) and LDL-cholesterol (P = 0·01) in the treatment group compared with the control group. No significant difference was seen between the two groups in serum concentration of alkaline phosphatase. Overall, garlic powder supplementation improved hepatic features and lipid profile among NAFLD patients.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Insulin resistance, oxidative stress, and obesity are major contributors to NAFLD pathogenesis. The effects of garlic powder supplementation on these risk factors in patients with NAFLD was investigated., Methods: In this 12-wk, randomized controlled clinical trial, ninety patients with NAFLD were randomly assigned to two groups. The treatment group received four tablets of garlic (each coated tablet contained 400 mg garlic powder) daily and the control group received four tablets of placebo (each coated tablet contained 400 mg starch)., Results: A significant decrease was seen in the treatment group compared to the control group in waist circumference (P = 0.001), body fat percent (P < 0.001), serum concentration of fasting blood sugar (P = 0.01), insulin (P < 0.001), homeostatic model assessment for insulin resistance (P < 0.001), and malondialdehyde (P < 0.001), as well as significant increase in skeletal muscle mass (P = 0.002), serum concentration of superoxide dismutase (P < 0.001), and total antioxidant capacity (P < 0.001)., Conclusion: Garlic powder supplementation improved risk factors of NAFLD. Further studies are needed to determine the effects of garlic on hepatic features in patients with NAFLD. The study protocol was registered at Iranian clinical trials website under code IRCT20170206032417N4., Competing Interests: Declaration of Competing Interest The authors have declared no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Type 2 diabetes mellitus (T2DM) is a serious public health problem accompanies with several complications. This study was conducted to evaluate the effects of chromium picolinate (CrPic) supplementation on the glycemic status and lipid profile in patients with T2DM. The patients with T2DM (n = 52) were randomly allocated into 2 groups. One group received 400 µg CrPic per day and the other group took placebo; the intervention duration was 8 weeks. Anthropometric indices and metabolic factors were measured at the beginning, and at end of the study. The patients were recommended not to change their normal diet, life style and medication. No significant changes were observed for weight, body mass index, and fasting blood glucose (FBG) in both groups; while intra-groups changes in homeostatic model assessment for insulin resistance (HOMA-IR) value was significant (p < 0.05). Results of analysis of covariance showed that there were significance differences between groups in total cholesterol, low density lipoprotein cholesterol and HOMA-IR at the end of the intervention adjusting for baseline levels (p = 0.035, 0.030 and < 0.001, respectively). In this study, oral supplementation with 400 µg CrPic for eight weeks did not alter FBG concentration as well as anthropometric parameters in individuals with T2DM. However, the modest beneficial effects of chromium supplementation on insulin resistance as indicated by HOMA-IR and lipid profile were found., Competing Interests: Conflict of Interest: The authors declare that they have no competing interests., (Copyright © 2020. The Korean Society of Clinical Nutrition.)

Strategies to achieve a therapy for Alzheimer's disease (AD) aimed at reducing the effects of amyloid-β (Aβ) have largely involved inhibiting or modifying the activities of the β- or γ -secretases or by the use of monoclonal antibodies (MAb). We previously offered the potential for a new, early and effective approach for the treatment of AD by a strategy that does not target the secretases. We showed that a family of peptides containing the DEEEDEEL sequence and another independent peptide, all derived from the amino terminus of PS-1, are each capable of markedly reducing the production of Aβ in vitro and in mThy1-hAPP transgenic mice. These peptides gave a strong and specific binding with the ectodomain of amyloid-β protein precursor (AβPP) and did not affect the catalytic activities of β- or γ -secretase, or the level of AβPP. Critical to the development of any therapeutic for AD is the requirement that it is stable and can be delivered to the brain. We report here data on the metabolic stability and delivery to the rat brain of our lead candidate P8 by intravenous (IV), intranasal (IN), and subcutaneous (SC) administration. Pharmacokinetics (PK) of P8 in rat plasma and CSF following a single dose of P8 demonstrate that SC administration gives better absorption compared to IN and is the delivery method of choice for the further development of P8 as a clinical candidate.

Statement of the Problem: Hydrogen peroxide (H2O2) has been suggested to be used in sequence or in combination with chlorhexidine (CHX) to enhance the antibacterial activity against Enterococcus faecalis, but there is no research in the literature on the safety and effectiveness of this irrigation protocol., Purpose: This study aimed to assess the cytocompatibility and antibacterial activity of different concentrations of CHX combined with H2O2in comparison with the activity of 5.25 and 2.5% sodium hypochlorite (NaOCl)., Materials and Method: Different concentrations of H2O2 (10, 5, 3 and 1%) were exposed to the PDL cells. Then, the solution with minimal cytotoxicity was selected (3% H2O2). The cytocompatibility and antibacterial activity of 0.1, 0.2, 1 and 2% CHX combined with 3% H2O2 were evaluated and compared with 5.25 and 2.5% NaOCl. The differences in the mean viability of PDL cells were evaluated by one-way ANOVA. Kruskal-Wallis and post-hoc Dunn's tests were adopted to compare the antibacterial activity of the solutions against E.faecalis., Results: The viability of PDL cells was lower when treated with 5.25 or 2.5% NaOCl than all combinations of CHX and H2O2.There was no significant difference in the antibacterial activity of the solutions against E.faecalis, except for the 0.1% CHX + 3% H2O2 combination, which had significantly lower efficacy than other groups., Conclusion: All combinations of CHX and H2O2 (used in this study)except 0.1% CHX + 3% H2O2 were efficient irrigants against planktonic E.faecalis and had a better cytocompatibility with PDL cells than 5.25 and 2.5% NaOCl.

Statement of the Problem: The first step towards appropriately planning orthodontic treatment and prevention services is to understand the needs and demands of the target population. However, this is ignored in most developing countries., Purpose: This study aims to evaluate the attitudes of patients in Fars province towards travelling to the provincial capital (Shiraz) to receive orthodontic treatments., Materials and Method: This cross-sectional study randomly selected 420 patients referring to two public and four private orthodontic centers in Shiraz, coming from other regions of Fars province. The patients were interviewed about their demographic status, residing area and the reasons of deciding to receive orthodontic treatment in Shiraz. Data were analyzed by SPSS software, using Chi-square and ANOVA statistical tests., Results: The response rate was 96% (N=403). Near half of the patients (176; 43.7 %) lived 100-200km, and 80 (19.9%) patients lived farther than 200km from Shiraz. Having no orthodontist (54.8%) and no dentist providing orthodontic treatment (39.2%) in their region were the most important factors bringing the patients to provincial capital for orthodontic treatments. High costs of treatment in their home county and hoping to receive treatment of higher quality were the other important motives for lower and higher socio-economic backgrounds, respectively. Friends'/relatives' recommendation was a more important factor in patients using public clinics for choosing their therapist, while referral from dentists was more important for patients going to private clinics. The patients who lived in counties farther than 200km from Shiraz were more concerned about quality of treatment results than those who lived closer (p= 0.010)., Conclusion: A multifactorial approach is needed to provide the desired orthodontic services for people in Fars province so that they would not need to travel to the capital for such treatments.

A leading nicotine conjugate vaccine was only efficacious for one-third of clinical trial participants, likely due in part to its use of racemic nicotine hapten, (±)-3'-AmNic. Immunization of male Wistar rats with (+)-, (-)-, or (±)-3'-AmNicSucTT and subsequent antibody immunoassays suggest that a vaccine using enantiopure (-)-3'-AmNic hapten imparts superior capacity to bind (-)-nicotine. Future nicotine vaccine clinical candidates must incorporate this design consideration (i.e., hapten enantiopurity) in order to maximize efficacy.

Background: A strong antimicrobial synergism between chlorhexidine (CHX) and hydrogen peroxide (H2O2) has been reported, but there is not enough data on the cytotoxicity of this combination. The primary aim of this study was to evaluate the cytotoxicity of CHX-H2O2 combination in different concentrations and secondary aim is to assess the influence of H2O2 on cytotoxicity of CHX on cultured human periodontal ligament (PDL) fibroblasts., Materials and Methods: The PDL cells were cultured from healthy human third molar teeth and were exposed to six prepared solutions (0.2% and 2% CHX separately and in combination with 1% and 3% H2O2). The MTT assay was applied to assess their effects on the viability of the PDL cells. Two-way analysis of variance approach and subgroup analysis was performed to evaluate the differences in mean cell viability values. A level of P < 0.05 was considered as statistically significant., Results: All tested solutions were toxic to PDL cells. There was a significant interaction effect between CHX and H2O2. The 2% CHX combined with 3% H2O2 was the most and 0.2% CHX was the least cytotoxic solutions. The 2% CHX was significantly more toxic than 0.2% CHX and H2O2 combinations. The cytotoxicity of 0.2% CHX and H2O2 combinations did not significantly rise by increasing the concentration of H2O2 from 1% to 3%., Conclusion: H2O2 affected the cytotoxicity of CHX in a variable concentration-dependent manner. Based on the results of this study, it can be concluded that 2% CHX alone and in combination with either 1 or 3% H2O2 are significantly more toxic than 0.2% CHX alone and in combination with 1 and 3% H2O2. Therefore, to benefit from the synergistic antimicrobial effect between CHX and H2O2, with a minimal cytotoxicity, it is recommended to use 0.2% concentration of CHX combined with 3% H2O2.

A substituted aryl amide derivative of 6-naltrexamine--17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-trimethylfluoro)benzamido]morphinan-hydrochloride--(compound 5), previously shown to be a potent κ-opioid receptor antagonist, was used to characterize the physicochemical properties and efficacy to decrease alcohol self-administration in alcohol-preferring rats (P-rats) and binge-like P-rats. Previous studies showed that compounds closely related to compound 5 possessed favorable properties regarding penetration of the blood-brain barrier. Pharmacokinetic studies showed that compound 5 had acceptable bioavailability. In contrast to other κ-receptor antagonists, in particular norbinaltorphimine, compound 5 showed favorable drug-like properties. Based on these findings, further studies were done. Safety studies showed that compound 5 was not hepatotoxic at doses 200-fold greater than an efficacious dose. The effects of compound 5 or naltrexone on the hepatotoxicity of thiobenzamide were investigated. In contrast to naltrexone, which exacerbated thiobenzamide-mediated hepatotoxicity, compound 5 was observed to be hepatoprotective. Based on the physicochemical properties of compound 5, the compound was examined in rat animal models of alcohol self-administration. The inhibition of ethanol self-administration by compound 5 in alcohol-dependent and alcohol-nondependent P-rats trained to self-administer a 10% (w/v) ethanol solution, using operant techniques, showed very potent efficacy (i.e., estimated ED50 values of 4-5 μg/kg). In a binge-like P-rat animal model, inhibition of alcohol self-administration by compound 5 had an estimated ED50 value of 8 μg/kg. The results suggest that compound 5 is a potent drug-like κ-opioid receptor antagonist of utility in alcohol cessation medications development., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: The importance of using technologies such as e-learning in different disciplines is discussed in the literature. Researchers have measured the effectiveness of e-learning in a number of fields.Considering the lack of research on the effectiveness of online learning in dental education particularly in Iran, the advantages of these learning methods and the positive university atmosphere regarding the use of online learning. This study, therefore, aims to compare the effects of two methods of teaching (virtual versus traditional) on student learning., Methods: This post-test only design study approached 40, fifth year dental students of Shiraz University of Medical Sciences. From this group, 35 students agreed to participate. These students were randomly allocated into two groups, experimental (virtual learning) and comparison (traditional learning). To ensure similarity between groups, we compared GPAs of all participants by the Mann-Whitney U test (P > 0.05). The experimental group received a virtual learning environment courseware package specifically designed for this study, whereas the control group received the same module structured in a traditional lecture form. The virtual learning environment consisted of online and offline materials. Two identical valid, reliable post-tests that consisted of 40 multiple choice questions (MCQs) and 4 essay questions were administered immediately (15 min) after the last session and two months later to assess for knowledge retention. Data were analyzed by SPSS version 20., Results: A comparison of the mean knowledge score of both groups showed that virtual learning was more effective than traditional learning (effect size = 0.69)., Conclusion: The newly designed virtual learning package is feasible and will result in more effective learning in comparison with lecture-based training. However further studies are needed to generalize the findings of this study.

Renal transplantation is considered the best treatment option for patients with end-stage renal disease. In this study, the prevalence of oral lesions was studied in a cohort of renal transplant recipients before and after transplantation. Fifty-nine kidney transplant recipients were examined one week before and four months after transplantation. The information gathered included age, sex, smoking history, duration on dialysis, drugs and their doses. There were 41 males (69.5%) and 18 females (30.5%) with a mean age of 37 years. Before surgery, two patients had non-specific lesions and two other patients had leukoedema. Following transplantation, 24 patients (40.7%) did not have any specific lesion. In six patients, we observed non-specific erythematous lesions (10.2%). Other recorded observations are as follows: Gingival hyperplasia in five patients (8.5%), oral candidiasis of the erythematous type in five patients (8.5%), hairy leukoplakia in four patients (6.8%) and leukoedema in seven patients (11.9%). In our study patients, the prevalence of oral lesions increased after transplantation, although it was lower than that reported in other studies. This could be due to the differences in sample size, differences between Iranian race and other races and different pharmaceutical formulation of the drug produced in Iran.

The inclusion of Ln(III) ions into the 12-MC-4 framework generates the first heterotrimetallic complexes of this molecular class. The controllable and deliberate preparations of these compounds are demonstrated through 12 crystal structures of the Ln(III)M(I)(OAc)4[12-MCMn(III)(N)shi-4](H2O)4·6DMF complex, where OAc(-) is acetate, shi(3-) is salicylhydroximate, and DMF is N,N-dimethylformamide. Compounds 1-12 have M(I) as Na(I), and Ln(III) can be Pr(III) (1), Nd(III) (2), Sm(III) (3), Eu(III) (4), Gd(III) (5), Tb(III) (6), Dy(III) (7), Ho(III) (8), Er(III) (9), Tm(III) (10), Yb(III) (11), and Y(III) (12). An example with M(I) = K(I) and Ln(III) = Dy(III) is also reported (Dy(III)K(OAc)4[12-MCMn(III)(N)shi-4](DMF)4·DMF (14)). When La(III), Ce(III), or Lu(III) is used as the Ln(III) ions to prepare the Ln(III)Na(I)(OAc)4[12-MCMn(III)(N)shi-4] complex, the compound Na2(OAc)2[12-MCMn(III)(N)shi-4](DMF)6·2DMF·1.60H2O (13) results. For compounds 1-12, the identity of the Ln(III) ion affects the 12-MCMn(III)(N)shi-4 framework as the largest Ln(III), Pr(III), causes an expansion of the 12-MCMn(III)(N)shi-4 framework as demonstrated by the largest metallacrown cavity radius (0.58 Å for 1 to 0.54 Å for 11), and the Pr(III) causes the 12-MCMn(III)(N)shi-4 framework to be the most domed structure as evident in the largest average angle about the axial coordination of the ring Mn(III) ions (103.95° for 1 to 101.69° for 11). For 14, the substitution of K(I) for Na(I) does not significantly affect the 12-MCMn(III)(N)shi-4 framework as many of the structural parameters such as the metallacrown cavity radius (0.56 Å) fall within the range of compounds 1-12. However, the use of the larger K(I) ion does cause the 12-MCMn(III)(N)shi-4 framework to become more planar as evident in a smaller average angle about the axial coordination of the ring Mn(III) ions (101.35°) compared to the analogous Dy(III)/Na(I) (7) complex (102.40°). In addition to broadening the range of structures available through the metallacrown analogy, these complexes allow for the mixing and matching of a diverse range of metals that might permit the fine-tuning of molecular properties where one day they may be exploited as magnetic materials or luminescent agents.

Despite being consistently ranked as the leading cause of preventable death in the United States, about 20% of the population continues to smoke. Current smoking cessation therapies offer limited success, show high rates of relapse, and have potentially dangerous side effects, consequently emphasizing the need for alternative therapies. Immunopharmacotherapy aims to use highly specific antibodies to sequester nicotine in the bloodstream thus blunting passage into the brain and minimizing positive reinforcing effects. A successful vaccination strategy is dependent upon the appropriate hapten design, carrier protein and adjuvant which affect both the magnitude and affinity of the immune response elicited. Our laboratory previously demonstrated the use of molecular constraint as a means to increase the intrinsic immunogenicity and antigenicity of a nicotine vaccine. The present study expands upon those initial results and explores the protective effects of vaccination with both constrained hapten CNI and its unconstrained counterpart NIC. Our results demonstrate how immunization with CNI-KLH produces large amounts of moderate affinity anti-nicotine antibodies even when formulated with ALUM adjuvant, making it particularly relevant for human use. In contrast, vaccination with NIC-KLH produced moderate amounts of high affinity anti-nicotine antibodies. These differential responses proved critical in offering protecting effects. Vaccination with CNI, but not NIC, resulted in an increase of self-administration responding on a progressive ratio schedule using a high nicotine dose (0.03 mg/kg/infusion; ≈ 2 cigarettes in human) as compared to KLH-controls. Furthermore, vaccination with CNI was able to antagonize the analgesic effects of a heavy bolus dose of nicotine (0.35 mg/kg). These results support our hypothesis that molecular constraint can be advantageously utilized to increase the immunogenicity of a nicotine vaccine. Furthermore in correlating the behavioral effects with the differential responses elicited, we shed light on the distinct roles of antibody concentration and affinity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Rationale: Despite increased education regarding its dangers, cigarette smoking remains a significant public health concern due to serious associated health consequences such as cancer and respiratory and cardiovascular diseases. Most smokers fail in their attempts to quit smoking, and current pharmacological interventions have relatively low levels of efficacy and are associated with significant adverse events. We have previously reported that combinations of metyrapone and oxazepam, administered at doses that were ineffective when delivered singly, resulted in dose-related decreases in cocaine self-administration in rats while not affecting food-maintained responding during the same sessions., Objectives: The current study was designed to test the effects of the administration of a metyrapone:oxazepam combination on nicotine self-administration in rats., Methods: Several dose combinations of metyrapone (12.5, 25 or 50 mg/kg) and oxazepam (5 or 10 mg/kg) were tested in rats trained to intravenously (IV) self-administer nicotine (0.03 mg/kg/infusion) during 1-h self-administration sessions using both fixed-ratio and progressive-ratio (PR) schedules of reinforcement., Results: The administration of low doses of metyrapone and oxazepam in combination significantly decreased IV nicotine self-administration in rats. At the lowest doses of 12.5 mg/kg of metyrapone and 5 mg/kg of oxazepam, the drugs alone did not decrease IV nicotine self-administration, but the combination was effective. Varenicline was also tested using the fixed-ratio schedule, and reductions in nicotine intake were similar to those seen with the moderate dose of the combination., Conclusions: The results of this study suggest a potential utility of the combination of metyrapone and oxazepam for smoking cessation in humans.

Rationale: Alleviating addiction to tobacco products could prevent millions of deaths. Investigating novel compounds selectively targeting α4β2 nAChRs hypothesized to have a key role in the rewarding effects of nicotine may be a useful approach for future treatment., Objectives: The present study was designed to evaluate 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine (4-nitro-PFEB), a potent competitive antagonist of neuronal α4β2 nAChRs, in several animal models related to nicotine reward: drug discrimination, intracranial self-stimulation (ICSS), conditioned place preference, and limited access to self-administration., Methods: Long Evans rats were trained in a two-lever discrimination procedure to discriminate 0.4 mg/kg nicotine (s.c.) from saline. Male Sprague-Dawley rats were stereotaxically implanted with electrodes and trained to respond for direct electrical stimulation of the medial forebrain bundle. ICR mice were evaluated using an unbiased place preference paradigm, and finally, male Wistar rats were implanted with intrajugular catheters and tested for nicotine self-administration under limited access (1 h/day)., Results: 4-Nitro-PFEB attenuated the discriminative stimulus effects of nicotine, but alone did not produce nicotine-like discriminative stimulus effects. Nicotine-induced facilitation of ICSS reward thresholds was reversed by 4-nitro-PFEB, which alone had no effect on thresholds. 4-Nitro-PFEB also blocked the conditioned place preference produced by nicotine, but alone had no effect on conditioned place preference. Finally, 4-nitro-PFEB dose-dependently decreased nicotine self-administration., Conclusions: These results support the hypothesis that neuronal α4β2 nAChRs play a key role in mediating the rewarding effects of nicotine and further suggest that targeting α4β2 nAChRs may yield a potential candidate for the treatment of nicotine dependence.

Rationale: Certain compounds that nonselectively inhibit a prominent human nicotine-metabolizing enzyme (i.e., human cytochrome P-450 2A6, hCYP 2A6) showed inhibition of smoking in humans. However, a comprehensive examination of hCYP 2A6 inhibitors to decrease nicotine self-administration in rats has not been reported., Objectives: We tested substituted heteroaromatic compounds designed to selectively inhibit hCYP 2A6 in a model system to (a) examine selective hCYP 2A6 inhibitors to decrease cotinine formation in vivo in rats administered with nicotine and (b) examine their efficacy to decrease nicotine self-administration in rats., Methods: Rats were trained to IV self-administer nicotine in 1-h sessions. Nicotine self-administration was carried out at a unit dose of 0.03 mg/kg/infusion in 0.1 ml/s. Pretreatment with substituted heteroaromatic test compounds (0.5-25 mg/kg, i.p., 30 min prior to nicotine self-administration sessions) resulted in dose-dependent decreases of nicotine self-administration. Using operant conditioning techniques, nicotine- vs. food-reinforced responding was evaluated for compounds 10 and 11., Results: Compounds 10 and 11 selectively decreased nicotine self-administration with estimated ED(50) values 4 and 2.8 mg/kg, respectively. Of the test compounds examined, none showed significant affinity for mammalian α4β2- or α7-neuronal nicotinic acetylcholine (nAChR) receptors and none were inhibitors of the human dopamine transporter (hDAT); thus, neither the endogenous nAChRs nor DAT apparently plays a role in decreasing nicotine self-administration for this series of compounds., Conclusion: The results indicate that chemical analogs of nicotine can play a role in nicotine self-administration harm reduction but a non-nAChR and a non-hDAT mechanism are likely involved.

Background: Root canal cleaning is an important step in endodontic therapy. In order to develop better techniques, a new generation of endodontic instruments has been designed. The aim of this study was to compare the effectiveness of manual K-files (Mani Co, Tokyo, Japan) and two rotary systems-Mtwo (Dentsply-Maillefer, Ballaigues, Switzerland) and ProTaper (VDW, Munich, Germany)-for root canal preparation in primary molars., Materials and Methods: India ink was injected to 160 mesiobuccal and distal root canals of mandibular primary molars. The teeth were randomly divided into three experimental groups and one control group. In each experimental group, either manual instruments (K-files) or rotary instruments (Mtwo or ProTaper) were used to prepare root canals. After cleaning the canals and clearing the teeth, ink removal was evaluated with a stereomicroscope. Statistical analysis was done with Kruskal-Wallis and Friedman tests., Results: There were no significant differences in cleaning efficiency between manual and rotary instruments. Only ProTaper files performed significantly better in the coronal and middle thirds than in the apical third of the root canal., Conclusion: Manual K-files and the Mtwo and ProTaper rotary systems showed equally acceptable cleaning ability in primary molar root canals.

Aim: To compare the cleaning ability and preparation time of rotary instruments (Mtwo) and conventional manual instruments (K-file) in preparing primary and permanent molar root canals., Materials and Methods: Access cavities were prepared in 70 primary and 70 permanent teeth and India ink was injected into 120 canals of selected molars. The teeth were randomly divided into two main subgroups (n=20) and three control groups (n=10). In each of these main subgroups, either the manual instrument (K-file) or the rotary system (Mtwo) was used to prepare root canals. After cleaning the canals and clearing the teeth, dye removal was evaluated with the help of a stereomicroscope. In addition, the time needed for root canal preparation was recorded by a chronometer., Statistical Analysis: Statistical analyses were done using the Kruskal-Wallis, Mann-Whitney and t tests., Results: With regard to the cleaning ability of root canals, there were no significant differences between the K-file and Mtwo rotary system in primary and permanent teeth in the apical, middle or coronal third of the canals. Moreover, there were no significant differences between primary and permanent teeth prepared with K-files and rotary instruments. In all the groups, shorter times were recorded with the rotary technique. The working time was shorter in primary than in permanent teeth., Conclusion: The Mtwo rotary system showed acceptable cleaning ability in both primary and permanent teeth, and achieved results similar to those of K-files in less time.

Purpose: To compare the fracture toughness (KIc) of tooth-colored restorative materials based on a four-point bending; to assess the effect of distilled water and a resin surface sealant (G-Coat Plus) on the resistance of the materials to fracture., Methods: Specimens were prepared from six materials: Quix Fil; Dyract (Dentsply), Freedom (SDI), Fuji VII (GC), Fuji IX (GC); Fuji II LC (GC). Fuji II LC and Fuji IX were tested both with and without applying G-Coat Plus (GC). The specimens were divided into the three groups which were conditioned in distilled water at 37 degrees C for 48 hours, 4 and 8 weeks. The specimens were loaded in a four-point bending test using a universal testing machine. The maximum load to specimen failure was recorded and the fracture toughness calculated., Results: There were significant differences among most of the materials (P < 0.001). Quix Fil had the highest mean KIc value and Fuji VII the lowest. Immersion in distilled water for the resin composite and polyacid-modified resin composites caused a significant decrease in KIc as the time interval increased. For glass-ionomer cements, KIc decreased significantly after 4 weeks, and after 8 weeks immersion slightly increased. G-Coat Plus affected Fuji II LC positively while it had no effect on the Fuji IX.

(S)-Nicotine is a psychostimulant legal drug responsible for causing addiction to tobacco smoking. Tobacco smoking has been irrevocably linked to a number of serious diseases and at present is considered the leading cause of preventable death in the United States. Despite well-documented adverse medical consequences, nicotine addiction has historically been one of the hardest to break. Current therapies have offered limited success and show high rates of relapse, emphasizing the need to engineer alternative therapies to aid nicotine cessation. The current study presents a protein-based immunopharmacotherapy approach for the treatment of nicotine addiction. Immunopharmacotherapy aims to use highly specific antibodies to blunt passage of drug into the brain thus minimizing reinforcing effects on the reward pathways of the central nervous system. Generation of a successful vaccine heavily relies on appropriate optimization of hapten design, immunogenic carrier and adjuvant. Modification of a classical nicotine hapten in conjugation with three distinct carrier proteins allowed for priming of a nicotine vaccine able to elicit significant amounts of nicotine-specific antibodies. Increased self-administration with use of a high drug dose (0.03 mg/kg/infusion; approximately 2 cigarettes in human) was observed in the vaccinated versus control animals suggesting a compensatory pattern and possibly reduced passage of nicotine to the brain. These results support the hypothesis that proper optimization of vaccine formulations could lead to successful nicotine vaccines for human use.

Rationale: Asenapine, a novel psychopharmacologic agent in the development for schizophrenia and bipolar disorder, has high affinity for serotonergic, alpha-adrenergic, and dopaminergic receptors, suggesting potential for antipsychotic and cognitive-enhancing properties., Objectives: The effects of asenapine in rat models of antipsychotic efficacy and cognition were examined and compared with those of olanzapine and risperidone., Materials and Methods: Amphetamine-stimulated locomotor activity (Amp-LMA; 1.0 or 3.0 mg/kg s.c.) and apomorphine-disrupted prepulse inhibition (Apo-PPI; 0.5 mg/kg s.c.) were used as tests for antipsychotic activity. Delayed non-match to place (DNMTP) and five-choice serial reaction (5-CSR) tasks were used to assess short-term spatial memory and attention, respectively. Asenapine doses varied across tasks: Amp-LMA (0.01-0.3 mg/kg s.c.), Apo-PPI (0.001-0.3 mg/kg s.c.), DNMTP (0.01-0.1 mg/kg s.c.), and 5-CSR (0.003-0.3 mg/kg s.c.)., Results: Asenapine was highly potent (active at 0.03 mg/kg) in the Amp-LMA and Apo-PPI assays. DNMTP or 5-CSR performance was not improved by asenapine, olanzapine, or risperidone. All agents (P < 0.01) reduced DNMTP accuracy at short delays; post hoc analyses revealed that only 0.1 mg/kg asenapine and 0.3 mg/kg risperidone differed from vehicle. All active agents (asenapine, 0.3 mg/kg; olanzapine, 0.03-0.3 mg/kg; and risperidone, 0.01-0.1 mg/kg) significantly impaired 5-CSR accuracy (P < 0.05)., Conclusions: Asenapine has potent antidopaminergic properties that are predictive of antipsychotic efficacy. Asenapine, like risperidone and olanzapine, did not improve cognition in normal rats. Rather, at doses greater than those required for antipsychotic activity, asenapine impaired cognitive performance due to disturbance of motor function, an effect also observed with olanzapine and risperidone.

A series of substituted aryl amide derivatives of 6-naltrexamine, 3 designed to be metabolically stable were synthesized and used to characterize the structural requirements for their potency to binding and functional activity of human mu (mu), delta (delta) and kappa (kappa) opioid and nociceptin (NOP) receptors. Binding assays showed that 4-10 had subnanomolar K(i) values for mu and kappa opioid receptors. Functional assays for stimulation of [(35)S]GTPgammaS binding showed that several compounds acted as partial or inverse agonists and antagonists of the mu and delta, kappa opioid or NOP receptors. The compounds showed considerable stability in the presence of rat, mouse or human liver preparations and NADPH. The inhibitory activity on the functional activity of human cytochrome P450s was examined to determine any potential inhibition by 4-9. Only modest inhibition of CYP3A4, CYP2C9 and CYP2C19 was observed for a few of the analogs. As a representative example, radiolabeled 6 was examined in vivo and showed reasonable brain penetration. The inhibition of ethanol self-administration in rats trained to self-administer a 10% (w/v) ethanol solution, utilizing operant techniques showed 5-8 to have very potent efficacy (ED(50) values 19-50 microg/kg).

Substituted aryl and aliphatic amide analogues of 6-naltrexamine were synthesized and used to characterize the binding to and functional activity of human mu-, delta-, and kappa-opioid receptors. Competition binding assays showed 11-25 and 27-31 bound to the mu (K(i) = 0.05-1.2 nM) and kappa (K(i) = 0.06-2.4 nM) opioid receptors. Compounds 11-18 possessed significant binding affinity for the delta receptor (K(i) = 0.8-12.4 nM). Functional assays showed several compounds acted as partial or full agonists of delta or kappa receptors while retaining an antagonist profile at the mu receptor. Structure-activity relationship for aryl amides showed that potent compounds possessed lipophilic groups or substituents capable of hydrogen bonding. Metabolic stability studies showed that 11, 12, and 14 possessed considerable stability in the presence of rat, mouse, or human liver preparations. The ED 50 of inhibition of 10% ethanol self-administration in trained rats, using operant techniques for 11, was 0.5 mg/kg.

Background and Aims: Accurate differential diagnosis between radicular cysts and periapical granulomas cannot be made from radiographs alone. Histological prevalence studies, therefore, assume special importance and may aid the clinician in making judgments regarding therapy. The incidence of radicular cysts has ranged with wide discrepancies in data. The purpose of this study was to evaluate recorded pathologic reports of two common types of chronic periapical lesion in Shiraz Dental School., Materials and Methods: In this study, biopsy reports of 227 specimens of chronic periapical lesions were reviewed. The following information was extracted from each report: patient's gender, age, tooth associated with the lesion and the pathological diagnosis. Probable significant differences in the occurrence of lesions between different ages and genders were analyzed using chi-square test., Results: 15.9% of the lesions were granulomas, and 84.1% were cysts. A slight difference in the occurrence of the lesions was found between males and females with no statistical significance (P > 0.005). The highest incidence of both lesions was in the third decade of life. No significant differences were found in age distribution of the lesions. The most common location for two lesions was the maxillary anterior teeth., Conclusion: Histological differentiation between cysts and granulomas is not always accurate and serial sectioning of excisional biopsies is more valuable than randomized sectioning of curetted biopsies.

Nicotine, the main psychoactive ingredient of tobacco, induces negative emotional symptoms during abstinence that contribute to a profound craving for nicotine. However, the neurobiological mechanisms underlying how nicotine produces dependence remains poorly understood. We demonstrate one mechanism for both the anxiety-like symptoms of withdrawal and excessive nicotine intake observed after abstinence, through recruitment of the extrahypothalamic stress peptide corticotropin-releasing factor (CRF) system and activation of CRF(1) receptors. Overactivation of the CRF-CRF(1) system may contribute to nicotine dependence and may represent a prominent target for investigating the vulnerability to tobacco addiction.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) occurs worldwide. The most common mutations in the CYP21A2 gene in 716 unrelated patients were analyzed and the mutations were grouped by ethnicity, as defined through self-declaration corroborated by review of pedigrees extending to two or three generations. Prevalent allelic mutations and genotypes were found to vary significantly among ethnic groups, and the predominance of the prevalent mutations and genotypes in several of these populations was significant. There are ethnic-specific mutations in the CYP21A2 gene. A large deletion is prevalent in the Anglo-Saxons; a V281L (1685 G to T) mutation is prevalent in Ashkenazi Jews; an R356W (2109 G to A) mutation is prevalent in the Croatians; an IVS2 AS -13 (A/C to G) mutation is prevalent in the Iranians and Yupik-speaking Eskimos of Western Alaska; and a Q318X (1994 C to T) mutation is prevalent in East Indians. Genotype/phenotype non-correlation was seen when at least one IVS2 AS -13 (A/C to G) mutation in the CYP21A2 gene was present.

Although nicotine is considered to be responsible for the addictive properties of tobacco, growing evidence underlines the importance of non-nicotine components in smoking reinforcement. It has been shown that tobacco smoke contains monoamine oxidase (MAO) A and B inhibitors and decreases MAO-A and MAO-B activity in smokers. Here, we investigated the effects of clorgyline hydrochloride (irreversible MAO-A inhibitor; 2 mg/kg/day), selegiline (irreversible MAO-B inhibitor; 4 mg/kg) and the beta-carboline norharmane hydrochloride (reversible MAO-B inhibitor; 5 mg/kg/day) treatments on nicotine self-administration (30 microg/kg/infusion, free base) in rats. Independent of the responsiveness to novelty and locomotor activity stimulation, only clorgyline hydrochloride treatment increased the intake of nicotine in a fixed-ratio schedule (FR5) of reinforcement. When a progressive-ratio schedule was implemented, both clorgyline hydrochloride and norharmane hydrochloride treatments potentiated the reinforcing effects of nicotine, whereas selegiline had no effect. Taken together, these results indicate that MAO-A inhibition interacts with nicotine to enhance its rewarding effects in rats and suggest that other compounds present in tobacco, such as beta-carboline, may also play an important role in sustaining smoking behavior in humans.

Nicotine is the major neuroactive compound of tobacco, which has, by itself, weak reinforcing properties. It is known that levels of the enzymes monoamine oxidase A (MAO-A) and MAO-B are reduced in the platelets and brains of smokers and that substances, other than nicotine, present in tobacco smoke have MAO-inhibitory activities. Here, we report that inhibition of MAO dramatically and specifically increases the motivation to self-administer nicotine in rats. These effects were more prominent in rats selected for high responsiveness to novelty than in rats with low responsiveness to novelty. The results suggest that the inhibition of MAO activity by compounds present in tobacco smoke may combine with nicotine to produce the intense reinforcing properties of cigarette smoking that lead to addiction.

Pharmacotherapy treatment for alcoholism is limited by poor compliance, adverse effects, and fluctuating drug levels after bolus administration. A long-term delivery system would improve upon these limitations. The current study describes the characterization of a sustained release implant containing nalmefene, an opioid antagonist, for treatment of alcoholism. Nalmefene was blended with ethylene vinyl acetate (EVA), extruded into 2.8 mm x 27 mm rods, and coated with EVA to optimize release. In vitro release was determined by HPLC, and in vivo release characteristics after subcutaneous implantation into rats were determined by LC-MS/MS analyses. Extrusion produced rods containing 80.09 +/- 6.0 mg nalmefene. In vitro release was high from the uncoated rods, and they were depleted of drug fairly quickly; however EVA coatings maintained release over longer periods. The 25 wt.% coated rods provided in vitro release of 0.36 mg/day/rod, and in vivo release of 0.29 mg/day/rod over 6 months, and showed dose-dependent nalmefene plasma concentrations (one rod: 3.33 +/- 0.56 ng/ml, three rods: 10.19 +/- 2.31 ng/ml). After explantation, nalmefene plasma concentrations were undetectable by 6 h. A sustained release nalmefene rod provides 6 months of drug with no adverse effects.

Opiate dependence in laboratory animals is commonly induced by two methods: (1) subcutaneous (s.c.) insertion of morphine pellets, and (2) daily injections of increasing doses of opiates. While both of these methods reliably induce opiate dependence, they do not allow one to discontinue, and subsequently reestablish steady state opiate plasma levels with minimal invasive procedures. We developed an "ON-OFF" gating device for repeatedly and non-invasively turning ON or OFF opiate delivery by standard osmotic minipumps. The reliability of this "device" was tested utilizing naloxone (NAL)-precipitated somatic signs of withdrawal, and body mass index (BMI) as measures of withdrawal. Rats were implanted with osmotic minipumps equipped with the gating device, containing heroin (2.66 mg per day). Three days after surgery, somatic signs of withdrawal were precipitated every 48 h by NAL (0.3mg/kg), with minipumps gated ON or OFF. For BMI, spontaneous withdrawal was repeatedly (three times) induced by turning OFF and ON the gating devices every 48 h. Body weights were measured every 4h from 06:00 to 22:00 h daily. Results show that NAL precipitated intense somatic signs of withdrawal when gating devices were ON. This effect was almost abolished when gating devices were OFF. BMI rapidly decreased after the gating devices were turned OFF with maximum weight loss occuring 12 h post-OFF position, and gradually returning to baseline values after gating devices were turned back ON. These results demonstrate the validity of the "ON-OFF" gating device for non-invasively and repeatedly inducing physical dependence to opiates over a prolonged time.

Rationale: Conditioned place aversion (CPA) is known to be a sensitive measure of the aversive motivational state produced by opioid withdrawal in rats made chronically dependent on opioids., Objective: The purpose of the present study was to examine the sensitivity of the CPA model in detecting a possible aversive state associated with naloxone-precipitated withdrawal from acute treatment with morphine., Methods: Doses of morphine and naloxone, as well as number of conditioning trials, were systematically varied to determine the minimum conditions that would result in a detectable CPA in male Wistar rats. Naloxone (0.003-16.7 mg/kg) was administered 4 h after an injection of vehicle or morphine (1.0, 3.3, or 5.6 mg/kg) and immediately prior to confinement to one compartment of the conditioning apparatus; rats received either one or two such naloxone-conditioning trials (separate by 48 h)., Results: Morphine (5.6 mg/kg) followed 4 h later by vehicle produced no significant preference or aversion. In morphine-naive rats, 10 mg/kg naloxone was required to produce a significant CPA with two cycles of conditioning. When increasing doses of morphine were administered (1.0, 3.3, 5.6 mg/kg), significant increases in naloxone potency to elicit a CPA were observed (16-, 211-, and 1018-fold potency shifts, respectively). Naloxone potency after two pretreatments with 5.6 mg/kg morphine was comparable to its potency to elicit a CPA after chronic exposure to morphine. Although naloxone was still effective in producing a CPA after a single conditioning cycle (and hence a single morphine exposure), its effects were dramatically reduced relative to those seen with two conditioning cycles., Conclusions: CPA is a reliable and sensitive index of the aversive motivational state accompanying withdrawal from acute opioid dependence.

Associations studies were attempted between the type of feeding, duration, and time of starting of solid foods in infancy and the incidence of insulin-dependent diabetes mellitus (IDDM). The study subjects comprised 52 IDDM patients and 52 control subjects matched for sex, age, social status, country, geographical location and selected from pediatric departments of different hospitals in Tehran. Diabetic children (21 boys, 31 girls) were of the ages of 1.5 to 14 years. Information about the pattern of their feeding at the first two years of life were collected through questionnaires administered to the mothers. The questionnaire was designed to evaluate the duration of complete or partial breast-feeding and the age at which dietary products containing cow's milk were introduced into the diet. A large proportion of the diabetic children rather than the control children had been breast-fed, and the risk of IDDM among children who had not been breast-fed was below unity. No significant difference in the duration of breast-feeding was observed between diabetic and control group. Our data do not support the existence of a protective effect of breast-feeding on the risk of IDDM, nor do the data indicate that early exposure to cow's milk and dairy products has any influence on the development of IDDM.

The present study was designed to investigate the possible role of genetic background and sex in the behavioral and neurochemical responses to early iron deficiency. Male and female C57 and DBA mice were provided either an iron deficient (ID) or control (CN) diet during early growth periods. Dopamine D2 receptor densities, and dopamine and serotonin transporter densities were determined in specific brain regions. Iron deficient DBA mice had significantly lower D2 receptor densities in the frontal cortex (FC) and caudate putamen (CP) (19 vs. 35fmol/mg and 145 vs. 215 fmol/mg, respectively). Serotonin (5-HT) transporter densities in FC of iron deficient C57 mice tended to be lower than in control animals (40 vs. 60 fmol/mg) while in the nucleus accumbens (NA) the 5-HT transporter increased in density relative to controls (350 vs. 210 fmol/mg). Open field behaviors in naïve and cocaine treated mice were also affected by diet, suggesting that iron deficiency causes decreased dopamine output. These data indicate a substantial genetic-based variability in brain responses to iron deficiency anemia, some of which are in direct contrast to what other experimental data would have predicted. Future studies clearly need to consider genetic background and sex in their analytical approach.

Male and female C57BL/6 (B6) and DBA/2 (D2) mice were subjected to either acute or 5 days of repeated restraint in ventilated, 50 ml centrifuge tubes. Control animals were not disturbed. The acute restraint animals were killed immediately following 15, 30 or 60 min of restraint and blood collected for corticosterone (CORT) analysis. The results of the acute restraint procedure revealed a strain difference in time to peak CORT in plasma with D2 animals showing an earlier peak. The males of both strains evinced similar maximum response and similar to B6 females; however, the D2 females showed a 2-fold greater CORT response than did the B6 females. Repeated restraint consisted of 5 days of 12 h in the tubes. At the end of 5 days, the animals were weighted and adrenalectomized in preparation for determination of brain corticosteroid receptors. Upon sacrifice, brains, thymus, adrenals and blood were harvested, the last for corticosteroid binding globulin (CBG). Five days of repeated restraint produced body weight loss in both strains, with B6s less affected than D2s. Repeated restraint reduced the mass of the adrenals in the B6s only. Restraint also reduced the mass of the thymus in both strains and sexes, but to a greater extent in the B6s. Plasma CBG densities were also sensitive to restraint, but only in females, showing a restraint-related decrease. Repeated restraint had no effect on hippocampal glucocorticoid or mineralocorticoid receptors; however for the latter, we observed significant strain and sex effects with D2 having higher Bmax than B6 and females having higher Bmax than males. In the pituitary, glucocorticoid receptors (GR) were reduced by repeated restraint in males, but increased in females, especially in the B6. These findings lend preliminary evidence for involvement of sex and genetics as sources of individual differences in bioadaptation to stress.

Apparent mineralocorticoid excess (AME) is a genetic disorder causing pre- and postnatal growth failure, juvenile hypertension, hypokalemic metabolic alkalosis, and hyporeninemic hypoaldosteronism due to a deficiency of 11 beta-hydroxysteroid dehydrogenase type 2 enzyme activity (11 beta HSD2). The 11 beta HSD2 enzyme is responsible for the conversion of cortisol to the inactive metabolite cortisone and therefore protects the mineralocorticoid receptors from cortisol intoxication. Several homozygous mutations are associated with this potentially fatal disease. We have examined the phenotype, biochemical features, and genotype of 14 patients with AME. All of the patients had characteristic signs of a severe 11 beta HSD2 defect. Birth weights were significantly lower than those of their unaffected sibs. The patients were short, underweight, and hypertensive for age. Variable damage of one or more organs (kidneys, retina, heart, and central nervous system) was found in all of the patients except one. The follow-up studies of end-organ damage after 2-13 yr of treatment in six patients demonstrated significant improvement in all patients. The urinary metabolites of cortisol demonstrated an abnormal ratio with predominance of cortisol metabolites, i.e. tetrahydrocortisol plus 5 alpha-tetrahydrocortisol/tetrahydrocortisone was 6.7-33, whereas the normal ratio is 1.0. Infusion of [11-3H]cortisol resulted in little release of tritiated water, indicating the failure of the conversion of cortisol to cortisone. Thirteen mutations in the HSD11B2 gene have been previously published, and we report three new genetic mutations in two patients, one of whom was previously unreported. All of the patients had homozygous defects except one, who was a compound heterozygote. Our first case had one of the most severe mutations, resulting in the truncation of the enzyme 11 beta HSD2, and died at the age of 16 yr while receiving treatment. Three patients with identical homozygous mutations from different families had varying degrees of severity of clinical and biochemical features. Due to the small number of patients with identical mutations, it is difficult to correlate genotype with phenotype. In some cases, early and vigilant treatment of AME patients may prevent or improve the morbidity and mortality of end-organ damage such as renal or cardiovascular damage and retinopathy. The outcome of treatment in more patients may establish the efficacy of treatment.