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101.
Andrea Cippitelli Jinhua Wu Kelly A Gaiolini Daniela Mercatelli Jennifer Schoch Michelle Gorman Alejandra Ramirez Roberto Ciccocioppo Taline V Khroyan Dennis Yasuda Nurulain T Zaveri Conrado Pascual Xinmin Xie Lawrence Toll 《British journal of pharmacology》2015,172(7):1834-1845
Background and Purpose
The α3β4 subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediating nicotine reinforcement processes. AT-1001 has been recently described as a high-affinity and selective α3β4 nAChR antagonist that blocks nicotine self-administration in rats. The aim of this study was to investigate the mechanism of action underlying the nicotine-suppressive effects of AT-1001.Experimental Approach
Effects of AT-1001 were determined using in vitro assays and rat models of nicotine addiction, and compared with varenicline.Key Results
AT-1001 and its analogue AT-1012 were functionally selective as antagonists for α3β4 over α4β2 nAChRs, but not to the same extent as the binding selectivity, and had partial agonist activity at α3β4 nAChRs. In contrast, varenicline was a partial agonist at α4β2, a weak agonist at α3β4 and inhibited α4β2 at a much lower concentration than it inhibited α3β4 nAChRs. AT-1001 and varenicline also had very different in vivo properties. Firstly, AT-1001 did not exhibit reinforcing properties per se while varenicline was self-administered. Secondly, systemic treatment with AT-1001 did not induce reinstatement of nicotine seeking but rather attenuated reinstatement induced by varenicline, as well as nicotine. Finally, unlike varenicline, AT-1001 selectively blocked nicotine self-administration without altering alcohol lever pressing as assessed in an operant co-administration paradigm.Conclusions and Implications
These findings describe a more complex AT-1001 in vitro profile than previously appreciated and provide further support for the potential of AT-1001 and congeners as clinically useful compounds for smoking cessation, with a mechanism of action distinct from currently available medications. 相似文献102.
Emma Ruiz José Manuel ávila Teresa Valero Susana del Pozo Paula Rodriguez Javier Aranceta-Bartrina ángel Gil Marcela González-Gross Rosa M. Ortega Lluis Serra-Majem Gregorio Varela-Moreiras 《Nutrients》2015,7(6):4739-4762
Energy intake, and the foods and beverages contributing to that, are considered key to understanding the high obesity prevalence worldwide. The relative contributions of energy intake and expenditure to the obesity epidemic, however, remain poorly defined in Spain. The purpose of this study was to contribute to updating data of dietary energy intake and its main sources from food and beverages, according to gender and age. These data were derived from the ANIBES (“Anthropometry, Intake, and Energy Balance in Spain”) study, a cross-sectional study of a nationally representative sample of the Spanish population (from 9–75 years old). A three-day dietary record, collected by means of a tablet device, was used to obtain information about food and beverage consumption and leftovers. The final sample comprised 2009 individuals (1,013 men, 996 women). The observed mean dietary energy intake was 7.6 ± 2.11 MJ/day (8.2 ± 2.22 MJ/day for men and 6.9 ± 1.79 MJ/day for women). The highest intakes were observed among adolescents aged 13–17 years (8.4 MJ/day), followed by children 9–12 years (8.2 ± 1.80 MJ/day), adults aged 18–64 (7.6 ± 2.14 MJ/day) and older adults aged 65–75 years (6.8 ± 1.88 MJ/day). Cereals or grains (27.4%), meats and derivatives (15.2%), oils and fats (12.3%), and milk and dairy products (11.8%) contributed most to daily energy intake. Energy contributions from non-alcoholic beverages (3.9%), fish and shellfish (3.6%), sugars and sweets (3.3%) and alcoholic beverages (2.6%) were moderate to minor. Contributions to caloric profile were 16.8%E from proteins; 41.1%E from carbohydrates, including 1.4%E from fiber; 38.5%E from fats; and 1.9%E from alcohol intake. We can conclude that energy intake is decreasing in the Spanish population. A variety of food and beverage groups contribute to energy intake; however, it is necessary to reinforce efforts for better adherence to the traditional Mediterranean diet. 相似文献
103.
Rosas J Ramos-Casals M Ena J García-Carrasco M Verdu J Cervera R Font J Caballero O Ingelmo M Pascual E 《Rheumatology (Oxford, England)》2002,41(6):670-675
OBJECTIVES: To examine salivary function in patients with primary Sj?gren's syndrome (SS) by assessing unstimulated and stimulated flows using 5 mg of pilocarpine in a 5% solution, in order to define their clinical usefulness in the evaluation of xerostomia in patients with primary SS as well as to identify those factors related to the increase in salivary flow after pilocarpine stimulation. METHODS: We investigated the clinical and immunological characteristics of 60 consecutive patients with primary SS. All patients fulfilled four or more of the preliminary diagnostic European criteria for SS. We measured unstimulated (basal) salivary flow (BSF) in all patients. In patients with BSF =1.5 ml, stimulated salivary flows (SSF) were also measured after stimulation with an ophthalmic 5% pilocarpine solution (0.1 ml=5 mg, administered sublingually). SSF was also measured after oral administration of 50 mg anetholetrithione (ANTT) in the same patients. These stimulated salivary flows were measured 1, 2 and 3 h after the stimulus. RESULTS: Of the 60 patients, 55 were women and five men, with a mean age at the SS onset of 61 yr (range 18-82 yr). The mean BSF for SS patients was 1.40+/-0.17 ml. Fifty (83%) patients showed a BSF less than 1.5 ml. The stimulated salivary flow after 1 h was 3.23 ml in the pilocarpine group and 0.57 in the ANTT group (P<0.001); after 2 h it was 1.32 ml in the pilocarpine group and 0.52 in the ANTT group (P=0.02) and after 3 h it was 0.80 ml in the pilocarpine group and 0.41 in the ANTT group (P=0.046). No clinical or immunological differences were found between SS patients with BSF more or less than 1.5 ml, although patients with a BSF less than 1.5 ml showed a parotid scintigraphy class III or IV more frequently (42 vs 0%, P=0.01). SS patients with a pilocarpine SSF less than 1.5 ml had a longer duration of SS (73.3 vs 31.3 months, P=0.03) and a higher prevalence of positive anti-Ro/SS-A (70 vs 36%, P=0.038), anti-La/SS-B (65 vs 32%, P=0.038), parotid scintigraphy class III-IV (79 vs 9%, P<0.001) and positive salivary gland biopsy (90 vs 43%, P<0.001). CONCLUSION: The study of xerostomia using basal and pilocarpine SSF is simple to perform, acceptable to patients and needs no special equipment. We describe a significant increase in SSF using a solution of 5% pilocarpine in comparison with salivary flow obtained after stimulation with ANTT. Twenty-two of the 46 patients with low BSF had stimulated flows over 1.5 ml. These 'responder' patients showed a shorter duration of sicca symptoms, a lower frequency of positive immunological markers and milder grades of scintigraphic patterns and lymphocytic infiltrates in salivary gland biopsies. This subset of patients probably maintain a residual capacity of their salivary glands, as opposed to the 'non-responder' patients, who had a longer duration of sicca syndrome evolution with more severe involvement of the salivary glands. 相似文献
104.
Hyperimmune γ-globulins have proven efficacious in the prevention and treatment of viral infections, including those caused by hepatitis A and B viruses, cytomegalovirus, parvovirus. Interest in the prevention and/or treatment of infections caused by human immunodeficiency virus (HIV) has led to clinical trials with anti-HIV immune plasma and purified immune globulin prepared from donors who are actively infected with HIV. The handling and fractionation of this or other infectious plasma requires the construction and operation of virus containment facilities designed to protect fractionation employees and the immediate environment. This requirement would be reduced substantially by applying virucidal procedures prior to or during plasma pooling. We have shown that heating plasma at 56°C for 1 h followed by treatment with 1% tri(n-butyl) phophate (TNBP) and 1% Triton X-100 for 4 h at 30°C resulted in the inactivation of ≥ 1012.1 tissue culture infectious doses (TCID50) of HIV. With this treatment, the recovery of IgG was 87±3%. Fractionation of treated plasma by cold ethanol precipitation proceeded normally, and overall recovery, purity, and potency against selected viral markers were unaffected. The additional treatment of plasma with 15 g/l Aerosil for 4 h at 45 °C removed 104.5 TCID50 of HIV but resulted in substantial IgG losses both prior to and following fractionation. We conclude that potentially infectious plasma can be treated at 56°C for 1 h and by TNBP/Triton X-100 at 30°C for 4 h prior to fractionation. These steps appear sufficient to assure safety and to permit routine fractionation of plasma. Aerosil treatment, under the condition evaluated, was less satisfactory, although lower concentrations or temperatures than those evaluated may prove advantageous. 相似文献
105.
Age-related physiologic changes together with high prevalence of chronic illness and the use of multiple medications predispose older adults to syncope. The causes of many of these patients' syncope are unexplained and most remained symptomatic. A thoughtful diagnostic strategy is essential to pinpoint the cause in each patient. The initial assessment includes a comprehensive medical history, preferably with an eye witness account, and a thorough physical examination. The decision for further diagnostic tests often depends on whether there is evidence of underlying structural heart disease. In the absence of heart disease, tilt table testing and the related autonomic function testing are usually most productive. Various cardiac studies will be more appropriate for those with suspected structural heart disease. A cause of syncope can only be concluded if there is a sufficiently strong correlation between syncopal symptoms and the detected abnormalities on investigations. A strategic evaluation of syncope of the elderly subjects should allow a correct diagnosis and appropriate management. 相似文献
106.
Pascual J 《Nefrología : publicación oficial de la Sociedad Espa?ola Nefrologia》2001,21(6):524-5; discussion 526-7
107.
Plasma concentration of asymmetric dimethylarginine,an endogenous inhibitor of nitric oxide synthase,is elevated in hyperthyroid patients 总被引:3,自引:0,他引:3
Hermenegildo C Medina P Peiró M Segarra G Vila JM Ortega J Lluch S 《The Journal of clinical endocrinology and metabolism》2002,87(12):5636-5640
Cardiovascular manifestations are frequent findings in patients with thyroid hormone disorders. Nitric oxide (NO) plays a key role in vascular, endothelial-mediated relaxation. NO is synthesized from L-arginine by NO synthase, an enzyme inhibited by endogenous compounds, mainly asymmetric dimethylarginine [asymmetric N(G),N(G)-dimethyl-L-arginine (ADMA)]. The aim of our work was to investigate whether plasma L-arginine and dimethylarginine concentrations and NO production are altered in hypo- and hyperthyroid patients, compared with control subjects. L-arginine, ADMA and symmetric dimethylarginine were analyzed by HPLC. NO was measured as plasma nitrite plus nitrate (NO(x)) concentration by a colorimetric method based on Griess reagent. L-arginine, ADMA, and symmetric dimethylarginine plasma levels in the hypothyroid group were similar to those of the control group; whereas in hyperthyroidism, these values were significantly increased. However, the L-arginine/ADMA ratio was decreased in hyperthyroid patients, resulting in diminished NO(x) production. When all subjects were analyzed together, free T(4) levels were directly correlated with ADMA and inversely correlated with NO(x). 相似文献
108.
109.
This article reviews the most significant developments reported between July 2006 and July 2007 in the fields of pediatric cardiology and congenital heart disease, in diagnosis and treatment in particular. In the area of imaging techniques, the increasing clinical roles of magnetic resonance imaging, tissue Doppler imaging and three-dimensional echocardiography are highlighted, as is the application of these techniques to fetal cardiology and its repercussions. The incidence and treatment of arrhythmias in children are also discussed and, with regard to heart failure, there is an assessment of recent findings in epidemiology and diagnosis, new drugs, ventricular assist systems, and the current status of heart transplantation. In the area of interventional cardiology, present-day techniques for the closure of atrial and ventricular septal defects are reviewed and there is an assessment of early results with partially absorbable devices, percutaneous pulmonary valve implantation, and new types of stent (e.g., premounted, coated and absorbable stents). In cardiac surgery, the focus is on studies that evaluate outcome quality, the search for new biocompatible conduits, experience with new techniques for treating complex transpositions (e.g., the Nikaidoh procedure and its variants), the medium- and long-term results of treating aortic valvular disease with pulmonary autografts (i.e., the Ross and Ross-Konno procedures), and current findings on the treatment of pulmonary insufficiency after correction of either the tetralogy of Fallot or a dysfunctional Fontan circuit. 相似文献
110.
Serrano D Carrión R Balsalobre P Miralles P Berenguer J Buño I Gómez-Pineda A Ribera JM Conde E Díez-Martín JL;Spanish Cooperative Groups GELTAMO GESIDA 《Experimental hematology》2005,33(4):487-494
OBJECTIVE: To evaluate feasibility, safety, and efficacy of peripheral blood stem cell collection (PBSCC) and autologous stem cell transplantation (ASCT), to treat patients diagnosed of high-risk or relapsed HIV-associated lymphoma (HIV+ Ly), responding to highly active antiretroviral therapy (HAART). METHODS: Prospective and multicentric study in patients with high-risk or relapsed chemosensitive HIV+ Ly, candidate for consolidation with ASCT. Eligibility criteria were similar to those of HIV- lymphoma. HAART was aimed to be maintained during the procedure. RESULTS: Fourteen patients were admitted. Adequate PBSCC was obtained from all patients (median CD34+ cells was 4.7 x 10(6)/kg). Three patients died before ASCT; two had disease progression and one died from VHC-liver failure. Eleven transplanted patients showed neutrophil engraftment after a median time of 16 days (range, 9-33 days), and nine patients showed platelet engraftment after a median time of 20 days (range, 11-36 days). CD4+ cell counts and HIV viral load (VL) were appropriately preserved along the procedure. No patients died from treatment-related complications. One patient died from lymphoma progression (day +19), and another died in complete remission (CR) with undetectable VL, 15 months after transplant, due to infection. One patient relapsed at 32 months after ASCT. The remaining eight patients are alive in CR with an event-free survival of 65% and a median follow-up of 30 months after ASCT (range, 7-36 months). CONCLUSIONS: These results show that feasibility, safety, and efficacy of PBSCC and ASCT in HIV+ Ly patients responding to HAART are similar to those observed in the HIV- lymphoma setting. 相似文献