Inhibition of monoacylglycerol lipase reduces nicotine withdrawal

Background and Purpose

Abrupt discontinuation of nicotine, the main psychoactive component in tobacco, induces a withdrawal syndrome in nicotine-dependent animals, consisting of somatic and affective signs, avoidance of which contributes to drug maintenance. While blockade of fatty acid amide hydrolase, the primary catabolic enzyme of the endocannabinoid arachidonoylethanolamine (anandamide), exacerbates withdrawal responses in nicotine-dependent mice, the role of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of a second endocannabinoid 2-arachidonylglycerol (2-AG), in nicotine withdrawal remains unexplored.

Experimental Approach

To evaluate the role of MAGL enzyme inhibition in nicotine withdrawal, we initially performed a genetic correlation approach using the BXD recombinant inbred mouse panel. We then assessed nicotine withdrawal intensity in the mouse after treatment with the selective MAGL inhibitor, JZL184, and after genetic deletion of the enzyme. Lastly, we assessed the association between genotypes and smoking withdrawal phenotypes in two human data sets.

Key Results

BXD mice displayed significant positive correlations between basal MAGL mRNA expression and nicotine withdrawal responses, consistent with the idea that increased 2-AG brain levels may attenuate withdrawal responses. Strikingly, the MAGL inhibitor, JZL184, dose-dependently reduced somatic and aversive withdrawal signs, which was blocked by rimonabant, indicating a CB₁ receptor-dependent mechanism. MAGL-knockout mice also showed attenuated nicotine withdrawal. Lastly, genetic analyses in humans revealed associations of the MAGL gene with smoking withdrawal in humans.

Conclusions and Implications

Overall, our findings suggest that MAGL inhibition maybe a promising target for treatment of nicotine dependence.     

Tuberculosis despite latent infection screening and treatment in patients receiving TNF inhibitor therapy

Clinical Rheumatology - Although latent tuberculosis infection (LTBI) treatment is given before anti-tumor necrosis factor (TNF) treatment, tuberculosis (TB) still develops in these patients and...     

Prognostic value of blood pressure in ambulatory heart failure: a meta-analysis and systematic review. Ambulatory blood pressure predicts heart failure prognosis

Heart Failure Reviews - Previous primary studies have explored the association between blood pressure (BP) and mortality in ambulatory heart failure (HF) patients reporting varying and contrasting...     

Does the Myocardial Performance Index Affect Pulmonary Artery Pressure in Patients With Mitral Stenosis? A Tissue Doppler Imaging Study

BACKGROUND: The relation between systolic pulmonary artery pressure (PAP) and mitral stenosis (MS) has been poorly understood. Although the mitral valve area (MVA) is an important factor affecting the PAP, there is a wide spectrum of the PAP in patients with MS despite a similar MVA. So, we analyzed whether the left and right ventricular myocardial performance index (MPI) correlated with the PAP. METHODS: Two-dimensional Doppler echocardiography was performed in 46 patients with MS. The left atrial diameter, mean mitral gradient, and MVA were measured. The PAP was derived from the tricuspid regurgitant jet velocity. The ejection time (ET), isovolumetric relaxation time (IRT), and contraction time (ICT) were measured on annulus of interventricular septum, lateral, inferior and anterior wall of left ventricle, and right ventricle free wall from apical two- and four-chamber views in patients with MS and 40 age-matched healthy patients by tissue Doppler imaging (TDI). Then the MPI was calculated as (IRT + ICT)/ET for both left and right ventricle. The correlation of PAP with MVA, mean mitral gradient, left atrial diameter, and left and right ventricular MPI was evaluated. RESULTS: MVA and PAP were measured as 1.57 +/- 0.39 cm2 (0.8-2.5 cm2)and 42 +/- 16 mmHg, respectively. It was determined that the MPI increased in patients with MS(0.59 +/- 0.1 vs 0.48 +/- 0.07, P < 0.001). It was also demonstrated that the MVA, left atrial diameter, mean diastolic gradient, and left ventricular MPI were correlated with PAP(r =-0.39 [P = 0.007], r = 0.43 [P = 0.003], r = 0.58 [P < 0.001], and r = 0.65 [P < 0.001], respectively). In multivariate analysis, although the PAP correlated with mean diastolic gradient and MPI (r = 0.39 [P = 0.013], and r = 0.48 [P < 0.001]), it did not correlate with left atrial diameter and MVA. The PAP also correlated with right ventricular MPI(r = 0.63 [P < 0.001]). CONCLUSION: This study demonstrates that the left ventricular MPI obtained by TDI is an important marker of PAP, and right ventricular MPI correlates with the PAP in patients with MS.     

Safety and efficacy of angiography-guided stent placement in small native coronary arteries of < 3.0 mm in diameter

Background and hypothesis: Increased operator experience, greater insight in stent deployment techniques, and improved poststent medication regimen have significantly reduced the risk of thrombotic stent closure following stent placement in large coronary arteries ( 3.0 mm in diameter). Whether equally favorable results are afforded by stent placement in small vessels (> 3.0 mm), however, remains unclear. Accordingly, the aim of this study was the specific examination of the risk of stent placement in small native coronary vessels, using stent deployment technique consisting of supplementary dilatations with larger balloons or high-pressure inflations, and aggressive aspirin-ticlopidine and short-term oral anticoagulation poststent therapy. Methods: Forty-seven balloon-expandable stents (20 Gianturco-Roubin, 21 NIR, 6 Palmaz-Schatz) were successfully implanted without intravascular guidance in 45 native coronary arteries (mean reference diameter of 2.5 mm) in 44 consecutive patients (31 men, 13 women), the majority of whom (87%) were stented for the treatment of failed or suboptimal balloon angioplasty outcome. Results: Successful stent placement reduced the lesion diameter stenosis from 91 ± 9% to 3 ± 7% (p = 0.0001). There were no early stent thrombosis or major cardiovascular events prior to hospital discharge. During a 12-month follow-up period, most patients remained symptomatically improved and no myocardial infarction, stroke, or death was observed. Five-month angiographic reassessment revealed an in-stent restenosis rate of 41%, which was higher in vessels 2.5 mm in size (47 vs. 33% for vessels > 2.5 mm, p = 0.2747). Conclusions: In selected patients with small native coronary vessels < 3.0 mm in diameter, angiography-guided optimal stent placement is associated with a low risk of stent thrombosis and bleeding complications. However, the in-stent restenosis rate is high with the stents used in this study.     

Lipid abnormalities and renal disease: is dyslipidemia a predictor of progression of renal disease?

Dyslipidemia is a cardiovascular disease (CVD) risk factor that is associated with enhanced atherosclerosis and plaque instability. Renal insufficiency is associated with abnormalities in lipoprotein metabolism in both the early and the advanced stages of chronic renal failure. These include alterations in apolipoprotein A (apo A)- and B- containing lipoproteins, high-density lipoproteins, and triglycerides. In animal models, these alterations in lipid metabolism and action lead to macrophage activation and infiltration in the kidney with resultant tubulointerstitial and endothelial cell injury. Limited data in humans suggest that, in addition to contributing to CVD, dyslipidemia may be a risk factor for the progression of renal disease. The effects of dyslipidemia on the kidney are mainly observed in those with other risk factors for renal disease progression such as hypertension, diabetes, and proteinuria. Renal disease is a strong risk factor for CVD and African Americans have high rates of renal disease. Therefore, examining the effects of dyslipidemia on the development or progression or renal disease will be an important question for the Jackson Heart Study and is the topic of this review.     

Repeated Remissions of Cushing's Disease Due to Recurrent Infarctions of an ACTH-Producing Pituitary Macroadenoma

Infarction of prolactin-secreting or growth hormone-secreting pituitary adenomas is not unusual. However, Infarction of ACTH-secreting adenomas has rarely been reported. Cyclical course of Cushing's syndrome alternating with adrenal insufficiency due to recurrent infarction of an ACTH-secreting pituitary adenoma has not been reported. We report here a 20-year-old lady who presented with florid signs of Cushing's syndrome but was found to have adrenal insufficiency on biochemical evaluation. Magnetic resonance imaging (MRI) of the pituitary gland showed that she had infarction of an ACTH-secreting macroadenoma. Over the next 6 years, her disease ran a cyclical course characterized by periods of hypercortisolism alternating with adrenal insufficiency due to repeated episodes of infarctions of the ACTH-secreting pituitary macroadenoma with corresponding changes in the pituitary adenoma on serial MRIs. The case alerts clinicians to this possibility when a patient presents with clinical picture of Cushing's syndrome but has adrenal insufficiency on biochemical testing. It also suggests that silent or subclinical infarction of pituitary adenomas is not uncommon and is probably under diagnosed.     

激素敏感脂酶基因高度表达对泡沫细胞形成的作用

中国仓鼠卵细胞在给予β－ＶＬＤＬ后，细胞内蓄积胆固醇酯，形成泡沫样细胞。以腺病毒基因转移方法书激素敏感脂酶基因转染到中国仓鼠卵细胞中，得到了来自激素敏感脂酶的胆固醇酯水解活性高度表达，此时，β－ＶＬＤＬ导致的胆固醇酯蓄积作用被阻断，提示增加胆固醇酯水解可以防止泡沫细胞形成。     

Sulfasalazine-induced pulmonary disease.

We report the findings in two patients with sulfasalazine-induced pulmonary disease. The first patient developed pulmonary interstitial fibrosis after more than 4 yr of treatment for Crohn's disease. Pulmonary symptoms and chest roentgenographic and pulmonary function abnormalities gradually reversed after stopping the drug. No specific treatment was given. The second patient, who had rheumatoid arthritis without pulmonary disease, received the drug for 1 yr without experiencing any problems. Readministration seven months later resulted in the development of an acute interstitial pulmonary disease. Discontinuing the drug and treatment with corticosteroids produced rapid improvement. We discuss these patients in relation to other reports of sulfasalazine-induced pulmonary toxicity, highlighting their atypical features.