Effect of topiramate on weight gain in patients receiving atypical antipsychotic agents.

BACKGROUND: Clinical antipsychotic trials of intervention effectiveness showed that atypical antipsychotics (AAPs) were associated with significant weight gain and glucose intolerance. A few trials have shown topiramate to reduce weight gain in patients receiving AAPs, although this benefit has not been present in all trials. OBJECTIVE: This study aimed to determine topiramate therapy's impact on weight gain in patients receiving AAPs. DATA SOURCE: A systematic literature search of MEDLINE (1948 to July 8, 2011) and Cochrane CENTRAL (4th Quarter 2011) was conducted. STUDY SELECTION: Eight trials (n = 336 participants) met our inclusion criteria: randomized controlled trial, evaluated topiramate in patients taking AAPs, and reported weight change during the treatment course. DATA EXTRACTION: Two investigators (S.M. and C.I.C.) used a standardized data abstraction tool to independently collect data, with disagreement resolved through discussion. The difference between the mean weight in the topiramate and control groups was calculated as the weighted mean difference with accompanying 95% confidence interval. A random effect model was used for all analyses. DATA SYNTHESIS: Upon meta-analysis, we found that patients receiving topiramate lost weight or had attenuated weight gain compared to control patients (weighted mean difference, -2.83 kg; 95% confidence interval, -4.62 to -1.03). CONCLUSIONS: Our meta-analysis shows that using topiramate can prevent or reduce weight gain associated with AAPs.

Atherosclerotic cardiovascular disease screening in adults: American College Of Preventive Medicine position statement on preventive practice.

CONTEXT: Atherosclerotic cardiovascular diseases, including coronary heart disease (CHD), carotid artery stenosis (CAS), peripheral artery disease (PAD), and abdominal aortic aneurysm (AAA), affect millions of U.S. adults and are leading causes of morbidity and mortality. There is some uncertainty regarding the utility of certain screening tests for prevention of cardiovascular morbidity and mortality. EVIDENCE ACQUISITION: Current guidelines and studies pertaining to CHD, CAS, PAD, and AAA screening in the adult population were reviewed. EVIDENCE SYNTHESIS: CHD risk can be estimated by the Framingham Risk Score (FRS), which is valuable in identifying high-risk asymptomatic adults who may benefit from preventive treatments. There is moderate certainty that the benefits of screening do not outweigh the harms for individuals with asymptomatic CAS. The potential harms associated with routine PAD screening in asymptomatic adults are also likely to exceed benefits. Ultrasonography is a safe, noninvasive, and reliable screening test used to identify AAAs for treatment in men aged >65 years who have ever smoked. CONCLUSIONS: American College of Preventive Medicine (ACPM) recommends CHD risk assessment using the FRS to guide risk-based therapy. ACPM does not recommend routine screening of the general adult population using electrocardiogram, exercise-stress testing, computed tomography scanning, ankle-brachial index, carotid intima medial thickness, or emerging risk factors, including high-sensitivity C-reactive protein (hs-CRP). ACPM does not recommend routine screening of the general adult population for CAS or PAD. ACPM recommends one-time AAA screening in men aged 65-75 years who have ever smoked. Routine AAA screening in women is not recommended.

Inflammasome-mediated regulation of hepatic stellate cells.

The inflammasome is a cytoplasmic multiprotein complex that has recently been identified in immune cells as an important sensor of signals released by cellular injury and death. Analogous to immune cells, hepatic stellate cells (HSC) also respond to cellular injury and death. Our aim was to establish whether inflammasome components were present in HSC and could regulate HSC functionality. Monosodium urate (MSU) crystals (100 microg/ml) were used to experimentally induce inflammasome activation in LX-2 and primary mouse HSC. Twenty-four hours later primary mouse HSC were stained with alpha-smooth muscle actin and visualized by confocal microscopy, and TGF-beta and collagen1 mRNA expression was quantified. LX-2 cells were further cultured with or without MSU crystals for 24 h in a transwell chemotaxis assay with PDGF as the chemoattractant. We also examined inhibition of calcium (Ca(2+)) signaling in LX-2 cells treated with or without MSU crystals using caged inositol 1,4,5-triphosphate (IP(3)). Finally, we confirmed an important role of the inflammasome in experimental liver fibrosis by the injection of carbon tetrachloride (CCl(4)) or thioacetamide (TAA) in wild-type mice and mice lacking components of the inflammasome. Components of the inflammasome are expressed in LX-2 cells and primary HSC. MSU crystals induced upregulation of TGF-beta and collagen1 mRNA and actin reorganization in HSCs from wild-type mice but not mice lacking inflammasome components. MSU crystals inhibited the release of Ca(2+) via IP(3) in LX-2 cells and also inhibited PDGF-induced chemotaxis. Mice lacking the inflammasome-sensing and adaptor molecules, NLRP3 and apoptosis-associated speck-like protein containing CARD, had reduced CCl(4) and TAA-induced liver fibrosis. We concluded that inflammasome components are present in HSC, can regulate a variety of HSC functions, and are required for the development of liver fibrosis.

Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome.

Hepatocyte death results in a sterile inflammatory response that amplifies the initial insult and increases overall tissue injury. One important example of this type of injury is acetaminophen-induced liver injury, in which the initial toxic injury is followed by innate immune activation. Using mice deficient in Tlr9 and the inflammasome components Nalp3 (NACHT, LRR, and pyrin domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and caspase-1, we have identified a nonredundant role for Tlr9 and the Nalp3 inflammasome in acetaminophen-induced liver injury. We have shown that acetaminophen treatment results in hepatocyte death and that free DNA released from apoptotic hepatocytes activates Tlr9. This triggers a signaling cascade that increases transcription of the genes encoding pro-IL-1beta and pro-IL-18 in sinusoidal endothelial cells. By activating caspase-1, the enzyme responsible for generating mature IL-1beta and IL-18 from pro-IL-1beta and pro-IL-18, respectively, the Nalp3 inflammasome plays a crucial role in the second step of proinflammatory cytokine activation following acetaminophen-induced liver injury. Tlr9 antagonists and aspirin reduced mortality from acetaminophen hepatotoxicity. The protective effect of aspirin on acetaminophen-induced liver injury was due to downregulation of proinflammatory cytokines, rather than inhibition of platelet degranulation or COX-1 inhibition. In summary, we have identified a 2-signal requirement (Tlr9 and the Nalp3 inflammasome) for acetaminophen-induced hepatotoxicity and some potential therapeutic approaches.