Citations

Peripheral administration of a specific neurokinin-1 receptor (NK-1R) antagonist to mice leads to reduced weight gain and circulating levels of insulin and leptin after high-fat diet (HFD). Here, we assessed the contribution of substance P (SP) and NK-1R in diet-induced obesity using NK-1R deficient [knockout (KO)] mice and extended our previous findings to show the effects of SP-NK-1R interactions on adipose tissue-associated insulin signaling and glucose metabolic responses. NK-1R KO and wild-type (WT) littermates were fed a HFD for 3 wk, and obesity-associated responses were determined. Compared with WT, NK-1 KO mice show reduced weight gain and circulating levels of leptin and insulin in response to HFD. Adiponectin receptor mRNA levels are higher in mesenteric fat and liver in NK-1 KO animals compared with WT, after HFD. Mesenteric fat from NK-1R KO mice fed with HFD has reduced stress-activated protein kinase/c-Jun N-terminal kinase and protein kinase Cθ activation compared with WT mice. After glucose challenge, NK-1R KO mice remove glucose from the circulation more efficiently than WT and pair-fed controls, suggesting an additional peripheral effect of NK-1R-mediated signaling on glucose metabolism. Glucose uptake experiments in isolated rat adipocytes showed that SP directly inhibits insulin-mediated glucose uptake. Our results further establish a role for SP-NK-1R interactions in adipose tissue responses, specifically as they relate to obesity-associated pathologies such as glucose intolerance and insulin resistance. Our results highlight this pathway as an important therapeutic approach for type 2 diabetes.

Abstract The mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA (mtDNA) replication and transcription. Disruption of TFAM results in heart failure and premature aging in mice. But very little is known about the role of TFAM in cancer development. Here, we report the identification of frequent frameshift mutations in the coding mononucleotide repeat of TFAM in sporadic colorectal cancer (CRC) cell lines and in primary tumors with microsatellite instability (MSI), but not in microsatellite stable (MSS) CRC cell lines and tumors. The presence of the TFAM truncating mutation, in CRC cells with MSI, reduced the TFAM protein level in vivo and in vitro and correlated with mtDNA depletion. Furthermore, forced overexpression of wild-type TFAM in RKO cells carrying a TFAM truncating mutation suppressed cell proliferation and inhibited RKO cell-induced xenograft tumor growth. Moreover, these cells showed more susceptibility to cisplatin-induced apoptosis due to an increase of cytochrome b (Cyt b) expression and its release from mitochondria. An interaction assay between TFAM and the heavy-strand promoter (HSP) of mitochondria revealed that mutant TFAM exhibited reduced binding to HSP, leading to reduction in Cyt b transcription. Collectively, these data provide evidence that a high incidence of TFAM truncating mutations leads to mitochondrial copy number reduction and mitochondrial instability, distinguishing most CRC with MSI from MSS CRC. These mutations may play an important role in tumorigenesis and cisplatin-induced apoptotic resistance of most microsatellite-unstable CRCs. Cancer Res; 71(8); 2978–87. ©2011 AACR.

Background— Atrial fibrillation (AF) is a common finding in patients with myocardial infarction (MI). Atrial fibrillation is not generally perceived by clinicians as a critical event during the acute phase of MI; however, its prognostic influence in MI remains controversial. Furthermore, contradictory data exist concerning the risk of death according to AF timing. This article, a systematic review and first meta-analysis, aims to quantify the mortality risk associated with AF in MI patients and its timing. Methods and Results— A comprehensive search of several electronic databases (1970 to 2010; adults, any language) identified MI studies that evaluated mortality related to AF. Evidence was reviewed by 2 blinded reviewers with a formal assessment of the methodological quality of the studies. Adjusted odds ratios were pooled across studies using the random-effects model. The I 2 statistic was used to assess heterogeneity. In the 43 included studies (278 854 subjects), the mortality odds ratio associated with AF was 1.46 (95% confidence interval, 1.35 to 1.58; I 2 =76%; 23 studies). This worse prognosis persisted regardless of the timing of AF; the odds ratio of mortality for new AF with no prior history of AF was 1.37 (95% confidence interval, 1.26 to 1.49), I 2 =28%, 9 studies), and for prior AF was 1.28 (95% confidence interval, 1.16 to 1.40; I 2 =24%; 4 studies). The sensitivity analysis of new AF studies adjusting for confounding factors did not show a decrease in risk of death. Conclusions— Atrial fibrillation is associated with increased risk of mortality in MI patients. New AF with no history of AF before MI remained associated with an increased risk of mortality even after adjustment for several important AF risk factors. These subsequent increases in mortality suggest that AF can no longer be considered a nonsevere event during MI.

Pulmonary vasculitis can occur in apparent isolation, as part of a primary systemic vasculitis, or with an underlying systemic inflammatory autoimmune disorder. The presentation of pulmonary vasculitis in the intensive care unit (ICU) can be fulminant and will often overlap with more common disorders that affect the critically ill. Although diffuse alveolar hemorrhage (DAH) is the clinical feature that often initiates the concern for an underlying vasculitis, hemoptysis may not be apparent or its presentation can be mistaken for an alternative disease process. As a result, the diagnosis of pulmonary vasculitis in the ICU may be delayed or be completely unrecognized. A high level of suspicion is essential to obtain a timely diagnosis and for effective therapies to be implemented. There have been significant advances this past decade in diagnostic strategies as well as in the therapeutic options for patients with pulmonary vasculitis. We review here the clinical presentations, diagnostic strategies, and treatment options of the critically ill patients presenting with pulmonary vasculitis. The reader is referred to other resources for a more comprehensive review of specific vasculitic entities.

Propofol is an alkylphenol derivative named 2, 6, diisopropylphenol and is a potent intravenous short-acting hypnotic agent. It is commonly used as sedation, as well as an anesthetic agent in both pediatric and adult patient populations. There have been numerous case reports describing a constellation of findings including metabolic derangements and organ system failures known collectively as propofol infusion syndrome (PRIS). Although there is a high mortality associated with PRIS, the precise mechanism of action has yet to be determined. The best preventive measure for this syndrome is awareness and avoidance of clinical scenarios associated with development of PRIS. There is no established treatment for PRIS; care is primarily supportive in nature and may include the full array of advanced cardiopulmonary support, including extracorporeal membrane oxygenation (ECMO). This article reviews the reported cases of PRIS and describes the current understanding of the underlying pathophysiology and treatment options.

We reviewed surrogate calls (i.e. those made on behalf of the patient) to a national triage call centre to determine whether there were differences between calls made by surrogates and self calls. During a three-year period there were 14,646 calls (14% of the total) made by a surrogate on behalf of the patient. Surrogate calls, as a percentage of total calls, increased with the age of the patient from 12% in the 18–34 year age group to 43% in the 80 and over age group ( P < 0.0001). The symptoms of vomiting or nausea and dizziness or light-headedness were significantly more likely to be reported by surrogate callers than self callers. Surrogates reported a higher original intention of taking patients to the hospital emergency department (ED) compared with self callers across all adult age groups (OR 1.64; 95% CI 1.57 to 1.71). A higher proportion (38%) of surrogate calls ended with the nurse recommending an ED visit compared with only 26% of self calls (OR 1.72; 95% CI 1.66 to 1.79). Calls about men accounted for 54% of surrogate calls but only 26% of self calls (OR 3.3; 95% CI 3.2 to 3.4), suggesting that surrogate calls may be a way of increasing medical access for men.