Takotsubo cardiomyopathy and QT interval prolongation: who are the patients at risk for torsades de pointes?

Objectives

QT interval prolongation is prevalent among patients with Takotsubo cardiomyopathy (TC), whereas torsades de pointes (TdP) has rarely been reported in these patients. We studied all peer-reviewed reports on TC-associated QT interval prolongation and all peer-reviewed reports on TC-associated TdP to characterize the clinical circumstances leading to TdP in patients with TC.

Methods

The literature search yielded 14 reports on TC-associated TdP and 26 reports on TC-associated QT interval prolongation. Overall, 15 patients with TC-associated TdP and 86 patients with TC-associated QT interval prolongation were reported. We systematically reviewed each report and recorded the risk factors for TdP as well as the clinical circumstances of TC.

Results

The prevalence of the male sex was higher among patients with TC-associated TdP relative to patients with TC-associated QT interval prolongation (26.7% vs 5.8%; P = .01). There was a trend in the mean maximal corrected QT interval being longer among patients with TC-associated TdP relative to patients with TC-associated QT interval prolongation (679.9 ± 230.6 vs 555.9 ± 63.8 milliseconds; P = .06). There were no differences between patients with TC-associated TdP and patients with TC-associated QT interval prolongation in mean age, maximal troponin levels, and lowest ejection fraction. Overall, 12 (80.0%) patients with TC-associated TdP had risk factors for TdP other than the female sex and systolic dysfunction, including suspicion of congenital long QT syndrome, bradycardia, hypokalemia, recent conversion from atrial fibrillation to sinus rhythm, and using QT prolonging agents.

Conclusions

Men with TC-associated QT interval prolongation are at risk for TdP. Most patients with TC-associated TdP have risk factors for TdP other than the female sex and systolic dysfunction.     

Did Duty Hour Reform Lead to Better Outcomes Among the Highest Risk Patients?

Background

Earlier work demonstrated that ACGME duty hour reform did not adversely affect mortality, with slight improvement noted among specific subgroups.

Objective

To determine whether resident duty hour reform differentially affected the mortality risk of high severity patients or patients who experienced post-operative complications (failure-to-rescue).

Design

Observational study using interrupted time series analysis with data from July 1, 2000 - June 30, 2005. Fixed effects logistic regression was used to examine the change in the odds of mortality or failure-to-rescue (FTR) in more versus less teaching-intensive hospitals before and after duty hour reform.

Participants

All unique Medicare patients (n = 8,529,595) admitted to short-term acute care non-federal hospitals and all unique VA patients (n = 318,636 patients) with principal diagnoses of acute myocardial infarction, congestive heart failure, gastrointestinal bleeding, stroke or a DRG classification of general, orthopedic or vascular surgery.

Measurements and Main Results

We measured mortality within 30 days of hospital admission and FTR, measured by death among patients who experienced a surgical complication. The odds of mortality and FTR generally changed at similar rates for higher and lower risk patients in more vs. less teaching intensive hospitals. For example, comparing the mortality risk for the 10% of Medicare patients with highest risk to the other 90% of patients in post-reform year 1 for combined medical an OR of 1.01 [95% CI 0.90, 1.13], for combined surgical an OR of 0.91 [95% CI 0.80, 1.04], and for FTR an OR of 0.94 [95% CI 0.80, 1.09]. Findings were similar in year 2 for both Medicare and VA. The two exceptions were a relative increase in mortality for the highest risk medical (OR 1.63 [95% CI 1.08, 2.46]) and a relative decrease in the high risk surgical patients within VA in post-reform year 1 (OR 0.52 [95% CI 0.29, 0.96]).

Conclusions

ACGME duty hour reform was not associated with any consistent improvements or worsening in mortality or failure-to-rescue rates for high risk medical or surgical patients.KEY WORDS: medical errors internship and residency, education, medical, graduate, personnel staffing and scheduling, continuity of patient care     

Suppression of hepatocellular carcinoma growth in mice via leptin, is associated with inhibition of tumor cell growth and natural killer cell activation

BACKGROUND/AIMS: Leptin exerts potent immune modulatory properties. The aim of this study was to determine leptin's anti-tumor effect in a murine model of hepatocellular carcinoma (HCC). METHODS: In vivo, athymic nude mice were transplanted with Hep3B cells, followed by daily leptin administration for 6 weeks. RESULTS: Leptin administration induced a significant reduction in tumor size, improved survival rate, and was associated with a significant increase in peripheral natural killer (NK) cell number. Splenocytes from leptin-treated mice featured decreased expression of CIS mRNA. SCID mice featured a similar leptin-associated tumor suppression. In contrast, NK-deficient SCID-beige mice developed larger tumors which were unresponsive to leptin. NK cells incubated in vitro with increasing doses of leptin demonstrated increased cytotoxicity and proliferation. Incubation of leptin with hepatoma cells induced a dose-dependent reduction in proliferation, suggesting a direct anti-tumor effect. Leptin induced increased mRNA expression of STAT2 and SOCS1 on HCC cell lines. CONCLUSIONS: Leptin administration induces a significant suppression of human HCC. This effect is mediated by induction of natural killer cell proliferation and activation, along with direct inhibition of tumor growth. Decreased NK expression of inhibitory CIS and over-expression of the antiproliferative STAT2 and SOCS1 proteins in HCC lines may underline the anti-cancerous effects of leptin.     

Motivation,cohesion, satisfaction,and their relation to stress fracture among female military recruits

The purpose of this study was to compare ratings of motivation, satisfaction, self-efficacy, and cohesion between male and female soldiers undergoing basic training (BT) in a gender-integrated unit and to study whether the ratings differ in a subgroup of women who suffered stress fractures (SF) during the course of training. Data were collected from 3 different companies of an integrated combat unit using questionnaires that were completed by 41 male and 160 female soldiers (age 18.5 +/- 0.4 years) at 3 phases during their BT (0, 2, and 4 months). In these questionnaires, the subjects were asked to evaluate their motivation, cohesion, satisfaction and self-efficacy. The presence or absence of bone overuse injuries was assessed by magnetic resonance imaging (MRI) or bone scintigraphy (BS). In addition to comparing parameters between females and males, female soldiers who sustained SF during BT (n = 18) were analyzed as a separate sub-group (FSF). In general, females in a gender-integrated combat unit were more motivated and satisfied with their service than their male counterparts. Overall, the stress fractures were associated with lower ratings of motivation, self-efficacy, and satisfaction expressed by the FSF sub-group.     

Heparanase enhances early hepatocyte inclusion in the recipient liver after transplantation in partially hepatectomized rats

Hepatocyte transplantation is an emerging approach for the treatment of liver diseases. However, broad clinical application of this method has been limited by restricted source of cells and low efficiency of cell integration within the recipient liver. Heparanase cleaves heparan sulfate proteoglycans in the extracellular matrix and basement membrane, activity that affects cellular invasion associated with cancer metastasis and inflammation. This activity has a multifunctional effect on cell-cell interaction, cell adhesion, and angiogenesis. All these factors are important for successful integration of transplanted hepatocytes. Male donor hepatocytes pretreated with heparanase or untreated were transplanted into recipient female rat spleen following partial hepatectomy. Engraftment efficacy was evaluated by PCR for Y chromosome, histology and PCNA, and heparanase immunohistochemistry. In addition, proliferative activity of hepatocytes in vitro was determined by bromodeoxyuridine immunostaining. The number of heparanase-treated cells detected in the recipient liver was significantly increased three- to fivefold within 24-48 h posttransplantation and twofold at 14 days compared with untreated cells. The transplanted hepatocytes treated with heparanase were clearly seen inside portal vein radicles as cell aggregates up to 72 h posttransplantation. The number of portal radicles filled with heparanase-treated hepatocytes was increased compared to control early after transplantation. Heparanase treatment enhanced hepatocyte and sinusoidal endothelial cell proliferation in the liver, and hepatocyte proliferation within the spleen tissue. Preliminary in vitro studies with isolated hepatocytes treated with heparanase showed increased proliferative activity within 24-48 h of cell culture. These results suggest that preincubation of hepatocytes with heparanase increases the presence of hepatocytes within the recipient liver early following cell transplantation and stimulates both hepatocyte and sinusoidal endothelial cell proliferation.     

NKT lymphocyte polarization determined by microenvironment signaling: a role for CD8+ lymphocytes and beta-glycosphingolipids

Natural killer T-cell (NKT) regulatory lymphocytes have been shown to behave differently in various immune settings. The aim of the present study was to determine the effect of microenvironmental signaling on NKT polarization and the process of active CD8 and NKT intrahepatic lymphocyte sequestration. In an in vitro assay, double negative (DN) NKT hybridoma cells were incubated with Hep3B hepatoma cells. This caused a significant increase in the secretion of alpha-fetoprotein (AFP) from Hep3B cells. When NKT cells were exposed to beta-glucoslyceramide (beta-GC) prior to incubation, Hep3B cells exhibited increased proliferation, increased IFN secretion, and reduced AFP secretion. In vivo, the adoptive transfer of na?ve DN NKT cells into athymic nude-nu mice transplanted with human Hep3B hepatocellular carcinoma (HCC) caused accelerated tumor growth. This effect was inhibited by prior ex vivo exposure of DN NKT lymphocytes to beta-GC. To assess the effect of the immunological environment on NKT cells, immune mediated hepatitis and colitis were induced simultaneously in mice. Induction of TNBS colitis prior to administration of concanavalin A (Con A) hepatitis resulted in an aggravation of the liver damage caused by Con A hepatitis alone. This effect was associated with reduced intrahepatic CD8+ T cell trapping and an increase in intrahepatic NKT cells. The presence of different ligands altered host microenvironment signaling and influenced the fate and polarization of NKT cells and the sequestration of active intrahepatic lymphocytes. These data support the notion that NKT regulatory lymphocytes have an inherent plasticity that may be important for their regulatory function.     

From anti-Parkinson's drug rasagiline to novel multitarget iron chelators with acetylcholinesterase and monoamine oxidase inhibitory and neuroprotective properties for Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial syndrome involving a complex array of different, while related, factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel hybrid molecules with multimodal activity, including: i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity; ii) HLA20, a brain permeable metal chelator with neuroprotective activity; iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity; iv) M30D, an AChE and MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity; and v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency and AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including modulation of amyloid-β and amyloid-β protein precursor expression/processing; induction of cell cycle arrest; inhibition of neuronal death markers; and upregulation of neurotrophic factors, as well as activation of protein kinase signaling pathways.