Citations

Background —We previously demonstrated that in vivo electron-beam computed tomography (EBCT)–based indicator-dilution methods provide an estimate of intramyocardial blood volume (BV) and perfusion (F), which relate as BV=aF+b√F, where a characterizes the recruitable (exchange) and b the nonrecruitable (conduit) component of the myocardial microcirculation. In the present study, we compared BV and F with intracoronary Doppler ultrasound–based coronary blood flow (CBF) as a method for detecting and quantifying differential responses of these microvascular components to vasoactive drugs in normal (control) and hypercholesterolemic (HC) pigs. Methods and Results —BV and F values were obtained from contrast-enhanced EBCT studies in 14 HC and 14 control pigs. BV, F, and CBF values were obtained at baseline (intracoronary infusion of saline) and after 5 minutes each of intracoronary infusion of adenosine (100 μg · kg − 1 · min − 1 ) and nitroglycerin (40 μg/min). BV and CBF reserves in response to adenosine were attenuated in HC pigs compared with controls (90±36% versus 127±42%, P <0.03, and 485±182% versus 688±160%, P <0.01, respectively). The relationship between BV and F showed consistently lower recruitable BV in HC versus control pigs. Nonrecruitable BV reserve in response to adenosine was attenuated in HC compared with controls (77±20% versus 135±28%, P <0.001). Our findings are consistent with HC-induced impairment of intramyocardial resistance vessel function. Conclusions —EBCT technology allows minimally invasive evaluation of intramyocardial microcirculatory function and permits assessment of microvascular BV distribution in different functional components. This method may be of value in evaluating the coronary microcirculation in pathophysiological states such as hypercholesterolemia.

Oxygen saturation of arterial and central venous blood was measured continuously during the Valsalva maneuver in patients with and without intracardiac defects. The majority of patients with atrial septal defects and patients with ventricular septal defects and high right ventricular pressure showed a sharp decrease in saturation of radial artery blood shortly after the maneuver. These changes were not recorded accurately by ear oximetry. The patients with shunts uniformly showed a rapid increase in saturation of pulmonary artery blood during the initial period of increased airway pressure. This effect was not observed in patients without shunts. These reactions may be of special diagnostic value under certain circumstances.

Indicator-dilution curves were recorded by oximeters at the ears and the right radial artery following the injection of Evans blue (T 1824) into the superior vena cava and pulmonary arteries of 37 subjects who had no evidence of cardiovascular disease. The variability and ranges of various time and concentration components of these dilution curves are presented. These values can be used as standards of reference in the interpretation of abnormal dilution curves. Some of the factors responsible for the variability of these values in healthy subjects are assessed and discussed.

Object Timing of clinical grading has not been fully studied in patients with aneurysmal subarachnoid hemorrhage (SAH). The primary objective of this study was to identify at which time point clinical assessment using the World Federation of Neurosurgical Societies (WFNS) grading scale and the Glasgow Coma Scale (GCS) is most predictive of poor functional outcome. Methods This study is a retrospective cohort study on the association between poor outcome and clinical grading determined at presentation, nadir, and postresuscitation. Poor functional outcome was defined as a Glasgow Outcome Scale score of 1–3 at 6 months after SAH. Results The authors identified 186 consecutive patients admitted to a teaching hospital between January 2002 and June 2008. The patients' mean age (± SD) was 56.9 ± 13.7 years, and 63% were women. Twenty-four percent had poor functional outcome (the mortality rate was 17%). On univariable logistic regression analyses, GCS score determined at presentation (OR 0.80, p < 0.0001), nadir (OR 0.73, p < 0.0001), and postresuscitation (OR 0.53, p < 0.0001); modified Fisher scale (OR 2.21, p = 0.0013); WFNS grade assessed at presentation (OR 1.92, p < 0.0001), nadir (OR 3.51, < 0.0001), and postresuscitation (OR 3.91, p < 0.0001); intracerebral hematoma on initial CT (OR 4.55, p < 0.0002); acute hydrocephalus (OR 2.29, p = 0.0375); and cerebral infarction (OR 4.84, p < 0.0001) were associated with poor outcome. On multivariable logistic regression analysis, only cerebral infarction (OR 5.80, p = 0.0013) and WFNS grade postresuscitation (OR 3.43, p < 0.0001) were associated with poor outcome. Receiver operating characteristic/area under the curve (AUC) analysis demonstrated that WFNS grade determined postresuscitation had a stronger association with poor outcome (AUC 0.90) than WFNS grade assessed upon admission or at nadir. Conclusions Timing of WFNS grade assessment affects its prognostic value. Outcome after aneurysmal SAH is best predicted by assessing WFNS grade after neurological resuscitation.

AbstractMicroRNAs (miRNAs) are small, regulatory non‐coding RNAs that have potent effects on gene expression. Several miRNA are deregulated in cellular processes involved in human liver diseases and regulation of cellular processes. Recent studies have identified the involvement of miR‐29 in hepatic fibrosis and carcinogenesis. Although several targets of miR‐29 have been identified, there is limited information regarding the cell‐type specific roles of miR‐29 in the liver, and we sought to evaluate the role of this miRNA in hepatic pathobiology. We report the generation of a tissue–specific knockout mouse to evaluate the role of miR‐29 in hepatic fibrosis and carcinogenesis in response to injury. We hypothesized that miR‐29 contributes to the hepatocyte driven response to chronic cellular injury that results in fibrosis. In support of this hypothesis, fibrosis and mortality were enhanced in miR29 knockout mice in response to carbon tetrachloride. Genome‐wide gene expression analysis identified an over‐representation of genes associated with fibrosis. The oncofetal RNA H19 was modulated in a miR‐29 dependent manner following exposure to carbon tetrachloride in vivo. The impact of a hepatocyte specific miR‐29 knockout on survival following chronic hepatic injury in vivo implicates this miRNA as a potential target for intervention. These results provide evidence of the involvement of miR‐29 in chronic hepatic injury, and suggest a role for deregulated hepatocyte expression of miR‐29 in the response to hepatic injury, fibrosis and carcinogenesis.

Abstract The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.

Background and Purpose— Patients with aneurysmal subarachnoid hemorrhage are typically kept in the intensive care unit to be monitored for signs of delayed cerebral ischemia (DCI). Identifying patients at lower risk for DCI could have a positive financial impact by allowing earlier transfer from the intensive care unit. Methods— We analyzed 307 consecutive patients admitted to the intensive care unit. Demographic, clinical, and neuroimaging data were recorded. The relationship with absent DCI was analyzed using univariate and multivariate logistic regression models. Results— DCI did not develop in 169 patients (57.9%). Among factors at admission, age 68 years or older ( P =0.0003; OR, 3.16; 95% CI, 1.66–6.39), World Federation of Neurological Surgeons (WFNS) I to III at presentation ( P =0.0003; OR, 2.73; 95% CI, 1.57–4.79), WFNS I to III at worst ( P =0.0003; OR, 2.39; 95% CI, 1.48–3.87), WFNS I to III after resuscitation ( P =0.0006; OR, 2.85; 95% CI, 1.56–5.32), modified Fisher grade 1 to 2 ( P =0.0021; OR, 2.43; 95% CI, 1.37–4.47), absence of intracranial hematoma ( P =0.0042; OR, 2.26; 95% CI, 1.29–4.01), and aneurysm in the posterior circulation ( P =0.025; OR, 1.74; 95% CI, 1.07–2.87) were associated with absence of DCI. On multivariate analysis, a model including age 68 years or older, WFNS I to III at presentation and a modified Fisher grade 1 to 2 were independently predictive of the absence of DCI, with a specificity of 100% and a positive predictive value of 100%. Conclusions— We propose a new model that can reliably identify patients with aneurysmal subarachnoid hemorrhage who are at very low risk for DCI. These patients could be candidates for early transfer to the general ward.