Citations

Objective: A significant cohort of patients who have undergone carotid artery stenting (CAS) will have in-stent restenosis (ISR). The optimal management of symptomatic or severe ISR remains poorly defined. The purpose of this study was to describe the indications, treatment, and mid- to long-term outcomes of patients undergoing CAS explantation for ISR. Methods: All patients undergoing internal carotid artery stent explantation with carotid artery reconstruction at Mayo Clinic Rochester, Dartmouth-Hitchcock Medical Center, and Beth-Israel Deaconess Medical Center from 2003 to 2013 were retrospectively reviewed. Isolated common carotid artery stents were excluded. Demographics, comorbidities, indications for explantation, operative details, and perioperative and postoperative outcomes were reviewed. Results: Over the study interval, a total of 971 patients underwent carotid stenting across the 3 centers. Of these, 8 patients ultimately underwent CAS explantation with carotid artery reconstruction. Mean age was 69 years and 5 patients were male. Index stent placement was for symptomatic stenosis in 4 patients, asymptomatic restenosis after endarterectomy in 2 patients, asymptomatic high lesion in 1 patient, and asymptomatic critical stenosis in 1 patient. Indications for explantation were symptomatic ISR in 4 patients and asymptomatic severe ISR in 4 patients. Method of repair was stent explantation and patch angioplasty in 5 and en bloc carotid resection with bypass in 3 patients. There were no perioperative neurologic events or cranial nerve injuries. At a mean follow-up of 38.7 months, there were 2 late disabling ipsilateral strokes (14.4 months and 19.1 months). Conclusion: A significant cohort of patients who have undergone CAS will have ISR. Although excellent perioperative results after surgical explantation can be obtained, this patient subgroup remains at risk for late neurologic events. Appropriate patient selection and diligent long-term follow-up are mandated to obtain optimal outcomes.

Using the reservoir-wave approach (RWA) we previously characterized pulmonary vasculature mechanics in a normal canine model. We found reflected backward-traveling waves that decrease pressure and increase flow in the proximal pulmonary artery (PA). These waves decrease right ventricular (RV) afterload and facilitate RV ejection. With pathological alterations to the pulmonary vasculature, these waves may change and impact RV performance. Our objective in this study was to characterize PA wave reflection and the alterations in RV performance in cardiac patients, using the RWA. PA pressure, Doppler-flow velocity, and pulmonary arterial wedge pressure were measured in 11 patients with exertional dyspnea. The RWA was employed to analyze PA pressure and flow; wave intensity analysis characterized PA waves. Wave-related pressure was partitioned into two components: pressures due to forward-traveling and to backward-traveling waves. RV performance was assessed by examining the work done in raising reservoir pressure and that associated with the wave components of systolic PA pressure. Wave-related work, the mostly nonrecoverable energy expended by the RV to eject blood, tended to vary directly with mean PA pressure. Where PA pressures were lower, there were pressure-decreasing/flow-increasing backward waves that aided RV ejection. Where PA pressures were higher, there were pressure-increasing/flow-decreasing backward waves that impeded RV ejection. Pressure-increasing/flow-decreasing backward waves were responsible for systolic notches in the Doppler flow velocity profiles in patients with the highest PA pressure. Pulmonary hypertension is characterized by reflected waves that impede RV ejection and an increase in wave-related work. The RWA may facilitate the development of therapeutic strategies.

ObjectiveIn observational epidemiologic studies, higher plasma high‐density lipoprotein cholesterol (HDL‐C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL‐C; as such, medicines that inhibit CETP and raise HDL‐C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL‐C also increase risk for ICH.MethodsWe performed 2 candidate‐gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL‐C as well as ICH risk.ResultsTwelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10−4) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL‐C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10−6).InterpretationGenetic variants in CETP associated with increased HDL‐C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL‐raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730–740

Abstract Known gene mutations account for approximately 50% of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C>T:p.Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer–affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair–deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (ORBC = 1.53, ORER+ = 1.73), particularly for the estrogen receptor–positive subset (P < 0.007). Significance: A functionally significant recurrent ERCC3 mutation increased the risk for breast cancer in a genetic isolate. Mutated cell lines showed lower survival after in vitro exposure to DNA-damaging agents. Thus, similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC3 could constitute potential therapeutic targets in a subset of hereditary breast cancers. Cancer Discov; 6(11); 1267–75. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 1197

Abstract Recent studies applying the principles of respiratory mechanics to respiratory disease have used inconsistent and mutually exclusive definitions of the term “transpulmonary pressure.” By the traditional definition, transpulmonary pressure is the pressure across the whole lung, including the intrapulmonary airways, (i.e., the pressure difference between the opening to the pulmonary airway and the pleural surface). However, more recently transpulmonary pressure has also been defined as the pressure across only the lung tissue (i.e., the pressure difference between the alveolar space and the pleural surface), traditionally known as the “elastic recoil pressure of the lung.” Multiple definitions of the same term, and failure to recognize their underlying assumptions, have led to different interpretations of lung physiology and conclusions about appropriate therapy for patients. It is our view that many current controversies in the physiological interpretation of disease are caused by the lack of consistency in the definitions of these common physiological terms. In this article, we discuss the historical uses of these terms and recent misconceptions that may have resulted when these terms were confused. These misconceptions include assertions that normal pleural pressure must be negative (subatmospheric) and that a pressure in the pleural space may not be substantially positive when a subject is relaxed with an open airway. We urge specificity and uniformity when using physiological terms to define the physical state of the lungs, the chest wall, and the integrated respiratory system.

Summary: This revision to the EEG Guidelines is an update incorporating current EEG technology and practice. The role of the EEG in making the determination of brain death is discussed as are suggested technical criteria for making the diagnosis of electrocerebral inactivity.