The influence of hyperglycemia on outcome of cerebral infarction.

OBJECTIVE: To determine whether hyperglycemia in the acute stroke period is associated with worse survival and functional outcome after accounting for acute stress response and chronic hyperglycemia. DESIGN: Prospective, county-wide, multicenter cohort study. SETTING: A community hospital, a university hospital, and a Veterans Affairs hospital. PATIENTS: A cohort of 146 patients hospitalized with new atherothrombotic stroke. MEASUREMENTS: Admission blood glucose concentration, demographic characteristics of patients, 24-hour urinary catecholamine, serum cortisol, and glycosylated hemoglobin levels; outcomes included mortality and functional outcome (Barthel index and Fugl-Meyer score) at 5, 30, 90, and 180 days after stroke. RESULTS: Of the 996 patients with possible acute stroke who were screened, 146 (15%) were eligible for and consented to participate in the study; in most cases, exclusion from study was based on the absence of acute, atherothrombotic stroke. Overall, no evidence was found of a significant univariate association between admission blood glucose level and survival (relative risk, 1.02; 95% Cl, 0.94 to 1.09) or functional outcome (univariate regression coefficient for adjusted Fugl-Meyer score at day 30, - 0.36; Cl, - 1.08 to 0.27). This absence of an association persisted after adjustment for significant predictors of outcome in a multivariate model. CONCLUSIONS: These data do not support an association between level of glycemia and outcome from acute stroke.     

Endoscopic retrograde cholangiography in the diagnosis of biliary malformations in infants

The differentiation of infantile biliary malformations from primary parenchymal diseases is difficult. The recent development of a pediatric side-viewing endoscope (PJF Endoscope; Olympus Corporation of America) provided an opportunity to investigate the usefulness of endoscopic retrograde cholangiography (ERC) for precise visualization of the extrahepatic biliary passages in infants with persistent cryptogenic cholestasis. ERC was performed in 12 patients, with visualization of the existing extrahepatic bile ducts in 4. The entire biliary system was visualized in one, excluding extrahepatic biliary atresia and choledochal cyst. The reduced caliber of the intrahepatic bile ducts and histological observations in a percutaneous liver biopsy supported the diagnosis of intrahepatic biliary hypoplasia in this case. An intact hepatic portochole cystostomy was documented in one, although the intrahepatic biliary system was not delineated. Atresia of the hepatic bile ducts proximal to the gallbladder was documented in two. Of the eight patients in whom extrahepatic bile ducts were not visualized by ERC, six had extrahepatic biliary atresia confirmed at exploratory laparotomy. The papilla of Vater could not be located in four of these six infants. The remaining two had neonatal hepatitis. ERC may offer a useful alternative to operative cholangiography in selected infants with persistent cholestasis and acholic stools.     

Correlates of Depression Among Chinese and Korean Immigrant Elders in the United States

This study examines the effects of life stresses, religiosity and family coping resources on depression in a regional probability sample of older Chinese (n?=?105) and older Korean (n?=?100) immigrants. A major focus is placed on assessing the ethnic differences found in the relationship between religiosity and depressive symptoms, as experienced by the two Asian ethnic groups. The data for this secondary analysis was derived from a landmark study, Asian American Elders in New York City Survey. Findings suggest that about 46 % of the Chinese sample and 24 % of the Korean sample were depressed, indicating higher depression rates than those found among older Americans of other ethnicities in the literature. Data also show that Korean immigrant elders reported higher levels of religiosity (attended religious services at least once a week and felt that religion was very important in their lives) than their Chinese counterparts. Multivariate analyses confirm ethnic differences in depressive symptoms. Other things being equal, factors of religiosity have an overall significant positive impact on depression among the Korean group, but appear to have no effect on the Chinese group. This data shows that the impact of religiosity on psychological well-being is crucial for mental health professionals in maintaining cultural competency when working with clients from different Asian immigrant subgroups.     

Orthopedic Multidimensional Prognostic Index (Ortho-MPI) in the elderly with hip or neck femur fracture: A pilot study

The Orthopedic Multidimensional Prognostic Index (Ortho-MPI) was performed and validated in order to ameliorate the decision-making process as regards the elderly with hip or neck femur fractures. A retrospective study was performed. 95 patients 65 years old and over with a diagnosis of hip or femur fracture were enrolled. A standardized comprehensive orthopedic geriatric assessment was performed. It included information on: depressive symptoms, functional and instrumental activities of daily living, cognitive and nutritional status, laboratory tests, risk of pressure sore, comorbidities and comorbidity. The Ortho-MPI was calculated. After six months their initial assessment, patients were recalled in order to know if they live too or not. The survival condition was associated to the prognostic capacity calculated by the Ortho-MPI. Results showed that higher Ortho-MPI Index value was associated with higher six months-later mortality. In an unvaried analysis model the Ortho-MPI index was associated with death event of the elderly patients enrolled (OR = 1.05; 95% CI, 1.01–1.10; z = 2.27; p = 0.023). This association was also validated by considering different ages between participants (OR = 1.05; 95% CI, 1.004–1.11; z = 2.13; p = 0.033). Furthermore, each specific index considered in the total Ortho-MPI was associated with the death event of the elderly patients. In conclusion it was shown that the Ortho-MPI Index could be used to predict outcome in the elderly with hip or femur fracture.     

CtIP-mediated resection is essential for viability and can operate independently of BRCA1

Homologous recombination (HR) is initiated by DNA end resection, a process in which stretches of single-strand DNA (ssDNA) are generated and used for homology search. Factors implicated in resection include nucleases MRE11, EXO1, and DNA2, which process DNA ends into 3′ ssDNA overhangs; helicases such as BLM, which unwind DNA; and other proteins such as BRCA1 and CtIP whose functions remain unclear. CDK-mediated phosphorylation of CtIP on T847 is required to promote resection, whereas CDK-dependent phosphorylation of CtIP-S327 is required for interaction with BRCA1. Here, we provide evidence that CtIP functions independently of BRCA1 in promoting DSB end resection. First, using mouse models expressing S327A or T847A mutant CtIP as a sole species, and B cells deficient in CtIP, we show that loss of the CtIP-BRCA1 interaction does not detectably affect resection, maintenance of genomic stability or viability, whereas T847 is essential for these functions. Second, although loss of 53BP1 rescues the embryonic lethality and HR defects in BRCA1-deficient mice, it does not restore viability or genome integrity in CtIP^−/− mice. Third, the increased resection afforded by loss of 53BP1 and the rescue of BRCA1-deficiency depend on CtIP but not EXO1. Finally, the sensitivity of BRCA1-deficient cells to poly ADP ribose polymerase (PARP) inhibition is partially rescued by the phospho-mimicking mutant CtIP (CtIP-T847E). Thus, in contrast to BRCA1, CtIP has indispensable roles in promoting resection and embryonic development.Individuals with mutations in BRCA1 have a high risk of developing breast and ovarian cancer. Although BRCA1 is implicated in many cellular processes, its role in HR (Moynahan et al., 1999; Stark et al., 2004) is thought to be critical for tumor suppression and maintenance of genomic stability (Silver and Livingston, 2012). Tumor suppressor functions of BRCA1 are mediated by the BRCA1 carboxyl-terminal (BRCT) domain (Shakya et al., 2011), a motif that binds phosphorylated serine motifs in three different DNA repair proteins: BACH1 (BRIP1), ABRAXAS (CCDC98), and CtIP (Rbbp8; Li and Greenberg, 2012). Among these complexes, BRCA1 association with CtIP has been implicated in nucleolytic resection of DNA double strand breaks (DSBs; Sartori et al., 2007; Chen et al., 2008). Although the BRCA1–CtIP complex is not known to possess nuclease activity itself, it enhances the nuclease activity of the MRE11–RAD50–NBS1 DSB sensor complex, which is required for effective resection (Sartori et al., 2007). According to the current “two-step” model, the BRCA1–CtIP–MRE11 complex initiates end processing, then EXO1 and BLM generate longer stretches of ssDNA, which are stabilized by RPA (Symington and Gautier, 2011). Finally, formation of the RAD51–ssDNA nucleoprotein filament promotes strand invasion and HR. In the absence of BRCA1 or CtIP, RAD51 binding to DSB sites and HR are reduced, resulting in mutagenic DNA repair, genome instability, and tumorigenesis (Bunting and Nussenzweig, 2013).CtIP is directly phosphorylated by cyclin-dependent kinases (CDKs; Ferretti et al., 2013). CDK phosphorylation of CtIP at T847 promotes ssDNA generation, RPA recruitment and chromosome integrity (Huertas and Jackson, 2009). Whereas changing T847 to alanine impairs resection, mutating T847 to glutamic acid mimics constitutive phosphorylation, which promotes limited resection (Huertas and Jackson, 2009). The BRCA1–CtIP interaction (Wong et al., 1998; Yu et al., 1998) is mediated by CDK phosphorylation of CtIP at S327 (equivalent to S326 in mouse) during G2 phase of the cell cycle (Yu and Chen, 2004). In chicken DT40 cells expressing human CtIP, mutation of S327 into a nonphosphorytable residue inhibits HR repair (Yun and Hiom, 2009). Moreover, in mammalian cells, CtIP–BRCA1 complex formation facilitates removal of 53BP1 binding protein RIF1 from DSB regions, which otherwise blocks resection (Escribano-Díaz et al., 2013). However, the physiological role of S327 phosphorylation has been questioned by the finding that the chicken CtIP-S332A protein can efficiently promote DSB repair by HR, apparently independently of BRCA1 interaction (Nakamura et al., 2010) and by the fact that that knock-in mice homozygous for CtIP-S326A allele are neither tumor prone or HR deficient (Reczek et al., 2013). Thus, the biological importance of the BRCA1–CtIP interaction remains unclear.Further progress in understanding how BRCA1 promotes HR was made by demonstrating that loss of 53BP1 rescues the lethality, tumorigenesis, and genome instability of BRCA1-deficient mice (Cao et al., 2009; Bouwman et al., 2010; Bunting et al., 2010). It was shown that 53BP1 inhibits resection, but that BRCA1 antagonizes 53BP1, allowing the nucleolytic processing of DNA ends in S phase (Bunting et al., 2010; Chapman et al., 2012). Furthermore PTIP and RIF1, both of which act downstream of 53BP1, inhibit BRCA1-associated DNA metabolism (Callen et al., 2013; Chapman et al., 2013; Escribano-Díaz et al., 2013; Feng et al., 2013; Zimmermann et al., 2013). Nevertheless, the mediators of resection in BRCA1/53BP1, BRCA1/PTIP, and BRCA1/RIF double-deficient cells have not been identified.Here, we establish that both the increased resection associated with the loss of 53BP1 and the rescue of HR defects in doubly deficient 53BP1/BRCA1 cells are dependent on CtIP but independent of EXO1. Loss of CtIP or its ability to be phosphorylated on T847 leads to embryonic lethality, constitutive DNA damage signaling, genome instability, and defective resection. In contrast, constitutive activation of CtIP by expressing a CtIP phospho-mimicking mutant CtIP (CtIP-T847E) reverts the embryonic lethality, and partially rescues BRCA1-deficient chromosomal instability even in the presence of 53BP1. Thus, whereas BRCA1 is dispensable for HR under some conditions, CtIP-mediated resection is an essential activity that can proceed independently of BRCA1.     

Administration of Anticancer Drugs: Exposure in Hospital Nurses

Background

Even though anticancer drugs are prepared in dedicated pharmaceutical units, nurses remain exposed to cytotoxic agents during administration to patients.

Objective

The aim of this study was to assess this occupational exposure during the intravenous line–purging procedure at the patient’s bedside before administration in oncology departments.

Methods

This prospective study was conducted over a 4-week period in the hematology and oncology departments at a university hospital. Amounts of doxorubicin and cyclophosphamide on the surface of nurses’ gloves were measured after the intravenous line purge of the infusion bag and the connection to the patient. For this purpose, gloves were washed with sterile water, following a validated procedure. Quantification of the 2 drugs into the water was performed using LC-MS/MS.

Results

After 59 chemotherapy administrations, 30.5% of gloves were contaminated. Despite extremely low volumes of contamination (0.08–6.28 µL), amounts collected ranged from 190 to 2500 ng per pair of gloves that tested positive for doxorubicin (median, 1600 ng) and from 130 to 32,600 ng with cyclophosphamide (median, 2700 ng).

Conclusions

The intravenous line purge preceding antineoplastic infusion bag administration is a potential source of contamination in nurses. Contaminations appear to be invisible but frequent (in >30% of cases). Therefore, intravenous line purging performed under appropriately safe conditions should be mandated in pharmaceutical units dedicated to injectable-drug preparation. This measure should be included as a standard hospital practice as a matter of urgency.     

Tricuspid valve chordal rupture due to airbag injury and review of pathophysiological mechanisms

Blunt trauma to the chest is associated with significant morbidity and mortality. The latter is usually due to an aortic transection, whereas the former is related to myocardial contusion, cardiac valve injury, coronary artery disruption and intracardiac shunts due to the formation of septal defects. The main mechanisms causing these injuries are due to the sudden deceleration force and compression within the chest cavity. Moreover, there is also the sudden increase in intravascular pressure due to a mechanical compression effect and a hormonal adrenergic surge during the event. We report a case of a tricuspid valve injury caused by the deployment of the airbag during a high-speed impact car accident and the subsequent damage to the tricuspid valve chordal mechanism. The patient's management and the pathophysiological mechanisms involved in the injury are reviewed.     

Retinal tissue develops an inflammatory reaction to tobacco smoke and electronic cigarette vapor in mice

Journal of Molecular Medicine - Cigarette smoke has been identified as a major risk factor for the development of age-related macular degeneration (AMD). As an alternative to conventional...