A Knock-In Mouse Model of Thymoma With the GTF2I L424H Mutation.

INTRODUCTION: The pathogenesis of thymic epithelial tumors remains largely unknown. We previously identified GTF2I L424H as the most frequently recurrent mutation in thymic epithelial tumors. Nevertheless, the precise role of this mutation in tumorigenesis of thymic epithelial cells is unclear. METHODS: To investigate the role of GTF2I L424H mutation in thymic epithelial cells in vivo, we generated and characterized a mouse model in which the Gtf2i L424H mutation was conditionally knocked-in in the Foxn1+ thymic epithelial cells. Digital spatial profiling was performed on thymomas and normal thymic tissues with GeoMx-mouse whole transcriptome atlas. Immunohistochemistry staining was performed using both mouse tissues and human thymic epithelial tumors. RESULTS: We observed that the Gtf2i mutation impairs development of the thymic medulla and maturation of medullary thymic epithelial cells in young mice and causes tumor formation in the thymus of aged mice. Cell cycle-related pathways, such as E2F targets and MYC targets, are enriched in the tumor epithelial cells. Results of gene set variation assay analysis revealed that gene signatures of cortical thymic epithelial cells and thymic epithelial progenitor cells are also enriched in the thymomas of the knock-in mice, which mirrors the human counterparts in The Cancer Genome Atlas database. Immunohistochemistry results revealed similar expression pattern of epithelial cell markers between mouse and human thymomas. CONCLUSIONS: We have developed and characterized a novel thymoma mouse model. This study improves knowledge of the molecular drivers in thymic epithelial cells and provides a tool for further study of the biology of thymic epithelial tumors and for development of novel therapies.

The regulation of CD73 in non-small cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of global cancer-related mortality. Although immune checkpoint therapy has achieved remarkable results in lung cancer, EGFR-mutant or ALK-positive non-smallcell lung cancer patients show limited benefit. Besides the low tumor mutational burden, PD-L1 expression and CD8+ tumor-infiltrating T cells, upregulation of CD73/adenosine pathway also contributes to the immune-inert microenvironment of EGFR-mutant NSCLC. However, the detailed mechanism underlying the regulation of CD73 is unclear. METHODS: TCGA data was used to analyze the CD73 expression in cancer patients. Western blotting, qPCR, and ChIP-PCR were performed in multiple NSCLC cancer cell lines and patient derived organoids were used to explore the regulation of CD73 expression using western blotting. RESULTS: CD73 expression was highly expressed in multiple cancer types. Pharmacological or genetic inhibition of EGFR, MEK, KRAS, or ALK dramatically reduced the CD73 mRNA and protein expression in NSCLC cancer cells and patient-derived organoids with EGFR mutation, KRAS mutation or ALK-rearrangement. C-Jun overexpression-induced CD73 mRNA and protein expression. ChIP assay showed that c-Jun bind to CD73 genomic regions. CONCLUSIONS: Higher CD73 expression in NSCLC cancer cells and patient-derived organoids with EGFR mutation, KRAS mutation or ALK-rearrangement. Mechanistically, CD73 is regulated by ERK-Jun pathway, wherein c-Jun regulates CD73 expression via binding to CD73 genomic regions.

Exploiting mesothelin in thymic carcinoma as a drug delivery target for anetumab ravtansine.

BACKGROUND: Thymic epithelial tumours (TETs) are rare tumours comprised of thymomas and thymic carcinoma. Novel therapies are needed, especially in thymic carcinoma where the 5-year survival rate hovers at 30%. Mesothelin (MSLN), a surface glycoprotein that is cleaved to produce mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF), is expressed in limited tissues. However, its expression is present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases. METHODS: We utilised flow cytometry, in vitro cytotoxicity assays, and an in vivo xenograft model in order to demonstrate the ability of the MSLN targeting antibody-drug conjugate (ADC) anetumab ravtansine (ARav) in inhibiting the growth of thymic carcinoma. RESULTS: Thymoma and thymic carcinoma cell lines express MSLN, and anetumab, the antibody moiety of ARav, was capable of binding MSLN expressing thymic carcinoma cells and internalising. ARav was effective at inhibiting the growth of thymic carcinoma cells stably transfected with mMSLN in vitro. In vivo, 15 mg/kg ARav inhibited T1889 xenograft tumour growth, while combining 7.5 mg/kg ARav with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumour growth. CONCLUSIONS: These data demonstrate that anetumab ravtansine inhibits the growth of MSLN positive thymic carcinoma cells in vitro and in vivo.

m6A RNA Methylation Controls Neural Development and Is Involved in Human Diseases.

RNA modifications are involved in many aspects of biological functions. N6-methyladenosine (m6A) is one of the most important forms of RNA methylation and plays a vital role in regulating gene expression, protein translation, cell behaviors, and physiological conditions in many species, including humans. The dynamic and reversible modification of m6A is conducted by three elements: methyltransferases ("writers"), such as methyltransferase-like protein 3 (METTL3) and METTL14; m6A-binding proteins ("readers"), such as the YTH domain family proteins (YTHDFs) and YTH domain-containing protein 1 (YTHDC1); and demethylases ("erasers"), such as fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5). In this review, we summarize the current knowledge on mapping mRNA positions of m6A modification and revealing molecular processes of m6A. We further highlight the biological significance of m6A modification in neural cells during development of the nervous system and its association with human diseases. m6A RNA methylation is becoming a new frontier in neuroscience and should help us better understand neural development and neurological diseases from a novel point of view.

Impact of Reperfusion Calcium and pH on the Resuscitation of Hearts Donated After Circulatory Death.

BACKGROUND: Hearts donated after circulatory death may represent an additional donor source. The influx of sodium and calcium ions across the sarcolemma play a central role in the pathogenesis of ischemia-reperfusion injury; however, this process may be inhibited if the initial reperfusion solution is rendered hypocalcemic and acidic. We sought to determine the calcium concentration and pH of the initial reperfusion solution that yielded optimal functional recovery of hearts donated after circulatory death during ex vivo heart perfusion. METHODS: Pigs were anesthetized, mechanical ventilation was discontinued, and a 15-minute standoff period was observed after circulatory arrest. Hearts were reperfused with a normothermic cardioplegia of varying calcium concentrations (part 1 [50 µmol/L, n = 4; 220 µmol/L, n = 9; 500 µmol/L, n = 4; and 1,250 µmol/L, n = 5]) and pH (part 2 [7.9, n = 5; 7.4, n = 9; 6.9, n = 8; and 6.4, n = 6]). Myocardial function was then assessed in a physiologic working model 1 hour after initiation of normothermic ex vivo heart perfusion. RESULTS: The calcium concentration and pH of the cardioplegic solution affected the development of myocardial edema (part 1: 50 µmol/L = 5.8% ± 0.9%; 220 µmol/L = 4.3% ± 0.4%; 500 µmol/L = 7.0% ± 0.6%; and 1,250 µmol/L = 6.6% ± 0.8% weight gain, p = 0.015; part 2: 7.9 = 3.6% ± 0.4%, 7.4 = 4.3% ± 0.4%, 6.9 = 3.7% ± 0.6%, and 6.4 = 6.4% ± 1.3% weight gain, p = 0.056) and the recovery of myocardial function (cardiac index part 1: 50 µmol/L = 2.6 ± 0.6; 220 µmol/L = 6.0 ± 0.8; 500 µmol/L = 2.3 ± 0.5; and 1,250 µmol/L = 1.9 ± 0.6 mL · m-1 · g-1, p < 0.001; part 2: 7.9 = 1.5 ± 0.7; 7.4 = 6.0 ± 0.8; 6.9 = 8.4 ± 1.8; and 6.4 = 3.1 ± 0.8 mL · m-1 · g-1, p = 0.003) during ex vivo heart perfusion. CONCLUSIONS: Initial reperfusion of hearts donated after circulatory death with a hypocalcemic and moderately acidic cardioplegia minimizes edema and optimizes functional recovery during subsequent ex vivo heart perfusion.

Perception and reality of particulate matter exposure in New York City taxi drivers.

Exposure to fine particulate matter (PM2.5) and black carbon (BC) have been linked to negative health risks, but exposure among professional taxi drivers is understudied. This pilot study measured drivers' knowledge, attitudes, and beliefs (KAB) about air pollution compared with direct measures of exposures. Roadside and in-vehicle levels of PM2.5 and BC were continuously measured over a single shift on each subject, and exposures compared with central site monitoring. One hundred drivers completed an air pollution KAB questionnaire, and seven taxicabs participated in preliminary in-cab air sampling. Taxicab PM2.5 and BC concentrations were elevated compared with nearby central monitoring. Average PM2.5 concentrations per 15-min interval were 4-49 µg/m3. BC levels were also elevated; reaching>10 µg/m3. Fifty-six of the 100 drivers surveyed believed they were more exposed than non-drivers; 81 believed air pollution causes health problems. Air pollution exposures recorded suggest that driver exposures would likely exceed EPA recommendations if experienced for 24 h. Surveys indicated that driver awareness of this was limited. Future studies should focus on reducing exposures and increasing awareness among taxi drivers.

High Spinal Anesthesia Enhances Anti-Inflammatory Responses in Patients Undergoing Coronary Artery Bypass Graft Surgery and Aortic Valve Replacement: Randomized Pilot Study.

BACKGROUND: Cardiac surgery induces many physiologic changes including major inflammatory and sympathetic nervous system responses. Here, we conducted a single-centre pilot study to generate hypotheses on the potential immune impact of adding high spinal anaesthesia to general anaesthesia during cardiac surgery in adults. We hypothesized that this strategy, previously shown to blunt the sympathetic response and improve pain management, could reduce the undesirable systemic inflammatory responses caused by cardiac surgery. METHODS: This prospective randomized unblinded pilot study was conducted on 14 patients undergoing cardiac surgery for coronary artery bypass grafting and/or aortic valve replacement secondary to severe aortic stenosis. The primary outcome measures examined longitudinally were serum pro-inflammatory (IL-6, IL-1b, CCL2), anti-inflammatory (IL-10, TNF-RII, IL-1Ra), acute phase protein (CRP, PTX3) and cardiovascular risk (sST2) biomarkers. RESULTS: The kinetics of pro- and anti-inflammatory biomarker was determined following surgery. All pro-inflammatory and acute phase reactant biomarker responses induced by surgical stress were indistinguishable in intensity and duration between control groups and those who also received high spinal anaesthesia. Conversely, IL-10 levels were markedly elevated in both intensity and duration in the group receiving high spinal anesthesia (p = 0.005). CONCLUSIONS: This hypothesis generating pilot study suggests that high spinal anesthesia can alter the net inflammatory response that results from cardiac surgery. In appropriately selected populations, this may add incremental benefit by dampening the net systemic inflammatory response during the week following surgery. Larger population studies, powered to assess immune, physiologic and clinical outcomes in both acute and longer term settings, will be required to better assess potential benefits of incorporating high spinal anesthesia. TRIAL REGISTRATION: ClinicalTrials.gov NCT00348920.

Use of Hospital-Based Food Pantries Among Low-Income Urban Cancer Patients.

To examine uptake of a novel emergency food system at five cancer clinics in New York City, hospital-based food pantries, and predictors of use, among low-income urban cancer patients. This is a nested cohort study of 351 patients who first visited the food pantries between October 3, 2011 and January 1, 2013. The main outcome was continued uptake of this food pantry intervention. Generalized estimating equation (GEE) statistical analysis was conducted to model predictors of pantry visit frequency. The median number of return visits in the 4 month period after a patient's initial visit was 2 and the mean was 3.25 (SD 3.07). The GEE model showed that younger patients used the pantry less, immigrant patients used the pantry more (than US-born), and prostate cancer and Stage IV cancer patients used the pantry more. Future long-term larger scale studies are needed to further assess the utilization, as well as the impact of food assistance programs such as the this one, on nutritional outcomes, cancer outcomes, comorbidities, and quality of life. Cancer patients most at risk should be taken into particular consideration.

The expression pattern of systemically injected AAV9 in the developing mouse retina is determined by age.

Systemic delivery of AAV9 offers the potential for widespread and efficient gene delivery to the retina, and may thus be a useful approach for treatment of disease where intraocular injections are not possible, for syndromes affecting multiple organs, or where early intervention is required. The expression resulting from intravenous injection of AAV9 is more efficient in neonates than adults, and here we characterize the effect of age on retinal transduction of AAV9 in the mouse retina. We find that the pattern of expression in neonatal mice is correlated to the development of the retinal vasculature, and that the area of the retinal transduction as well as the cell types infected vary depending on the age at injection. Furthermore, we demonstrate that sequential injections of AAV9 vectors carrying two different transgenes infect adjacent areas of the retina, providing a larger area of coverage. Lastly, we show that the retina's endogenous spatiotemporal expression pattern of Mfsd2a, a protein associated with the maturation of a functional blood-brain barrier, coincides with suppression of retinal transduction by intravenously-delivered AAV9, suggesting that AAV9 crosses the blood-retina barrier through transcytosis.

Do our patients have enough to eat?: Food insecurity among urban low-income cancer patients.

This study assessed the prevalence and predictors of food insecurity among a cohort of underserved oncology patients at New York City cancer clinics. A demographic survey and the U.S. Household Food Security Survey Module were administered. A multivariate General Linear Model Analysis of Covariance was used to evaluate predictors of food insecurity. Four hundred and four (404) completed the surveys. Nearly one-fifth (18%) had very low, 38% low, 17% marginal, and 27% high food security. The Analysis of Covariance was statistically significant (F[7, 370] = 19.08; p < .0001; R-Square = 0.26). Younger age, Spanish language, poor health care access, and having less money for food since beginning cancer treatment were significantly associated with greater food insecurity. This cohort of underserved cancer patients had rates of food insecurity nearly five times those of the state average. More research is needed to understand better the causes and impact of food insecurity among cancer and chronic disease patients.

Off-label use of recombinant activated factor VII in surgical and non-surgical patients at 16 Canadian hospitals from 2007 to 2010 (Canadian Registry Report).

PURPOSE: Recombinant activated factor VII (rFVIIa) is a pro-hemostatic drug that is approved for treatment of bleeding in hemophilia patients, but it is frequently used off-label in non-hemophiliacs. The purpose of this study was to determine if the off-label use of rFVIIa is expanding and whether this poses a net harm to patients. METHODS: For this historical cohort study, data were collected on all non-hemophilia patients who received rFVIIa from 2007 to 2010 at 16 Canadian centres, and the pattern of use was examined. Logistic regression was used to determine the prognostic importance of severity of bleeding and the presence of an rFVIIa dose-effect relationship with major adverse events. RESULTS: One thousand three hundred seventy-eight patients received rFVIIa off-label, and 987 (72%) of these patients underwent cardiac surgery. The median [interquartile range] dose was 57 [36-85] µg·kg(-1). Usage increased from 2007 to 2008 (n = 341 and 380, respectively) but decreased in 2009 and 2010 (n = 350 and 307, respectively). Dose of rFVIIa and bleeding severity were associated with measured adverse events (P < 0.05). After adjusting for bleeding severity, dose was not associated with any of the adverse events. CONCLUSIONS: The off-label use of rFVIIa in Canada remains stable. Since severity of bleeding is prognostically important, the benefits of rapidly gaining control of bleeding that is non-responsive to conventional therapies may at times warrant the use of potent hemostatic drugs with established risk profiles, such as rFVIIa.

Support needs of Chinese immigrant cancer patients.

PURPOSE: To enable better psychosocial, informational, and practical support of Chinese patients with cancer, this study was conducted to identify the specific support needs of Chinese immigrant cancer patients. METHODS: The Cancer Portal Project at Memorial Sloan-Kettering Cancer Center's Center for Immigrant Health and Cancer Disparities is a patient navigation program that assists underserved and minority cancer patients in obtaining social and economic assistance at ten New York City cancer clinics. This need assessment was conducted as part of the Portal Project. Sixty-four questions were added to the existing Portal Intake Form about the needs and preferences for Chinese-language support and survivorship services. Descriptive analysis was performed, as well as an exploratory principal component's factor analysis to determine if there were any patterns in the services and programs in which patients were interested. RESULTS: Ninety-six patients were approached for participation; 59 agreed to participate. Eighty-eight percent of participants were born in China. Ninety-seven percent preferred to speak Mandarin, Cantonese, or Fujianese in the healthcare setting. When asked about general interest in support programs, 53 % of the participants were "very interested," 27 % were "maybe interested," and 17 % were "not interested." Programs in which more participants were "very interested" included those that would provide information about obtaining financial assistance (79 %) and social assistance (74 %), information on treatment options (67 %), help in coping with the burden of illness on the family (65 %), and information about general healthcare (63 %). The factor analysis resulted in the identification of five factors: social/financial/treatment and care issues, nutrition and exercise/networking/general health care, coping with fear and stress, herbs and dietary supplements, and acupuncture and acupressure. CONCLUSION: In this study, 80 % of the participants expressed interest in programs tailored for Chinese cancer patients. The most frequently preferred topics for potential services were information-based. Findings provide a foundation for future research and the development of culturally and linguistically targeted support programs and interventions for this unique population.

AAV-mediated, optogenetic ablation of Müller Glia leads to structural and functional changes in the mouse retina.

Müller glia, the primary glial cell in the retina, provide structural and metabolic support for neurons and are essential for retinal integrity. Müller cells are closely involved in many retinal degenerative diseases, including macular telangiectasia type 2, in which impairment of central vision may be linked to a primary defect in Müller glia. Here, we used an engineered, Müller-specific variant of AAV, called ShH10, to deliver a photo-inducibly toxic protein, KillerRed, to Müller cells in the mouse retina. We characterized the results of specific ablation of these cells on visual function and retinal structure. ShH10-KillerRed expression was obtained following intravitreal injection and eyes were then irradiated with green light to induce toxicity. Induction of KillerRed led to loss of Müller cells and a concomitant decrease of Müller cell markers glutamine synthetase and cellular retinaldehyde-binding protein, reduction of rhodopsin and cone opsin, and upregulation of glial fibrillary acidic protein. Loss of Müller cells also resulted in retinal disorganization, including thinning of the outer nuclear layer and the photoreceptor inner and outer segments. High resolution imaging of thin sections revealed displacement of photoreceptors from the ONL, formation of rosette-like structures and the presence of phagocytic cells. Furthermore, Müller cell ablation resulted in increased area and volume of retinal blood vessels, as well as the formation of tortuous blood vessels and vascular leakage. Electrophysiologic measures demonstrated reduced retinal function, evident in decreased photopic and scotopic electroretinogram amplitudes. These results show that loss of Müller cells can cause progressive retinal degenerative disease, and suggest that AAV delivery of an inducibly toxic protein in Müller cells may be useful to create large animal models of retinal dystrophies.

A cardioprotective preservation strategy employing ex vivo heart perfusion facilitates successful transplant of donor hearts after cardiocirculatory death.

BACKGROUND: Ex vivo heart perfusion (EVHP) has been proposed as a means to facilitate the resuscitation of donor hearts after cardiocirculatory death (DCD) and increase the donor pool. However, the current approach to clinical EVHP may exacerbate myocardial injury and impair function after transplant. Therefore, we sought to determine if a cardioprotective EVHP strategy that eliminates myocardial exposure to hypothermic hyperkalemia cardioplegia and minimizes cold ischemia could facilitate successful DCD heart transplantation. METHODS: Anesthetized pigs sustained a hypoxic cardiac arrest and a 15-minute warm ischemic standoff period. Strategy 1 hearts (S1, n = 9) underwent initial reperfusion with a cold hyperkalemic cardioplegia, normothermic EVHP, and transplantation after a cold hyperkalemic cardioplegic arrest (current EVHP strategy). Strategy 2 hearts (S2, n = 8) underwent initial reperfusion with a tepid adenosine-lidocaine cardioplegia, normothermic EVHP, and transplantation with continuous myocardial perfusion (cardioprotective EVHP strategy). RESULTS: At completion of EVHP, S2 hearts exhibited less weight gain (9.7 ± 6.7 [S2] vs 21.2 ± 6.7 [S1] g/hour, p = 0.008) and less troponin-I release into the coronary sinus effluent (4.2 ± 1.3 [S2] vs 6.3 ± 1.5 [S1] ng/ml; p = 0.014). Mass spectrometry analysis of oxidized pleural in post-transplant myocardium revealed less oxidative stress in S2 hearts. At 30 minutes after wean from cardiopulmonary bypass, post-transplant systolic (pre-load recruitable stroke work: 33.5 ± 1.3 [S2] vs 19.7 ± 10.9 [S1], p = 0.043) and diastolic (isovolumic relaxation constant: 42.9 ± 6.7 [S2] vs 65.2 ± 21.1 [S1], p = 0.020) function were superior in S2 hearts. CONCLUSION: In this experimental model of DCD, an EVHP strategy using initial reperfusion with a tepid adenosine-lidocaine cardioplegia and continuous myocardial perfusion minimizes myocardial injury and improves short-term post-transplant function compared with the current EVHP strategy using cold hyperkalemic cardioplegia before organ procurement and transplantation.

Cooking oil fumes and lung cancer: a review of the literature in the context of the U.S. population.

There is growing evidence that exposure to cooking oil fumes (COF) is linked to lung cancer. Existing literature on this risk was reviewed, specifically as it may relate to potentially at-risk populations such as Chinese immigrants and restaurant workers in the United States. Studies were identified by searching the NCBI database with key terms. All studies that examined the significance, prevalence, and/or mechanism(s) of the association between COF exposure and cancer (all types) were included. A majority of epidemiologic studies found associations between lung cancer and COF exposure. All studies that examined the mechanisms underlying the risk found evidence for mutagenic and/or carcinogenic compounds in COF extract and/or molecular mechanisms for COF-induced DNA damage or carcinogenesis. The evidence reviewed underscores the need to thoroughly investigate the association among at-risk groups in the United States, as well as to develop and assess concrete interventions to reduce these risks.

"Doctor, what do i have?" Knowledge of cancer diagnosis among immigrant/migrant minorities.

This study explores patient knowledge of cancer diagnosis among underserved immigrant/migrant minorities. Patients were recruited at a hospital-based cancer clinic in New York City. Demographic and self-reported diagnosis and treatment information were collected; charts were reviewed to ascertain cancer diagnosis. Four hundred thirty-four patients were included. Eighty-seven percent preferred to speak a language other than English in the health care setting. Sixteen percent had incorrect knowledge of their cancer diagnosis. Multivariate analysis indicated that both preference for a non-English language and diagnosis of a "below the belt" cancer were jointly predictive of incorrect knowledge (LR = 17.01; p = 0.0002). "Below the belt" cancers included bladder, colorectal, gynecological, penile, prostate, and testicular cancers. Among this cohort of immigrant/migrant cancer patients, a considerable proportion was unaware of their correct cancer diagnoses. This may have a significant impact on subsequent cancer education, treatment, and care. Limited-English-proficiency patients may be at particular risk.

Identifying the informational and psychosocial needs of Chinese immigrant cancer patients: a focus group study.

PURPOSE: The Chinese immigrant community faces multiple barriers to quality cancer care and cancer survivorship. Psychosocial interventions can positively impact quality of life, anxiety, and distress in cancer patients. In this study, we explored the informational and psychosocial needs of Chinese cancer patients to inform the development of culturally targeted support and survivorship interventions. METHODS: We conducted four focus groups with a total of 28 Chinese cancer patients to elucidate their cancer informational and psychosocial needs. The groups were conducted using standard methodology and guided by community-based participatory research principles. Sessions were audio recorded, transcribed, and translated into English. The research team conducted the analysis. RESULTS: Frequently occurring themes included (1) the need for accurate information on cancer and treatment options, (2) the role of language barriers in accessing cancer care, (3) the role of food in cancer and the need for nutritional information, and (4) the role of Chinese medicine in cancer treatment. Participants expressed significant dissatisfaction with the amount, reliability, and/or comprehensibility of available information. CONCLUSIONS: Support groups and programs should be developed to address participants' needs for more information on cancer and its treatment. Programs should educate and empower patients on how to find further Chinese language information and resources and effectively communicate their questions and needs to providers in an interpreted encounter. System-level approaches should be implemented to ensure provision of interpretation services. Additionally, programs should incorporate the unique cultural needs of this population related to food/nutrition and Chinese medicine.

LiGluR restores visual responses in rodent models of inherited blindness.

Inherited retinal degeneration results from many different mutations in either photoreceptor-specific or nonphotoreceptor-specific genes. However, nearly all mutations lead to a common blinding phenotype that initiates with rod cell death, followed by loss of cones. In most retinal degenerations, other retinal neuron cell types survive for long periods after blindness from photoreceptor loss. One strategy to restore light responsiveness to a retina rendered blind by photoreceptor degeneration is to express light-regulated ion channels or transporters in surviving retinal neurons. Recent experiments in rodents have restored light-sensitivity by expressing melanopsin or microbial opsins either broadly throughout the retina or selectively in the inner segments of surviving cones or in bipolar cells. Here, we present an approach whereby a genetically and chemically engineered light-gated ionotropic glutamate receptor (LiGluR) is expressed selectively in retinal ganglion cells (RGCs), the longest-surviving cells in retinal blinding diseases. When expressed in the RGCs of a well-established model of retinal degeneration, the rd1 mouse, LiGluR restores light sensitivity to the RGCs, reinstates light responsiveness to the primary visual cortex, and restores both the pupillary reflex and a natural light-avoidance behavior.

Total spinal anesthesia for cardiac surgery: does it make a difference in patient outcomes?

BACKGROUND: Heart disease is a major cause of morbidity and mortality. While cardiac surgery is a viable treatment option, it is a potent physiological stressor. The surgical stress response may result in patient decompensation and negative patient outcomes. The goal of a novel anesthetic approach, which combines high spinal anesthesia with intrathecal morphine and general anesthesia (TSA), is to attenuate this stress response. PURPOSE: The primary purpose of this pilot study (n = 70) was to describe and compare the outcomes of TSA cardiac surgery with a matched control sample of patients who received the "standard general anesthetic" (GA). METHOD: A retrospective, descriptive, correlational design was used for a matched pair total sample of (n = 70). Following ethics approval, patient consents were obtained and chart review data collection was completed. FINDINGS: TSA patients were more likely to be extubated in the operating room (p < 0.0001) and also had significantly shorter overall duration of endotracheal intubation (p < 0.0008). During the initial 24 hours after surgery, the TSA group received significantly less morphine (p < 0.0001). The mean difference in postoperative hospital length of stay did not reach statistical significance. However, on average, the TSA group was discharged three days earlier than the GA group. CONCLUSION: This evidence highlights the clinical nursing relevance of the type of anesthesia on postoperative care and outcomes. The knowledge gained from these findings will help to enable the multidisciplinary critical care team to anticipate TSA patient outcomes and to facilitate the development of appropriate and effective evidence-based, patient-focused plans of care. This pilot study establishes sound rationale for subsequent larger prospective cohort research of the TSA patient population.

Comprehensive Canadian review of the off-label use of recombinant activated factor VII in cardiac surgery.

BACKGROUND: This observational study sought to identify the off-label use pattern of recombinant activated factor VII (rFVIIa) in cardiac surgery and to identify predictors of its effectiveness and risk. METHODS AND RESULTS: At 18 Canadian centers, 522 nonhemophiliac cardiac surgical patients received rFVIIa during the period 2003 through 2006; data were available, and retrospectively collected, on 503 patients. The median (quartile 1, quartile 3) units of red blood cells transfused from surgery to therapy and in the 24 hours after therapy were 8 (5, 12) and 2 (1, 5), respectively (P<0.0001). Mortality rate was 32%, and mortality or major morbidity rate was 44%. These rates were within expected ranges (mortality, 27% to 35%; mortality or morbidity, 39% to 48%), which were calculated with a separate cohort of cardiac surgical patients who did not receive rFVIIa used as reference. Independent predictors of complications included instability before therapy (multiple inotropes or intra-aortic balloon pump) and increasing red blood cell units transfused before and after therapy. Variables independently associated with nonresponse included abnormal coagulation parameters and >15 red blood cell units transfused before therapy. CONCLUSIONS: In Canada, rFVIIa is used primarily when standard interventions have failed to control bleeding. In this setting, rFVIIa is associated with reduced blood product transfusions and, after risk adjustment, does not appear to be associated with increased or decreased complication rates. The effectiveness of the drug may be enhanced if it is given early in the course of refractory blood loss in the setting of adequate amounts of circulating coagulation factors.