Expression, induction and regulation of the cytochrome P450 monooxygenase system in the rat glioma C6 cell line

The cytochrome P450 monooxygenase system consists of NADPH- cytochrome P450 reductase (P450 reductase) and cytochromes P450, which can catalyze the oxidation of a wide variety of endogenous and exogenous compounds, including steroid hormones, fatty acids, drugs, and pollutants. The functions of this system are as diverse as the substrates. P450 reductase transfers reducing equivalents from NADPH to P450, which in turn catalyzes metabolic reactions. This enzyme system has the highest level of activity in the liver. It is also present in other tissues, including brain. The functions of this enzyme system in brain seem to include: neurotransmission, neuroendocrinology, developmental and behavioral modulation, regulation of intracellular levels of cholesterol, and potential neurotoxicity.^ In this study, we have set up the rat glioma C6 cell line as an in vitro model system to examine the expression, induction, and tissue-specific regulation of P450s and P450 reductase. Rat glioma C6 cells were treated with P450 inducers phenobarbital (PB) or benzo(a)anthracene (BA). The presence of P450 reductase and of cytochrome P450 1A1, 1A2, 2A1, 2B1/2, 2C7, 2D1-5 and 2E1 was detected by reverse transcription followed by polymerase chain reaction (RT-PCR) and confirmed by restriction digestion. The induction of P450 1A1 and 2B1/2 and P450 reductase was quantified using competitive PCR. Ten- and five-fold inductions of P450 1A and 2B mRNA after BA or PB treatments, respectively, were detected. Western blot analysis of microsomal preparations of glioma C6 cells demonstrated the presence of P450 1A, 2B and P450 reductase at the protein level. ELISAs showed that BA and PB induce P450 1A and 2B proteins 7.3- and 13.5-fold, respectively. Microsomes prepared from rat glioma C6 cells showed cytochrome P450 CO difference spectra with absorption at or near 450 nm. Microsomes prepared from rat glioma C6 cells demonstrated much higher levels of ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-dealkylase (PROD) activity, when treated with BA or PB, respectively. These experiments provide further evidence that the rat glioma C6 cell line contains an active cytochrome P450 monooxygenase system which can be induced by P450 inducers. The mRNAs of P450 1A1 and 2B1/2 can not bind to the oligo(dT) column efficiently, indicating they have very short poly(A) tails. This finding leads us to study the tissue specific regulation of P450s at post-transcriptional level. The half lives of P450 1A1 and 2B1/2 mRNA in glioma C6 cells are only 1/10 and 1/3 of that in liver. This may partly contribute to the low expression level of P450s in glial cells. The induction of P450s by BA or PB did not change their mRNA half lives, indicating the induction may be due to transcriptional regulation. In summary of this study, we believe the presence of the cytochrome P450 monooxygenase system in glial cells of the brain may be important in chemotherapy and carcinogenesis of brain tumors. ^

Status epilepticus and multiple organ system dysfunction

Recent reports have suggested the possible association of status epilepticus and multiple organ system failure. The purpose of this case control study was to investigate this association and to identify factors that predispose individuals with status epilepticus (SE) or aborted status epilepticus (ASE) to develop multiple organ system failure (MOSF) or multiple organ system dysfunction (MODS).^ For the purpose of the study, definitions of SE, ASE, MOSF, and MODS were operationalized as follows: SE was defined as any seizure lasting for a duration of $\ge$30 minutes or intermittent seizures lasting for $\ge$30 minutes from which the patient does not regain consciousness. ASE was defined as any seizure lasting for a duration of $\ge$10 minutes but $<$30 minutes and which was aborted as a result of a medical intervention. MOSF was defined as the failure of $\ge$2 organ systems in the same patient; organ system failure was said to be present whenever standard MOSF criteria were met. MODS was defined as the dysfunction of $\ge$2 organ systems in the same patient; organ system dysfunction was said to be present, whenever the monitor(s) of that organ's function exceeded the normal range for the physiological or laboratory parameters.^ Medical records of 686 individuals between the age of 5 and 44 years, with history of seizures needing hospitalization at the Texas Children's Hospital or Methodist Hospital, Houston, Texas, between 1991-95 were reviewed and 100 individuals with SE/ASE were identified. Of these 100 individuals with SE/ASE, 45 developed MOSF/MODS during their hospitalization and 9 of these individuals died. Using multivariate analyses, it was found that adult individuals who had an "acute" etiology of their seizure disorder (OR = 5.23; 95%CI: 0.41, 66.24) and children who had a "remote" etiology of their seizure disorder (OR = 3.92; 95%CI: 0.53, 29.22), were more likely to develop MOSF/MODS compared with those who had other etiologies of the seizure disorder. Individuals with SE lasting more than one hour were more likely to develop MOSF/MODS compared with individuals with SE lasting less than 1 hour (OR = 6.51; 95%CI: 1.63, 25.92). Individuals who presented with the SE/ASE episode as their first seizure episode were more likely to develop MOSF/MODS compared to those with a previous history of seizure episodes (OR = 1.78; 95%CI: 0.36, 8.82).^ The major limitations of this study includes the relatively small sample size and the study being performed in only two institutions. However, this is the first study of this kind and should therefore be viewed as largely exploratory in nature. Future studies should investigate the relationship of the risk factors identified in this study using a larger number of institutions and patients. ^

Genes to blood pressure: The effects of variation in genes of the renin-angiotensin system on the hormonal and renal control of blood pressure

Objective. Essential hypertension affects 25% of the US adult population and is a leading contributor to morbidity and mortality. Because BP is a multifactorial phenotype that resists simple genetic analysis, intermediate phenotypes within the complex network of BP regulatory systems may be more accessible to genetic dissection. The Renin-Angiotensin System (RAS) is known to influence intermediate and long-term blood pressure regulation through alterations in vascular tone and renal sodium and fluid resorption. This dissertation examines associations between renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1) gene variation and interindividual differences in plasma hormone levels, renal hemodynamics, and BP homeostasis.^ Methods. A total of 150 unrelated men and 150 unrelated women, between 20.0 and 49.9 years of age and free of acute or chronic illness except for a history of hypertension (11 men and 7 women, all off medications), were studied after one week on a controlled sodium diet. RAS plasma hormone levels, renal hemodynamics and BP were determined prior to and during angiotensin II (Ang II) infusion. Individuals were genotyped by PCR for a variable number tandem repeat (VNTR) polymorphism in REN, and for the following restriction fragment length polymorphisms (RFLP): AGT M235T, ACE I/D, and AT1 A1166C. Associations between clinical measurements and allelic variation were examined using multiple linear regression statistical models.^ Results. Women homozygous for the AT1 1166C allele demonstrated higher intracellular levels of sodium (p = 0.044). Men homozygous for the AGT T235 allele demonstrated a blunted decrement in renal plasma flow in response to Ang II infusion (p = 0.0002). There were no significant associations between RAS gene variation and interindividual variation in RAS plasma hormone levels or BP.^ Conclusions. Rather than identifying new BP controlling genes or alleles, the study paradigm employed in this thesis (i.e., measured genes, controlled environments and interventions) may provide mechanistic insight into how candidate genes affect BP homeostasis. ^

Contribution of the genes of the renin-angiotensin system to interindividual differences in blood pressure levels in Caucasians from Rochester, Minnesota

The Renin-Angiotensin system (RAS) regulates blood pressure through its effects on vascular tone, renal hemodynamics, and renal sodium and fluid balance. The genes encoding the four major components of the RAS, angiotensinogen, renin, angiotensin I-converting enzyme (ACE), and angiotensin II receptor type 1 (AT1), have been investigated as candidate genes in the pathogenesis of essential hypertension. However, studies have primarily focused on small samples of diseased individuals, and, therefore, have provided little information about the determinants of interindividual variation in blood pressure (BP) in the general population.^ Using data from a large population-based sample from Rochester, MN, I have evaluated the contribution of variation in the region of the RAS genes to interindividual variation in systolic, diastolic, and mean arterial pressure in the population-at-large. Marker genotype data from four polymorphisms located within or very near these genes were first collected on 3,974 individuals from 583 randomly ascertained three-generation pedigrees. Haseman-Elston regression and variance component methods of linkage analysis were then carried out to estimate the proportion of interindividual variance in BP attributable to the effects of variation at these four measured loci.^ A significant effect of the ACE locus on interindividual variation in mean arterial pressure (MAP) was detected in a sample of siblings belonging to the youngest generation. After allowing for measured covariates, this effect accounted for 15-25% of the interindividual variance in MAP, and was even greater in a subset with a positive family history of hypertension. When gender-specific analyses were carried out, this effect was significant in males but not in females. Extended pedigree analyses also provided evidence for an effect of the ACE locus on interindividual variation in MAP, but no difference between males and females was observed. Circumstantial evidence suggests that the ACE gene itself may be responsible for the observed effects on BP, although the possibility that other genes in the region may be at play cannot be excluded.^ No definitive evidence for an effect of the renin, angiotensinogen, or AT1 loci on interindividual variation in BP was obtained in this study, suggesting that the impact of these genes on BP may not be great in the Caucasian population-at-large. However, this does not preclude a larger effect of these genes in some subsets of individuals, especially among those with clinically manifest hypertension or coronary heart disease, or in other populations. ^

Risk, outcomes, and cost of emergency center visits in cancer patients

Cancer is a chronic disease that often necessitates recurrent hospitalizations, a costly pattern of medical care utilization. In chronically ill patients, most readmissions are for treatment of the same condition that caused the preceding hospitalization. There is concern that rather than reducing costs, earlier discharge may shift costs from the initial hospitalization to emergency center visits. ^ This is the first descriptive study to measure the incidence of emergency center visits (ECVs) after hospitalization at The University of M. D. Anderson Cancer Center (UTMDACC), to identify the risk factors for and outcomes of these ECVs, and to compare 30-day all-cause mortality and costs for episodes of care with and without ECVs. ^ We identified all hospitalizations at UTMDACC with admission dates from September 1, 1993 through August 31, 1997 which met inclusion criteria. Data were electronically obtained primarily from UTMDACC's institutional database. Demographic factors, clinical factors, duration of the index hospitalization, method of payment for care, and year of hospitalization study were variables determined for each hospitalization. ^ The overall incidence of ECVs was 18%. Forty-five percent of ECVs resulted in hospital readmission (8% of all hospitalizations). In 1% of ECVs the patient died in the emergency center, and for the remaining 54% of ECVs the patient was discharged home. Risk factors for ECVs were marital status, type of index hospitalization, cancer type, and duration of the index hospitalization. The overall 30-day all-cause mortality rate was 8.6% for hospitalizations with an ECV and 5.3% for those without an ECV. In all subgroups, the 30-day all-cause mortality rate was higher for groups with ECVs than for those without ECVs. The most important factor increasing cost was having an ECV. In all patient subgroups, the cost per episode of care with an ECV was at least 1.9 times the cost per episode without an ECV. ^ The higher costs and poorer outcomes of episodes of care with ECVs and hospital readmissions suggest that interventions to avoid these ECVs or mitigate their costs are needed. Further research is needed to improve understanding of the methodological issues involved in relation to health care issues for cancer patients. ^

The transformation of a health care system: An ecology perspective

Beginning in the early 1980s, the health care system experienced momentous realignments. Fundamental changes in structures of traditional health care organizations, shifts in authority and relationships of professionals and institutions, and the increasing influence of managed care contributed to a relatively stable industry entering into a state of turbulence. The dynamics of these changes are recurring themes in the health services literature. The purpose of this dissertation was to examine the content of this literature over a defined time period and within the perspective of a theory of organizational change. ^ Using a theoretical framework based upon the organizational theory known as Organizational Ecology, secondary data from the period between 1983 and 1994 was reviewed. Analysis of the literature identified through a defined search methodology was focused upon determining the manner in which the literature characterized changes that were described. Using a model constructed from fundamentals of Organizational Ecology with which to structure an assessment of content, literature was summarized for the manner and extent of change in specific organizational forms and for the changes in emphasis by the environmental dynamics directing changes in the population of organizations. Although it was not the intent of the analysis to substantiate causal relationships between environmental resources selected as the determinants of organizational change and the observed changes in organizational forms, the structured review of content of the literature established a strong basis for inferring such a relationship. ^ The results of the integrative review of the literature and the power of the appraisal achieved through the theoretical framework constructed for the analysis indicate that there is considerable value in such an approach. An historical perspective on changes which have transformed the health care system developed within a defined organizational theory provide a unique insight into these changes and indicate the need for further development of such an analytical model. ^

Managing the risks of medical technology: Do hazard surveillance systems provide an early warning of medical device problems?

The Food and Drug Administration (FDA) is responsible for risk assessment and risk management in the post-market surveillance of the U.S. medical device industry. One of the FDA regulatory mechanisms, the Medical Device Reporting System (MDR) is an adverse event reporting system intended to provide the FDA with advance warning of device problems. It includes voluntary reporting for individuals, and mandatory reporting for device manufacturers. ^ In a study of alleged breast implant safety problems, this research examines the organizational processes by which the FDA gathers data on adverse events and uses adverse event reporting systems to assess and manage risk. The research reviews the literature on problem recognition, risk perception, and organizational learning to understand the influence highly publicized events may have on adverse event reporting. Understanding the influence of an environmental factor, such as publicity, on adverse event reporting can provide insight into the question of whether the FDA's adverse event reporting system operates as an early warning system for medical device problems. ^ The research focuses on two main questions. The first question addresses the relationship between publicity and the voluntary and mandatory reporting of adverse events. The second question examines whether government agencies make use of these adverse event reports. ^ Using quantitative and qualitative methods, a longitudinal study was conducted of the number and content of adverse event reports regarding breast implants filed with the FDA's medical device reporting system during 1985–1991. To assess variation in publicity over time, the print media were analyzed to identify articles related to breast implant failures. ^ The exploratory findings suggest that an increase in media activity is related to an increase in voluntary reporting, especially following periods of intense media coverage of the FDA. However, a similar relationship was not found between media activity and manufacturers' mandatory adverse event reporting. A review of government committee and agency reports on the FDA published during 1976–1996 produced little evidence to suggest that publicity or MDR information contributed to problem recognition, agenda setting, or the formulation of policy recommendations. ^ The research findings suggest that the reporting of breast implant problems to FDA may reflect the perceptions and concerns of the reporting groups, a barometer of the volume and content of media attention. ^

Automated low flow pump system for the treatment of refractory ascites: A multi-center safety and efficacy study

BACKGROUND & AIMS: Refractory ascites (RA) affects 10% of patients with advanced cirrhosis and ascites. Usual therapy includes large volume paracentesis, and in selected patients, a transjugular portosystemic shunt (TIPS). These therapies may be associated with increased morbidity: paracentesis may induce circulatory dysfunction and impair quality of life and TIPS may induce encephalopathy and is associated with increased mortality in patients with severe liver dysfunction. We present the results of a multicenter, non-randomized trial to assess the safety and efficacy of a new automated pump system for treatment of RA. METHODS: Forty patients at 9 centers (February 2010-June 2011) received an implanted pump for the automated removal of ascites from the peritoneal cavity into the bladder, from where it was eliminated through normal urination. Patients were followed-up for 6months. The primary study outcome was safety. Secondary outcomes included recurrence of tense ascites and pump performance. RESULTS: Surgical complications occurred early in the study and became less frequent. The pump system removed 90% of the ascites and significantly reduced the median number of large volume paracentesis per month [3.4 (range 1-6) vs. 0.2 (range 0-4); p <0.01]. Cirrhosis-related adverse events decreased along follow-up. CONCLUSIONS: The automated pump seems an efficacious tool to move out ascites from the peritoneal cavity to the bladder. Its safety is still moderate, but a broad use in different countries will improve the surgical technique as well as the medical surveillance. A prospective randomized clinical trial vs. large volume paracentesis is underway to confirm these preliminary results.

Analysis of caesarean section rates over time in a single Swiss centre using a ten-group classification system.

OBJECTIVE Caesarean section (CS) rates have risen over the past two decades. The aim of this observational study was to identify time-dependent variations in CS and vaginal delivery rates over a period of 11 years. METHOD All deliveries (13,701 deliveries during the period 1999-2009) at the University Women's Hospital Bern were analysed using an internationally standardised and approved ten-group classification system. Caesarean sections on maternal request (CSMR) were evaluated separately. RESULTS We detected an overall CS rate of 36.63% and an increase in the CS rate over time (p <0.001). Low-risk profile groups were the two largest populations and displayed low CS rates, with significantly decreasing relative size over time. The relative size of groups with induced labour increased significantly, but this did not have an impact on the overall CS rate. Pregnancies complicated by breech position, multiple pregnancies and abnormal lies did not have an impact on overall CS rate. The biggest contributor to a high CS rate was preterm delivery and the existence of a uterine scar from a previous CS. CSMR was 1.45% and did not have an impact on the overall CS rate. CONCLUSION The observational study identified wide variations in caesarean section and vaginal delivery rates across the groups over time, and a shift towards high-risk populations was noted. The biggest contributors to high CS rates were identified; namely, previous uterine scar and preterm delivery. Interventions aiming to reduce CS rates are planned.

A web-based non-intrusive ambient system to measure and classify activities of daily living.

BACKGROUND The number of older adults in the global population is increasing. This demographic shift leads to an increasing prevalence of age-associated disorders, such as Alzheimer's disease and other types of dementia. With the progression of the disease, the risk for institutional care increases, which contrasts with the desire of most patients to stay in their home environment. Despite doctors' and caregivers' awareness of the patient's cognitive status, they are often uncertain about its consequences on activities of daily living (ADL). To provide effective care, they need to know how patients cope with ADL, in particular, the estimation of risks associated with the cognitive decline. The occurrence, performance, and duration of different ADL are important indicators of functional ability. The patient's ability to cope with these activities is traditionally assessed with questionnaires, which has disadvantages (eg, lack of reliability and sensitivity). Several groups have proposed sensor-based systems to recognize and quantify these activities in the patient's home. Combined with Web technology, these systems can inform caregivers about their patients in real-time (e.g., via smartphone). OBJECTIVE We hypothesize that a non-intrusive system, which does not use body-mounted sensors, video-based imaging, and microphone recordings would be better suited for use in dementia patients. Since it does not require patient's attention and compliance, such a system might be well accepted by patients. We present a passive, Web-based, non-intrusive, assistive technology system that recognizes and classifies ADL. METHODS The components of this novel assistive technology system were wireless sensors distributed in every room of the participant's home and a central computer unit (CCU). The environmental data were acquired for 20 days (per participant) and then stored and processed on the CCU. In consultation with medical experts, eight ADL were classified. RESULTS In this study, 10 healthy participants (6 women, 4 men; mean age 48.8 years; SD 20.0 years; age range 28-79 years) were included. For explorative purposes, one female Alzheimer patient (Montreal Cognitive Assessment score=23, Timed Up and Go=19.8 seconds, Trail Making Test A=84.3 seconds, Trail Making Test B=146 seconds) was measured in parallel with the healthy subjects. In total, 1317 ADL were performed by the participants, 1211 ADL were classified correctly, and 106 ADL were missed. This led to an overall sensitivity of 91.27% and a specificity of 92.52%. Each subject performed an average of 134.8 ADL (SD 75). CONCLUSIONS The non-intrusive wireless sensor system can acquire environmental data essential for the classification of activities of daily living. By analyzing retrieved data, it is possible to distinguish and assign data patterns to subjects' specific activities and to identify eight different activities in daily living. The Web-based technology allows the system to improve care and provides valuable information about the patient in real-time.

In the aftermath of medical error : Caring for patients, family, and the healthcare workers involved

Medical errors, in particular those resulting in harm, pose a serious situation for patients ("first victims") and the healthcare workers involved ("second victims") and can have long-lasting and distressing consequences. To prevent a second traumatization, appropriate and empathic interaction with all persons involved is essential besides error analysis. Patients share a nearly universal, broad preference for a complete disclosure of incidents, regardless of age, gender, or education. This includes the personal, timely and unambiguous disclosure of the adverse event, information relating to the event, its causes and consequences, and an apology and sincere expression of regret. While the majority of healthcare professionals generally support and honest and open disclosure of adverse events, they also face various barriers which impede the disclosure (e.g., fear of legal consequences). Despite its essential importance, disclosure of adverse events in practice occurs in ways that are rarely acceptable to patients and their families. The staff involved often experiences acute distress and an intense emotional response to the event, which may become chronic and increase the risk of depression, burnout and post-traumatic stress disorders. Communication with peers is vital for people to be able to cope constructively and protectively with harmful errors. Survey studies among healthcare workers show, however, that they often do not receive sufficient individual and institutional support. Healthcare organizations should prepare for medical errors and harmful events and implement a communication plan and a support system that covers the requirements and different needs of patients and the staff involved.

Regulation of hematopoietic and leukemic stem cells by the immune system.

Hematopoietic stem cells (HSCs) are rare, multipotent cells that generate via progenitor and precursor cells of all blood lineages. Similar to normal hematopoiesis, leukemia is also hierarchically organized and a subpopulation of leukemic cells, the leukemic stem cells (LSCs), is responsible for disease initiation and maintenance and gives rise to more differentiated malignant cells. Although genetically abnormal, LSCs share many characteristics with normal HSCs, including quiescence, multipotency and self-renewal. Normal HSCs reside in a specialized microenvironment in the bone marrow (BM), the so-called HSC niche that crucially regulates HSC survival and function. Many cell types including osteoblastic, perivascular, endothelial and mesenchymal cells contribute to the HSC niche. In addition, the BM functions as primary and secondary lymphoid organ and hosts various mature immune cell types, including T and B cells, dendritic cells and macrophages that contribute to the HSC niche. Signals derived from the HSC niche are necessary to regulate demand-adapted responses of HSCs and progenitor cells after BM stress or during infection. LSCs occupy similar niches and depend on signals from the BM microenvironment. However, in addition to the cell types that constitute the HSC niche during homeostasis, in leukemia the BM is infiltrated by activated leukemia-specific immune cells. Leukemic cells express different antigens that are able to activate CD4(+) and CD8(+) T cells. It is well documented that activated T cells can contribute to the control of leukemic cells and it was hoped that these cells may be able to target and eliminate the therapy-resistant LSCs. However, the actual interaction of leukemia-specific T cells with LSCs remains ill-defined. Paradoxically, many immune mechanisms that evolved to activate emergency hematopoiesis during infection may actually contribute to the expansion and differentiation of LSCs, promoting leukemia progression. In this review, we summarize mechanisms by which the immune system regulates HSCs and LSCs.

Infection rate of emergency bolt-kit vs. non-emergency conventional implanted silver bearing external ventricular drainage catheters.

BACKGROUND Bolt-kit systems are increasingly used as an alternative to conventional external cerebrospinal fluid (CSF) drainage systems. Since 2009 we regularly utilize bolt-kit external ventricular drainage (EVD) systems with silver-bearing catheters inserted manually with a hand drill and skull screws for emergency ventriculostomy. For non-emergency situations, we use conventional ventriculostomy with subcutaneous tunneled silver-bearing catheters, performed in the operating room with a pneumatic drill. This retrospective analysis compared the two techniques in terms of infection rates. METHODS 152 patients (aged 17-85 years, mean=55.4 years) were included in the final analysis; 95 received bolt-kit silver-bearing catheters and 57 received conventionally implanted silver-bearing catheters. The primary endpoint combined infection parameters: occurrence of positive CSF culture, colonization of catheter tips, or elevated CSF white blood cell counts (>4/μl). Secondary outcome parameters were presence of microorganisms in CSF or on catheter tips. Incidence of increased CSF cell counts and number of patients with catheter malposition were also compared. RESULTS The primary outcome, defined as analysis of combined infection parameters (occurrence of either positive CSF culture, colonization of the catheter tips or raised CSF white blood cell counts >4/μl)was not significantly different between the groups (58.9% bolt-kit group vs. 63.2% conventionally implanted group, p=0.61, chi-square-test). The bolt-kit group was non-inferior and not superior to the conventional group (relative risk reduction of 6.7%; 90% confidence interval: -19.9% to 25.6%). Secondary outcomes showed no statistically significant difference in the incidence of microorganisms in CSF (2.1% bolt-kit vs. 5.3% conventionally implanted; p=0.30; chi-square-test). CONCLUSIONS This analysis indicates that silver-bearing EVD catheters implanted with a bolt-kit system outside the operating room do not significantly elevate the risk of CSF infection as compared to conventional implant methods.

Novel emboli protection system during cardiac surgery: a multi-center, randomized, clinical trial.

BACKGROUND Stroke is a major cause of morbidity and mortality during open-heart surgery. Up to 60% of intraoperative cerebral events are emboli induced. This randomized, controlled, multicenter trial is the first human study evaluating the safety and efficacy of a novel aortic cannula producing simultaneous forward flow and backward suction for extracting solid and gaseous emboli from the ascending aorta and aortic arch upon their intraoperative release. METHODS Sixty-six patients (25 females; 68±10 years) undergoing elective aortic valve replacement surgery, with or without coronary artery bypass graft surgery, were randomized to the use of the CardioGard (CardioGard Medical, Or-Yehuda, Israel) Emboli Protection cannula ("treatment") or a standard ("control") aortic cannula. The primary endpoint was the volume of new brain lesions measured by diffusion-weighted magnetic resonance imaging (DW-MRI), performed preoperatively and postoperatively. Device safety was investigated by comparisons of complications rate, namely neurologic events, stroke, renal insufficiency and death. RESULTS Of 66 patients (34 in the treatment group), 51 completed the presurgery and postsurgery MRI (27 in the treatment group). The volume of new brain lesion for the treatment group was (mean±standard error of the mean) 44.00±64.00 versus 126.56±28.74 mm3 in the control group (p=0.004). Of the treatment group, 41% demonstrated new postoperative lesions versus 66% in the control group (p=0.03). The complication rate was comparable in both groups. CONCLUSIONS The CardioGard cannula is safe and efficient in use during open-heart surgery. Efficacy was demonstrated by the removal of a substantial amount of emboli, a significant reduction in the volume of new brain lesions, and the percentage of patients experiencing new brain lesions.