Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes

Uncoupling of the endothelial nitric oxide synthase (eNOS) resulting in superoxide anion (O(2)(-)) formation instead of nitric oxide (NO) causes diabetic endothelial dysfunction. eNOS regulates mobilization and function of endothelial progenitor cells (EPCs), key regulators of vascular repair. We postulate a role of eNOS uncoupling for reduced number and function of EPC in diabetes. EPC levels in diabetic patients were significantly reduced compared with those of control subjects. EPCs from diabetic patients produced excessive O(2)(-) and showed impaired migratory capacity compared with nondiabetic control subjects. NOS inhibition with N(G)-nitro-l-arginine attenuated O(2)(-) production and normalized functional capacity of EPCs from diabetic patients. Glucose-mediated EPC dysfunction was protein kinase C dependent, associated with reduced intracellular BH(4) (tetrahydrobiopterin) concentrations, and reversible after exogenous BH(4) treatment. Activation of NADPH oxidases played an additional but minor role in glucose-mediated EPC dysfunction. In rats with streptozotocin-induced diabetes, circulating EPCs were reduced to 39 +/- 5% of controls and associated with uncoupled eNOS in bone marrow. Our results identify uncoupling of eNOS in diabetic bone marrow, glucose-treated EPCs, and EPCs from diabetic patients resulting in eNOS-mediated O(2)(-) production. Subsequent reduction of EPC levels and impairment of EPC function likely contributes to the pathogenesis of vascular disease in diabetes.     

Clinical trials in nephrology: success or failure

PURPOSE OF REVIEW: A large amount of clinical and epidemiologic evidence has been gathered supporting the importance of blood pressure control in reducing chronic kidney disease progression. Suppression of the rennin-angiotensin-aldosterone system should also be considered in any patient with chronic kidney disease, in particular if albuminuria is present. RECENT FINDINGS: Analysis of renal outcome by estimating glomerular filtration rate in trials primarily devoted to cardiovascular protection in hypertensive patients, in particular the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial trial, has come to question the effectiveness of suppressing the rennin-angiotensin-aldosterone system in controlling blood pressure and thus protecting the kidney in hypertensive patients. This subject is particularly interesting because the existence of an increased cardiovascular risk associated with renal function decline has been demonstrated in many different clinical conditions including arterial hypertension. The increase in global cardiovascular risk accompanying chronic kidney disease would necessitate the use of drugs suppressing the rennin-angiotensin-aldosterone system for cardiovascular protection irrespective of the influence on renal outcome. SUMMARY: This review includes the most recent data evaluating renal endpoints in clinical trials primarily devoted to renal function as well as those dedicated to arterial hypertension and its cardiovascular consequences.     

Beating heart aortic valve replacement after previous coronary artery bypass surgery with a patent internal mammary artery graft

Re-sternotomy for aortic valve replacement (AVR) in patients with a patent internal mammary artery (IMA) graft may present a challenging surgical problem. Thus, strategies to prevent IMA graft injury include avoiding its dissection and leaving the graft open. However, when aortic cross clamping and cardioplegia are required, this approach may be associated with cardioplegia washout, suboptimal myocardial protection, and anterior myocardial wall injury. We herein describe an alternative technique for AVR on the beating heart in 4 patients with patent IMA grafts. The IMA was left unclamped and continuous retrograde coronary sinus perfusion (RCSP) was administered. Additional simultaneous antegrade venous bypass graft perfusion was established according to the extent of native coronary artery disease as well as patency and level of aortic proximal anastomoses. Using additional coronary ostia backflow control, the aortic valve was successfully replaced on the beating heart in all four cases without perivalvular leak. Postoperatively, low creatine kinase-MB fraction levels and preserved or improved ventricular function suggested very good myocardial protection. No myocardial infarction occurred in any patient. In our experience, aortic valve replacement on the beating heart using simultaneous antegrade-retrograde blood perfusion is a safe and effective method in this challenging subset of patients to prevent myocardial injury and to minimize the risk of patent IMA injury.     

Surgical Biomechanics of the Patellofemoral Joint

This review presents objective data, as far as possible, about the current understanding of the biomechanics of the patellofemoral joint as it pertains to the management of patellofemoral problems. When faced with a patellofemoral malfunction, it is important to check all the soft-tissue and articular geometry factors relating to the patella locally and not to neglect the overall lower limb alignment and function. It is important to remember that small alterations in alignment can result in significant alterations in patellofemoral joint stresses and that changes in the mechanics of the patellofemoral joint can also result in changes in the tibiofemoral compartments. Surgical intervention for patellofemoral problems needs to be planned carefully and take into account an individual’s anatomy.     

A randomized controlled trial of the effect of spironolactone on left ventricular mass in hemodialysis patients

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Severe Cerebral Venous and Sinus Thrombosis: Clinical Course,Imaging Correlates,and Prognosis

Background

Severe cerebral venous-sinus thrombosis (CVT) is a rare disease, and its clinical course, imaging correlates, as well as long-term prognosis have not yet been investigated systematically.

Methods

Multicenter retrospective study. Inclusion criteria were CVT, Glasgow coma scale ≤9, and treatment in the intensive care unit. Primary outcome was death or dependency, assessed by a modified Rankin Score (mRS) >2 at last follow-up.

Results

114 patients were included. At last follow-up (median 2.5 years), 38 patients (33.3 %) showed no or minor residual symptoms (mRS = 0 or 1), 12 (10.5 %) had a mild (mRS = 2), 13 (11.4 %) a moderate (mRS = 3), 12 (10.5 %) a severe disability (mRS = 4 or 5), and 39 (34.2 %) had died. In bivariate analysis, predictors of poor outcome were any signs of mass effect on imaging, clinical deterioration after admission, and age. In contrast, clinical symptoms on admission and parenchymal lesions per se, such as edema, infarction, or hemorrhage were not predictive. Multivariate predictors of poor outcome were an increase in National Institutes of Health Stroke Scale ≥3 after admission [odds ratio (OR) 6.7], bilateral motor signs in the further course (OR 9.2), and midline shift (OR 5.1).

Conclusion

The outcome of severe CVT is almost equally divided between severe impairment or death and survival with no or only mild handicap. Specifically, space-occupying mass effect and associated neurologic deterioration seem to determine a poor outcome. Therefore, early detection and treatment of mass effect should be the focus of critical care.

     

On the variability of the McGurk effect: audiovisual integration depends on prestimulus brain states

The McGurk effect demonstrates the influence of visual cues on auditory perception. Mismatching information from both sensory modalities can fuse to a novel percept that matches neither the auditory nor the visual stimulus. This illusion is reported in 60-80% of trials. We were interested in the impact of ongoing brain oscillations-indexed by fluctuating local excitability and interareal synchronization-on upcoming perception of identical stimuli. The perception of the McGurk effect is preceded by high beta activity in parietal, frontal, and temporal areas. Beta activity is pronounced in the left superior temporal gyrus (lSTG), which is considered as a site of multimodal integration. This area is functionally (de)coupled to distributed frontal and temporal regions in illusion trials. The disposition to fuse multisensory information is enhanced as the lSTG is more strongly coupled to frontoparietal regions. Illusory perception is accompanied by a decrease in poststimulus theta-band activity in the cuneus, precuneus, and left superior frontal gyrus. Event-related activity in the left middle temporal gyrus is pronounced during illusory perception. Thus, the McGurk effect depends on fluctuating brain states suggesting that functional connectedness of left STS at a prestimulus stage is crucial for an audiovisual percept.     

Man is fashioned, not born: the contributions of George J. Heuer to surgical education

George Heuer undertook his medical education and residency training in surgery at Johns Hopkins. He then joined the surgical faculty under Halsted. He became Chair of Surgery at the University of Cincinnati in 1922, where he developed the second formal surgical training program modeled on Halsted's principles. Subsequently, he became Chair of Surgery at Cornell where he founded another surgical residency. His training programs stressed broad and thorough experience, and he championed increasing resident responsibility and independence. The demonstrated efficacy of his surgical residencies assisted greatly in the formation of subsequent resident training programs across this country.     

Nonheart-beating kidney donation: current practice and future developments

BACKGROUND: Nonheart-beating kidney donation (NHBD) is gaining acceptance as a method of donor pool expansion. However, a number of practitioners have concerns over rates of delayed graft function, acute rejection, and long-term graft survival. The ethical issues associated with NHBD are complex and may be a further disincentive. Tailored strategies for preservation, viability prediction, and immunosuppression for kidneys from this source have the potential to maximize the number of available organs. This review article presents the current practice of NHBD kidney transplantation, examines the results and draws comparisons with cadaveric kidneys, and explores some areas of potential development. METHODS: A review of the current literature on NHBD kidney donation was performed. RESULTS: The renewed interest in NHBD kidneys is driven by a continuing shortfall in available organs. Those centers involved in NHBD report an increase in kidney transplants of the order of 16% to 40% and there is no evidence that the financial costs are higher with NHBDs. The majority of experience comes from Maastricht category 2 NHBDs, where an estimation of warm time is possible. This is generally limited to 40 minutes. There are variations in the technique for kidney preservation prior to retrieval, but most centers use an aortic balloon catheter. Much work has looked at the ideal technique for kidney preservation prior to implantation. Evidence suggests that machine perfusion produces the best initial function rates, decreased use of adjuvant immunotherapy and fewer haemodialysis sessions than static cold storage. CONCLUSION: Despite being associated with poorer initial graft function, the long-term allograft survival of NHBD kidneys does not differ from the results of transplantation from cadaveric kidneys. Further, serum creatinine levels are generally equivalent. Constant reassessment of the ethical issues is required for donation to be increased while respecting public concerns. Use of viability assessment and tailoring of immune suppression for NHBD kidneys may allow a further increase in donation from this source.