Expression profiling identifies the CRH/CRH-R1 system as a modulator of neurovascular gene activity.

Corticotropin-releasing hormone receptor type 1 (CRH-R1)-deficient mice display reduced anxiety-like behavior, a chronic corticosterone deficit, and an impaired neuroendocrine stress response caused by disruption of the hypothalamic-pituitary-adrenocortical (HPA) axis. The molecular substrates and pathways of CRH/CRH-R1-dependent signaling mechanisms underlying the behavioral phenotype as well as the consequences of lifelong glucocorticoid deficit remain largely obscure. To dissect involved neuronal circuitries, we performed comparative expression profiling of brains of CRH-R1 mutant and wild-type mice using our custom made MPIP (Max Planck Institute of Psychiatry) 17k cDNA microarray. Microarray analysis yielded 107 genes showing altered expression levels when comparing CRH-R1 knockout mice with wild-type littermates. A significant proportion of differentially expressed genes was related to control of HPA and hypothalamic-pituitary-thyroid (HPT) axes reflecting not only the disturbance of the HPA axis in CRH-R1 mutant mice but also the interplay of both neuroendocrine systems. The spatial analysis of regulated genes revealed a prevalence for genes expressed in the cerebral microvasculature. This phenotype was confirmed by the successful cross-validation of regulated genes in CRH overexpressing mice. Analysis of the cerebral vasculature of CRH-R1 mutant and CRH overexpressing mice revealed alterations of functional rather than structural properties. A direct role of the CRH/CRH-R1 system was supported by demonstrating Crhr1 expression in the adult murine cerebral vasculature. In conclusion, these data suggest a novel, previously unknown role of the CRH/CRH-R1 system in modulating neurovascular gene expression and function.     

Time course of metabolic findings in coronary occlusion and reperfusion and their role for assessing myocardial salvage

The techniques currently used to assess myocardial infarction are limited in their ability to determine the amount of viable myocardium after a temporary ischemic event. Blood flow and segmental function may not necessarily demonstrate salvage, whereas metabolic parameters will determine cell survival. In an open chest dog model, short occlusion times of 20 min and subsequent reperfusion using C-11 palmitate as an index of fatty acid metabolism showed depression of fatty acid oxidation, which recovered after 3 hours of reperfusion, indicating the partial reversibility of the ischemic condition. In more extensive studies, using positron emission tomography (PET) and, as an indicator of glucose metabolism, fluoro-F-18-deoxyglucose (FDG); N-13 ammonia in addition to C-11 palmitate for the determination of blood flow; and ultrasonic crystals to measure shortening in the reperfused and control territories, the duration of occlusion was 3 h. Metabolic studies were repeated 24 h, 1 week, and 4 weeks after the ischemic injury. Reperfused viable myocardium exhibited residual glucose metabolism with FDG, whereas fatty acid oxidation remained impaired for a longer period. Gradual metabolic recovery during a 4-week period was associated with the prolonged recovery of regional function, whereas a lack of residual metabolic activity indicated that little change in function was likely to occur. Increased FDG uptake and impaired C-11 palmitate turnover are characteristic of reversibly injured tissue. Therefore, PET studies may offer a unique potential for the evaluation of therapeutic measures such as thrombolysis and early revascularization.

     

Characterization of normal and infarcted rat myocardium using a combination of small-animal PET and clinical MRI.

The combination of small-animal PET and MRI data provides quantitative in vivo insights into cardiac pathophysiology, integrating information on biology and morphology. We sought to determine the feasibility of PET and MRI for the quantification of ischemic injury in the rat model. METHODS: Fourteen healthy male Wistar rats were studied with 18F-FDG PET and cine MRI. Myocardial viability was determined in a transmural myocardial infarction model in 12 additional rats, using 18F-FDG PET and delayed-enhancement MRI with gadolinium-diethylenetriaminepentaacetic acid. All PET was acquired with a dedicated small-animal PET system. MRI was performed on a 1.5-T clinical tomograph with a dedicated small-animal electrocardiographic triggering device and a small surface coil. RESULTS: In normal rats, 18F-FDG uptake was homogeneous throughout the left ventricle. The lowest mean uptake of the 18F-FDG was found in the apical regions (79% +/- 6.0% of maximum) and the highest uptake was in the anterior wall (93% +/- 4.3 % of maximum). Myocardial infarct size as determined by histology correlated well with defects of glucose metabolism obtained with 18F-FDG PET (r = 0.89) and also with delayed-enhancement MRI (r = 0.91). Left ventricular ejection fraction in normal rats measured by cine MRI was 57% +/- 5.4% and decreased to 38% +/- 12.9% (P < 0.001) in the myocardial infarction model. CONCLUSION: Integrating information from small-animal PET and clinical MRI instrumentation allows for the quantitative assessment of cardiac function and infarct size in the rat model. The MRI measurements of scar can be complemented by metabolic imaging, addressing the extent and severity of ischemic injury and providing endpoints for therapeutic interventions.     

Nonfluent aphasia in a patient with Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia (WM) is an uncommon low-grade lymphoma. Cognitive impairment due to central nervous system infiltration by lymphoplasmocytoid cells (Bing-Neel syndrome) has been rarely reported. We describe a 54-year-old man who was referred to a memory disorder clinic with a 9-month history of clinically obvious nonfluent aphasia and WM. He underwent extensive neuropsychological testing, clinical examination and structural and functional brain imaging. The diagnosis of the diffuse form of the Bing-Neel syndrome was supported by abnormal lymphoid cells found in the cerebrospinal fluid. Structural and functional brain imaging revealed impairment of brain areas due to white matter changes and subsequent functional deficits mimicking the neuropsychological syndrome encountered in progressive nonfluent aphasia. The diffuse form of Bing-Neel syndrome and neurological deficits are assumed to be the result of leptomeningeal infiltration by malignant cells and/or neoplastic vascular obstruction.     

In vivo effects of hypothermia on the microcirculation during extracorporeal circulation.

OBJECTIVE: Induced hypothermia has been shown to be protective during cardiac surgery, but also in traumatic, ischemic, burn, and neurological injury. In previous in vivo animal experiments, we documented increased leukocyte/endothelial (L/E) cell interaction following normothermic extracorporeal blood circulation (ECC). This study was carried out to investigate whether reduced core temperature during ECC affects the damage to the microcirculation as evidenced by leukocyte adherence and edema formation. METHODS: Intravital fluorescence microscopy was used on the dorsal skinfold chamber preparation in Syrian golden hamsters. ECC was introduced via a micro-rollerpump (1 ml/min) and a 60 cm silicon tube (1mm inner diameter) shunted between the carotid artery and the jugular vein after application of 300IE Heparin/kg per body weight. Experiments were performed in chronically instrumented, awake animals (age 10-14 weeks, weight 65-75 g). Animals of the experimental group were cooled to 18 degrees C body temperature while ECC, followed by a rewarming period (n=7), controls experienced ECC under normothermia (37 degrees C, n=7). RESULTS: 30 min ECC at 18 degrees C resulted in a decrease of rolling and adherent leucocytes (stickers) in postcapillary venules after 1, 4 and 8h compared with the control group (119+/-46 vs. 274+/-113 n/mm2, P<0.05, mean+/-SD; n=7 in each group). Functional capillary density was significantly reduced during hypothermia (80+/-16 vs. 148+/-16 cm/cm2, P<0.05), but restored after rewarming. In contrast, edema formation was markedly increased during hypothermia. CONCLUSIONS: Hypothermia during ECC significantly reduced L/E cell interaction in the early post-ECC period. Hypothermia markedly reduced microvascular perfusion, but was completely restored upon rewarming. Despite a reduced number of adherent leukocytes, no protection of endothelial barrier function was seen as a consequence of induced hypothermia.     

Risk stratification with cardiac troponin I in patients undergoing elective coronary artery bypass surgery.

OBJECTIVE: Cardiac troponin I (cTnI) is a highly sensitive and specific marker for postoperative prediction of patients outcome after coronary artery bypass surgery (CABG). Whether preoperatively elevated cTnI levels similarly predict the outcome in patients scheduled for elective CABG is currently unknown. METHODS: Therefore, a possible correlation between preoperative cTnI levels and perioperative major adverse events and in-hospital mortality after CABG was investigated. CTnI was measured within 24h before surgery in 1405 out of 3124 consecutive elective CABG patients. Out of these patients, 1178 had a preoperative cTnI level below 0.1ng/ml (group 1), 163 patients had a cTnI level between 0.11 and 1.5ng/ml (group 2), and 64 patients had a cTnI level above 1.5ng/ml (group 3). CTnI levels, electrocardiograms, clinical data, adverse events and in-hospital mortality were recorded prospectively. Patients with ST-elevation myocardial infarction less than 7 days before surgery were excluded from the study. RESULTS: Perioperative myocardial infarction (PMI) occurred in 69/1178 patients (5.9%) in group 1, 14/163 patients (8.6%; odds ratio (OR) 1.5, 95% confidence interval (CI): 0.8-2.8) in group 2, and 11/64 patients (17.2%; OR 3.3, CI: 1.6-7.0) in group 3 (overall: P<0.001, Cochran-Armitage trend test). Low cardiac output syndrome (LCOS) occurred in 19/1178 patients (1.6%), 9/163 (5.5%; OR 3.6, CI: 1.5-8.5), and 7/64 patients (10.9%; OR 7.5, CI: 2.7-19.8) (overall: P<0.001, group 1 vs. group 2: P<0.002), respectively. In-hospital mortality was 1.7% in group 1 and 3.1% in group 2, but 6.3% (OR 3.9, CI: 1.1-12.5) in group 3 (overall: P<0.01, group 1 vs. group 2: P=NS). Intensive care and hospital stay were significantly longer in group 3 compared to groups 1 and 2. Univariate and multivariate logistic regression analysis confirmed the statistically significant relationship between cTnI and PMI, LCOS and in-hospital mortality, respectively (P<0.001). CONCLUSIONS: Risk stratification by measurement of cTnI levels within 24h before elective CABG clearly identifies a subgroup of patients with increased risk for postoperative adverse outcome and in-hospital mortality.     

Prefrontal cortex dysfunction and depression in atypical parkinsonian syndromes.

Depressive symptoms are common in patients with neurodegenerative disorders. Imaging studies suggest that a disruption of frontal-subcortical pathways may underlie depression associated with basal ganglia disease. This pilot study tested the hypothesis that frontal dysfunction contributes to depression associated with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Depressed patients with MSA (n = 11), PSP (n = 9), and age-matched controls (n = 25) underwent measures of cerebral glucose metabolism applying positron emission tomography with (18)F-fluorodeoxyglucose. Regional metabolism in the patient groups was compared to the normal subjects using the voxel-based statistical parametric mapping. Depressive symptom severity (Hamilton Depression Rating) and degree of locomotor disability (Hoehn & Yahr) were assessed in the patient groups. The association between prefrontal metabolism and the occurrence of depressive symptoms and the degree of locomotor disability was investigated. When compared to controls, MSA patients revealed significant metabolic decreases in bilateral frontal, parietal, and cerebellar cortex and in the left putamen. In PSP patients, significant hypometabolism was demonstrated in bilateral frontal cortex, right thalamus, and midbrain. Depression severity but not the patients' functional condition was significantly associated with dorsolateral prefrontal glucose metabolism in both patient groups. The findings of this pilot study support the hypothesis that depressive symptoms in MSA and PSP are associated with prefrontal dysfunction.     

Calcification and the usual suspect phosphate: still guilty but there are other guys behind the scenes.

In patients with renal failure, the high prevalence of vascular,valvular and soft-tissue calcifications and their consequencesfor cardiovascular outcomes have recently received much attention.Several studies documented that the calcification burden isassociated with increased morbidity and mortality in uraemia.In vitro and in vivo research has demonstrated that tissue calcificationis not just based on passive calcium and phosphate precipitation,but that active cellular processes such as osteogenic differentiationof vascular smooth muscle cells (VSMC) are involved and thata number of local and systemic calcium-regulatory factors controland prevent unwanted extra-osseous calcification. An importantfinding was the new understanding that calcium and phosphateare immediate inducers of osteogenic     

Increased response of renal perfusion to the antioxidant vitamin C in type 2 diabetes.

BACKGROUND: Reactive oxygen species play a major role in the development of endothelial dysfunction. It is as yet unspecified whether increased oxidative stress contributes to endothelial dysfunction of the renal vasculature in patients with type 2 diabetes. METHODS: Renal haemodynamics were studied in 20 patients with type 2 diabetes and arterial hypertension (age 62 +/- 5 years) and 20 non-diabetic hypertensive patients at baseline and following infusions of the nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg); the substrate of nitric oxide synthase, L-arginine (100 mg/kg); and the antioxidant, vitamin C (3 g, co-infused with L-arginine 100 mg/kg). RESULTS: The response of renal plasma flow (RPF) to L-NMMA (-54 +/- 62 and -45 +/- 42 ml/min/1.73 m(2); P = NS) and L-arginine (+46 +/- 36 and +49 +/- 25 ml/min/1.73 m(2); P = NS) was not different between diabetic and non-diabetic patients. In contrast, vitamin C induced a more pronounced increase in RPF in diabetic than in non-diabetic patients when co-infused with L-arginine (+71+/-47 and +43+/-33 ml/min/1.73 m(2); P<0.05). CONCLUSIONS: The difference in the response of renal perfusion to an antioxidant suggests increased formation of reactive oxygen species and thereby reduced nitric oxide bioavailability in the renal vasculature of patients with type 2 diabetes.