56 resultados para 12930-040
Resumo:
Ocular anatomy and radiation-associated toxicities provide unique challenges for external beam radiation therapy. For treatment planning, precise modeling of organs at risk and tumor volume are crucial. Development of a precise eye model and automatic adaptation of this model to patients' anatomy remain problematic because of organ shape variability. This work introduces the application of a 3-dimensional (3D) statistical shape model as a novel method for precise eye modeling for external beam radiation therapy of intraocular tumors.
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Allelic variants of the human P-glycoprotein encoding gene MDR1 (ABCB1) are discussed to be associated with different clinical conditions including pharmacoresistance of epilepsy. However, conflicting data have been reported with regard to the functional relevance of MDR1 allelic variants for the response to antiepileptic drugs. To our knowledge, it is not known whether functionally relevant genetic polymorphisms also occur in the two genes (Mdr1a/Abcb1a, Mdr1b/Abcb1b) coding for P-glycoprotein in the brain of rodents. Therefore, we have started to search for polymorphisms in the Mdr1a gene, which governs the expression of P-glycoprotein in brain capillary endothelial cells in rats. In the kindling model of temporal lobe epilepsy, subgroups of phenytoin-sensitive and phenytoin-resistant rats were selected in repeated drug trials. Sequencing of the Mdr1a gene coding sequence in the subgroups revealed no general differences between drug-resistant and drug-sensitive rats of the Wistar outbred strain. A comparison between different inbred and outbred rat strains also gave no evidence for polymorphisms in the Mdr1a coding sequence. However, in exon-flanking intron sequences, four genetic variants were identified by comparison between these rats strains. In conclusion, the finding that Wistar rats vary in their response to phenytoin, while having the same genetic background, argues against a major impact of Mdr1a genetics on pharmacosensitivity to antiepileptic drugs in the amygdala kindling model.
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Novel magnetic resonance imaging sequences have and still continue to play an increasing role in neuroimaging and neuroscience. Among these techniques, diffusion-weighted imaging (DWI) has revolutionized the diagnosis and management of diseases such as stroke, neoplastic disease and inflammation. However, the effects of aging on diffusion are yet to be determined. To establish reference values for future experimental mouse studies we tested the hypothesis that absolute apparent diffusion coefficients (ADC) of the normal brain change with age. A total of 41 healthy mice were examined by T2-weighted imaging and DWI. For each animal ADC frequency histograms (i) of the whole brain were calculated on a voxel-by-voxel basis and region-of-interest (ROI) measurements (ii) performed and related to the animals' age. The mean entire brain ADC of mice <3 months was 0.715(+/-0.016) x 10(-3) mm2/s, no significant difference to mice aged 4 to 5 months (0.736(+/-0.040) x 10(-3) mm2/s) or animals older than 9 months 0.736(+/-0.020) x 10(-3) mm2/s. Mean whole brain ADCs showed a trend towards lower values with aging but both methods (i + ii) did not reveal a significant correlation with age. ROI measurements in predefined areas: 0.723(+/-0.057) x 10(-3) mm2/s in the parietal lobe, 0.659(+/-0.037) x 10(-3) mm2/s in the striatum and 0.679(+/-0.056) x 10(-3) mm2/s in the temporal lobe. With advancing age, we observed minimal diffusion changes in the whole mouse brain as well as in three ROIs by determination of ADCs. According to our data ADCs remain nearly constant during the aging process of the brain with a small but statistically non-significant trend towards a decreased diffusion in older animals.
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11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is essential for the local activation of glucocorticoid receptors (GR). Unlike unliganded cytoplasmic GR, 11beta-HSD1 is an endoplasmic reticulum (ER)-membrane protein with lumenal orientation. Cortisone might gain direct access to 11beta-HSD1 by free diffusion across membranes, indirectly via intracellular binding proteins or, alternatively, by insertion into membranes. Membranous cortisol, formed by 11beta-HSD1 at the ER-lumenal side, might then activate cytoplasmic GR or bind to ER-lumenal secretory proteins. Compartmentalization of 11beta-HSD1 is important for its regulation by hexose-6-phosphate dehydrogenase (H6PDH), which regenerates cofactor NADPH in the ER lumen and stimulates oxoreductase activity. ER-lumenal orientation of 11beta-HSD1 is also essential for the metabolism of the alternative substrate 7-ketocholesterol (7KC), a major cholesterol oxidation product found in atherosclerotic plaques and taken up from processed cholesterol-rich food. An 11beta-HSD1 mutant adopting cytoplasmic orientation efficiently catalyzed the oxoreduction of cortisone but not 7KC, indicating access to cortisone from both sides of the ER-membrane but to 7KC only from the lumenal side. These aspects may be relevant for understanding the physiological role of 11beta-HSD1 and for developing therapeutic interventions to control glucocorticoid reactivation.
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BACKGROUND AND OBJECTIVE: The decision to maintain intensive treatment in cardiac surgical patients with poor initial outcome is mostly based on individual experience. The risk scoring systems used in cardiac surgery have no prognostic value for individuals. This study aims to assess (a) factors possibly related to poor survival and functional outcomes in cardiac surgery patients requiring prolonged (> or = 5 days) intensive care unit (ICU) treatment, (b) conditions in which treatment withdrawal might be justified, and (c) the patient's perception of the benefits and drawbacks of long intensive treatments. METHODS: The computerized data prospectively recorded for every patient in the intensive care unit over a 3-year period were reviewed and analyzed (n=1859). Survival and quality of life (QOL) outcomes were determined in all patients having required > or =5 consecutive days of intensive treatment (n=194/10.4%). Long-term survivors were interviewed at yearly intervals in a standardized manner and quality of life was assessed using the dependency score of Karnofsky. No interventions or treatments were given, withhold, or withdrawn as part of this study. RESULTS: In-hospital, 1-, and 3-year cumulative survival rates reached 91.3%, 85.6%, and 75.1%, respectively. Quality of life assessed 1 year postoperatively by the score of Karnofsky was good in 119/165 patients, fair in 32 and poor in 14. Multivariate logistic regression analysis of 19 potential predictors of poor outcome identified dialysis as the sole factor significantly (p=0.027) - albeit moderately - reducing long-term survival, and sustained neurological deficit as an inconstant predictor of poor functional outcome (p=0.028). One year postoperatively 0.63% of patients still reminded of severe suffering in the intensive station and 20% of discomfort. Only 7.7% of patients would definitely refuse redo surgery. CONCLUSIONS: This study of cardiac surgical patients requiring > or =5 days of intensive treatment did not identify factors unequivocally justifying early treatment limitation in individuals. It found that 1-year mortality and disability rates can be maintained at a low level in this subset of patients, and that severe suffering in the ICU is infrequent.
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The recommended dose (bolus 0.4 mg/kg followed by 0.15 mg/kg per hour) of lepirudin, a direct thrombin inhibitor licensed for treatment of heparin-induced thrombocytopenia (HIT), is too high. Starting in 2001, we omitted the bolus and reduced maintenance dose by at least one-third. Analyzing 53 HIT patients treated between January 2001 and February 2007, we observed that therapeutic anticoagulation intensity already 4 hours after lepirudin start had been reached with the following initial lepirudin doses (median): 0.078 mg/kg per hour [creatinine clearance (CrCl) more than 60 mL/min], 0.040 mg/kg per hour (CrCl 30-60 mL/min), and 0.013 mg/kg per hour (CrCl < 30 mL/min). The efficacy of this treatment was documented by increasing platelets and decreasing D-dimers. Based on this experience, we derived a lepirudin dosing regimen, which was prospectively evaluated treating 15 HIT patients between March 2007 and February 2008. We show that omitting the initial lepirudin bolus and administering 0.08 mg/kg per hour in patients with CrCl more than 60 mL/min, 0.04 mg/kg per hour in patients with CrCl 30-60 mL/min, and 0.01 to 0.02 mg/kg per hour in those with CrCl less than 30 mL/min is efficacious and safe, as documented by increasing platelet counts, decreasing D-dimer levels, and rare thrombotic (1 of 46) and major bleeding (4 of 46) complications.
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This randomized trial compared procedural complications and 30-day clinical outcomes of 3 patent foramen ovale (PFO) closure devices (Amplatzer, Helex, and CardioSEAL-STARflex). It examined 660 patients (361 men, 299 women, mean age 49.3+/-1.9 years), with 220 patients per group. All patients had a history of paradoxical embolism. All PFO closures were successful technically. Exchange of devices for others was most frequently required for the Helex occluder (7 of 220) and 2 of 220 in either of the other groups. Three device embolizations in the Helex group were retrieved and replaced successfully. One patient with a Helex occluder developed a transient ischemic attack and recovered without treatment. A hemopericardium in that group was punctured without affecting the device. One tamponade in the Amplatzer group required surgical device explantation. In 8 of 660 patients in the CardioSEAL-STARflex group, thrombi resolved after anticoagulation. Sixteen patients (11 in the CardioSEAL-STARflex group, 3 in the Amplatzer group, and 2 in the Helex group) had episodes of atrial fibrillation. PFOs were closed completely in 143 of 220 patients (65%) in the Amplatzer group, 116 of 220 patients (52.7%) in the Helex group, and 137 of 220 patients (62.3%) in the CardioSEAL-STARflex group at 30 days with significant differences between the Helex and Amplatzer occluders (p=0.0005) and the Helex and CardioSEAL-STARflex occluders (p=0.0003). PFO closure can be performed safely with each device. In conclusion, the Helex occluder embolized more frequently. Device thrombus formation and paroxysmal atrial fibrillation were more common with the CardioSEAL-STARflex occluder.
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OBJECTIVE: The burnout syndrome has been associated with an increased risk of cardiovascular disease. The physiological mechanisms potentially involved in this link are underexplored. Knowing that a chronic low-grade systemic inflammatory state contributes to atherosclerosis, we investigated circulating cytokine levels in relation to burnout symptoms. METHODS: We studied 167 schoolteachers (median, 48 years; range, 23-63 years; 67% women) who completed the Maslach Burnout Inventory with its three subscales emotional exhaustion (EE), lack of accomplishment (LA), and depersonalization (DP). Levels of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha and of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10 were determined in fasting morning plasma samples. The TNF-alpha/IL-4 ratio and the TNF-alpha/IL-10 ratio were computed as two indices of increased inflammatory activity. Analyses were adjusted for demographic factors, medication, lifestyle factors (including sleep quality), metabolic factors, and symptoms of depression and anxiety. RESULTS: Higher levels of total burnout symptoms aggregating the EE, LA, and DP subscales independently predicted higher TNF-alpha levels (DeltaR(2)=.024, P=.046), lower IL-4 levels (DeltaR(2)=.021, P=.061), and a higher TNF-alpha/IL-4 ratio (DeltaR(2)=.040, P=.008). Higher levels of LA predicted decreased IL-4 levels (DeltaR(2)=.041, P=.008) and a higher TNF-alpha/IL-4 ratio (DeltaR(2)=.041, P=.007). The categorical dimensions of the various burnout scales (e.g., burnout yes vs. no) showed no independent relationship with any cytokine measure. CONCLUSION: Burnout was associated with increased systemic inflammation along a continuum of symptom severity rather than categorically. Given that low-grade systemic inflammation promotes atherosclerosis, our findings may provide one explanation for the increased cardiovascular risk previously observed in burned-out individuals.
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BACKGROUND: Psychological factors are important in the etiology and prognosis of coronary heart disease (CHD). Cardiac rehabilitation (CR) aims to reduce psychological distress, besides other somatic risk factors. Studies have shown that CR is effective in reducing psychological distress, but little is known about gender-specific outcome differences. Our objective was to examine whether women and men benefit equally from outpatient CR in terms of reduction in psychological distress and whether women show more impaired psychological health at baseline of CR than do men. METHODS: We enrolled 441 CHD patients (mean age 58+/-11 years, 79.8% men) who underwent a 12-week outpatient CR program. Psychological dimensions, namely, anxiety, depression, vital exhaustion, social inhibition, and negative affect, were assessed at baseline and post-CR. Multivariate analysis of variance (MANOVA), controlling for age, disease severity, and exercise capacity, was applied to test for gender-specific differences at baseline and change between baseline and post-CR. In addition, gender-specific effect sizes were calculated for the change on psychological dimensions. RESULTS: Women and men did not differ on any psychological measure at baseline of CR. The effect sizes show small to moderate treatment effects on the psychological dimensions assessed. Gender had a significant impact on change on the dimensions vital exhaustion (F=5.040(df=1), p<0.05) and social inhibition (F=5.74(df=1), p<0.05). Women showed larger change on social inhibition and smaller change on vital exhaustion than men. CONCLUSIONS: Women and men do not differ in the extent of psychological distress at baseline of CR, which could be explained also by the exclusion of highly distressed women from treatment. CR is less effective among women with regard to vital exhaustion and more effective with regard to social inhibition compared with men in a sample of low distressed patients.
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BACKGROUND: The traditional approach to stable blunt thoracic aortic injuries (TAI) is immediate repair, with delayed repair reserved for patients with major associated injuries. In recent years, there has been a trend toward delayed repair, even in low-risk patients. This study evaluates the current practices in the surgical community regarding the timing of aortic repair and its effects on outcomes. METHODS: This was a prospective, observational multicenter study sponsored by the American Association for the Surgery of Trauma. The study included patients with blunt TAI scheduled for aortic repair by open or endovascular procedure. Patients in extremis and those managed without aortic repair were excluded. The data collection included demographics, initial clinical presentation, Injury Severity Scores, type and site of aortic injury, type of aortic repair (open or endovascular repair), and time from injury to aortic repair. The study patients were divided into an early repair (< or = 24 hours) and delayed repair groups (> 24 hours). The outcome variables included survival, ventilator days, intensive care unit (ICU) and hospital lengths of stay, blood transfusions, and complications. The outcomes in the two groups were compared with multivariate analysis after adjusting for age, Glasgow Coma Scale, hypotension, major associated injuries, and type of aortic repair. A second multivariate analysis compared outcomes between early and delayed repair, in patients with and patients without major associated injuries. RESULTS: There were 178 patients with TAI eligible for inclusion and analysis, 109 (61.2%) of which underwent early repair and 69 (38.8%) delayed repair. The two groups had similar epidemiologic, injury severity, and type of repair characteristics. The adjusted mortality was significantly higher in the early repair group (adjusted OR [95% CI] 7.78 [1.69-35.70], adjusted p value = 0.008). The adjusted complication rate was similar in the two groups. However, delayed repair was associated with significantly longer ICU and hospital lengths of stay. Analysis of the 108 patients without major associated injuries, adjusting for age, Glasgow Coma Scale, hypotension, and type of aortic repair, showed that in early repair there was a trend toward higher mortality rate (adjusted OR 9.08 [0.88-93.78], adjusted p value = 0.064) but a significantly lower complication rate (adjusted OR 0.4 [0.18-0.96], adjusted p value 0.040) and shorter ICU stay (adjusted p value = 0.021) than the delayed repair group. A similar analysis of the 68 patients with major associated injuries, showed a strong trend toward higher mortality in the early repair group (adjusted OR 9.39 [0.93-95.18], adjusted p value = 0.058). The complication rate was similar in both groups (adjusted p value = 0.239). CONCLUSIONS: Delayed repair of stable blunt TAI is associated with improved survival, irrespective of the presence or not of major associated injuries. However, delayed repair is associated with a longer length of ICU stay and in the group of patients with no major associated injuries a significantly higher complication rate.
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BACKGROUND: Atraumatic splenic rupture (ASR) is an ill defined clinicopathological entity. METHODS: The aim was to characterize aetiological and risk factors for ASR-related mortality in order to aid disease classification and treatment. A systematic literature review (1980-2008) was undertaken and logistic regression analysis employed. RESULTS: Some 632 publications reporting 845 patients were identified. The spleen was normal in 7.0 per cent (atraumatic-idiopathic rupture). One, two or three aetiological factors were found in 84.1, 8.2 and 0.7 per cent respectively (atraumatic-pathological rupture). Six major aetiological groups were defined: neoplastic (30.3 per cent), infectious (27.3 per cent), inflammatory, non-infectious (20.0 per cent), drug- and treatment-related (9.2 per cent) and mechanical (6.8 per cent) disorders, and normal spleen (6.4 per cent). Treatment comprised total splenectomy (84.1 per cent), organ-preserving surgery (1.2 per cent) or conservative measures (14.7 per cent). The ASR-related mortality rate was 12.2 per cent. Splenomegaly (P = 0.040), age above 40 years (P = 0.007) and neoplastic disorders (P = 0.008) were associated with increased ASR-related mortality on multivariable analysis. CONCLUSION: The condition can be classified simply into atraumatic-idiopathic (7.0 per cent) and atraumatic-pathological (93.0 per cent) splenic rupture. Splenomegaly, advanced age and neoplastic disorders are associated with increased ASR-related mortality.
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Differential expression of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban (PLB) has been shown in heart failure and atrial arrhythmias. We investigated the influence of volume overload and age on their expression in pediatric atrial myocardium. Right atrial specimens from 18 children with volume overloaded right atrium (VO) and 12 patients without overload were studied. Each group was further divided into patients less than and older than 12 months of age. Only in the younger patients SERCA2a was significantly reduced in the VO group. In younger patients PLB mRNA level tended to be lower in VO. The PLB:SERCA protein ratio was significantly reduced in the VO group. Age itself did not influence the SERCA2a and PLB expression, if the hemodynamic overload was not taken into account. This study is the first to show a combined influence of volume overload and age on atrial SERCA2a expression.
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Five cases of fatal babesiosis in free-ranging chamois (Rupicapra r. rupicapra) attributed to infections with Babesia capreoli were recently recorded in two regions of the Swiss Alps. To investigate the ecologic factors that possibly lead to those fatal B. capreoli infections in chamois, blood, ticks, and demographic data of 46 roe deer (Capreolus c. capreolus), 48 chamois, and nine red deer (Cervus elaphus) were collected in 2006 and 2007 in both affected regions. Whereas no parasitic inclusions were found by microscopical examination of blood smears, B. capreoli was identified by polymerase chain reaction/sequencing in blood of 12 roe deer (26%, 95% confidence interval [CI]: 14.3-41.1), one chamois (2%, CI: 0-6.1), and one red deer (11%, CI: 0.3-48.2). Prevalence of B. capreoli was significantly higher in roe deer compared with chamois (P<0.001). All 214 ticks were identified as Ixodes ricinus, and significantly more roe deer (63%, CI: 47.5-76.8) were infested compared with chamois (21%, CI: 10.5-35.0, P<0.001). Overall, prevalences of both tick infestation and Babesia infection increased significantly (P<0.001) with decreasing altitude, and Babesia-positive samples were detected significantly more often from animals with tick infestation compared with animals without ticks (P = 0.040). Our results indicate that roe deer may play an important reservoir role for B. capreoli. It is hypothesized that the expansion of the presumed vector I. ricinus to higher elevations and its increased abundance in overlapping habitats of roe deer and chamois may favor the spillover of B. capreoli from roe deer to chamois.