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Biomedical subjects

Michael Schmidt

Publications and source records attributed to Michael Schmidt.

At least 19 recordsLinked to original sources
PubMed2006

Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small-cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group.

PURPOSE: The aim of this study was to examine whether, after preceding induction chemotherapy, simultaneous chemoradiotherapy is superior to radiotherapy alone. PATIENTS AND METHODS: Patients with non-small-cell lung cancer in inoperable stage IIIA or IIIB received induction chemotherapy with two cycles of paclitaxel 200 mg/m2 and carboplatin area under the curve 6 every 3 weeks. Patients without progression at restaging after induction chemotherapy were randomly assigned to radiotherapy (60 Gy) or chemoradiotherapy (paclitaxel 60 mg/m2 weekly). The primary end point was overall survival; secondary end points were time to progression, response, and toxicity. RESULTS: Three hundred three patients entered the study, and 276 completed induction chemotherapy. Two hundred fourteen patients were randomly assigned (radiotherapy alone: n = 113; simultaneous chemoradiotherapy: n = 101). Median follow-up time of all randomly assigned patients was 13.6 months (interquartile range [IQR], 6.4 to 29.0 months), and median follow-up time of the subgroup of censored patients (n = 52) was 37.4 months (IQR, 5.9 to 57.0 months; maximum, 76.1 months). Toxicities during the induction phase were mild. During radiotherapy, overall toxicity rates were not significantly different between the two arms. Median survival times in the radiotherapy group and chemoradiotherapy group were 14.1 months (95% CI, 11.8 to 16.3 months) and 18.7 months (95% CI, 14.1 to 23.3 months; difference not statistically significant, P = .091). Median time to progression significantly favored simultaneous chemoradiotherapy (11.5 months; 95% CI, 8.3 to 14.7 months) versus radiotherapy alone (6.3 months; 95% CI, 5.0 to 7.6 months; P < .001, log-rank test). CONCLUSION: Induction chemotherapy followed by chemoradiotherapy with weekly paclitaxel is feasible. Response, time to progression, and survival favor chemoradiotherapy compared with radiotherapy alone.

Aged↗
PubMed2006

Oral vinorelbine and cisplatin with concomitant radiotherapy in stage III non-small cell lung cancer (NSCLC): a feasibility study.

BACKGROUND: Concurrent chemoradiotherapy has improved survival in inoperable stage III non-small cell lung cancer (NSCLC). This phase I trial was performed in order to establish a dose recommendation for oral vinorelbine in combination with cisplatin and simultaneous radiotherapy. PATIENTS AND METHODS: Previously untreated patients with stage IIIB NSCLC received concurrent chemoradiotherapy with 66 Gy and 2 cycles of cisplatin and oral vinorelbine which was administered at 3 different levels (40, 50 and 60 mg/m2). This was to be followed by 2 cycles of cisplatin/ vinorelbine oral consolidation chemotherapy. The study goal was to determine the maximal recommended dose of oral vinorelbine during concurrent treatment. RESULTS: 11 stage IIIB patients were entered into the study. The median radiotherapy dose was 66 Gy. Grade 3-4 toxicity included neutropenia, esophagitis, gastritis and febrile neutropenia. The dose-limiting toxicity for concurrent chemoradiotherapy was esophagitis. 9 patients received consolidation chemotherapy, with neutropenia and anemia/thrombocytopenia grade 3 being the only toxicities. The overall response was 73%. CONCLUSION: Oral vinorelbine 50 mg/m2 (days 1, 8, 15 over 4 weeks) in combination with cisplatin 20 mg/m2 (days 1-4) is the recommended dose in combination with radiotherapy (66 Gy) and will be used for concurrent chemoradiotherapy in a forthcoming phase III trial testing the efficacy of consolidation chemotherapy in patients not progressing after chemoradiotherapy.

Administration, Oral↗
PubMed2006

Hepatitis B virus genotype G monoinfection and its transmission by blood components.

An acute hepatitis B virus (HBV) infection was diagnosed in a regular apheresis (plasma/platelet) donor by the hepatitis B surface antigen (HBsAg) assay and minipool nucleic acid amplification technology (NAT). The acute infection was confirmed by detection of anti-HBc (IgM) and anti-HBs 2 weeks later. The donor showed no clinical symptoms and had normal alanine aminotransferase levels. He had a history of weekly apheresis plasma or platelet donations. Archived material from the donor and the respective recipients was investigated by sensitive HBV NATs as part of a look-back procedure. HBV DNA was detectable in previous donations as well as in two recipients transfused with platelet concentrates. The rare HBV genotype G was identified in all HBV-DNA-positive samples. Strong evidence of genotype G monoinfection was obtained by clonal sequencing, HBV genotype line probe assay, genotype-specific NATs, and restriction pattern analysis. In contrast to previously described genotype G infections, which all appeared as coinfections with genotype A, neither the hepatitis B e antigen (HBeAg) nor anti-HBe was detectable in any of the samples. This shows that HBeAg is dispensable for viral replication. The delay in detecting HBsAg in both the donor and recipient samples may be explained by either decreased genotype G-specific synthesis of incomplete viral forms in early HBV infection or the lower sensitivity to genotype G of the current HBsAg assays. In conclusion, this reported case of an HBV infection was caused exclusively by genotype G.

Acute Disease↗
PubMed2006

Stress doses of hydrocortisone reduce chronic stress symptoms and improve health-related quality of life in high-risk patients after cardiac surgery: a randomized study.

OBJECTIVES: Improvement in health-related quality of life is a major object of cardiac surgery. However, high stress exposure during the perioperative period of cardiac surgery can result in the formation of traumatic memories and symptoms of chronic stress or even posttraumatic stress disorder, which can have negative effects on health-related quality-of-life outcome. In this controlled study we examined whether exogenously administered stress doses of hydrocortisone during cardiac surgery reduce perioperative stress exposure and the long-term incidence of chronic stress symptoms and improve health-related quality of life after cardiac surgery. METHODS: Thirty-six high-risk patients undergoing cardiac surgery were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Of 28 available patients at 6 months after cardiac surgery, 14 had received hydrocortisone, and 14 had received placebo. Traumatic memories, chronic stress symptoms (posttraumatic stress disorder scores), and health-related quality of life were measured by using validated questionnaires. RESULTS: Compared with patients from the placebo group, patients from the hydrocortisone group had a significantly shorter duration of intensive care unit treatment, required lower doses of the stress hormone norepinephrine during cardiac surgery, and had significantly fewer stress symptoms and a better health-related quality of life regarding physical function, chronic pain, general health, vitality, and mental health during follow-up. The groups did not differ with regard to the number or type of intensive care unit-related traumatic memories. CONCLUSIONS: The use of stress doses of hydrocortisone in high-risk cardiac surgical patients reduces perioperative stress exposure, decreases chronic stress symptoms, and improves health-related quality of life at 6 months after cardiac surgery.

Aged↗
PubMed2006

Effects of general anesthesia on anandamide blood levels in humans.

BACKGROUND: The endocannabinoid system includes G-protein-coupled cannabinoid receptors, the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and multiple enzymes involved in the biosynthesis and degradation of endocannabinoids, including the anandamide metabolizing enzyme fatty acid amide hydrolase. Endocannabinoids play an important role in the physiologic control of sleep, pain processing, and emesis. The authors therefore investigated the effects of general anesthesia on the endocannabinoid system in humans. METHODS: The authors measured whole blood levels of anandamide in 12 patients after induction of general anesthesia with etomidate (an agent shown to have no effect on anandamide levels) and maintenance of anesthesia with the volatile agent sevoflurane as well as in 12 patients undergoing total intravenous anesthesia with propofol, a known inhibitor of fatty acid amide hydrolase in the mouse brain. Anandamide levels were measured using high-performance liquid chromatography-tandem mass spectrometry at four time points (before and at 10, 20, 30, and 40 min after induction of anesthesia). RESULTS: Patients of the sevoflurane group showed a significant decline in anandamide levels from induction of anesthesia to 40 min after induction, whereas anandamide levels in patients of the propofol group remained unchanged (type III sum of squares = 1725.66, F = 162.60, P < 0.001, repeated-measures analysis of variance). CONCLUSION: General anesthesia influences the endocannabinoid system in a drug-dependent way, which may explain side effects of general anesthetics such as psychomimetic and antiemetic properties of propofol and the high incidence of postoperative nausea and vomiting after volatile anesthetics. These findings suggest new targets for anesthetic drug development.

Aged↗
PubMed2006

A comparison of three rapid bacterial detection methods under simulated real-life conditions.

BACKGROUND: Bacterial screening of all produced platelet concentrates (PCs) is implemented in many countries to reduce the risk of transfusion-transmitted sepsis. This study compares three rapid bacterial detection methods by imitating real-life conditions. STUDY DESIGN AND METHODS: The sensitivity of a solid-phase scanning cytometer (optimized Scansystem, Hemosystem), fluorescence-activated cell sorting (FACS) analysis, and 16S RNA in-house nucleic acid testing (NAT) was evaluated by spiking PCs with four transfusion relevant bacteria (Staphylococcus aureus, Bacillus cereus, Klebsiella pneumoniae, and Escherichia coli ). Two different inocula (10 colony-forming units [CFUs]/mL and 10 CFUs/bag) were used to simulate real-life conditions. Samples were taken at 12, 16, 20, and 24 hours after spiking. RESULTS: With the high inoculum, NAT had a 100 percent rate of positive testing for all four types of bacteria (10/10 replicates) at each time point. With the exception of E. coli, the sensitivity of FACS and optimized Scansystem was comparable for the high inoculum. With the low inoculum, 60 percent of E. coli, 80 percent of B. cereus, 90 percent of K. pneumoniae, and 100 percent of S. aureus were NAT-positive 12 hours after spiking. In contrast, only 20 percent of E. coli, 10 percent of B. cereus, and 70 percent of K. pneumoniae were FACS-positive with the low inoculum 12 hours after spiking. CONCLUSIONS: In summary, the preliminary data revealed a higher sensitivity for NAT in comparison to FACS and optimized Scansystem under the defined study conditions. To imitate real-life conditions, further spiking studies with a low inoculum (10 CFUs/bag) and slower growing organisms should be conducted to examine the sensitivity of available detection systems.

Bacterial Infections↗
PubMed2006

Gangliosides are essential for bovine adeno-associated virus entry.

Recombinant adeno-associated viruses (AAV) are promising gene therapy vectors. We have recently identified a bovine adeno-associated virus (BAAV) that demonstrates unique tropism and transduction activity compared to primate AAVs. To better understand the entry pathway and cell tropism of BAAV, we have characterized the initial cell surface interactions required for transduction with BAAV vectors. Like a number of AAVs, BAAV requires cell surface sialic acid groups for transduction and virus attachment. However, glycosphingolipids (GSLs), not cell surface proteins, were required for vector entry and transduction. Incorporation of gangliosides, ceramide-based glycolipids containing one or more sialic acid groups, into the cytoplasmic cell membranes of GSL-depleted COS cells partially reconstituted BAAV transduction. The dependency of BAAV on gangliosides for transduction was further confirmed by studies with C6 cells, a rat glioma cell line that is deficient in the synthesis of complex gangliosides. C6 cells were resistant to transduction by BAAV. Addition of gangliosides to C6 cells prior to transduction rendered the cells susceptible to transduction by BAAV. Therefore, gangliosides are a likely receptor for BAAV.

Animals↗
PubMed2006

Identification and characterization of novel adeno-associated virus isolates in ATCC virus stocks.

Adeno-associated viruses (AAVs) depend on a helper virus for efficient replication. To identify novel AAV isolates, we screened a diverse set of virus isolates for the presence of AAV DNA. AAVs found in 10 simian adenovirus isolates showed greater than 96% homology to AAV1 and AAV6 but had distinct biological properties. Two representatives of this group, AAV(VR-195) and AAV(VR-355), were studied in more detail. While the novel AAVs had high sequence homologies and required sialic acid for cell binding and transduction, differences were observed in lectin competition, resulting in distinct tropisms in human cancer cell lines.

Capsid Proteins↗
PubMed2006

Prognostic significance of continuous EEG monitoring in patients with poor-grade subarachnoid hemorrhage.

INTRODUCTION: Predicting outcome in patients with poor-grade subarachnoid hemorrhage (SAH) may help guide therapy and assist in family discussions. The objective of this study was to determine if continuous electroencephalogram (cEEG) monitoring results are predictive of 3-month outcome in critically ill patients with SAH. METHODS: We prospectively studied 756 patients with SAH over a 7-year period. Functional outcome was assessed at 3 months with the modified Rankin Scale (mRS). Patients that underwent cEEG monitoring were retrospectively identified and EEG findings were collected. Multivariate logistic regression analysis was performed to identify EEG findings associated with poor outcome, defined as mRS 4 to 6 (dead or moderately to severely disabled). RESULTS: In 116 patients with SAH, cEEG monitoring and 3-month mRS were available. Of these patients, 88% had a Hunt & Hess grade of 3 or worse on admission. After controlling for age, Hunt & Hess grade, and presence of intraventricular hemorrhage on admission CT scan, poor outcome was associated with the absence of sleep architecture (80 versus 47%; odds ratio [OR] 4.3, 95%-confidence interval [CI] 1.1-17.2) and the presence of periodic lateralized epileptiform discharges (PLEDS) (91 versus 66% OR 18.8, 95%-CI 1.6-214.6). In addition, outcome was poor in all patients with absent EEG reactivity (n = 8), generalized periodic epileptiform discharges (n = 12), or bilateral independent PLEDs (n = 5), and in 92% (11 of 12) of patients with nonconvulsive status epilepticus. CONCLUSIONS: cEEG monitoring provides independent prognostic information in patients with poor-grade SAH, even after controlling for clinical and radiological findings. Unfavorable findings include periodic epileptiform discharges, electrographic status epilepticus, and the absence of sleep architecture.

Cohort Studies↗
PubMed2005

Hyperglycemia after SAH: predictors, associated complications, and impact on outcome.

BACKGROUND AND PURPOSE: Hyperglycemia is common after subarachnoid hemorrhage (SAH). The extent to which prolonged hyperglycemia contributes to in-hospital complications and poor outcome after SAH is unknown. METHODS: We studied an inception cohort of 281 SAH patients with an initial serum glucose level obtained within 3 days of SAH onset and who had at least 7 daily glucose measurements between SAH days 0 and 10. We defined mean glucose burden (GB) as the average peak daily glucose level >5.8 mmol/L (105 mg/dL). Hospital complications were recorded prospectively, and 3-month outcome was assessed with the modified Rankin scale. RESULTS: The median GB was 1.8 mmol/L (33 mg/dL). Predictors of high-GB included age > or =54 years, Hunt and Hess grade III-V, poor Acute Physiology and Chronic Health Evaluation (APACHE)-2 physiological subscores, and a history of diabetes mellitus (all P< or =0.001). In a multivariate analysis, GB was associated with increased intensive care unit length of stay (P=0.003) and the following complications: congestive heart failure, respiratory failure, pneumonia, and brain stem compression from herniation (all P<0.05). After adjusting for Hunt-Hess grade, aneurysm size, and age, GB was an independent predictor of death (odds ratio, 1.10 per mmol/L; 95% CI, 1.01 to 1.21; P=0.027) and death or severe disability (modified Rankin scale score of 4 to 6; odds ratio, 1.17 per mmol/L; 95% CI 1.07 to 1.28, P<0.001). CONCLUSIONS: Hyperglycemia after SAH is associated with serious hospital complications, increased intensive care unit length of stay, and an increased risk of death or severe disability.

Adult↗
PubMed2005

Linkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing.

OBJECTIVES: Describe the inflation in nonparametric multipoint LOD scores due to inter-marker linkage disequilibrium (LD) across many markers with varied allele frequencies. METHOD: Using simulated two-generation families with and without parents, we conducted nonparametric multipoint linkage analysis with 2 to 10 markers with minor allele frequencies (MAF) of 0.5 and 0.1. RESULTS: Misspecification of population haplotype frequencies by assuming linkage equilibrium caused inflated multipoint LOD scores due to inter-marker LD when parental genotypes were not included. Inflation increased as more markers in LD were included and decreased as markers in equilibrium were added. When marker allele frequencies were unequal, the r2 measure of LD was a better predictor of inflation than D'. CONCLUSION: This observation strongly supports the evaluation of LD in multipoint linkage analyses, and further suggests that unaccounted for LD may be suspected when two-point and multipoint linkage analyses show a marked disparity in regions with elevated r2 measures of LD. Given the increasing popularity of high-density genome-wide SNP screens, inter-marker LD should be a concern in future linkage studies.

Computer Simulation↗
PubMed2005

A shortened adeno-associated virus expression cassette for CFTR gene transfer to cystic fibrosis airway epithelia.

Adeno-associated viruses (AAVs) such as AAV5 that transduce airway epithelia from the apical surface are attractive vectors for gene transfer in cystic fibrosis (CF). However, their utility in CF has been limited because packaging of the insert becomes inefficient when its length exceeds approximately 4,900-5,000 bp. To partially circumvent this size constraint, we previously developed a CF transmembrane conductance regulator (CFTR) transgene that deleted a portion of the R domain (CFTRDeltaR). In this study, we focused on shortening the other elements in the AAV expression cassette. We found that portions of the CMV immediate/early (CMVie) enhancer/promoter could be deleted without abolishing activity. We also tested various intervening sequences, poly(A) signals, and an intron to develop an expression cassette that meets the size restrictions imposed by AAV. We then packaged these shortened elements with the CFTRDeltaR transgene into AAV5 and applied them to the apical surface of differentiated CF airway epithelia. Two to 4 weeks later, the AAV5 vectors partially corrected the CF Cl(-) transport defect. These results demonstrate that a single AAV vector can complement the CF defect in differentiated airway epithelia and thereby further the development of effective CF gene transfer.

Cells, Cultured↗
PubMed2005

Cluster B personality disorders are associated with allelic variation of monoamine oxidase A activity.

Genetic variants of the monoamine oxidase A (MAOA) have been associated with aggression-, anxiety-, and addiction-related behavior in several nonclinical and clinical populations. Here, we investigated the influence of allelic variation of MAOA activity on aggression-related personality traits and disease risk in patients with personality disorders. Personality disorders were diagnosed with the Structured Clinical Interview of DSM-IV and were allocated to cluster A, B, and C. Personality features were assessed by the revised NEO Personality Inventory and the Tridimensional Personality Questionnaire. The genotype of the MAOA gene-linked polymorphic region (MAOA-LPR) was determined in 566 patients with personality disorders and in 281 healthy controls. MAOA genotype was significantly associated with cluster B personality disorders (chi2=7.77, p=0.005, df=1) but not with cluster C personality disorders. In total, 26.0% of cluster B patients were hemi- or homozygous for the low-activity variant of the MAOA genotype, compared to 16.4% in the control group. Associations between MAOA variants and personality domains related to impulsivity and aggressiveness were inconsistent. Our findings further support the notion that allelic variation of MAOA activity contributes modestly to the balance of hyper- (impulsive-aggressive) and hyporeactive (anxious-depressive) traits.

Adolescent↗
PubMed2005

Functional and metabolic recovery of the right ventricle during Bosentan therapy in idiopathic pulmonary arterial hypertension.

An impaired high-energy phosphate metabolism might play a critical role in the pathogenesis of right ventricular (RV) failure due to chronic pulmonary arterial hypertension (PAH). 31P-NMR spectroscopy is well established for measurements of high-energy phosphate metabolites in various left ventricular heart diseases, however, mainly for technical and sensitivity reasons, its successful transfer for measurements in the RV is currently missing. In the present study, the usefulness of this non-invasive approach is not only shown in RV failure due to PAH but also tested during subsequent therapy.

Antihypertensive Agents↗
PubMed2005

Xenon attenuates cerebral damage after ischemia in pigs.

BACKGROUND: Cerebral blood flow may be compromised in a variety of anesthetic procedures, and ischemic cerebral complications represent the leading cause of morbidity after cardiac operations. With the growing importance of neuroprotective strategies, the current study was designed to determine whether xenon would attenuate cardiac arrest-induced brain injury in pigs. METHODS: Twenty-four pigs (aged 12-16 weeks) were investigated in a randomized design. General hemodynamics, intracranial pressure, brain tissue oxygenation, and cerebral microdialysis parameters were investigated. The animals were assigned to two groups to receive anesthesia with either xenon (75%) in oxygen (25%) or total intravenous anesthesia combined with air in oxygen (25%) ventilation 15 min before cardiac arrest. After induction (t0) of cardiac arrest of 4 min, cardiopulmonary resuscitation was performed for 1 min, and the induced ventricular fibrillation was terminated by electrical defibrillation. The investigation time was 240 min. RESULTS: Approximately 60 s after cardiac arrest, brain tissue oxygenation decreased to a critical level of less than 5 mmHg, paralleled by a decrease in electroencephalographic activity. Glycerol as a damage marker increased significantly (> 200 m; P < 0.05), with a peak 90 min after cardiac arrest in both groups. Glycerol concentrations during reperfusion were significantly lower and normalized faster in the xenon group as compared with the total intravenous anesthesia group. CONCLUSION: Although the primary ischemic lesion in this model was similar in both groups, the cerebral microdialysis data show that xenon induces a differential neurochemical benefit in cerebral cell damage and metabolism as compared with total intravenous anesthesia in vivo during cerebral reperfusion after cardiac arrest in a pig model.

Anesthesia, Intravenous↗
PubMed2005

High-resolution whole-body magnetic resonance image tumor staging with the use of parallel imaging versus dual-modality positron emission tomography-computed tomography: experience on a 32-channel system.

OBJECTIVE: The objective of this study was to compare the accuracy in staging of various malignant tumors with whole-body magnetic resonance imaging (WB-MRI) using parallel imaging (PAT) and positron emission tomography-computed tomography (PET-CT). MATERIALS AND METHODS: In a prospective study, 41 patients withoncologic diseases underwent [F]-fluoro-2-deoxy-D-glucose PET-CT for tumor staging and WB-MRI on a 32-channel-scanner with the use of PAT. Coronal T1w and STIR sequences at 5 body levels, axial HASTE imaging of the lung, and contrast-enhanced T1w sequences of the liver, brain, and abdomen were performed. TNM stage was assessed for both modalities in a separate consensus reading using histologic results and radiologic follow up within 6 months as the standard of reference. RESULTS: Three primary and 4 recurrent tumors were detected; one recurrent tumor was missed with WB-MRI. Sixty benign and 60 malignant lymph nodes were detected with a sensitivity of 98% and specificity of 83% for PET-CT and 80%/75% for WB-MRI, respectively. One hundred ninety-one malignant and 77 benign distant lesions were detected with a sensitivity/specificity of 82% for PET-CT and 96%/82% for WB-MRI. Accuracy for correct TNM staging was 96% for PET-CT and 91% for WB-MRI. CONCLUSION: WB-MRI and PET-CT are reliable imaging modalities for tumor staging. WB-MRI is highly sensitive in detecting distant metastases; PET-CT is superior in lymph node staging. PAT makes high-resolution WB-MRI feasible within less than 1 hour.

Adult↗
PubMed2005

Optimized Scansystem platelet kit for bacterial detection with enhanced sensitivity: detection within 24 h after spiking.

BACKGROUND AND OBJECTIVES: The prevention and detection of bacterial contamination of platelet concentrates remains a major challenge for transfusion medicine. To be suitable for blood-transfusion services, the contamination detection method must be highly sensitive, easy to perform and preferably of low cost. In this spiking study, we evaluated the new optimized Scansystem Platelet Kit detection method for use on apheresis platelets. STUDY DESIGN AND METHODS: Apheresis platelet concentrates (APCs) were individually spiked with 10 colony-forming units (CFU)/ml of one of 10 different strains of bacteria. The spiked APCs were analysed at specific time-points during incubation by using the optimized Scansystem Platelet Kit. Bacterial enumeration was performed by plating onto blood agar. RESULTS: All the bacterial strains tested were detected by using the optimized Scansystem Platelet Kit when sampled 24 h after spiking. Compared to the Scansystem standard kit, sensitivity was increased to < 50 CFU/ml. The identity of the spiked bacteria was confirmed by Gram staining and DNA fingerprinting. CONCLUSION: The optimized Scansystem Platelet Kit was able to reliably detect, within 70 min, 10 transfusion-relevant bacterial species in APCs when a sample volume was taken 24 h after spiking. This is the first study carried out by using the optimized Scansystem bacterial detection that was found to have an enhanced sensitivity compared to the standard kit.

Bacteria↗