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  • 1
    Language: English
    In: BMC Medical Informatics and Decision Making, 01 May 2009, Vol.9(1), p.25
    Description: Abstract Background Revised consensus sepsis definitions have been published in 2003. The present study was performed to compare the prevalence of different stages of sepsis and ICU mortality rates and find out the case mix within the same collective of postoperative/posttraumatic patients applying either the original 1992 ACCP/SCCM or the revised 2003 SCCM/ESICM/ACCP/ATS/SIS sepsis definitions. Methods Retrospective observational single-centre study in surgical critically ill patients admitted to an University adult ICU. From 01/2007 to 12/2007, 742 patients were surveyed daily computer-assisted with respect to different stages of sepsis. Results Within the same patient collective, applying the 2003 definitions instead of the 1992 definitions, prevalence of severe sepsis (61 vs. 56) and septic shock (205 vs. 162) was higher (p 〈 0.001). In patients with septic shock according to the 2003 definitions, mortality rate of 22% was lower than that of 27%, when the 1992 definitions were used. Risk of death was increased for those patients classified to be in septic shock with any of the definitions (OR 6.5, p = 0.001). Sensitivity to predict deaths was slightly higher with the 2003 definitions (92%) than with the 1992 definitions (88%), and specificity was lower (31% vs. 49%). Conclusion The prevalence and mortality rates of various sepsis severity stages differ if defined by the 1992 or the 2003 definitions. Thus, transferring conclusions drawn from data sets regarding severity of sepsis generated with the 1992 definitions to the same population applying the 2003 definitions may be misleading. The 1992 definitions may under-classify patients with severe sepsis.
    Keywords: Medicine
    ISSN: 1472-6947
    E-ISSN: 1472-6947
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  • 2
    In: Circulation, 2015, Vol.132(2), pp.82-92
    Description: BACKGROUND—: Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanism-based approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K2P3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K channel–related acid-sensitive K channel-1]) 2-pore-domain K (K2P) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. METHODS AND RESULTS—: Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage- and current-clamp techniques. K2P3.1 subunits exhibited predominantly atrial expression, and atrial K2P3.1 transcript levels were highest among functional K2P channels. K2P3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD90) compared with patients in sinus rhythm. In contrast, K2P3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K2P3.1 inhibition prolonged APD90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. CONCLUSIONS—: Enhancement of atrium-selective K2P3.1 currents contributes to APD shortening in patients with chronic AF, and K2P3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K2P3.1 as a novel drug target for mechanism-based AF therapy.
    Keywords: Medicine ; Anatomy & Physiology;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 3
    Language: English
    In: European journal of clinical investigation, July 2017, Vol.47(7), pp.504-512
    Description: Despite decades of clinical use, the pharmacokinetics and the effects of acetylsalicylic acid (ASA) in critically ill patients remain ill-defined. We aimed to investigate the pharmacokinetics and the effects of different ASA formulations during critical illness. A cross-sectional study and a randomized, parallel-group trial were performed. Critically ill patients under chronic oral ASA treatment (100 mg enteric-coated) were screened for high 'on-treatment' platelet reactivity (HTPR) according to arachidonic acid-induced whole-blood aggregometry. Thirty patients with HTPR were randomized to receive 100 mg ASA intravenously, 100 mg enteric-coated ASA bid (bis in die) or 81 mg chewable ASA (n = 10 per group). Serum thromboxane B2 (TXB2) levels, ASA and salicylic acid levels were quantified. Of 66 patients, 85% (95% confidence intervals 74-93%) had HTPR. Compared to baseline infusion of 100 mg, ASA significantly reduced platelet aggregation after 24 h to median 80% (Quartiles: 66-84%). Intake of 81 mg chewable ASA significantly reduced platelet aggregation to 75% (54-86%) after four hours, but increased it to 117% after 24 h (81-163%). Treatment with 100 mg enteric-coated ASA bid decreased platelet aggregation after 24 h to median 56% (52-113%). Baseline TXB2 levels were median 0·35 ng/mL (0·07-0·94). Infusion of ASA or intake of 100 mg ASA bid reduced TXB2 levels to 0·07-0·18 ng/mL after 24 h, respectively. Chewable ASA reduced TXB2 levels only transiently. Pharmacokinetic analysis revealed highly variable absorption patterns of oral ASA formulations. There is a very high prevalence of HTPR in critically ill patients on peroral ASA therapy, caused by an incomplete suppression of TXB2 and/or by impaired absorption of ASA.
    Keywords: Acetylsalicylic Acid ; Critically Ill ; Pharmacokinetics ; Platelet Aggregation ; Thromboxane ; Aspirin -- Pharmacokinetics ; Critical Illness -- Therapy ; Platelet Aggregation Inhibitors -- Pharmacokinetics
    ISSN: 00142972
    E-ISSN: 1365-2362
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  • 4
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, May 2002, Vol.8(5), pp.1051-6
    Description: A multicenter Phase II trial was performed to investigate the efficacy and tolerance of combined docetaxel and gemcitabine +/- recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer. Fifty-two patients participated in this trial, 51 of whom are evaluable for response. Thirty-eight patients received this combination as first-line chemotherapy, and 14 patients received this combination as second-line chemotherapy, including 10 patients who had failed anthracyclines. Therapy consisted of 1500 mg/m2 gemcitabine and 50 mg/m2 docetaxel, both administered on days 1 and 15 every 4 weeks. Depending on the absolute neutrophil counts on the day of scheduled chemotherapeutic drug administration, a 5-day course of 5 microg/kg G-CSF was given. The overall response rate was 60.5% (95% confidence interval, 43.4-75.9%) in patients receiving docetaxel plus gemcitabine as first-line chemotherapy, including 4 complete responses (10.5%) and 19 partial remissions (50%); 9 patients (24%) had disease stabilization, and only 5 (13%) progressed. Second-line treatment with this regimen resulted in 6 of 14 (43%) objective responses, 5 had stable disease, and 3 progressive disease. The median time to progression was 8.5 months in the first-line setting and 6.6 months in the second-line setting, respectively. After a median follow-up time of 15 months, 36 patients (69%) are still alive with metastatic disease. Myelosuppression was commonly observed; WHO grade 3 or 4 neutropenia, however, occurred in only 15 (29%) patients and was complicated by septicemia in 2 cases; grade 3 anemia was seen in 1 patient (2%). Severe (grade 3) nonhematological toxicity except for alopecia was rarely observed and included nausea/vomiting in 3 (6%), stomatitis in 2 (4%), anaphylaxis in 2, and peripheral neuropathy, skin toxicity, and increase of liver enzymes each in one patient. Our data suggest that docetaxel and gemcitabine with and without G-CSF is an effective and fairly well-tolerated regimen for the treatment of advanced breast cancer. It might be particularly useful in patients exposed previously to adjuvant or palliative anthracyclines and/or alkylating agents.
    Keywords: Taxoids ; Antineoplastic Combined Chemotherapy Protocols -- Therapeutic Use ; Breast Neoplasms -- Drug Therapy ; Deoxycytidine -- Analogs & Derivatives ; Paclitaxel -- Analogs & Derivatives
    ISSN: 1078-0432
    E-ISSN: 15573265
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 5
    Language: English
    In: Scientific reports, 07 September 2018, Vol.8(1), pp.13430
    Description: Recessive dystrophic epidermolysis bullosa (RDEB) patients suffer from chronic and repeatedly infected wounds predisposing them to the development of aggressive and life-threatening skin cancer in these areas. Vitamin D3 is an often neglected but critical factor for wound healing. Intact skin possesses the entire enzymatic machinery required to produce active 1-alpha,25-dihydroxyvitamin D3 (calcitriol), underscoring its significance to proper skin function. Injury enhances calcitriol production, inducing the expression of calcitriol target genes including the antimicrobial peptide cathelicidin (hCAP18), an essential component of the innate immune system and an important wound healing factor. We found significantly reduced hCAP18 expression in a subset of RDEB keratinocytes which could be restored by calcipotriol treatment. Reduced scratch closure in RDEB cell monolayers was enhanced up to 2-fold by calcipotriol treatment, and the secretome of calcipotriol-treated cells additionally showed increased antimicrobial activity. Calcipotriol exhibited anti-neoplastic effects, suppressing the clonogenicity and proliferation of RDEB tumor cells. The combined wound healing, anti-microbial, and anti-neoplastic effects indicate that calcipotriol may represent a vital therapeutic option for RDEB patients which we could demonstrate in a single-patient observation study.
    Keywords: Wound Healing ; Anti-Bacterial Agents -- Pharmacology ; Antineoplastic Agents -- Pharmacology ; Calcitriol -- Analogs & Derivatives ; Dermatologic Agents -- Pharmacology ; Epidermolysis Bullosa -- Metabolism ; Keratinocytes -- Drug Effects
    ISSN: Scientific Reports
    E-ISSN: 2045-2322
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  • 6
    In: Stroke, 2019, Vol.50(2), pp.349-356
    Description: BACKGROUND AND PURPOSE—: Several risk factors are known to increase mid- and long-term mortality of ischemic stroke patients. Information on predictors of early stroke mortality is scarce but often requested in clinical practice. We therefore aimed to develop a rapidly applicable tool for predicting early mortality at the stroke unit. METHODS—: We used data from the nationwide Austrian Stroke Unit Registry and multivariate regularized logistic regression analysis to identify demographic and clinical variables associated with early (≤7 days poststroke) mortality of patients admitted with ischemic stroke. These variables were then used to develop the Predicting Early Mortality of Ischemic Stroke score that was validated both by bootstrapping and temporal validation. RESULTS—: In total, 77 653 ischemic stroke patients were included in the analysis (median age: 74 years, 47% women). The mortality rate at the stroke unit was 2% and median stay of deceased patients was 3 days. Age, stroke severity measured by the National Institutes of Health Stroke Scale, prestroke functional disability (modified Rankin Scale 〉0), preexisting heart disease, diabetes mellitus, posterior circulation stroke syndrome, and nonlacunar stroke cause were associated with mortality and served to build the Predicting Early Mortality of Ischemic Stroke score ranging from 0 to 12 points. The area under the curve of the score was 0.879 (95% CI, 0.871–0.886) in the derivation cohort and 0.884 (95% CI, 0.863–0.905) in the validation sample. Patients with a score ≥10 had a 35% (95% CI, 28%–43%) risk to die within the first days at the stroke unit. CONCLUSIONS—: We developed a simple score to estimate early mortality of ischemic stroke patients treated at a stroke unit. This score could help clinicians in short-term prognostication for management decisions and counseling.
    Keywords: Stroke -- Prognosis ; Stroke -- Patient Outcomes;
    ISSN: 0039-2499
    E-ISSN: 15244628
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  • 7
    Language: English
    In: Oncology, December 2003, Vol.65(3), pp.211-217
    Description: Purpose: A phase II trial was performed to determine the antitumor efficacy and tolerance of combined docetaxel and cisplatin with or without hematopoietic growth factor support in patients with advanced gastroesophageal cancer. Patients and Methods: Thirty-seven patients with histologically confirmed metastatic gastroesophageal cancer were entered in this trial. Treatment consisted of 4-weekly courses of docetaxel 50 mg/m2 and cisplatin 50 mg/m2 both given on day 1 and 15. Depending on absolute neutrophil counts on the days of scheduled chemotherapeutic drug administration (1,000–2,000/µl), a 5-day course of human granulocyte colony-stimulating factor (G-CSF) 5 µg/kg/day was given subcutaneously; in addition, if hemoglobin was 〈12.0 mg/dl, erythropoietin 10,000 IU was administered subcutaneously 3 times per week. Results: The confirmed overall response rate (intent-to-treat) was 46%, including 4 complete responses (11%) and 13 partial responses (35%). Eleven patients (30%) had stable disease and 9 (24%) progressed while on treatment. The median time to response was 3 months, the median time to progression was 7 months and the median overall survival time was 11.5 months with 16 (43%) patients currently alive. Hematologic toxicity was common, though WHO grade 4 neutropenia occurred only in 3 patients. Nonhematologic adverse reaction were usually mild to moderate; grade 3 toxicities included alopecia in 5 patients (14%), infection in 1 (3%), neutrotoxicity in 2 (5%) and anaphylaxis in 1 patient. Conclusion: Our data suggest that the combination of docetaxel and cisplatin with or without G-CSF and/or erythropoietin has a promising therapeutic index in patients with advanced gastroesophageal cancer.
    Keywords: Clinical Study ; Palliative Chemotherapy ; Advanced Gastric Cancer ; Docetaxel ; Cisplatin ; Granulocyte Colony-Stimulating Factor ; Erythropoietin ; Medicine
    ISSN: 0030-2414
    E-ISSN: 1423-0232
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  • 8
    Language: English
    In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 01 April 2003, Vol.21(7), pp.1307-12
    Description: Capecitabine and oxaliplatin, two new agents with potential synergistic activity, have demonstrated promising antitumor efficacy in advanced colorectal cancer (ACC). Preclinical and clinical evidence indicating that dose intensification of the oral fluorouracil prodrug might result in improved therapeutic results led us to the present randomized multicenter phase II study. Eighty-nine patients with bidimensionally measurable ACC previously untreated for metastatic disease were randomly allocated to receive oxaliplatin 130 mg/m(2) day 1 plus capecitabine 2,000 mg/m(2)/d days 1 to 14 every 3 weeks (arm A) or to receive oxaliplatin 85 mg/m(2) days 1 and 14 combined with capecitabine 3,500 mg/m(2) days 1 to 7 and 14 to 21 every 4 weeks (arm B). In both treatment arms, chemotherapy was continued for a total of 6 months unless there was prior evidence of progression of disease. Patients allocated to the high-dose capecitabine combination arm B had a higher radiologically confirmed response rate (54.5% v 42.2%) and a significantly longer median progression-free survival time than those allocated to control arm A (10.5 v 6.0 months; P =.0013). Median overall survival times cannot be calculated for either treatment arm at this point. Despite a 34% higher dose intensity of capecitabine in arm B, there was no difference in hematologic toxicity between treatment arms (neutropenia/thrombocytopenia: 60%/43% in arm B v 56%/33% in arm A). Similarly, the incidence rate and degree of nonhematologic adverse events were comparable: The most commonly encountered symptoms (all grades, arm A and arm B) included nausea/emesis (A: 58%; B: 62%), diarrhea (A: 44%; B: 31%), peripheral sensory neuropathy (A: 80%; B: 83%), and fatigue (A: 40%; B: 50%). Results of this study indicate that both combination regimens are feasible, tolerable, and clinically active. The dose-intensified bimonthly capecitabine arm, however, seems to be more effective in increasing both response rate and progression-free survival time.
    Keywords: Antimetabolites, Antineoplastic -- Administration & Dosage ; Antineoplastic Combined Chemotherapy Protocols -- Administration & Dosage ; Colorectal Neoplasms -- Drug Therapy ; Deoxycytidine -- Administration & Dosage ; Organoplatinum Compounds -- Administration & Dosage
    ISSN: 0732-183X
    E-ISSN: 15277755
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  • 9
    In: Journal of Investigative Dermatology, 2001, Vol.116(6), p.891
    Description: Vitiligo is a skin and hair disorder characterized by circumscribed depigmented lesions due to lack of melanocytes in the respective areas. It has been suggested that vitiligo is caused by an autoimmune-mediated destruction of melanocytes. Recently, the presence of a high frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in the peripheral blood of patients with vitiligo was reported. Our study examines the frequency of melanocyte-specific cytotoxic T lymphocytes in vitiligo patients and its relationship to disease activity. Thirty-two patients with moderate to active vitiligo and 17 control subjects were included. Melanocyte specific reactive CD8(+) T cells were identified by enzyme-linked immunospot assay after stimulation with five peptides from gp100, four peptides from MelanA/MART1, and two peptides from tyrosinase. In selected patients, intracellular interferon-gamma staining for the detection of specific reactive CD8(+) T cells was additionally performed. In seven of 10 patients (70%) with actively progressive disease CD8(+) T cells directed against melanocyte epitopes were detected, whereas only in four of 22 patients (18%) with moderate disease activity such specific reactivity was found. MelanA/MART1 peptides were immunodominant in nine patients reacting against EAAGIGILTV and three patients reacting against ILTVILGVL. Intracellular interferon-gamma staining confirmed the findings obtained by the enzyme-linked immunospot technique. The present study supports the hypothesis that vitiligo is a cytotoxic T lymphocyte-mediated autoimmune disease. The presence of melanocyte-specific reactive CD8(+) T cells seems to be closely related to disease activity.
    Keywords: Cd8-Positive T-Lymphocytes -- Immunology ; HLA-A2 Antigen -- Immunology ; Melanocytes -- Immunology ; Vitiligo -- Immunology;
    ISSN: 0022-202X
    E-ISSN: 15231747
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  • 10
    Language: English
    In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 01 January 2002, Vol.20(1), pp.165-72
    Description: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting. Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m(2) plus irinotecan 175 mg/m(2) or raltitrexed 3 mg/m(2) given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected. Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P =.0025) and longer progression-free survival (median, 7.1 v 5.0 months; P =.0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P =.3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m(2), tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%). Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.
    Keywords: Adenocarcinoma -- Drug Therapy ; Antineoplastic Combined Chemotherapy Protocols -- Therapeutic Use ; Camptothecin -- Analogs & Derivatives ; Colorectal Neoplasms -- Drug Therapy
    ISSN: 0732-183X
    E-ISSN: 15277755
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