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1.  A score to quantify coronary plaque vulnerability in high-risk patients with type 2 diabetes: an optical coherence tomography study 
Cardiovascular Diabetology  2014;13(1):117.
Patients with type 2 diabetes are at a high risk for acute cardiovascular events, which usually arise from the rupture of a vulnerable coronary lesion characterized by specific morphological plaque features. Thus, the identification of vulnerable plaques is of utmost clinical importance in patients with type 2 diabetes. However, there is currently no scoring system available to identify vulnerable lesions based on plaque characteristics. Thus, we aimed to characterize the diagnostic value of optical coherence tomography (OCT) - derived lesion characteristics to quantify plaque vulnerability both as individual parameters and when combined to a score in patients with type 2 diabetes.
OCT was performed in the coronary culprit lesions of 112 patients with type 2 diabetes. The score, which quantifies plaque vulnerability, was defined as the predicted probability that a lesion is the cause for an acute coronary syndrome (ACS) (vs. stable angina (SAP)) based on its specific plaque morphology.
Multivariable logistic regression analysis demonstrated that plaque vulnerability was independently predicted by the minimal fibrous cap thickness overlying a lesion’s lipid core (odds ratio (OR) per 10 μm 0.478, p = 0.002), the medium lipid arc (OR per 90° 13.997, p < 0.001), the presence of macrophages (OR 4.797, p = 0.015) and the lipid plaque length (OR 1.290, p = 0.098).
Receiver-operating-characteristics (ROC) analyses demonstrated that these parameters combined to a score demonstrate an excellent diagnostic efficiency to identify culprit lesions of patients with ACS (vs. SAP, AUC 0.90, 95% CI 0.84-0.96).
This is the first study to present a score to quantify lesion vulnerability in patients with type 2 diabetes. This score may be a valuable adjunct in decision-making and useful in guiding coronary interventions.
PMCID: PMC4148556  PMID: 25248966
Optical coherence tomography; Plaque vulnerability; Type 2 diabetes mellitus; Acute coronary syndrome
2.  The growth of Staphylococcus aureus and Escherichia coli in low-direct current electric fields 
Electrical potentials up to 800 mV can be observed between different metallic dental restorations. These potentials produce fields in the mouth that may interfere with microbial communities. The present study focuses on the impact of different electric field strengths (EFS) on the growth of Staphylococcus aureus (ATCC 25923) and Escherichia coli (ATCC 25922) in vitro. Cultures of S. aureus and E. coli in fluid and gel medium were exposed to different EFS. Effects were determined by calculation of viable counts and measurement of inhibition zones. In gel medium, anodic inhibition zones for S. aureus were larger than those for E. coli at all field strength levels. In fluid medium, the maximum decrease in the viable count of S. aureus cells was at 10 V⋅m−1. Field-treated S. aureus cells presented ruptured cell walls and disintegrated cytoplasm. Conclusively, S. aureus is more sensitive to increasing electric field strength than E. coli.
PMCID: PMC3967302  PMID: 24008271
direct current; Escherichia coli; electrogalvanism; gold electrode; Staphylococcus aureus
3.  Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma 
We assessed the profile and frequency of malignancy subtypes in a large single-centre UK cohort for patients with scleroderma (systemic sclerosis; SSc). We evaluated the cancer risk among SSc patients with different antibody reactivities and explored the temporal association of cancer with the duration between SSc onset and cancer diagnosis.
We conducted a retrospective study of a well-characterised cohort of SSc patients attending a large tertiary referral centre, with clinical data collected from our clinical database and by review of patient records. We evaluated development of all cancers in this cohort, and comparison was assessed with the SSc cohort without cancer. The effect of demographics and clinical details, including antibody reactivities, were explored to find associations relevant to the risk for development of cancer in SSc patients.
Among 2,177 patients with SSc, 7.1% had a history of cancer, 26% were positive for anticentromere antibodies (ACAs), 18.2% were positive for anti-Scl-70 antibodies and 26.6% were positive for anti-RNA polymerase III (anti-RNAP) antibody. The major malignancy cancer subtypes were breast (42.2%), haematological (12.3%), gastrointestinal (11.0%) and gynaecological (11.0%). The frequency of cancers among patients with RNAP (14.2%) was significantly increased compared with those with anti-Scl-70 antibodies (6.3%) and ACAs (6.8%) (P < 0.0001 and P < 0.001, respectively). Among the patients, who were diagnosed with cancer within 36 months of the clinical onset of SSc, there were more patients with RNAP (55.3%) than those with other autoantibody specificities (ACA = 23.5%, P < 0.008; and anti-Scl-70 antibodies = 13.6%, P < 0.002, respectively). Breast cancers were temporally associated with onset of SSc among patients with anti-RNAP, and SSc patients with anti-RNAP had a twofold increased hazard ratio for cancers compared to patients with ACAs (P < 0.0001).
Our study independently confirms, in what is to the best of our knowledge the largest population examined to date, that there is an association with cancer among SSc patients with anti-RNAP antibodies in close temporal relationship to onset of SSc, which supports the paraneoplastic phenomenon in this subset of SSc cases. An index of cautious suspicion should be maintained in these cases, and investigations for underlying malignancy should be considered when clinically appropriate.
PMCID: PMC3978927  PMID: 24524733
4.  Plaque vulnerability of coronary artery lesions is related to left ventricular dilatation as determined by optical coherence tomography and cardiac magnetic resonance imaging in patients with type 2 diabetes 
Patients with type 2 diabetes are at increased risk for both, left ventricular (LV)-dilatation and myocardial infarction (MI) following the rupture of a vulnerable plaque. This study investigated the to date incompletely understood relationship between plaque vulnerability and LV-dilatation using optical coherence tomography (OCT) and cardiac magnetic resonance imaging (CMR) in patients with type 2 diabetes and stable coronary artery disease.
CMR was performed in 58 patients with type 2 diabetes, in which 81 coronary lesions were investigated using OCT.
A decreased minimal fibrous cap thickness (FCT) of coronary lesions was associated with an increase of several CMR-derived parameters including LV-end diastolic volume (LVEDV, r = 0.521, p < 0.001), LV-end diastolic diameter (r = 0.502, p < 0.001) and LV-end systolic volume (r = 0.467, p = 0.001). Similar results were obtained for mean FCT.
Furthermore, patients with dilated versus non-dilated LV differed significantly in several cardiovascular risk factors including previous MI (47.1% vs. 14.6%, p = 0.009), HDL-cholesterol (40.35 ± 5.57 mg/dl vs. 45.20 ± 10.79 mg/dl, p = 0.029) and smoking (82.4% vs. 51.2%, p = 0.027). However, minimal FCT is associated to LV-dilatation independent of previous MIs (odds ratio 0.679, p = 0.022).
Receiver-operating curve analysis demonstrated that CMR-derived LVEDV predicts plaque vulnerability with low-moderate diagnostic efficiency (area under the curve 0.699) and considerate specificity (83.3%) at the optimal cut-off value (159.0 ml).
These data suggest that vulnerability of coronary lesions is associated with LV-dilatation in high risk patients with type 2 diabetes. CMR may be a useful adjunct to the risk-stratification in this population. Future studies are warranted to investigate potential mechanisms linking plaque vulnerability and LV-dilatation.
PMCID: PMC3716884  PMID: 23844855
Type 2 diabetes mellitus; Cardiac magnetic resonance imaging; Optical coherence tomography; Minimal fibrous cap thickness; Coronary plaque morphology
5.  Nasal irrigation as an adjunctive treatment in allergic rhinitis: A systematic review and meta-analysis 
Saline nasal irrigation (SNI) is often recommended as additional nonpharmacologic treatment, having proven its efficacy in acute and chronic rhinosinusitis and for therapy after sinonasal surgery. To date, however, no systematic review or meta-analysis exists showing the influence of SNI on allergic rhinitis (AR). This study aimed to establish the impact of SNI on symptoms of AR in different patient groups.
We conducted a systematic search of Medline, Embase, Cochrane Central Register of Controlled Trials, and ISI Web of Science databases for literature published from 1994 to 2010 on SNI in AR. Prospective, randomized, controlled trials that assessed the effects of SNI on four different outcome parameters were included. The evaluation focused on primary (symptom score) and secondary parameters (medicine consumption, mucociliary clearance, and quality of life).
Three independent reviewers chose 10 originals that satisfied the inclusion criteria (>400 participants total) from 50 relevant trials. SNI performed regularly over a limited period of up to 7 weeks was observed to have a positive effect on all investigated outcome parameters in adults and children with AR. SNI produced a 27.66% improvement in nasal symptoms, a 62.1% reduction in medicine consumption, a 31.19% acceleration of mucociliary clearance time, and a 27.88% improvement in quality of life.
SNI using isotonic solution can be recommended as complementary therapy in AR. It is well tolerated, inexpensive, easy to use, and there is no evidence showing that regular, daily SNI adversely affects the patient's health or causes unexpected side effects.
PMCID: PMC3904042  PMID: 23168142
Adjunctive treatment; allergic rhinitis; hypertonic saline solution; isotonic saline solution; nasal douche; nasal lavage; nasal obstruction; pollinosis; saline nasal irrigation; sneezing
6.  Use of a Simple Criteria Set for Guiding Echocardiography in Nosocomial Staphylococcus aureus Bacteremia 
A set of simple clinical prediction criteria for patients with nosocomial Staphylococcus aureus bacteremia was developed to identify patients at low risk of infective endocarditis in whom transesophageal echocardiography might be dispensable and was validated with two independent cohorts.
(see the editorial commentary and Soriano and Mensa, on pages 10–12.)
Background. Infective endocarditis (IE) is a severe complication in patients with nosocomial Staphylococcus aureus bacteremia (SAB). We sought to develop and validate criteria to identify patients at low risk for the development of IE in whom transesophageal echocardiography (TEE) might be dispensable.
Methods. Consecutive patients with nosocomial SAB from independent cohorts in Europe (Invasive S. aureus Infection Cohort [INSTINCT]) and North America (S. aureus Bacteremia Group [SABG]) were evaluated for the presence of clinical criteria predicting an increased risk for the development of IE (ie, prolonged bacteremia of >4 days' duration, presence of a permanent intracardiac device, hemodialysis dependency, spinal infection, and nonvertebral osteomyelitis). Patients were observed closely for clinical signs and symptoms of IE during hospitalization and a 3-month follow-up period.
Results. IE was present in 13 (4.3%) of 304 patients in the INSTINCT cohort and in 40 (9.3%) of 432 patients in the SABG cohort. Within 14 days after the first positive blood culture result, echocardiography was performed in 39.8% and 57.4% of patients in the INSTINCT and SABG cohorts, respectively. In patients with IE, the most common clinical prediction criteria present were prolonged bacteremia (69.2% vs 90% for INSTINCT vs SABG, respectively) and presence of a permanent intracardiac device (53.8% vs 32.5%). In total, 13 of 13 patients in the INSTINCT cohort and 39 of 40 patients in the SABG cohort with documented IE fulfilled at least 1 criterion (sensitivity, 100% vs. 97.5%; negative predictive value, 100% vs 99.2%).
Conclusions. A simple criteria set for patients with nosocomial SAB can identify patients at low risk of IE. Patients who meet these criteria may not routinely require TEE.
PMCID: PMC3149212  PMID: 21653295
7.  Integrating Palliative Medicine into Comprehensive Breast Cancer Therapy – a Pilot Project 
Breast Care  2011;6(3):215-220.
To comply with the World Health Organization (WHO) recommendations, our institution's administrative directives were adopted to advocate the provision of palliative care (PC) early in the disease trajectory of breast cancer (BC). To assess the outcome of this recommendation, this study evaluated the effects of this approach.
A retrospective systematic chart analysis of a 2-year period was performed. The first PC consultation of patients was analyzed according to (a) physical condition, (b) symptom burden of the patients, and (c) reasons for PC consultation.
Many patients were already in a reduced physical state and experienced burdening symptoms when first counselled by PC. After a 1-year experience with PC consultations, the number of burdening symptoms identified at first PC consultation decreased and senologists increasingly requested PC support also for non-somatic issues.
A development towards a better understanding of PC competencies after a 1-year initiation period could be demonstrated, but BC patients continued to be in late stages of the disease at the time of first PC contact. Disease-specific guidelines may facilitate and optimize the integration of PC into breast cancer therapy.
PMCID: PMC3132969  PMID: 21779227
Comprehensive cancer care; Palliative medicine; Simultaneous care; Shared care; Quality of life; Symptom control
8.  Dendritic Cell Based Tumor Vaccination in Prostate and Renal Cell Cancer: A Systematic Review and Meta-Analysis 
PLoS ONE  2011;6(4):e18801.
More than 200 clinical trials have been performed using dendritic cells (DC) as cellular adjuvants in cancer. Yet the key question whether there is a link between immune and clinical response remains unanswered. Prostate and renal cell cancer (RCC) have been extensively studied for DC-based immunotherapeutic interventions and were therefore chosen to address the above question by means of a systematic review and meta-analysis.
Methodology/Principal Findings
Data was obtained after a systematic literature search from clinical trials that enrolled at least 6 patients. Individual patient data meta-analysis was performed by means of conditional logistic regression grouped by study. Twenty nine trials involving a total of 906 patients were identified in prostate cancer (17) and RCC (12). Objective response rates were 7.7% in prostate cancer and 12.7% in RCC. The combined percentages of objective responses and stable diseases (SD) amounted to a clinical benefit rate (CBR) of 54% in prostate cancer and 48% in RCC. Meta-analysis of individual patient data (n = 403) revealed the cellular immune response to have a significant influence on CBR, both in prostate cancer (OR 10.6, 95% CI 2.5–44.1) and in RCC (OR 8.4, 95% CI 1.3–53.0). Furthermore, DC dose was found to have a significant influence on CBR in both entities. Finally, for the larger cohort of prostate cancer patients, an influence of DC maturity and DC subtype (density enriched versus monocyte derived DC) as well as access to draining lymph nodes on clinical outcome could be demonstrated.
As a ‘proof of principle’ a statistically significant effect of DC-mediated cellular immune response and of DC dose on CBR could be demonstrated. Further findings concerning vaccine composition, quality control, and the effect of DC maturation status are relevant for the immunological development of DC-based vaccines.
PMCID: PMC3080391  PMID: 21533099
9.  Hemorrhage rate after coblation tonsillectomy: a meta-analysis of published trials 
After the surgical procedure of tonsillectomy, hemorrhage ranks among its serious postoperative complications. In this systematic review, we analyze hemorrhage following tonsillectomies performed using the coblation technique. 24 prospective, randomized, and controlled studies were included in the meta-analysis. Data of 796 patients who had undergone coblation tonsillectomy were analyzed. Hemorrhages occurred in 33 patients: 2 classified as primary and 26 as secondary hemorrhages. 5 could not be classified into either group. Overall, the total hemorrhage rate for the coblation procedure was 4.1% with a 95% confidence interval from 2.8 to 5.5%. The overall hemorrhage rate of 4.1% found in this meta-analysis shows that coblation is a safe and effective technique for tonsillectomies with a secondary bleeding rate similar to what is reported for comparable techniques such as bipolar diathermia.
PMCID: PMC3087106  PMID: 21373898
Tonsillectomy; Hemorrhage; Coblation; Radiofrequency-based plasma dissection; Complication
10.  Serial Assessment of Cardiac Function during and following Mitoxantrone Infusion in 30 Consecutive Patients with Multiple Sclerosis 
Immunosuppressive therapy is an established therapeutic option in patients suffering from multiple sclerosis (MS). In an open nonrandomized study we serially assessed cardiac function in 30 consecutive patients with MS before, during, and after mitoxantrone therapy. Mitoxantrone (12 mg/m2) was administered intravenously at 3-month intervals. Before each infusion, cardiac function was assessed by history taking, resting electrocardiogram, and echocardiography. Whereas no patient experienced clinical signs of heart failure, left ventricular pump function decreased continuously during mitoxantrone therapy and did not recover after cessation. The presented data suggest a dose-dependent and long-lasting toxic cardiac effect of low-dose mitoxantrone therapy in MS.
PMCID: PMC3196257  PMID: 22096623
11.  Beta1-Adrenoceptor Polymorphism Predicts Flecainide Action in Patients with Atrial Fibrillation 
PLoS ONE  2010;5(7):e11421.
Antiarrhythmic action of flecainide is based on sodium channel blockade. Beta1-adrenoceptor (β1AR) activation induces sodium channel inhibition, too. The aim of the present study was to evaluate the impact of different β1AR genotypes on antiarrhythmic action of flecainide in patients with structural heart disease and atrial fibrillation.
Methodology/Principal Findings
In 145 subjects, 87 with atrial fibrillation, genotyping was performed to identify the individual β1AR Arg389Gly and Ser49Gly polymorphism. Resting heart rate during atrial fibrillation and success of flecainide-induced cardioversion were correlated with β1AR genotype. The overall cardioversion rate with flecainide was 39%. The Arg389Arg genotype was associated with the highest cardioversion rate (55.5%; OR 3.30; 95% CI; 1.34–8.13; p = 0.003) compared to patients with Arg389Gly (29.5%; OR 0.44; 95% CI; 0.18–1.06; p = 0.066) and Gly389Gly (14%; OR 0.24; 95% CI 0.03–2.07; p = 0.17) variants. The single Ser49Gly polymorphism did not influence the conversion rate. In combination, patients with Arg389Gly-Ser49Gly genotype displayed the lowest conversion rate with 20.8% (OR 0.31; 95% CI; 0.10–0.93; p = 0.03). In patients with Arg389Arg variants the heart rate during atrial fibrillation was significantly higher (110±2.7 bpm; p = 0.03 vs. other variants) compared to Arg389Gly (104.8±2.4 bpm) and Gly389Gly (96.9±5.8 bpm) carriers. The Arg389Gly-Ser49Gly genotype was more common in patients with atrial fibrillation compared to patients without atrial fibrillation (27.6% vs. 5.2%; HR 6.98; 95% CI; 1.99–24.46; p<0.001).
The β1AR Arg389Arg genotype is associated with increased flecainide potency and higher heart rate during atrial fibrillation. The Arg389Gly-Ser49Gly genotype might be of predictive value for atrial fibrillation.
PMCID: PMC2896398  PMID: 20625396
12.  Sleep deprivation increases oleoylethanolamide in human cerebrospinal fluid 
Journal of Neural Transmission  2009;116(3):301-305.
This study investigated the role of two fatty acid ethanolamides, the endogenous cannabinoid anandamide and its structural analog oleoylethanolamide in sleep deprivation of human volunteers. Serum and cerebrospinal fluid (CSF) samples were obtained from 20 healthy volunteers before and after a night of sleep deprivation with an interval of about 12 months. We found increased levels of oleoylethanolamide in CSF (P = 0.011) but not in serum (P = 0.068) after 24 h of sleep deprivation. Oleoylethanolamide is an endogenous lipid messenger that is released after neural injury and activates peroxisome proliferator-activated receptor-α (PPAR-α) with nanomolar potency. Exogenous PPAR-α agonists, such as hypolipidemic fibrates and oleoylethanolamide, exert both neuroprotective and neurotrophic effects. Thus, our results suggest that oleoylethanolamide release may represent an endogenous neuroprotective signal during sleep deprivation.
PMCID: PMC2757605  PMID: 19137236
Oleoylethanolamide; Endocannabinoids; PPAR-α; Sleep deprivation; Neuroprotection; Oxidative stress
13.  Predicting drug susceptibility of non–small cell lung cancers based on genetic lesions 
The Journal of Clinical Investigation  2009;119(6):1727-1740.
Somatic genetic alterations in cancers have been linked with response to targeted therapeutics by creation of specific dependency on activated oncogenic signaling pathways. However, no tools currently exist to systematically connect such genetic lesions to therapeutic vulnerability. We have therefore developed a genomics approach to identify lesions associated with therapeutically relevant oncogene dependency. Using integrated genomic profiling, we have demonstrated that the genomes of a large panel of human non–small cell lung cancer (NSCLC) cell lines are highly representative of those of primary NSCLC tumors. Using cell-based compound screening coupled with diverse computational approaches to integrate orthogonal genomic and biochemical data sets, we identified molecular and genomic predictors of therapeutic response to clinically relevant compounds. Using this approach, we showed that v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations confer enhanced Hsp90 dependency and validated this finding in mice with KRAS-driven lung adenocarcinoma, as these mice exhibited dramatic tumor regression when treated with an Hsp90 inhibitor. In addition, we found that cells with copy number enhancement of v-abl Abelson murine leukemia viral oncogene homolog 2 (ABL2) and ephrin receptor kinase and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) kinase family genes were exquisitely sensitive to treatment with the SRC/ABL inhibitor dasatinib, both in vitro and when it xenografted into mice. Thus, genomically annotated cell-line collections may help translate cancer genomics information into clinical practice by defining critical pathway dependencies amenable to therapeutic inhibition.
PMCID: PMC2689116  PMID: 19451690
14.  Silent night: retrospective database study assessing possibility of “weekend effect” in palliative care 
Objective To compare the mortality of patients in a palliative care unit on working days with that on weekends and public holidays.
Design Retrospective database study.
Setting Palliative care unit in Germany.
Population All admissions to palliative care unit between 1 January 1997 and 31 December 2008.
Main outcome measure The impact of day type (working days or weekends and public holidays) on mortality was analysed using Poisson regression models.
Results A total of 2565 admitted patients and 1325 deaths were recorded. Of the deaths, 448 (33.8%) occurred on weekends and public holidays. The mortality rate on weekends and public holidays was 18% higher than that on working days (mortality rate ratio 1.18, 95% confidence interval 1.05 to 1.32; P=0.005).
Conclusion Patients in the palliative care unit were at higher risk of dying on weekends and public holidays. In the absence of a prospective study, the exact reasons for this correlation are unclear.
PMCID: PMC4267701  PMID: 25515670

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