Rainer Muche

Contribution of androgens to the gender difference in leptin production in obese children and adolescents.

Recent studies demonstrated significantly higher serum leptin concentrations in females as compared with males, even after correction for differences in body fat mass. The aim of our study was to measure serum leptin concentrations in a large group of obese children and adolescents to determine the possible role of sex steroid hormones on both leptin serum concentrations and production in human adipocytes. Obese girls were found to have significantly higher leptin concentrations than boys at the same degree of adiposity (25.2+/-14.1 vs. 17.2+/-12.6 ng/ml, P < 0.001). In a multiple regression analysis with age and body mass index (percent body fat) as fixed variables, it turned out that testosterone had a potent negative effect on serum leptin in boys, but not in girls. In vitro experiments using newly developed human adipocytes in primary culture showed that both testosterone and its biologically active metabolite dihydrotestosterone are able to reduce leptin secretion into the culture medium by up to 62%. Using a semiquantitative reverse transcriptase-PCR method, testosterone was found to suppress leptin mRNA to a similar extent. These results suggest that, apart from differences in body fat mass, the higher androgen concentrations in obese boys are responsible for the lower leptin serum concentrations compared with obese girls.

Systemic Hypothermia After Neonatal Encephalopathy: Outcomes of neo.nEURO.network RCT

OBJECTIVE: Mild hypothermia after perinatal hypoxic-ischemic encephalopathy (HIE) reduces neurologic sequelae without significant adverse effects, but studies are needed to determine the most-efficacious methods. METHODS: In the neo.nEURO.network trial, term neonates with clinical and electrophysiological evidence of HIE were assigned randomly to either a control group, with a rectal temperature of 37°C (range: 36.5–37.5°C), or a hypothermia group, cooled and maintained at a rectal temperature of 33.5°C (range: 33–34°C) with a cooling blanket for 72 hours, followed by slow rewarming. All infants received morphine (0.1 mg/kg) every 4 hours or an equivalent dose of fentanyl. Neurodevelopmental outcomes were assessed at the age of 18 to 21 months. The primary outcome was death or severe disability. RESULTS: A total of 129 newborn infants were enrolled, and 111 infants were evaluated at 18 to 21 months (53 in the hypothermia group and 58 in the normothermia group). The rates of death or severe disability were 51% in the hypothermia group and 83% in the normothermia group (P = .001; odds ratio: 0.21 [95% confidence interval [CI]: 0.09–0.54]; number needed to treat: 4 [95% CI: 3–9]). Hypothermia also had a statistically significant protective effect in the group with severe HIE (n = 77; P = .005; odds ratio: 0.17 [95% CI: 0.05–0.57]). Rates of adverse events during the intervention were similar in the 2 groups except for fewer clinical seizures in the hypothermia group. CONCLUSION: Systemic hypothermia in the neo.nEURO.network trial showed a strong neuroprotective effect and was effective in the severe HIE group.

IgG antibodies against measles, rubella, and varicella zoster virus predict conversion to multiple sclerosis in clinically isolated syndrome.

Background Multiple sclerosis (MS) is characterized by a polyspecific B-cell response to neurotropic viruses such as measles, rubella and varicella zoster, with the corresponding antibodies measurable in CSF as the so-called “MRZ reaction” (MRZR). We aimed to evaluate the relevance of MRZR to predict conversion of patients with clinically isolated syndrome (CIS) to MS, and to compare it to oligoclonal bands (OCB) and MRI. Methodology/Principal Findings MRZR was determined in a prospective study over 2 years including 40 patients that remained CIS over follow-up (CIS-CIS) and 49 patients that developed MS (CIS-RRMS) using ELISA. Using logistic regression, a score (MRZS) balancing the predictive value of the antibody indices included in MRZR was defined (9 points measles, 8 points rubella, 1 point varicella zoster, cutpoint: sum of scores greater 10). MRZR and MRZS were significantly more frequent in CIS-RRMS as compared to CIS-CIS (p = 0.04 and p = 0.02). MRZS showed the best positive predictive value (PPV) of all parameters investigated (79%, 95%-CI: 54–94%), which could be further increased by combination with MRI (91%, 95%-CI: 59–99%). Conclusions/Significance Our data indicate the relevance of MRZR to predict conversion to MS. It furthermore shows the importance of weighting the different antibody indices included in MRZR and suggest that patients with positive MRZR are candidates for an early begin of immunomodulatory therapy.

Hemorrhagic complications associated with tension-free vaginal tape procedure

OBJECTIVE: We sought to assess the frequency, symptoms, and management of hemorrhagic complications in patients undergoing tension-free vaginal tape (TVT) procedure. METHODS: Over a 5-year period the clinical course of all 336 consecutive patients undergoing TVT procedure in our hospital was recorded, including diagnostic approaches and management strategies for both increased intraoperative blood loss and clinically relevant hematoma. RESULTS: In 87 patients (26%), TVT procedure was combined with other gynecologic surgeries, and 249 patients (74%) underwent TVT alone. In 7 cases (2.1%), increased intraoperative blood loss (250–400 mL) was managed by electro-coagulation, manual compression, tamponade, and/or insertion of a drain. The postoperative course in these patients was uncomplicated. In 14 women (4.1%) who did not show increased bleeding during the operation, retropubic hematoma developed, the volume of which exceeded 300 mL in 4 cases (1.2%). These required surgical intervention. In the first case we performed open laparotomy, whereas in the following cases the hematoma could be successfully drained by endoscopy. Postoperative development of a hematoma did not lead to recurrence of stress incontinence. CONCLUSION: Bleeding complications during or after TVT procedure are rare events. Increased intraoperative bleeding can usually be managed with electro-coagulation, compression, and drainage. LEVEL OF EVIDENCE: II-3

Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial

BACKGROUND Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death. METHODS In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743. RESULTS Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36). INTERPRETATION Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection. FUNDING Deutsche Forschungsgemeinschaft.

Protocol for MInimizing the Risk of Metachronous Adenomas of the CoLorectum with Green Tea Extract (MIRACLE): a randomised controlled trial of green tea extract versus placebo for nutriprevention of metachronous colon adenomas in the elderly population

BackgroundPrevention of colorectal cancer is a major health care issue. People who have undergone colonoscopy screening and had colorectal polyps removed have a higher risk of being diagnosed with polyps again compared to the normal population. Therefore, it would be ideal to find appropriate means that effectively help to prevent the reoccurrence of polyps after polypectomy. So far, pharmaceutical chemoprevention with NSAIDs including aspirin has been shown to be effective but not gained general acceptance due to side effects. Nutraceuticals such as polyphenols from tea plants have demonstrated remarkable therapeutic and preventive effects in molecular, epidemiological and clinical trials. However, placebo-controlled trials demonstrating the efficacy of nutraceuticals for the (secondary) prevention of colorectal polyps as precursors for colorectal cancer are missing.Methods/DesignWe present the design of a randomized, placebo controlled, multicentre trial to investigate the effect of diet supplementation with green tea extract containing 300 mg epigallocatechin gallate (EGCG), the major polyphenol in green tea, on the recurrence of colon adenomas. Patients who have undergone polypectomy for colonic polyps will be randomized to receive either green tea extract containing 150 mg EGCG two times daily or a placebo over the course of three years. After a one month run-in period in which all patients will receive the active intervention, 2534 patients will be randomized, and 2028 patients are expected to complete the whole study course. Incidence, number and histology of adenoma at endpoint colonoscopy at three years will be compared in both groups.DiscussionThe beneficial safety profile of decaffeinated green tea extract, the quantifiable and known active content EGCG, and the accumulating evidence of its cancer preventive potential require, in our view, a validation of this compound for the nutriprevention of colorectal adenoma. Good accessibility and low costs might render this neutraceutical a top candidate for wider use as food supplement in colon cancer prevention.Trial registrationClinicalTrials.gov: NCT01360320

Radioimmunotherapy-based conditioning for hematopoietic cell transplantation in children with malignant and nonmalignant diseases

Targeted irradiation of the bone marrow with radiolabeled monoclonal antibodies (radioimmunotherapy) represents a novel therapeutic approach with both myeloablative and antileukemic potential. In an open-label, single-center pilot study, 30 pediatric and adolescent patients undergoing hematopoietic cell transplantation for malignant (n = 16) and nonmalignant (n = 14) disorders received treatment with a ⁹⁰Y-labeled anti-CD66 monoclonal antibody. Patients with a high risk of relapse (n = 7) received additional treatment with standard conditioning based on either total body irradiation or busulfan to intensify the antileukemic effect. In patients with comorbidities (n = 23), radioimmunotherapy was combined with a reduced-intensity conditioning regimen to reduce systemic toxicity. Preferential irradiation of the bone marrow was achieved in all patients. Nonrelapse mortality was 4 (13%) of 30 patients. In patients with malignant diseases, the probabilities of overall and disease-free survival at 2 years were 0.69 (95% confidence interval 0.37-0.87) and 0.46 (95% confidence interval 0.19-0.70), respectively. In patients with nonmalignant diseases, the probability of both overall and disease-free survival at 2 years was 0.94 (95% confidence interval 0.63-0.99). This pilot study demonstrates that radioimmunotherapy is effective in achieving myeloablation with low additional toxicity when used in combination with standard or reduced-intensity conditioning in young patients.

Prediction of Nodal Involvement in Breast Cancer Based on Multiparametric Protein Analyses from Preoperative Core Needle Biopsies of the Primary Lesion

Purpose: Identification of molecular characteristics that are useful to define subgroups of patients fitting into differential treatment schemes is considered a most promising approach in cancer research. In this first study of such type, we therefore investigated the potential of multiplexed sandwich immunoassays to define protein expression profiles indicative of clinically relevant properties of malignant tumors. Experimental Design: Lysates prepared from large core needle biopsies of 113 invasive breast carcinomas were analyzed with bead-based miniaturized sandwich immunoassays specific for 54 preselected proteins. Results: Five protein concentrations [fibroblast growth factor-2 (FGF-2), Fas, Fas ligand, tissue inhibitor of metalloproteinase-1, and RANTES] were significantly different in the groups of patients with or without axillary lymph node metastasis. All 15 protein parameters that resulted in P values <0.2 and other diagnostic information [estrogen receptor (ER) status, tumor size, and histologic grading] were analyzed together by multivariate logistic regression. This yielded sets of five (FGF-2, Fas, Fas ligand, IP10, and PDGF-AB/BB) or six (ER staining intensity, FGF-2, Fas ligand, matrix metalloproteinase-13, PDGF-AB/BB, and IP10) parameters for which receiver-operator characteristic analyses revealed high sensitivities and specificities [area under curve (AUC) = 0.75 and AUC = 0.83] to predict the nodal status. A similar analysis including all identified parameters of potential value (15 proteins, ER staining intensity, T) without selection resulted in a receiver-operator characteristic curve with an AUC of 0.87. Conclusion: We clearly showed that this approach can be used to quantify numerous proteins from breast biopsies accurately in parallel and define sets of proteins whose combined analyses allow the prediction of nodal involvement with high specificity and sensitivity.

Assessment of COPD severity by computed tomography: correlation with lung functional testing

CT scans of 474 patients with suspected chronic obstructive pulmonary disease (COPD) were retrospectively evaluated by automated software. There was a correlation between the total lung capacity (TLC) and the total lung volume (TLV) (r=.675, P<.001), between the TLC and the total emphysema volume (r=.571, P<.001), as well as between the TLC and the emphysema index (r=.532, P<.001), respectively. The correlation between the TLC and the TLV was dependent on the COPD severity according to the Global Initiative for Chronic Obstructive Lung Disease classification (chi(2)=6.3079, P=.043). The TLC allows a prediction of clinical illness severity.

Effectiveness of Trauma-Focused Cognitive Behavioral Therapy for Children and Adolescents: A Randomized Controlled Trial in Eight German Mental Health Clinics

Background: Trauma-focused cognitive behavioral therapy (Tf-CBT) is efficacious for children and adolescents with posttraumatic stress symptoms (PTSS). Its effectiveness in clinical practice has still to be investigated. Aims: To determine whether Tf-CBT is superior to waiting list (WL), and to investigate the predictors of treatment response. Method: We conducted a single-blind parallel-group randomized controlled trial in eight German outpatient clinics with the main inclusion criteria of age 7-17 years, symptom score ≥35 on the Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA), and caregiver participation. Patients were randomly assigned to 12 sessions of Tf-CBT (n = 76) or a WL (n = 83). The primary outcome was the CAPS-CA symptom score assessed at 4 months by blinded evaluators. The secondary measures were diagnostic status, the Childrens Global Assessment Scale (CGAS), self-reported and caregiver-reported PTSS (UCLA-PTSD Reaction Index), the Child Posttraumatic Cognitions Inventory (CPTCI), the Childrens Depression Inventory (CDI), the Screen for Child Anxiety- Related Emotional Disorders (SCARED), the Child Behavior Checklist (CBCL/4-18), and the Quality of Life Inventory for Children. Results: Intention-to-treat analyses showed that Tf-CBT was significantly superior to WL on the CAPS-CA (Tf-CBT: baseline = 58.51 ± 17.41; 4 months = 32.16 ± 26.02; WL: baseline = 57.39 ± 16.05; 4 months = 43.29 ± 25.2; F1, 157 = 12.3; p = 0.001; d = 0.50), in terms of secondary measures of the CGAS, UCLA-PTSD-RI, CPTCI, CDI, SCARED, and CBCL/4-18, but not in terms of quality of life. Age and comorbidity significantly predicted treatment response. Conclusions: Tf-CBT is effective for children and adolescents with heterogeneous trauma types in German service settings. Younger patients with fewer comorbid disorders show most improvement.