Refine
Year of publication
- 2013 (285) (remove)
Document Type
- Article (242)
- Conference Proceeding (13)
- Part of Periodical (12)
- Doctoral Thesis (9)
- Contribution to a Periodical (6)
- Book (1)
- Part of a Book (1)
- Periodical (1)
Is part of the Bibliography
- no (285) (remove)
Keywords
- Video (19)
- Capsule endoscopy (12)
- Small bowel (10)
- Endoscopy (7)
- Balloon enteroscopy (6)
- Enteroscopy (6)
- Endoscopic retrograde cholangiopancreatography (4)
- Apoptosis (3)
- IAP proteins (3)
- Smac (3)
Institute
- Medizin (285) (remove)
Background: A number of scientific papers on yellow fever have been published but no broad scientometric analysis on the published research of yellow fever has been reported. The aim of the article based study was to provide an in-depth evaluation of the yellow fever field using large-scale data analysis and employment of bibliometric indicators of production and quantity.
Methods: Data were retrieved from the Web of Science database (WoS) and analyzed as part of the NewQis platform. Then data were extracted from each file, transferred to databases and visualized as diagrams. Partially by means of density-equalizing mapping makes the findings clear and emphasizes the output of the analysis.
Results: In the study period from 1900 to 2012 a total of 5,053 yellow fever-associated items were published by 79 countries. The United States (USA) having the highest publication rate at 42% (n = 751) followed by far from Brazil (n = 203), France (n = 149) and the United Kingdom (n = 113). The most productive journals are the "Public Health Reports", the "American Journal of Tropical Medicine and Hygiene" and the "Journal of Virology". The gender analysis showed an overall steady increase of female authorship from 1950 to 2011. Brazil is the only country of the five most productive countries with a higher proportion of female scientists.
Conclusions: The present data shows an increase in research productivity over the entire study period, in particular an increase of female scientists. Brazil shows a majority of female authors, a fact that is confirmed by other studies.
Background: Tobacco is a leading environmental factor in the initiation of respiratory diseases and causes chronic obstructive pulmonary disease (COPD). Suppressor of cytokine signaling (SOCS) family members are involved in the pathogenesis of many inflammatory diseases and SOCS-3 has been shown to play an important role in the regulation, onset and maintenance of airway allergic inflammation indicating that SOCS-3 displays a potential therapeutic target for anti-inflammatory respiratory drugs development. Since chronic obstructive pulmonary disease (COPD) is also characterized by inflammatory changes and airflow limitation, the present study assessed the transcriptional expression of SOCS-3 in COPD.
Methods: Real-time PCR was performed to assess quantitative changes in bronchial biopsies of COPD patients in comparison to unaffected controls.
Results: SOCS-3 was significantly down-regulated in COPD at the transcriptional level while SOCS-4 and SOCS-5 displayed no change.
Conclusions: It can be concluded that the presently observed inhibition of SOCS-3 mRNA expression may be related to the dysbalance of cytokine signaling observed in COPD.
Vasoactive intestinal polypeptide (VIP) is a putative neurotransmitter of the inhibitory non-adrenergic non-cholinergic nervous system and influences the mammalian airway function in various ways. Hence known for bronchodilatory, immunomodulatory and mucus secretion modulating effects by interacting with the VIP receptors VPAC1 and VPAC2, it is discussed to be a promising target for pharmaceutical intervention in common diseases such as COPD and bronchial asthma. Here we examined the expression and transcriptional regulation of VPAC1 in the lungs of allergic mice using an ovalbumin (OVA) -induced model of allergic asthma. Mice were sensitized to OVA and challenged with an OVA aerosol. In parallel a control group was sham sensitized with saline. VPAC1 expression was examined using RT-PCR and real time-PCR studies were performed to quantify gene transcription. VPAC1 mRNA expression was detected in all samples of OVA-sensitized and challenged animals and control tissues. Further realtime analysis did not show significant differences at the transcriptional level.
Although the present studies did not indicate a major transcriptional regulation of VPAC1 in states of allergic airway inflammation, immunomodulatory effects of VPAC1 might still be present due to regulations at the translational level.
Background: Interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection yields sustained virological response (SVR) rates of 50–80%. Several factors such as non-1 genotype, beneficial IL28B genetic variants, low baseline IP-10, and the functionality of HCV-specific T cells predict SVR. With the pending introduction of new therapies for HCV entailing very rapid clearance of plasma HCV RNA, the importance of baseline biomarkers likely will increase in order to tailor therapy. CD26 (DPPIV) truncates the chemokine IP-10 into a shorter antagonistic form, and this truncation of IP-10 has been suggested to influence treatment outcome in patients with chronic HCV infection patients. In addition, previous reports have shown CD26 to be a co-stimulator for T cells. The aim of the present study was to assess the utility of CD26 as a biomarker for treatment outcome in chronic hepatitis C and to define its association with HCV-specific T cells.
Methods: Baseline plasma from 153 genotype 1 and 58 genotype 2/3 infected patients enrolled in an international multicenter phase III trial (DITTO-HCV) and 36 genotype 1 infected patients participating in a Swedish trial (TTG1) were evaluated regarding baseline soluble CD26 (sCD26) and the functionality of HCV-specific CD8+ T cells.
Results: Genotype 1 infected patients achieving SVR in the DITTO (P = 0.002) and the TTG1 (P = 0.02) studies had lower pretreatment sCD26 concentrations compared with non-SVR patients. Sixty-five percent of patients with sCD26 concentrations below 600 ng/mL achieved SVR compared with 39% of the patients with sCD26 exceeding 600 ng/mL (P = 0.01). Patients with sCD26 concentrations below 600 ng/mL had significantly higher frequencies of HCV-specific CD8+ T cells (P = 0.02).
Conclusions: Low baseline systemic concentrations of sCD26 predict favorable treatment outcome in chronic HCV infection and may be associated with higher blood counts of HCV-specific CD8+ T cells.
Oral presentation: 23rd World Congress of the World Society of Cardio-Thoracic Surgeons. Split, Croatia. 12-15 September 2013.
Background: Partial upper sternotomy (PUS) is established less invasive approach for single and double valve surgery. Reports of aortic surgery performed through PUS are rare.
Methods: The records of 52 patients undergoing primary elective surgery on the proximal aorta through PUS between 2005 and 2011 were reviewed. Patients mean age was 57 years, 35% were in NYHA Class III or IV, 59% had recent cardiac decompensation, and 17% had pulmonary hypertension. The PUS was taken down to the 4th left intercostal space in 44 patients (85%).
Results: No conversion to full sternotomy was necessary. The aortic cross-clamp, cardiopulmonary bypass and operative times averaged 136 ± 20 min., 186 ± 36 min. and 327 ± 83 min., respectively. In eight patients, the right axillary artery was cannulated for establishing cardiopulmonary bypass; the others were cannulated centrally. All patients except one received a procedure on the ascending aorta, either replacement in 30 (58%) or reduction aortoplasty in 21 (40%). Aortic root replacement was additionally performed in 31 patients (60%), including David in 20 (38%) and Ross procedure in 6 (11.5%). The aortic arch was replaced either partially in 5 (10%) or totally in 3 (6%) patients, in moderate hypothermia employing antegrade cerebral perfusion. Additional procedures, included mitral valve repair in 15 (29%) patients and coronary grafting. Ventilation time, intensive care unit and hospital stay averaged 17 ± 12 hours, 2 ± 1, and 11 ± 9 days. Chest drainage was 470 ± 380 ml/24 hours. Permanent neurologic deficit did not occur. Wound dehiscence was observed in a single patient (2%). Thirty-day and hospital mortality were not observed.
Conclusions: Less invasive surgery on the aortic root, ascending aorta and aortic arch can be performed safely and reproducibly. Potential benefits include a minimized risk of wound dehiscence and reduced postoperative bleeding. The PUS does not compromise the quality of the operation.
Oral presentation: 23rd World Congress of the World Society of Cardio-Thoracic Surgeons. Split, Croatia. 12-15 September 2013.
Background: In the past, questions have been raised, whether an open flexible annuloplasty band can reliably prevent recurrent mitral valve regurgitation. The purpose of this study was to evaluate the durability of mitral valve repair at midterm, using the Cosgrove-Edwards annuloplasty band in a homogenic patient cohort.
Methods: From January 2004 to December 2007, 157 consecutive patients with degenerative mitral valve disease were included in the study. All had quadrangular resection of a P2 prolapse and annuloplasty with a Cosgrove-Edwards annuloplasty band. Clinical and echocardiography follow-up was complete.
Results: There was no intraoperative or 30 day mortality. After a mean follow-up of 5.0 ± 1.9 years, survival was 94.3%. At midterm, freedom from reoperations was 98.9%, freedom from thromboembolism was 97.5% and freedom from endocarditis was 99.4%. Echocardiography follow-up showed recurrent mitral valve regurgitation higher than grade 2 in two patients. Mean ejection fraction was 60.3 ± 10.2%, left atrial diameter was 42 ± 7 mm, mean gradient was 3.2 ± 1.4 mmHg, effective orifice area was 3.3 ± 1.3cm², mitral leaflet coaptation length was 7.5 ± 1.9 mm and mitral leaflet tethering height was 6.2 ± 2.3 mm.
Conclusion: Mitral valve repair using the Cosgrove annuloplasty band for degenerative mitral valve disease provides an effective and durable form of reconstruction.
Persistent infections with hepatitis C virus (HCV) may result in life-threatening liver disease, including cirrhosis and cancer, and impose an important burden on human health. Understanding how the virus is capable of achieving persistence in the majority of those infected is thus an important goal. Although HCV has evolved multiple mechanisms to disrupt and block cellular signaling pathways involved in the induction of interferon (IFN) responses, IFN-stimulated gene (ISG) expression is typically prominent in the HCV-infected liver. Here, we show that Toll-like receptor 3 (TLR3) expressed within uninfected hepatocytes is capable of sensing infection in adjacent cells, initiating a local antiviral response that partially restricts HCV replication. We demonstrate that this is dependent upon the expression of class A scavenger receptor type 1 (MSR1). MSR1 binds extracellular dsRNA, mediating its endocytosis and transport toward the endosome where it is engaged by TLR3, thereby triggering IFN responses in both infected and uninfected cells. RNAi-mediated knockdown of MSR1 expression blocks TLR3 sensing of HCV in infected hepatocyte cultures, leading to increased cellular permissiveness to virus infection. Exogenous expression of Myc-MSR1 restores TLR3 signaling in MSR1-depleted cells with subsequent induction of an antiviral state. A series of conserved basic residues within the carboxy-terminus of the collagen superfamily domain of MSR1 are required for binding and transport of dsRNA, and likely facilitate acidification-dependent release of dsRNA at the site of TLR3 expression in the endosome. Our findings reveal MSR1 to be a critical component of a TLR3-mediated pattern recognition receptor response that exerts an antiviral state in both infected and uninfected hepatocytes, thereby limiting the impact of HCV proteins that disrupt IFN signaling in infected cells and restricting the spread of HCV within the liver.
Background: Whereas it is well established that various soluble biomarkers can predict level of liver fibrosis, their ability to predict liver-related clinical outcomes is less clearly established, in particular among HIV/viral hepatitis co-infected persons. We investigated plasma hyaluronic acid’s (HA) ability to predict risk of liver-related events (LRE; hepatic coma or liver-related death) in the EuroSIDA study.
Methods: Patients included were positive for anti-HCV and/or HBsAg with at least one available plasma sample. The earliest collected plasma sample was tested for HA (normal range 0–75 ng/mL) and levels were associated with risk of LRE. Change in HA per year of follow-up was estimated after measuring HA levels in latest sample before the LRE for those experiencing this outcome (cases) and in a random selection of one sixth of the remaining patients (controls).
Results: During a median of 8.2 years of follow-up, 84/1252 (6.7%) patients developed a LRE. Baseline median (IQR) HA in those without and with a LRE was 31.8 (17.2–62.6) and 221.6 ng/mL (74.9–611.3), respectively (p<0.0001). After adjustment, HA levels predicted risk of contracting a LRE; incidence rate ratios for HA levels 75–250 or ≥250 vs. <75 ng/mL were 5.22 (95% CI 2.86–9.26, p<0.0007) and 28.22 (95% CI 14.95–46.00, p<0.0001), respectively. Median HA levels increased substantially prior to developing a LRE (107.6 ng/mL, IQR 0.8 to 251.1), but remained stable for controls (1.0 ng/mL, IQR –5.1 to 8.2), (p<0.0001 comparing cases and controls), and greater increases predicted risk of a LRE in adjusted models (p<0.001).
Conclusions: An elevated level of plasma HA, particularly if the level further increases over time, substantially increases the risk of contracting LRE over the next five years. HA is an inexpensive, standardized and non-invasive supplement to other methods aimed at identifying HIV/viral hepatitis co-infected patients at risk of hepatic complications.
Early vascularization is a prerequisite for successful bone healing and endothelial progenitor cells (EPC), seeded on appropriate biomaterials, can improve vascularization. The type of biomaterial influences EPC function with bioglass evoking a vascularizing response. In this study the influence of a composite biomaterial based on polylactic acid (PLA) and either 20 or 40% bioglass, BG20 and BG40, respectively, on the differentiation and survival of EPCs in vitro was investigated. Subsequently, the effect of the composite material on early vascularization in a rat calvarial critical size defect model with or without EPCs was evaluated. Human EPCs were cultured with β-TCP, PLA, BG20 or BG40, and seeding efficacy, cell viability, cell morphology and apoptosis were analysed in vitro. BG40 released the most calcium, and improved endothelial differentiation and vitality best. This effect was mimicked by adding an equivalent amount of calcium to the medium and was diminished in the presence of the calcium chelator, EGTA. To analyze the effect of BG40 and EPCs in vivo, a 6-mm diameter critical size calvarial defect was created in rats (n = 12). Controls (n = 6) received BG40 and the treatment group (n = 6) received BG40 seeded with 5×105 rat EPCs. Vascularization after 1 week was significantly improved when EPCs were seeded onto BG40, compared to implanting BG40 alone. This indicates that Ca2+ release improves EPC differentiation and is useful for enhanced early vascularization in critical size bone defects.
Ataxin-2 (ATXN2) is implicated mainly in mRNA processing. Some ATXN2 associates with receptor tyrosine kinases (RTK), inhibiting their endocytic internalization through interaction of proline-rich domains (PRD) in ATXN2 with SH3 motifs in Src. Gain of function of ATXN2 leads to neuronal atrophy in the diseases spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). Conversely, ATXN2 knockout (KO) mice show hypertrophy and insulin resistance. To elucidate the influence of ATXN2 on trophic regulation, we surveyed interactions of ATXN2 with SH3 motifs from numerous proteins and observed a novel interaction with Grb2. Direct binding in glutathione S-transferase (GST) pull-down assays and coimmunoprecipitation of the endogenous proteins indicated a physiologically relevant association. In SCA2 patient fibroblasts, Grb2 more than Src protein levels were diminished, with an upregulation of both transcripts suggesting enhanced protein turnover. In KO mouse embryonal fibroblasts (MEF), the protein levels of Grb2 and Src were decreased. ATXN2 absence by itself was insufficient to significantly change Grb2-dependent signaling for endogenous Ras levels, Ras-GTP levels, and kinetics as well as MEK1 phosphorylation, suggesting that other factors compensate for proliferation control. In KO tissue with postmitotic neurons, a significant decrease of Src protein levels is prominent rather than Grb2. ATXN2 mutations modulate the levels of several components of the RTK endocytosis complex and may thus contribute to alter cell proliferation as well as translation and growth.
The effect of 10 Hz transcranial alternating current stimulation (tACS) on corticomuscular coherence
(2013)
Synchronous oscillatory activity at alpha (8–12 Hz), beta (13–30 Hz), and gamma (30–90 Hz) frequencies is assumed to play a key role for motor control. Corticomuscular coherence (CMC) represents an established measure of the pyramidal system's integrity. Transcranial alternating current stimulation (tACS) offers the possibility to modulate ongoing oscillatory activity. Behaviorally, 20 Hz tACS in healthy subjects has been shown to result in movement slowing. However, the neurophysiological changes underlying these effects are not entirely understood yet. The present study aimed at ascertaining the effects of tACS at 10 and 20 Hz in healthy subjects on CMC and local power of the primary sensorimotor cortex. Neuromagnetic activity was recorded during isometric contraction before and at two time points (2–10 min and 30–38 min) after tACS of the left primary motor cortex (M1), using a 306 channel whole head magnetoencephalography (MEG) system. Additionally, electromyography (EMG) of the right extensor digitorum communis (EDC) muscle was measured. TACS was applied at 10 and 20 Hz, respectively, for 10 min at 1 mA. Sham stimulation served as control condition. The data suggest that 10 Hz tACS significantly reduced low gamma band CMC during isometric contraction. This implies that tACS does not necessarily cause effects at stimulation frequency. Rather, the findings suggest cross-frequency interplay between alpha and low gamma band activity modulating functional interaction between motor cortex and muscle.
Important brain functions need to be conserved throughout organisms of extremely varying sizes. Here we study the scaling properties of an essential component of computation in the brain: the single neuron. We compare morphology and signal propagation of a uniquely identifiable interneuron, the HS cell, in the blowfly (Calliphora) with its exact counterpart in the fruit fly (Drosophila) which is about four times smaller in each dimension. Anatomical features of the HS cell scale isometrically and minimise wiring costs but, by themselves, do not scale to preserve the electrotonic behaviour. However, the membrane properties are set to conserve dendritic as well as axonal delays and attenuation as well as dendritic integration of visual information. In conclusion, the electrotonic structure of a neuron, the HS cell in this case, is surprisingly stable over a wide range of morphological scales.
Despite the availability of new antifungal compounds, invasive fungal infection remains a significant cause of morbidity and mortality in children and adults undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT recipients suffer from a long lasting defect of different arms of the immune system, which increases the risk for and deteriorates the prognosis of invasive fungal infections. In turn, advances in understanding these immune deficits have resulted in promising strategies to enhance or restore critical immune functions in allogeneic HSCT recipients. Potential approaches include the administration of granulocytes, since neutropenia is the single most important risk factor for invasive fungal infection, and preliminary clinical results suggest a benefit of adoptively transferred donor-derived antifungal T cells. In vitro data and animal studies demonstrate an antifungal effect of natural killer cells, but clinical data are lacking to date. This review summarizes and critically discusses the available data of immunotherapeutic strategies in allogeneic HSCT recipients suffering from invasive fungal infection.
The study objective was to assess the current status of HIV knowledge, attitudes and behavior (KAB) among employees of Namibian ministries. As most HIV campaigning takes place in the capital of Windhoek, an additional aim was to compare Windhoek to four regions (Hardap, Erongo, Oshana, and Caprivi). Between January and March 2011 a cross-sectional survey was conducted in two Namibian ministries, with participants selected randomly from the workforce. Data collection was based on questionnaires. 832 participants were included in the study (51.6% male). Nearly 90% of participants reported to have been tested for HIV before. Knowledge about HIV transmission ranged from 67% to 95% of correct answers, with few differences between the capital and regions. However, a knowledge gap regarding HIV transmission and prevention was seen. In particular, we found significantly lower knowledge regarding transmission from mother-to-child during pregnancy and higher rate of belief in a supernatural role in HIV transmission. In addition, despite many years of HIV prevention activities, a substantial proportion of employees had well-known HIV risk factors including multiple concurrent partnership rates (21%), intergenerational sex (19%), and lower testing rates for men (82% compared to women with 91%).
Aging is a complex process that is linked to an increased incidence of major diseases such as cardiovascular and neurodegenerative disease, but also cancer and immune disorders. MicroRNAs (miRNAs) are small non-coding RNAs, which post-transcriptionally control gene expression by inhibiting translation or inducing degradation of targeted mRNAs. MiRNAs target up to hundreds of mRNAs, thereby modulating gene expression patterns. Many miRNAs appear to be dysregulated during cellular senescence, aging and disease. However, only few miRNAs have been so far linked to age-related changes in cellular and organ functions. The present article will discuss these findings, specifically focusing on the cardiovascular and neurological systems.
Bbackground: We aimed to investigate the prognostic value of tumour-infiltrating lymphocytes’ (TILs) expression in pretreatment specimens from patients with head and neck squamous cell carcinoma (HNSCC) treated with definitive chemoradiotherapy (CRT).
Methods: The prevalence of CD3+, CD8+, CD4+ and FOXP3+ TILs was assessed using immunohistochemistry in tumour tissue obtained from 101 patients before CRT and was correlated with clinicopathological characteristics as well as local failure-free- (LFFS), distant metastases free- (DMFS), progression-free (PFS) and overall survival (OS). Survival curves were measured using the Kaplan–Meier method, and differences in survival between the groups were estimated using the log-rank test. Prognostic effects of TIL subset density were determined using the Cox regression analysis.
Results: With a mean follow-up of 25 months (range, 2.3–63 months), OS at 2 years was 57.4% for the entire cohort. Patients with high immunohistochemical CD3 and CD8 expression had significantly increased OS (P=0.024 and P=0.028), PFS (P=0.044 and P=0.047) and DMFS (P=0.021 and P=0.026) but not LFFS (P=0.90 and P=0.104) in multivariate analysis that included predictive clinicopathologic factors, such as age, sex, T-stage, N-stage, tumour grading and localisation. Neither CD4 nor FOXP3 expression showed significance for the clinical outcome. The lower N-stage was associated with improved OS in the multivariate analysis (P=0.049).
Conclusion: The positive correlation between a high number of infiltrating CD3+ and CD8+ cells and clinical outcome indicates that TILs may have a beneficial role in HNSCC patients and may serve as a biomarker to identify patients likely to benefit from definitive CRT.
Objectives: To describe changes in costs of managing hospitalised patients with acute myeloid leukaemia (AML) after chemotherapy in Germany over 3 yr, with a special focus on prophylaxis and treatment patterns as well as resource use related to invasive fungal infections (IFI).
Methods: The study was conducted as a retrospective, single-centre chart review in patients with AML hospitalised for chemotherapy, neutropenia and infections after myelosuppressive chemotherapy from January 2004 to December 2006 in Germany. The following resource utilisation data were collected: inpatient stay, mechanical ventilation, parenteral feeding, diagnostics, systemic antifungal medication and cost-intensive concomitant medication. Direct medical costs were calculated from hospital provider perspective.
Results: A total of 471 episodes in 212 patients were included in the analysis. Occurrence of IFI decreased from 5.9% in 2004 to 1.9% in 2006. Mean (± standard deviation) hospital stay decreased from 28.7 ± 17.9 d in 2004 to 22.4 ± 11.8 d in 2006. From 2004 to 2006, the use of a single antifungal drug increased from 30.4% to 46.9%, whereas the use of multiple antifungal drugs decreased from 24.4% to 13.1%. The use of liposomal amphotericin B declined between 2004 and 2006 (21.4% vs. 3.8%) and caspofungin between 2005 and 2006 (19.3% vs. 8.1%). Total costs per episode declined from €19051 ± 19024 in 2004 to €13531 ± 9260 in 2006; major reductions were observed in the use of antimycotics and blood products as well as length of hospital stay.
Conclusion: Analysis of real-life data from one single centre in Germany demonstrated a change in antifungal management of patients with AML between 2004/2005 and 2006, accompanied by a decline in total costs.
Background: This phase I/II-trial assessed the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of neoadjuvant radiochemotherapy (RCT) with docetaxel and oxaliplatin in patients with locally advanced adenocarcinoma of the oesophagogastric junction.
Methods: Patients received neoadjuvant radiotherapy (50.4 Gy) together with weekly docetaxel (20 mg/m2 at dose level (DL) 1 and 2, 25 mg/m2 at DL 3) and oxaliplatin (40 mg/m2 at DL 1, 50 mg/m2 at DL 2 and 3) over 5 weeks. The primary endpoint was the DLT and the MTD of the RCT regimen. Secondary endpoints included overall response rate (ORR) and progression-free survival (PFS).
Results: A total of 24 patients were included. Four patients were treated at DL 1, 13 patients at DL 2 and 7 patients at DL 3. The MTD of the RCT was considered DL 2 with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m2. Objective response (CR/PR) was observed in 32% (7/22) of patients. Eighteen patients (75%) underwent surgery after RCT. The median PFS for all patients (n = 24) was 6.5 months. The median overall survival for all patients (n = 24) was 16.3 months. Patients treated at DL 2 had a median overall survival of 29.5 months.
Conclusion: Neoadjuvant RCT with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m2 was effective and showed a good toxicity profile. Future studies should consider the addition of targeted therapies to current neoadjuvant therapy regimens to further improve the outcome of patients with advanced cancer of the oesophagogastric junction.
Trial Registration: NCT00374985
Background: Self-management support is a key component of effective chronic care management, yet in practice appears to be the least implemented and most challenging. This study explores whether and how self-management support is integrated into chronic care approaches in 13 European countries. In addition, it investigates the level of and barriers to implementation of support strategies in health care practice.
Methods: We conducted a review among the 13 participating countries, based on a common data template informed by the Chronic Care Model. Key informants presented a sample of representative chronic care approaches and related self-management support strategies. The cross-country review was complemented by a Dutch case study of health professionals’ views on the implementation of self-management support in practice.
Results: Self-management support for chronically ill patients remains relatively underdeveloped in Europe. Similarities between countries exist mostly in involved providers (nurses) and settings (primary care). Differences prevail in mode and format of support, and materials used. Support activities focus primarily on patients’ medical and behavioral management, and less on emotional management. According to Dutch providers, self-management support is not (yet) an integral part of daily practice; implementation is hampered by barriers related to, among others, funding, IT and medical culture.
Conclusions: Although collaborative care for chronic conditions is becoming more important in European health systems, adequate self-management support for patients with chronic disease is far from accomplished in most countries. There is a need for better understanding of how we can encourage both patients and health care providers to engage in productive interactions in daily chronic care practice, which can improve health and social outcomes.
Objectives: This study explores whether and how self-management support (SMS), a key element of well-coordinated chronic care, is integrated into existing chronic care approaches in 13 European countries.
Methodology: An expert review was conducted using a data template informed by the Chronic Care Model. Key informants (researchers and policymakers) from the 13 countries presented a sample of exemplary chronic care approaches and related SMS strategies. This was complemented by interviews with 27 Dutch care professionals investigating SMS implementation in practice.
Results: SMS remains relatively underdeveloped in Europe. Country-specific strategies are similar in involved providers (nurses) and settings (primary care), yet differ considerably in mode, format and materials used. SMS focuses mainly on patients medical and behavioral management, and less on emotional management. According to Dutch providers, barriers in financing and medical culture (e.g. length of consultation, patient-doctor communication) hamper implementation of SMS as an integral part of chronic care.
Conclusion: While Europe might increasingly be talking the talk of patient participation in chronic care, it appears far from walking the walk. Care professionals experience difficulties in operationalizing SMS in their daily routines. Stronger integration with the health promotion field may help patients and professionals to engage in productive partnerships.
Im Rahmen einer prospektiven Kohortenstudie wurde in der vorliegenden Arbeit die Epidemiologie und Ätiologie von Fieber während chemotherapiebedingter Neutropenie bei Patienten mit hämatologischen Neoplasien untersucht. Das diagnostische und therapeutische Vorgehen wurde beschrieben und die Übereinstimmung mit den Vorgaben einer hausinternen Leitlinie wurde evaluiert und der Verbrauch an antimikrobiellen Substanzen dokumentiert. Febrile Episoden konnten in 74% der Neutropenieepisoden dokumentiert werden; in 51% der Neutropenieepisoden kam es zu persistierendem Fieber ≥ 3 Tage. Eine dem Fieber zugrunde liegende Infektion wurde in 55% der Chemotherapiezyklen (Neutropeniedauer Median 16 Tage) mittels klinischer, apparativer und mikrobiologischer Diagnostik gefunden. Die häufigsten infektiösen Komplikationen waren Enteritiden mit Nachweis von C. difficile (11%), Enteritiden ohne Nachweis von C. difficile (29%), Pneumonien mit pilztypischen Infiltraten (12%) und Pneumonien mit unspezifischen Infiltraten (11%), sowie mikrobiologisch bestätigte Septikämien (18%). Im Vergleich zu Angaben in der Literatur wurde FUO in der vorliegenden Untersuchung häufiger diagnostiziert (11,8 Tage pro 1000 Patiententage vs. 8,2 Tage pro 1000 Patiententage). Die Gesamtmortalität des Kollektivs lag bei 7%. Die häufigste Todesursache war der septische Schock (8 von 5 Patienten; 63%), welcher sich auf dem Boden einer gramnegativen Septikämie mit multiresistenten Keimen entwickelt hatte (3 von 5 Septikämien; 60%). Die Mortalitätsrate war ähnlich hoch wie im Literaturvergleich bei Studien mit akuten myeloischen Leukämien. Prognoserelevante Faktoren, welche im Rahmen der vorliegenden Studie evaluiert wurden, sind durch schwer therapierbare Grunderkrankungen hervorgerufene prolongierte Neutropeniezeiten, sowie infektiöse Komplikationen, vor allem bei Nachweis multiresistenter Erreger.
Die Compliance bezüglich des diagnostischen und therapeutischen Vorgehens bei persistierendem Fieber betrug in der vorliegenden Arbeit zwischen 47% und 82%. Die Compliance mit den in der Leitlinie vorgeschlagenen antimikrobiellen prophylaktischen und initialen empirischen Therapien lag zwischen 83% und 85%. Der Gesamtverbrauch an antibiotischen und antimykotischen Substanzen war in der vorliegenden Studie höher als im Literaturvergleich (1647 DDD vs. 1140 DDD und 650 DDD vs. 430 DDD). Dabei fällt insbesondere der hohe Verbrauch an Reservemedikamenten gegen grampositive Bakterien auf. Allerdings fehlen aktuelle Vergleichsdaten vergleichbarer Patientenkollektive.
Bezüglich der Optimierung der diagnostischen Maßnahmen ist vor allem die Erhöhung der Sensitivität der Bronchoalveolären Lavage bei Pilzinfektionen, rechtzeitig und regelmäßig durchgeführte Surveillanceabstriche bei febriler Neutropenie, sowie die Diskussion der diagnostischen Ergebnisse und des weiteren therapeutischen Vorgehens mit infektiologischen Experten zu fordern. Patienten mit persistierendem Fieber - vor allem bei positivem Blutkulturnachweis - sollten, aufgrund des positiven prädiktiven Wertes erregerpositiver Blutkulturen für die Notwendigkeit einer intensivmedizinischen Betreuung und einer erhöhten Mortalität, Anlass sein, diagnostische und therapeutische Maßnahmen zu verbessern. Ziel ist es, durch verstärkten Einsatz diagnostischer Maßnahmen und Diskussion mikrobiologischer Befunde im Einzelfall, Reservesubstanzen seltener einzusetzen, gegebenenfalls Breitspektrum-Antibiotika oder ihre Kombinationen zu deeskalieren und somit die Kolonisation mit resistenten Erregern positiv zu beeinflussen, sowie das Ansprechen auf antimikrobielle Therapien zu optimieren.
Die Teilnahme an multizentrischen Surveillancestudien zur Inzidenzerfassung wichtiger, eindeutig definierter neutropener nosokomialer Infektionen wie radiologisch detektierter Pneumonien, mikrobiologisch bestätigter Septikämien und C. difficilepositiver Enteritiden, sowie zur Generierung von Antiinfektivaverbrauchszahlen, könnte helfen, die Beratung und Entscheidungsfindung am Krankenbett zu unterstützen. Auch könnten in diesem Rahmen Zahlen generiert werden, welche bisher zum Vergleich fehlten.
Die vorliegende Arbeit versteht sich im Rahmen der Erfassung von Ätiologie, Diagnostik und antimikrobieller Therapien bei febriler Neutropenie als Teil eines solchen Surveillanceprogrammes und hat somit eine Grundlagen für zukünftige Datenerhebungen geliefert.
Plus Puls : 2013, 3
(2013)
Plus Puls : 2013, 1
(2013)
Plus Puls : 2013, 2
(2013)
Plus Puls : 2013, 4
(2013)
Transcription factors play a crucial role in regulating differentiation processes during human life and are important in disease. The basic helix-loop-helix transcription factors Tal1 and Lyl1 play a major role in the regulation of gene expression in the hematopoietic system and are involved in human leukemia. Tal2, which belongs to the same family of transcription factors as Tal1 and Lyl1, is also involved in human leukaemia. However, little is known regarding the expression and regulation of Tal2 in hematopoietic cells. Here we show that Tal2 is expressed in hematopoietic cells of the myeloid lineage. Interestingly, we found that usage of the Tal2 promoter is different in human and mouse cells. Two promoters, hP1 and hP2 drive Tal2 expression in human erythroleukemia K562 cells, however in mouse RAW cells only the mP1 promoter is used. Furthermore, we found that Tal2 expression is upregulated during oesteoclastogenesis. We show that Tal2 is a direct target gene of the myeloid transcription factor PU.1, which is a key transcription factor for osteoclast gene expression. Strikingly, PU.1 binding to the P1 promoter is conserved between mouse and human, but PU.1 binding to P2 was only detected in human K562 cells. Additionally, we provide evidence that Tal2 influences the expression of the osteoclastic differentiation gene TRACP. These findings provide novel insight into the expression control of Tal2 in hematopoietic cells and reveal a function of Tal2 as a regulator of gene expression during osteoclast differentiation.
Aim: To evaluate the effectiveness of two different strategies using radiofrequency catheter ablation for redo procedures after cryoablation of atrial fibrillation.
Methods: Thirty patients (paroxysmal atrial fibrillation: 22 patients, persistent atrial fibrillation: 8 patients) had to undergo a redo procedure after initially successful circumferential pulmonary vein (PV) isolation with the cryoballoon technique (Arctic Front Balloon, CryoCath Technologies/Medtronic). The redo ablation procedures were performed using a segmental approach or a circumferential ablation strategy (CARTO; Biosense Webster) depending on the intra-procedural findings. After discharge, patients were scheduled for repeated visits at the arrhythmia clinic. A 7-day Holter monitoring was performed at 3, 12 and 24 mo after the ablation procedure.
Results: During the redo procedure, a mean number of 2.9 re-conducting pulmonary veins (SD ± 1.0 PVs) were detected (using a circular mapping catheter). In 20 patients, a segmental approach was sufficient to eliminate the residual pulmonary vein conduction because there were only a few recovered pulmonary vein fibres. In the remaining 10 patients, a circumferential ablation strategy was used because of a complete recovery of the PV-LA conduction. All recovered pulmonary veins could be isolated successfully again. At 2-year follow-up, 73.3% of all patients were free from an arrhythmia recurrence (22/30). There were no major complications.
Conclusion: In patients with an initial circumferential pulmonary vein isolation using the cryoballoon technique, a repeat ablation procedure can be performed safely and effectively using radiofrequency catheter ablation.
Suitable and reproducible experimental models of translational research in reconstructive surgery that allow in-vivo investigation of diverse molecular and cellular mechanisms are still limited. To this end we created a novel murine model of acute hindlimb ischemia-reperfusion to mimic a microsurgical free flap procedure. Thirty-six C57BL6 mice (n = 6/group) were assigned to one control and five experimental groups (subject to 6, 12, 96, 120 hours and 14 days of reperfusion, respectively) following 4 hours of complete hindlimb ischemia. Ischemia and reperfusion were monitored using Laser-Doppler Flowmetry. Hindlimb tissue components (skin and muscle) were investigated using histopathology, quantitative immunohistochemistry and immunofluorescence. Despite massive initial tissue damage induced by ischemia-reperfusion injury, the structure of the skin component was restored after 96 hours. During the same time, muscle cells were replaced by young myotubes. In addition, initial neuromuscular dysfunction, edema and swelling resolved by day 4. After two weeks, no functional or neuromuscular deficits were detectable. Furthermore, upregulation of VEGF and tissue infiltration with CD34-positive stem cells led to new capillary formation, which peaked with significantly higher values after two weeks. These data indicate that our model is suitable to investigate cellular and molecular tissue alterations from ischemia-reperfusion such as occur during free flap procedures.
Corneal scarring remains a major cause of blindness world-wide, with limited treatment options, all of which have side-effects. Here, we tested the hypothesis that topical application of Rosiglitazone, a Thiazolidinedione and ligand of peroxisome proliferator activated receptor gamma (PPARγ), can effectively block scar formation in a cat model of corneal damage. Adult cats underwent bilateral epithelial debridement followed by excimer laser ablation of the central corneal stroma to a depth of ~160 µm as a means of experimentally inducing a reproducible wound. Eyes were then left untreated, or received 50 µl of either 10 µM Rosiglitazone in DMSO/Celluvisc, DMSO/Celluvisc vehicle or Celluvisc vehicle twice daily for 2 weeks. Cellular aspects of corneal wound healing were evaluated with in vivo confocal imaging and post-mortem immunohistochemistry for alpha smooth muscle actin (αSMA). Impacts of the wound and treatments on optical quality were assessed using wavefront sensing and optical coherence tomography at 2, 4, 8 and 12 weeks post-operatively. In parallel, cat corneal fibroblasts were cultured to assess the effects of Rosiglitazone on TGFβ-induced αSMA expression. Topical application of Rosiglitazone to cat eyes after injury decreased αSMA expression and haze, as well as the induction of lower-order and residual, higher-order wavefront aberrations compared to vehicle-treated eyes. Rosiglitazone also inhibited TGFβ-induced αSMA expression in cultured corneal fibroblasts. In conclusion, Rosiglitazone effectively controlled corneal fibrosis in vivo and in vitro, while restoring corneal thickness and optics. Its topical application may represent an effective, new avenue for the prevention of corneal scarring with distinct advantages for pathologically thin corneas.
kurz und kn@pp news : Nr. 28
(2013)
Je besser Forscher es verstehen, defekte Gene zu reparieren oder beliebige Körperzellen zu reprogrammieren, desto gefahrloser wird die Gen- und Stammzell-Therapie für Patienten, die an heute noch unheilbaren Krankheiten leiden. Gleichzeitig zeichnet sich damit die Möglichkeit ab, in ferner Zukunft vielleicht das Genom kommender Generationen zu verändern oder Menschen zu klonieren. Der Internist Prof. Hubert Serve und die Politikwissenschaftlerin Dr. Anja Karnein wagen im Gespräch mit den beiden Redakteurinnen des Wissenschaftsmagazins »Forschung Frankfurt« Dr. Anne Hardy und Ulrike Jaspers einen Ausblick jenseits aller aktuellen Debatten. Sie diskutieren aber auch über die Themen, die Patienten wie Wissenschaftler zurzeit unmittelbar berühren.
Smac mimetic promotes apoptosis by neutralizing inhibitor of apoptosis (IAP) proteins and is considered as a promising cancer therapeutic. Although an autocrine/paracrine tumor necrosis factor-α (TNFα) loop has been implicated in Smac mimetic-induced cell death, little is yet known about additional factors that determine sensitivity to Smac mimetic. Using genome-wide gene expression analysis, we identify death receptor 5 (DR5) as a novel key mediator of Smac mimetic-induced apoptosis. Although several cell lines that are sensitive to the Smac mimetic BV6 die in a TNFα-dependent manner, A172 glioblastoma cells undergo BV6-induced apoptosis largely independently of TNFα/TNFR1, as the TNFα-blocking antibody Enbrel or TNFR1 knockdown provide little protection. Yet, BV6-stimulated nuclear factor-κB (NF-κB) activation is critically required for apoptosis, as inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) blocks BV6-induced apoptosis. Unbiased genome-wide gene expression studies in IκBα-SR-overexpressing cells versus vector control cells reveal that BV6 increases DR5 expression in a NF-κB-dependent manner. Importantly, this BV6-stimulated upregulation of DR5 is critically required for apoptosis, as transient or stable knockdown of DR5 significantly inhibits BV6-triggered apoptosis. In addition, DR5 silencing attenuates formation of a RIP1/FADD/caspase-8 cytosolic cell death complex and activation of caspase-8, -3 and -9. By identifying DR5 as a critical mediator of Smac mimetic-induced apoptosis, our findings provide novel insights into the determinants that control susceptibility of cancer cells to Smac mimetic.
Background: Classical dance comprises gender specific movement tasks. There is a lack of studies which investigate work related traumatic injuries in terms of gender specific differences in detail.
Objective: To define gender related differences of occupational accidents.
Methods: Basis for the evaluation were occupational injuries of professional dancers from three (n = 785; f: n = 358, m: n = 427) state theatres.
Results: The incidence rate (0.36 per year) was higher in males (m: 0.45, f: 0.29). There were gender specific differences as to the localizations of injuries, particularly the spine region (m: 17.3%, f: 9.8%, p = 0.05) and ankle joint (m: 23.7%, f: 35.5%, p = 0.003). Compared to male dancers, females sustained more injuries resulting from extrinsic factors. Significant differences could specifically be observed with dance floors (m: 8.8%, f: 15.1%, p = 0.02). There were also significant gender differences observed with movement vocabulary.
Conclusion: The clearly defined gender specific movement activities in classical dance are reflected in occupational accidents sustained. Organisational structures as well as work environment represent a burden likewise to male and female dancers. The presented differences support the development of gender specific injury prevention measures.
"PULS." – a blog-based online-magazine for students of medicine of the Goethe University Frankfurt
(2013)
In the context of nationwide protests 2009 also students of the faculty of medicine/dentistry at Goethe-University in Frankfurt demanded more transparency and communication. To satisfy these demands, a web 2.0-tool offered an innovative solution: A blog-based online-magazine for students and other faculty-members. The online-magazine "PULS." is realized with the share-ware blog-software (wordpress version 3.1.3) and is conceived and written by an online-journalist. "PULS." is available from https://newsmagazin.puls.med.uni-frankfurt.de/wp/. The articles are generated from own investigations and from ideas of different groups of the faculty– deanship, students and lecturers. A user-analysis is conducted with the open-source software Piwik and considers the data security. Additionally, every year an anonymous online-user-survey (Survey Monkey) is conducted. "PULS." is continuously online since 14.02.2010 and has published 806 articles (state: 27.11.2012) and has about 2400 readers monthly. The content focuses on the needs of Frankfurt medical students. The close cooperation with different groups of the faculty - deanship, students and lecturers - furthermore guarantees themes relevant to the academic faculty. "PULS." flanks complex projects and decisions with background-information and communicates them understandable. The user-evaluation shows a growing number of readers and a high acceptance for the online-magazine, its themes and its style. The web 2.0-tool "Blog" and the web-specific language comply with media habits of the main target group, the students of the faculty medicine/dentistry. Thus, "PULS." has proven as a suitable and strategic instrument. It pushes towards a higher transparency, more communication and a stronger identification of the students with their faculty.
Rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) are among the most common pediatric sarcomas (Arndt et al., 2012). Despite sarcomas representing a highly heterogeneous group of tumors, ES and alveolar RMS (ARMS) typically share one common genetic characteristic, namely a specific chromosomal translocation (Helman and Meltzer, 2003; Lessnick and Ladanyi, 2012). These translocations generate fusion proteins, which are composed of two transcription factors (TF). Typically, one TF is a developmentally regulated factor that is essential for proper specification of a given lineage and provides the DNA-binding domain, while the partner TF contributes a transactivation domain that drives aberrant expression of target genes. Based on these common genetic characteristics, the first ESF-EMBO research conference entitled “Molecular Biology and Innovative Therapies in Sarcomas of Childhood and Adolescence” with special focus on RMS and ES was held at the Polonia Castle in Pultusk, Poland. The conference gathered 70 participants from more than 15 countries and several continents representing most research groups that are active in this field.
Background: Regulatory T cells (Treg) expressing the transcription factor forkhead-box protein P3 (Foxp3) have been identified to counteract anti-tumor immune responses during tumor progression. Besides, Foxp3 presentation by cancer cells itself may also allow them to evade from effector T-cell responses, resulting in a survival benefit of the tumor. For colorectal cancer (CRC) the clinical relevance of Foxp3 has not been evaluated in detail. Therefore the aim of this study was to study its impact in colorectal cancer (CRC).
Methods and Findings: Gene and protein analysis of tumor tissues from patients with CRC was performed to quantify the expression of Foxp3 in tumor infiltrating Treg and colon cancer cells. The results were correlated with clinicopathological parameters and patients overall survival. Serial morphological analysis demonstrated Foxp3 to be expressed in cancer cells. High Foxp3 expression of the cancer cells was associated with poor prognosis compared to patients with low Foxp3 expression. In contrast, low and high Foxp3 level in tumor infiltrating Treg cells demonstrated no significant differences in overall patient survival.
Conclusions: Our findings strongly suggest that Foxp3 expression mediated by cancer cells rather than by Treg cells contribute to disease progression.
Inhibition of the proteasome is considered as a promising strategy to sensitize cancer cells to apoptosis. Recently, we demonstrated that the proteasome inhibitor Bortezomib primes neuroblastoma cells to TRAIL-induced apoptosis. In the present study, we investigated whether Bortezomib increases chemosensitivity of neuroblastoma cells. Unexpectedly, we discover an antagonistic interaction of Bortezomib and microtubule-interfering drugs. Bortezomib significantly attenuates the loss of cell viability and induction of apoptosis on treatment with Taxol and different vinca alkaloids but not with other chemotherapeutics, that is, Doxorubicin and Cisplatinum. Importantly, Bortezomib inhibits G2/M transition by inhibiting proteasomal degradation of cell cycle regulatory proteins such as p21, thereby preventing cells to enter mitosis, the cell cycle phase in which they are most vulnerable to antitubulin chemotherapeutics. Consequently, Bortezomib counteracts Taxol-induced mitotic arrest and polyploidy, as shown by reduced expression of PLK1 and phosphorylated histone H3. In addition, Bortezomib antagonizes Taxol-mediated degradation of MCL-1 during mitotic arrest by preventing cells to enter mitosis and by inhibiting the proteasome. Downregulation of MCL-1 is critically required for Taxol-induced apoptosis, as overexpression of a phosphomutant MCL-1 variant, which is resistant to degradation, significantly diminishes Taxol-triggered apoptosis. Vice versa, attenuation of Bortezomib-mediated accumulation of MCL-1 by knockdown of MCL-1 significantly enhances Taxol/Bortezomib-induced apoptosis. Thus, Bortezomib rescues Taxol-induced apoptosis by inhibiting G2/M transition and mitigating MCL-1 degradation. The identification of this antagonistic interaction of Bortezomib and microtubule-targeted drugs has important implications for the design of Bortezomib-based combination therapies.
OBJECTIVE: Traffic crashes and related injuries are important causes of morbidity and mortality and impose insofar an important burden on public health. However, research in this area is often under-funded. The aim of this study was to analyse quantity, evolution and geographic distribution of traffic medicine-related research. This multi-sectorial field covers both transport and health care sectors.
DESIGN: A scientometric approach in combination with visualizing density equalizing mapping was used to analyse published data related to the field of traffic medicine between 1900 and 2008 within the "Web of Science" (WoS) database.
RESULTS: In total, 5,193 traffic medicine-associated items were produced between 1900 and 2008. The United States was found to have the highest research activity with a production of n = 2,330 published items, followed by Germany (n = 298) and Canada (n = 219). Cooperation analyses resulted in a peak of published multilateral cooperations in the year of 2003. The country with the highest multilateral activity was the USA. The average number of cited references per publication varied heavily over the last 20 years with a maximum of 27.67 in 1995 and a minimum of 15.08 in 1998. Also, a further in-depth analysis was performed with a focus solely on public health aspects which revealed similar trends.
CONCLUSIONS: Summarizing the present data it can be stated traffic medicine-related research productivity grows annually. Also, an active networking between countries is present. The data of the present study may be used by scientific organisations in order to gain detailed information about research activities in this field which is extremely important for public health.
Cataract surgery is one of the oldest and the most frequent outpatient clinic operations in medicine performed worldwide. The clouded human crystalline lens is replaced by an artificial intraocular lens implanted into the capsular bag. During the last six decades, cataract surgery has undergone rapid development from a traumatic, manual surgical procedure with implantation of a simple lens to a minimally invasive intervention increasingly assisted by high technology and a broad variety of implants customized for each patient’s individual requirements. This review discusses the major advances in this field and focuses on the main challenge remaining – the treatment of presbyopia. The demand for correction of presbyopia is increasing, reflecting the global growth of the ageing population. Pearls and pitfalls of currently applied methods to correct presbyopia and different approaches under investigation, both in lens implant technology and in surgical technology, are discussed.
Blood levels of Glial Fibrillary Acidic Protein (GFAP) in patients with neurological diseases
(2013)
Background and Purpose: The brain-specific astroglial protein GFAP is a blood biomarker candidate indicative of intracerebral hemorrhage in patients with symptoms suspicious of acute stroke. Comparably little, however, is known about GFAP release in other neurological disorders. In order to identify potential “specificity gaps” of a future GFAP test used to diagnose intracerebral hemorrhage, we measured GFAP in the blood of a large and rather unselected collective of patients with neurological diseases.
Methods: Within a one-year period, we randomly selected in-patients of our university hospital for study inclusion. Patients with ischemic stroke, transient ischemic attack and intracerebral hemorrhage were excluded. Primary endpoint was the ICD-10 coded diagnosis reached at discharge. During hospital stay, blood was collected, and GFAP plasma levels were determined using an advanced prototype immunoassay at Roche Diagnostics.
Results: A total of 331 patients were included, covering a broad spectrum of neurological diseases. GFAP levels were low in the vast majority of patients, with 98.5% of cases lying below the cut-off that was previously defined for the differentiation of intracerebral hemorrhage and ischemic stroke. No diagnosis or group of diagnoses was identified that showed consistently increased GFAP values. No association with age and sex was found.
Conclusion: Most acute and chronic neurological diseases, including typical stroke mimics, are not associated with detectable GFAP levels in the bloodstream. Our findings underline the hypothesis that rapid astroglial destruction as in acute intracerebral hemorrhage is mandatory for GFAP increase. A future GFAP blood test applied to identify patients with intracerebral hemorrhage is likely to have a high specificity.
Im Rahmen des Vortrags wird zunächst ein Überblick über die aktuell angewandten Linsensysteme in der (refraktiven) Kataraktchirurgie sowie im Rahmen des RLA gesprochen. Hierzu zählen die monofokalen sphärischen Standardlinsen, aber auch asphärische, torische und multifokale Implantate.
Speziell wird auf die Ergebnisse einer Studie zu einem neuen multifokalen-torischen Implantat eingegangen. Der Schwerpunkt des Vortrages liegt dann weiterhin auf den trifokalen Korrektionsmöglichkeiten. Zum einen wird die sog. binokulare Trifokalität, bei der zwei multifokale Intraokularlinsen unterschiedlicher Addition implantiert werden, besprochen. Durch die Anpassung jeweils eines Auges an den Intermediär- bzw. Nahbereich soll so bei verringerten optischen Phänomenen ein deutliches Sehen in drei Hauptdistanzen ermöglicht werden. Weiterhin befasst sich der Vortrag aber auch mit den neuen echten trifokalen Optiksystemen, welche ebenfalls deutliches Sehen in verschiedenen Entfernungen gewährleisten können.
Im dritten Teil des Vortrages werden aktuelle Langzeitergebnisse aus einer FDA Studie zur Evaluation einer kammerwinkelgestützten phaken Intraokularlinse, mit speziellem Augenmerk auf den cornealen Endothelzellverlust, sowie eine neuartige sulcusgestütze phake Intraokularlinse mit zentralem Loch zur Glaukomvermeidung vorgestellt.
Since most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is expected to open new perspectives for the development of novel experimental treatment strategies to enhance the efficacy of cancer immunotherapy in the future.
While necroptosis has for long been viewed as an accidental mode of cell death triggered by physical or chemical damage, it has become clear over the last years that necroptosis can also represent a programmed form of cell death in mammalian cells. Key discoveries in the field of cell death research, including the identification of critical components of the necroptotic machinery, led to a revised concept of cell death signaling programs. Several regulatory check and balances are in place in order to ensure that necroptosis is tightly controlled according to environmental cues and cellular needs. This network of regulatory mechanisms includes metabolic pathways, especially those linked to mitochondrial signaling events. A better understanding of these signal transduction mechanisms will likely contribute to open new avenues to exploit our knowledge on the regulation of necroptosis signaling for therapeutic application in the treatment of human diseases.
Background: Group-based social skills training (SST) has repeatedly been recommended as treatment of choice in high-functioning autism spectrum disorder (HFASD). To date, no sufficiently powered randomised controlled trial has been performed to establish efficacy and safety of SST in children and adolescents with HFASD. In this randomised, multi-centre, controlled trial with 220 children and adolescents with HFASD it is hypothesized, that add-on group-based SST using the 12 weeks manualised SOSTA–FRA program will result in improved social responsiveness (measured by the parent rated social responsiveness scale, SRS) compared to treatment as usual (TAU). It is further expected, that parent and self reported anxiety and depressive symptoms will decline and pro-social behaviour will increase in the treatment group. A neurophysiological study in the Frankfurt HFASD subgroup will be performed pre- and post treatment to assess changes in neural function induced by SST versus TAU.
Methods/design: The SOSTA – net trial is designed as a prospective, randomised, multi-centre, controlled trial with two parallel groups. The primary outcome is change in SRS score directly after the intervention and at 3 months follow-up. Several secondary outcome measures are also obtained. The target sample consists of 220 individuals with ASD, included at the six study centres.
Discussion: This study is currently one of the largest trials on SST in children and adolescents with HFASD worldwide. Compared to recent randomised controlled studies, our study shows several advantages with regard to in- and exclusion criteria, study methods, and the therapeutic approach chosen, which can be easily implemented in non-university-based clinical settings.
Trial registration: ISRCTN94863788 – SOSTA – net: Group-based social skills training in children and adolescents with high functioning autism spectrum disorder.
Although motor tasks at most times do not require much attention, there are findings that attention can alter neuronal activity not only in higher motor areas but also within the primary sensorimotor cortex. However, these findings are equivocal as attention effects were investigated only in either the dominant or the nondominant hand; attention was operationalized either as concentration (i.e., attention directed to motor task) or as distraction (i.e., attention directed away from motor task), the complexity of motor tasks varied and almost no left-handers were studied. Therefore, in this study, both right- and left-handers were investigated with an externally paced button press task in which subjects typed with the index finger of the dominant, nondominant, or both hands. We introduced four different attention levels: attention-modulation-free, distraction (counting backward), concentration on the moving finger, and divided concentration during bimanual movement. We found that distraction reduced neuronal activity in both contra- and ipsilateral primary sensorimotor cortex when the nondominant hand was tapping in both handedness groups. At the same time, distraction activated the dorsal frontoparietal attention network and deactivated the ventral default network. We conclude that difficulty and training status of both the motor and cognitive task, as well as usage of the dominant versus the nondominant hand, are crucial for the presence and magnitude of attention effects on sensorimotor cortex activity. In the case of a very simple button press task, attention modulation is seen for the nondominant hand under distraction and in both handedness groups.
Background: In a previous analysis (Int J Radiat Oncol Biol Phys 70:828-835,2010), we assessed whether an adjuvant supplementation with selenium (Se) improves Se status and reduces the radiation-induced side-effects of patients treated by adjuvant radiotherapy (RT) for cervical and uterine cancer. Now, a potential relation between the planning target volume (PTV) of the RT and the Se effect concerning radiation induced diarrhoea was evaluated in detail.
Methods: Whole blood Se concentrations had been measured in patients with cervical (n=11) and uterine cancer (n=70) after surgical treatment, during, and at the end of RT. Patients with initial Se concentrations of less than 84 μg/l were categorized as Se-deficient and randomized before RT to receive Se (as sodium selenite) per os on the days of RT, or to receive no supplement during RT. Diarrhoea was graded according to the Common Toxicity Criteria system (CTC, Version 2a). The evaluation of the PTV of the RT was ascertained with the help of a specialised computer-assisted treatment planning software used for radiation planning procedure.
Results: A total of 81 patients had been randomized for the initial supplementation study, 39 of which received Se [selenium group, SeG] and 42 serving as controls [control group, CG]. Mean Se levels did not differ between SeG and CG upon study initiation, but were significantly higher in the SeG compared to the CG at the end of RT. The actuarial incidence of at least CTC 2 radiation induced diarrhoea in the SeG was 20.5% compared to 44.5% in the CG (p=0.04). The median PTV in both groups was 1302 ml (916–4608). With a PTV of <= 1302 ml (n=41) the actuarial incidence of at least CTC 2 diarrhoea in the SeG was 22.3% (4 of 18 patients) compared to 34.8% (8 of 23 patients) in the CG (p=0.50). In patients with a PTV of > 1302 ml (n=40) the actuarial incidence of at least CTC 2 diarrhoea in the SeG was 19.1% (4 of 21 patients) versus 52.6% (10 of 19 patients) in the CG (p=0.046).
Conclusions: Se supplementation during RT was effective to improve blood Se status in Se-deficient cervical and uterine cancer patients, and reduces episodes and severity of RT-induced diarrhoea. This effect was most pronounced and significant in patients with large PTV (> 1302 ml).
Background: Castleman’s disease is a rare lymphoproliferative disorder. It typically presents as mediastinal masses and causes a wide range of clinical symptoms. Histologically, Castleman’s disease is classified as either a hyalinic vascular or plasma cell variant. The prognosis mainly depends on the histological type and broadly varies. We herein report our sonographic findings in a patient with Castleman’s disease, including gray-scale ultrasonography, color Doppler ultrasonography, and sonoelastography ultrasonography, which have not been previously reported in the literature. These findings allowed for a preoperative diagnosis and avoidance of overly aggressive therapy.
Case presentation: A 28-year-old European female patient with unicentric Castleman’s disease of hyalinic vascular type (HV) restricted to the axilla was referred to us because of a 4-month history of a painless, solitary mass located in the left axilla. The patient’s medical history was unremarkable.
Conclusion: Castleman’s disease is a pathologic entity of unknown etiology and pathogenesis. In this case report of unicentric HV-type CD, we demonstrate that typical sonographic findings can lead to a preoperative diagnosis of Castleman’s disease. Core needle biopsy usually allows for a final diagnosis and helps to avoid unnecessary operations and overtreatment.
In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa.
"PULS." - Ein Blog als Online-Magazin für Medizinstudierende der Goethe-Universität Frankfurt
(2013)
Im Herbst 2009 forderten Studierende im Rahmen landesweiter Proteste auch am Fachbereich Medizin/Zahnmedizin der Goethe-Universität Frankfurt mehr Transparenz und Kommunikation zu Angelegenheiten ihres Studiums. Einen innovativen Lösungsansatz, um diesen Forderungen nachzukommen, bietet eines der Web 2.0 Werkzeuge: ein auf einer Blog-Software basierendes Online-Magazin für Studierende und andere Mitglieder des Fachbereichs.
Das öffentlich zugängliche Online-Magazin "PULS." (https://newsmagazin.puls.med.uni-frankfurt.de/wp/) wird mit einer freien Blog-Software (wordpress Version 3.1.3.) realisiert und von einer Online-Redakteurin konzipiert und geschrieben. Die Beiträge entstehen nach eigenen Recherchen sowie aus Anregungen und Gesprächen mit verschiedenen Personengruppen des Fachbereichs. Die datenschutzkonforme Auswertung der Zugriffe erfolgt über eine open-source Webanalyse-Software (Piwik). Zusätzlich werden jährlich mit dem Online-Umfrage-Tool Survey Monkey die Nutzer anonym befragt.
"PULS." ist seit dem 14.02.2010 ununterbrochen online und hat seitdem 806 Beiträge (Stand: 27.11.2012) publiziert und wird von ca. 2400 Besuchern monatlich gelesen. Das Themenspektrum ist zentriert auf die Anliegen der Frankfurter Medizin- und Zahnmedizinstudierenden. Die enge Zusammenarbeit mit verschiedenen Gruppierungen des Fachbereichs – Dekanat, Studierende und Lehrende – garantiert darüber hinaus ein fachbereichs-relevantes Themenspektrum. Das Online-Magazin begleitet komplexe Projekte und Entscheidungen mit Hintergrundinformationen und kommuniziert sie verständlich. Eine jährliche Nutzer-Evaluierung zeigt eine wachsende Leserzahl und eine sehr hohe Zustimmung für das Online-Magazin, seine Inhalte und seinen Stil. Das Web 2.0-Medium "Blog" und seine web-typische Sprache entsprechen dem Medienverhalten der Zielgruppe, d.h. den Studierenden des Fachbereichs Medizin.
"PULS." hat sich als ein geeignetes und strategisches Instrument erwiesen, um größere Transparenz, mehr Kommunikation und letztendlich eine stärkere Identifikation der Studierenden mit ihrem Fachbereich voranzutreiben.
In the current event-related potential (ERP) study, we investigated how speech rhythm impacts speech segmentation and facilitates the resolution of syntactic ambiguities in auditory sentence processing. Participants listened to syntactically ambiguous German subject- and object-first sentences that were spoken with either regular or irregular speech rhythm. Rhythmicity was established by a constant metric pattern of three unstressed syllables between two stressed ones that created rhythmic groups of constant size. Accuracy rates in a comprehension task revealed that participants understood rhythmically regular sentences better than rhythmically irregular ones. Furthermore, the mean amplitude of the P600 component was reduced in response to object-first sentences only when embedded in rhythmically regular but not rhythmically irregular context. This P600 reduction indicates facilitated processing of sentence structure possibly due to a decrease in processing costs for the less-preferred structure (object-first). Our data suggest an early and continuous use of rhythm by the syntactic parser and support language processing models assuming an interactive and incremental use of linguistic information during language processing.
Background: The students' perception of working conditions in hospitals hasn't been subject of research in Germany so far. However the perception plays an important role talking about the sustainability of working conditions. The iCept Study wants to examine the perception of medical students compared to the perception of practicing physicians.
Methods: The perception will be investigated with a redesigned questionnaire based upon two established and validated questionnaires. The two samples built for this study (students and physician) will be chosen from members of the labor union Marburger Bund. The iCept-Study is designed as an anonymized online-survey.
Discussion: The iCept-Study is thought to be the basis of ongoing further investigations regarding the perception of working conditions in hospitals. The results shall serve the facilitation of improving working conditions.
Background: Characterisation of risk groups who may benefit from pneumococcal vaccination is essential for the generation of recommendations and policy.
Methods: We reviewed the literature to provide information on the incidence and risk of invasive pneumococcal disease (IPD) in at-risk children in Europe and North America. The PubMed database was searched using predefined search terms and inclusion/exclusion criteria for papers reporting European or North American data on the incidence or risk of IPD in children with underlying medical conditions.
Results: Eighteen references were identified, 11 from North America and 7 from Europe, with heterogeneous study methods, periods and populations. The highest incidence was seen in US children positive for human immunodeficiency virus infection, peaking at 4167 per 100,000 patient-years in 2000. Studies investigating changes in incidence over time reported decreases in the incidence of IPD between the late 1990s and early 2000s. The highest risk of IPD was observed in children with haematological cancers or immunosuppression. Overall, data on IPD in at-risk children were limited, lacking incidence data for a wide range of predisposing conditions. There was, however, a clear decrease in the incidence of IPD in at-risk children after the introduction of 7-valent pneumococcal conjugate vaccine into immunisation programmes, as previously demonstrated in the general population.
Conclusion: Despite the heterogeneity of the studies identified, the available data show a substantial incidence of IPD in at-risk children, particularly those who are immunocompromised. Further research is needed to determine the true risk of IPD in at-risk children, particularly in the post-PCV period, and to understand the benefits of vaccination and optimal vaccination schedules.
kurz und kn@pp news : Nr. 29
(2013)
Inhibitor of Apoptosis (IAP) proteins are a family of proteins with antiapoptotic functions that contribute to the evasion of apoptosis, a form of programed cell death. IAP proteins are expressed at high levels in a variety of human cancers including childhood acute leukemia. This elevated expression has been associated with unfavorable prognosis and poor outcome. Therefore, IAP proteins are currently exploited as therapeutic targets for cancer drug discovery. Consequently, small-molecule inhibitors or antisense oligonucleotides directed against IAP proteins have been developed over the last years. Indeed, IAP antagonists proved to exhibit in vitro and in vivo antitumor activities against childhood pediatric leukemia in several preclinical studies. Thus, targeting IAP proteins represents a promising molecular targeted strategy to overcome apoptosis resistance in childhood leukemia, which warrants further exploitation.
In this manuscript a comprehensive coverage of recent developments in the drug therapy of vasospasm while providing the background information that neuroscientists need to understand its rationale. The range of new agents available for treatment of cerebral vasospasm is expanding rapidly along with rapid advances in pharmacology and physiology that are uncovering the mechanisms of this disease. Although there are many publications for treatment of cerebral vasospasm, most are focusing on different aspects of vasospasm treatment and many have limited value due to insufficient quality. Moreover, the complexity of this, in many cases deleterious condition, is enormous and the information needed to understand drug effects is accordingly often not readily available in a single source. A number of pharmacological and medical therapies are currently in use or being investigated in an attempt to reverse cerebral vasospasm, but only a few have proven to be useful. Current research efforts promise the eventual production of new medical therapies. At last, recommendations for the use of different treatment stages based on currently available clinical data are provided.
Object: Minimally invasive spine (MIS) procedures are increasingly being recognized as equivalent to open procedures with regard to clinical and radiographic outcomes. These techniques are also believed to result in less pain and disability in the immediate postoperative period. There are, however, little data to assess whether these procedures in combination with minimally invasive transforaminal interbody fusion (MI-TLIF) and percutaneous pedicle screw insertion are effective in complex cases of stenotic degenerative spondylolisthesis with severe facet joint osteoarthritis (FJO).
Methods: This study retrospectively reviewed all patients who underwent lumbar instrumentation, fusion and decompression for degenerative spondylolisthesis with severe stenosis and facet joint osteoarthritis (FJO) between June 2010 and June 2011. Blood loss, operative time and intraoperative complications were assessed in all surgically treated patients who were treated with MIS decompression, MI-TLIF and percutaneous transpedicular instrumentation. Clinical outcome was measured using the Oswestry Disability Index (ODI) and Visual Analogue Scale (VAS) for back pain, leg pain, and activity level. Satisfaction was assessed with VAS for satisfaction. Radiological follow-up includes x-ray films, computed tomography and in some cases magnetic tomography scan.
Results: Twenty four cases with severe stenotic changes accompanied by severe FJO were treated with minimally invasive procedure. The minimum follow-up was 6 months with a mean of 8 months. The mean preoperative ODI score was 46.8, decreasing to a mean of 23 postoperatively. The mean VAS leg and back pain scores were 67.5 improving to means of 25.8. Twenty one out of 24 cases experienced a clinical benefit according to VAS for satisfaction and ODI. Complications included wound healing disturbance (4%), CSF fistula (4%) and contralateral radiculopathy due to articular bone spurs (8%). The accuracy of pedicle screws was high and only one revision surgery was performed.
Conclusion: MIS for severe stenotic spondylolisthesis leads to adequate and safe decompression of lumbar stenosis and results in a highly significant reduction of symptoms and disability. MIS-TLIF and percutaneous pedicle screw insertion constitute a promising treatment alternative for patients with severe stenosis and facet joint osteoarthritis
Gegenstand dieser Arbeit ist die Untersuchung der Genexpression der axonalen wachstumsassoziierten Proteine NAP-22, GAP-43 und CAP-23 in den dopaminergen Neuronen der Substantia nigra pars compacta (SNc), einer im Mesencephalon gelegenen Zellregion, relativ zu der Genexpression eines Referenzgens. Als Versuchstiere dienten sechs Monate alte, männliche CB6F1 Wildtypmäuse sowie sechs Monate alte, männliche CAP-23 transgene (CAP-23tg) Tiere, die das wachstumsassoziierte Protein CAP-23 überexprimieren. Die dopaminergen Zellen der SNc wurden zunächst morphologisch charakterisiert und ihre Ausdehnung im Mittelhirn durch alternierende Immunfärbungen der Tyrosinhydroxylase, einem Schlüsselenzym der Dopaminsynthese, sowie Toluidinblaufärbungen ermittelt. Anschließend wurden die Neurone durch die Methode der Lasermikrodissektion (LMD) im Zellverband isoliert. Hierfür war die Optimierung der Toluidinblaufärbung erforderlich, mit dem Ziel, sowohl eine gute Färbung der Neurone als auch eine hohe RNA-Nativität zu erzielen. Die RNA wurde isoliert und nach Integritätsprüfung in cDNA umgeschrieben. Daraufhin erfolgte die Analyse der Genexpression der beschriebenen Gene durch die quantitative Echtzeit-Polymerase-Kettenreaktion (qRT-PCR). Dabei war feststellbar, dass das Transgen Cap-23 in den transgenen Tieren stärker exprimiert wird als das Endogen Nap-22. Es zeigte sich jedoch kein signifikanter Unterschied der Expression von endogenem Nap-22 und endogenem Gap-43 in den CAP-23tg Tieren im Vergleich zu der Expression in den Wildtypmäusen. Das bedeutet, dass die Überexpression von Cap-23 in den transgenen Tieren die Expression der mRNA der beiden endogenen wachstumsassoziierten Proteine NAP-22 und GAP-43 nicht beeinflusst. Auf Grundlage der in dieser Arbeit vorgelegten Ergebnisse soll in Folgeexperimenten untersucht werden, inwieweit die Überexpression von CAP-23 die Reorganisationsfähigkeit dopaminerger Neuronen der SNc nach einer Schädigung beeinflusst, wie sie zum Beispiel beim Menschen im Verlauf des Morbus Parkinson beobachtet wird.
Functional responses of natural killer (NK) cells including eradication of “harmful” cells and modulation of immune responses are regulated by a broad variety of activating and inhibitory NK receptors. Whereas the leukocyte receptor complex (LRC) encodes for NK receptors of the immunoglobulin superfamily, genes of C-type lectin-like NK receptors are clustered in the mammalian natural killer gene complex (NKC). Besides the thoroughly studied C-type lectin-like receptors NKG2D, CD94/NKG2x, and members of the murine Ly49 subfamily, the NKC also encodes for NK receptors of the less characterized NKRP1 subfamily. The prototypic mouse NKRP1 receptor is Nkrp1c (also known as NK1.1), while human members of the NKRP1 subfamily are NKRP1A, NKp80, and NKp65. The latter are not straight homologs of mouse NKRP1 receptors, but share distinct subfamily-specific traits classifying them as members of the NKRP1 subfamily. Ligands of the human NKPR1 receptors are likewise C-type lectin-like glycoproteins belonging to the CLEC2 subfamily (i.e., LLT1, AICL, and KACL), and are encoded in the NKC in tight genetic linkage to their respective receptors. Similarly, certain members of the mouse NKRP1 subfamily interact with genetically coupled CLEC2 glycoproteins, while the reasons for this intriguing tight genetic linkage remain unknown. Recent studies provided new and unique insights into the expression, interaction, and signaling of NKRP1 receptors and their ligands, thereby substantially advancing our understanding of their function and biology. Here, we review our current knowledge on NKRP1 receptors and their genetically linked CLEC2 ligands with an emphasis on the human receptor/ligand pairs NKRP1A-LLT1, NKp80-AICL, and NKp65-KACL.
Vasoplegia is a severe complication after cardiac surgery. Within the last years the administration of nitric oxide synthase inhibitor methylene blue (MB) became a new therapeutic strategy. Our aim was to investigate the role of MB on transendothelial migration of circulating blood cells, the potential role of cyclic cGMP, eNOS and iNOS in this process, and the influence of MB on endothelial cell apoptosis. Human vascular endothelial cells (HuMEC-1) were treated for 30 minutes or 2 hours with different concentrations of MB. Inflammation was mimicked by LPS stimulation prior and after MB. Transmigration of PBMCs and T-Lymphocytes through the treated endothelial cells was investigated. The influence of MB upon the different subsets of PBMCs (Granulocytes, T- and B-Lymphocytes, and Monocytes) was assessed after transmigration by means of flow-cytometry. The effect of MB on cell apoptosis was evaluated using Annexin-V and Propidium Iodide stainings. Analyses of the expression of cyclic cGMP, eNOS and iNOS were performed by means of RT-PCR and Western Blot. Results were analyzed using unpaired Students T-test. Analysis of endothelial cell apoptosis by MB indicated a dose-dependent increase of apoptotic cells. We observed time- and dose-dependent effects of MB on transendothelial migration of PBMCs. The prophylactic administration of MB led to an increase of transendothelial migration of PBMCs but not Jurkat cells. Furthermore, HuMEC-1 secretion of cGMP correlated with iNOS expression after MB administration but not with eNOS expression. Expression of these molecules was reduced after MB administration at protein level. This study clearly reveals that endothelial response to MB is dose- and especially time-dependent. MB shows different effects on circulating blood cell-subtypes, and modifies the release patterns of eNOS, iNOS, and cGMP. The transendothelial migration is modulated after treatment with MB. Furthermore, MB provokes apoptosis of endothelial cells in a dose/time-dependent manner.
BACKGROUND: In two clinical trials, low-grade fever was observed more frequently after coadministration than after separate administration of two recommended routine pediatric vaccines. Since fever is an important issue with vaccine tolerability, we performed this open-label study on the efficacy and safety of prophylactic use of paracetamol (acetaminophen, Benuron(R)) in children administered routine 7-valent pneumococcal conjugate vaccine (PCV-7) coadministered with hexavalent vaccine (diphtheria-tetanus-acellular pertussis-hepatitis B, polio, Haemophilus influenzae type b vaccine [DTPa-HBV-IPV/Hib]) in Germany.
METHODS: Healthy infants (N = 301) who received a 3-dose infant series of PCV-7 and DTPa-HBV-IPV/Hib plus a toddler dose were randomly assigned 1:1 to prophylactic paracetamol (125 mg or 250 mg suppositories, based on body weight) at vaccination, and at 6--8 hour intervals thereafter, or a control group that received no paracetamol. Rectal temperature and local and other systemic reactions were measured for 4 days post vaccination; adverse events were collected throughout the study.
RESULTS: In the intent-to-treat population, paracetamol reduced the incidence of fever >=38[degree sign]C, but this reduction was only significant for the infant series, with computed efficacy of 43.0% (95% confidence interval [CI]: 17.4, 61.2), and not significant after the toddler dose (efficacy 15.9%; 95% CI: -19.9, 41.3); results were similar in the per protocol (PP) population. Fever >39[degree sign]C was rare during the infant series, such that there were too few cases for assessment. After the toddler dose, paracetamol effectively reduced fever >39[degree sign]C, reaching statistical significance in the PP population only (efficacy 79%; 95% CI: 3.9, 97.7). Paracetamol also reduced reactogenicity, but there were few significant differences between groups after any dose. No vaccine-related serious adverse events were reported.
CONCLUSIONS: Paracetamol effectively prevented fever and other reactions, mainly during the infant series. However, as events were generally mild and of no concern in either group our data support current recommendations to administer paracetamol to treat symptoms only and not for routine prophylaxis.Trial registration: NCT00294294.
Introduction: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.
Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.
Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2].[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2].[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2].[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.
Conclusions: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration: ClinicalTrials.gov number NCT01209169.
Diffusion tensor imaging (DTI) based assessment of white matter fiber tract integrity can support the diagnosis of Alzheimer’s disease (AD). The use of DTI as a biomarker, however, depends on its applicability in a multicenter setting accounting for effects of different MRI scanners. We applied multivariate machine learning (ML) to a large multicenter sample from the recently created framework of the European DTI study on Dementia (EDSD). We hypothesized that ML approaches may amend effects of multicenter acquisition. We included a sample of 137 patients with clinically probable AD (MMSE 20.6±5.3) and 143 healthy elderly controls, scanned in nine different scanners. For diagnostic classification we used the DTI indices fractional anisotropy (FA) and mean diffusivity (MD) and, for comparison, gray matter and white matter density maps from anatomical MRI. Data were classified using a Support Vector Machine (SVM) and a Naïve Bayes (NB) classifier. We used two cross-validation approaches, (i) test and training samples randomly drawn from the entire data set (pooled cross-validation) and (ii) data from each scanner as test set, and the data from the remaining scanners as training set (scanner-specific cross-validation). In the pooled cross-validation, SVM achieved an accuracy of 80% for FA and 83% for MD. Accuracies for NB were significantly lower, ranging between 68% and 75%. Removing variance components arising from scanners using principal component analysis did not significantly change the classification results for both classifiers. For the scanner-specific cross-validation, the classification accuracy was reduced for both SVM and NB. After mean correction, classification accuracy reached a level comparable to the results obtained from the pooled cross-validation. Our findings support the notion that machine learning classification allows robust classification of DTI data sets arising from multiple scanners, even if a new data set comes from a scanner that was not part of the training sample.
Inflammation has been recognized as a common trait in the pathogenesis of multifactorial diseases including obesity, where a low-grade inflammation has been established and may be responsible for the cardiovascular risk related to the disease. Obesity has also been associated with the increased incidence and a worse outcome of rheumatoid arthritis (RA) and osteoarthritis (OA). RA is characterized by systemic inflammation, which is thought to play a key role in accelerated atherosclerosis and in the increased incidence of cardiovascular disease, an important comorbidity in patients with RA. The inflammatory process underlying the cardiovascular risk both in obesity and RA may be mediated by adipocytokines, a heterogeneous group of soluble proteins mainly secreted by the adipocytes. Many adipocytokines are mainly produced by white adipose tissue. Adipocytokines may also be involved in the pathogenesis of OA since a positive association with obesity has been found for weight-bearing and nonweight-bearing joints, suggesting that, in addition to local overload, systemic factors may contribute to joint damage. In this review we summarize the current knowledge on experimental models and clinical studies in which adipocytokines were examined in obesity, RA, and OA and discuss the potential of adipocytokines as comorbidity biomarkers for cardiovascular risk.
Nanoparticles (particles sized between 1 and 100 nanometers) are more and more used in all fields of science and medicine for their physicochemical properties. As gold has traditionally been considered as chemically inert and biocompatible, in particular, gold nanoparticles have been established as valuable tools in several areas of biomedical research. But in contrast to the multitude of studies that addressed the clinical use of gold nanoparticles, only little is known about potential toxicological effects such as induction of inflammatory immune responses, possible apoptotic cell death or developmental growth inhibition in embryos. Therefore the present study performed a systematic review of toxicological data, especially experimentally acquired data concerning in-vivo-toxicity, published in the PubMed. It can be stated that the data in this area of research is still largely limited. Especially, knowledge about size-, charge- and surface-chemistry dependent in-vivo-toxicity is needed to predict the hazard potential of auric nanoparticles (AuNPs) for humans.
Background: Patients suffering from acute type A aortic dissection undergo replacement of the ascending aorta, the proximal hemiarch or complete aortic arch, depending on the extent of the individual pathology. In a subset of these treated patients, secondary pathologies of the distal anastomosis or the remaining distal part of the aorta occur. The treatment of these pathologies is challenging, requiring major surgical re-do procedures with aortic arch replacement under extracorporeal circulation and hypothermic circulatory arrest.
Methods: We report our experience of five patients with complex aortic pathologies after previous aortic surgery treated with a single stage re-do hybrid procedure, consisting of bypass grafting of the supraaortic branches off-pump, stent graft placement for endovascular aortic repair (TEVAR) and surgical debranching of the aortic arch.
Results: In all patients the surgical vascular grafts and stent grafts were deployed successfully, there were no intraoperative deaths. Four out of five patients were discharged from hospital in good clinical condition. One patient died postoperatively due to cardiac tamponade. In one patient a type I endoleak persisted leading to occlusion of a bypass branch requiring surgical revision at one year after debranching.
Conclusion: We discuss the prerequisites, all steps and potential pitfalls of this hybrid aortic arch replacement. The current procedure avoids cardiopulmonary bypass and circulatory arrest, which may benefit early patient outcome; however, patient and device selection plays a key role for immediate success and midterm outcomes. In addition, precise procedural planning and development of customized stents may help to develop this procedure into a true alternative for conventional aortic arch replacement.
Background: In the revision of the Diagnostic and Statistical Manual (DSM-5), "Identity" is an essential diagnostic criterion for personality disorders (self-related personality functioning) in the alternative approach to the diagnosis of personality disorders in Section III of DSM-5. Integrating a broad range of established identity concepts, AIDA (Assessment of Identity Development in Adolescence) is a new questionnaire to assess pathology-related identity development in healthy and disturbed adolescents aged 12 to 18 years. Aim of the present study is to investigate differences in identity development between adolescents with different psychiatric diagnoses.
Methods: Participants were 86 adolescent psychiatric in- and outpatients aged 12 to 18 years. The test set includes the questionnaire AIDA and two semi-structured psychiatric interviews (SCID-II, K-DIPS). The patients were assigned to three diagnostic groups (personality disorders, internalizing disorders, externalizing disorders). Differences were analyzed by multivariate analysis of variance MANOVA.
Results: In line with our hypotheses, patients with personality disorders showed the highest scores in all AIDA scales with T>70. Patients with externalizing disorders showed scores in an average range compared to population norms, while patients with internalizing disorders lay in between with scores around T=60. The AIDA total score was highly significant between the groups with a remarkable effect size of f= 0.44.
Conclusion: Impairment of identity development differs between adolescent patients with different forms of mental disorders. The AIDA questionnaire is able to discriminate between these groups. This may help to improve assessment and treatment of adolescents with severe psychiatric problems.
Recent statistics indicate that the human population is ageing rapidly. Healthy, but also diseased, elderly people are increasing. This trend is particularly evident in Western countries, where healthier living conditions and better cures are available. To understand the process leading to age-associated alterations is, therefore, of the highest relevance for the development of new treatments for age-associated diseases, such as cancer, diabetes, Alzheimer and cardiovascular accidents. Mechanistically, it is well accepted that the accumulation of intracellular damage determined by reactive oxygen species (ROS) might orchestrate the progressive loss of control over biological homeostasis and the functional impairment typical of aged tissues. Here, we review how epigenetics takes part in the control of stress stimuli and the mechanisms of ageing physiology and physiopathology. Alteration of epigenetic enzyme activity, histone modifications and DNA-methylation is, in fact, typically associated with the ageing process. Specifically, ageing presents peculiar epigenetic markers that, taken altogether, form the still ill-defined “ageing epigenome”. The comprehension of mechanisms and pathways leading to epigenetic modifications associated with ageing may help the development of anti-ageing therapies.
Introduction: Langerhans Cell Histiocytosis (LCH) represents a rare benign disorder, previously designated as "Histiocytosis X", "Type II Histiocytosis" or "Langerhans Cell Granulomatosis". Clinical presentation includes osteolysis, ulcerations of skin and soft tissues but also involvement of the CNS is described.Because treatment concepts are not well defined the German Cooperative Group on Radiotherapy for Benign Diseases performed a retrospective analysis.
Methods and material: Eight closely cooperating centres collected patients' data of the past 45 years. As study endpoints disease free survival, recurrent disease, death and therapy related side effects were defined.
Results: A total of 80 patients with histologically proven LCH were irradiated within the past 45 years. According to the LCH classification of Greenberger et al. 37 patients had stage Ia, 21 patients stage Ib, 13 patients stage II and 9 patients stage IIIb and the median age was 29 years. The median Follow up was 54 months (range 9-134 months). A total of 39 patients had a surgical intervention and 23 patients a chemotherapy regimen.Radiation treatment was carried out with a median total dose of 15 Gy (range 3-50.4 Gy). The median single fraction was 2 Gy (range 1.8-3 Gy).Overall, 77% patients achieved a complete remission and 12.5% achieved a partial remission. The long-term control rate reached 80%. Within an actuarial overall 5-year survival of 90% no radiogenic side and late effects ≥EORTC/RTOG II° were observed.
Conclusion: In the present study a large collective of irradiated patients was analysed. Radiotherapy (RT) is a very effective and safe treatment option and even low RT doses show sufficient local control.
Ziel der vorliegenden prospektiven, experimentellen, randomisierten kontrollierten In-vitroStudie war es, zwei Dentinadhäsive, die der sechsten (One-Up-Bond F, Tokuyama) und siebten (G-Bond, GC Tokio) Generation angehören, unter ISO-Bedingungen zu untersuchen und einer Kontrollgruppe (Clearfil SE, Kuraray), die der sechsten Generation zugeordnet wird, gegenüberzustellen. Neunzig unversehrte humane Molaren der zweiten Dentition wurden eingebettet. Das Dentin wurde mit Siliziumcarbidscheiben der Körnung 600 bearbeitet, um eine Schmierschicht zu erhalten. Anschließend wurden die Dentinproben randomisiert in drei Gruppen eingeteilt und die jeweiligen Dentinadhäsive wurden nach Herstellerangaben appliziert. Mittels einer Versuchsapparatur, die in Anlehnung an die ISO/TS 11405:2003 hergestellt wurde, wurde das Kompositmaterial Tetric EvoCeram in der Farbe A2 aufgetragen und lichtgehärtet. Eine Alterung der Proben fand bei 500 Thermocycling-Zyklen bei Temperaturen von 5°C und 55°C statt. Mit einer Universalprüfmaschine Zwicki (Vorschubgeschwindigkeit 0,5 mm/min) wurde die Scherhaftfestigkeit der Proben bestimmt. Anschließend wurden die abgescherten Dentinproben unter dem Rasterelektronenmikroskop bei einer Vergrößerung von 20-fach und 2000-fach bezüglich der auftretenden Frakturmodi untersucht.
Die Haftkraft-Mittelwerte von Clearfil SE betrugen 4,22 MPa, von G-Bond 3,83 MPa und von One-Up-Bond F 7,11 MPa. Bei der statistischen Analyse mittels Kruskal-Wallis-Test wurde die Signifikanz ermittelt. Eine Signifikanz zwischen den Dentinadhäsiven One-UpBond F und G-Bond lag vor. Einzig Clearfil SE war statistisch nicht signifikant gegenüber den anderen Produkten. Die Bruchanalyse ergab, dass G-Bond eine hohe Anzahl (46,7 %) an kohäsiven Frakturen aufwies, Clearfil SE mehr als die Hälfte (66,7 %) gemischte Frakturen und dass One-Up-Bond F kaum adhäsive (3,3 %) Frakturen zeigte, sondern hauptsächlich (80 %) gemischte Brüche. Signifikante Unterschiede waren zwischen dem Bruchverhalten von Clearfil SE und G-Bond sowie zwischen G-Bond und One-Up-Bond F zu beobachten.
Unter der Limitation der vorliegenden In-vitro-Studie erscheint die Anwendung von G-Bond aufgrund der erhaltenen statistisch signifikant niedrigeren Haftwerten als nicht empfehlenswert.
Introduction. Cancellous bone is frequently used for filling bone defects in a clinical setting. It provides favourable conditions for regenerative cells such as MSC and early EPC. The combination of MSC and EPC results in superior bone healing in experimental bone healing models. Materials and Methods. We investigated the influence of osteogenic culture conditions on the endothelial properties of early EPC and the osteogenic properties of MSC when cocultured on cancellous bone. Additionally, cell adhesion, metabolic activity, and differentiation were assessed 2, 6, and 10 days after seeding.
Results. The number of adhering EPC and MSC decreased over time; however the cells remained metabolically active over the 10-day measurement period. In spite of a decline of lineage specific markers, cells maintained their differentiation to a reduced level. Osteogenic stimulation of EPC caused a decline but not abolishment of endothelial characteristics and did not induce osteogenic gene expression. Osteogenic stimulation of MSC significantly increased their metabolic activity whereas collagen-1α and alkaline phosphatase gene expressions declined. When cocultured with EPC, MSC’s collagen-1α gene expression increased significantly. Conclusion. EPC and MSC can be cocultured in vitro on cancellous bone under osteogenic conditions, and coculturing EPC with MSC stabilizes the latter’s collagen-1α gene expression.
Doping ist ein Thema, das den modernen Leistungssport – und nicht nur diesen – seit jeher begleitet. Immer wieder werden Sportler – oft noch nach Jahren – überführt, illegale Substanzen zur Leistungssteigerung eingenommen zu haben. Der Landessportbund Hessen e. V. hat im Sommer 2013 Professor Dr. Dr. Gerd Geißlinger zum Anti-Doping-Beauftragten berufen. Für den UniReport hat Dr. Beate Meichsner mit dem Direktor des Instituts für Klinische Pharmakologie am Klinikum der Goethe-Universität über die damit verbundenen Aufgaben, Ziele und
Möglichkeiten gesprochen.
Human deep sleep is characterized by reduced sensory activity, responsiveness to stimuli, and conscious awareness. Given its ubiquity and reversible nature, it represents an attractive paradigm to study the neural changes which accompany the loss of consciousness in humans. In particular, the deepest stages of sleep can serve as an empirical test for the predictions of theoretical models relating the phenomenology of consciousness with underlying neural activity. A relatively recent shift of attention from the analysis of evoked responses toward spontaneous (or “resting state”) activity has taken place in the neuroimaging community, together with the development of tools suitable to study distributed functional interactions. In this review we focus on recent functional Magnetic Resonance Imaging (fMRI) studies of spontaneous activity during sleep and their relationship with theoretical models for human consciousness generation, considering the global workspace theory, the information integration theory, and the dynamical core hypothesis. We discuss the venues of research opened by these results, emphasizing the need to extend the analytic methodology in order to obtain a dynamical picture of how functional interactions change over time and how their evolution is modulated during different conscious states. Finally, we discuss the need to experimentally establish absent or reduced conscious content, even when studying the deepest sleep stages.
Human adipose tissue derived stem cells promote liver regeneration in a rat model of toxic injury
(2013)
In the light of the persisting lack of donor organs and the risks of allotransplantations, the possibility of liver regeneration with autologous stem cells from adipose tissue (ADSC) is an intriguing alternative. Using a model of a toxic liver damage in Sprague Dawley rats, generated by repetitive intraperitoneal application of retrorsine and allyl alcohol, the ability of human ADSC to support the restoration of liver function was investigated. A two-thirds hepatectomy was performed, and human ADSC were injected into one remaining liver lobe in group 1 (n = 20). Injection of cell culture medium performed in group 2 (n = 20) served as control. Cyclosporine was applied to achieve immunotolerance. Blood samples were drawn weekly after surgery to determine liver-correlated blood values. Six and twelve weeks after surgery, animals were sacrificed and histological sections were analyzed. ADSC significantly raised postoperative albumin (P < 0.017), total protein (P < 0.031), glutamic oxaloacetic transaminase (P < 0.001), and lactate dehydrogenase (P < 0.04) levels compared to injection of cell culture medium alone. Transplanted cells could be found up to twelve weeks after surgery in histological sections. This study points towards ADSC being a promising alternative to hepatocyte or liver organ transplantation in patients with severe liver failure.
Potential abnormalities in the structure and function of the temporal lobes have been studied much less in bipolar disorder than in schizophrenia. This may not be justified because language-related symptoms, such as pressured speech and flight of ideas, and cognitive deficits in the domain of verbal memory are amongst the hallmark of bipolar disorder (BD), and contribution of temporal lobe dysfunction is therefore likely. In the current study, we examined resting-state functional connectivity (FC) between the auditory cortex (Heschl’s gyrus [HG], planum temporale [PT]) and whole brain using seed correlation analysis in n = 21 BD euthymic patients and n = 20 matched healthy controls and associated it with verbal memory performance. In comparison to controls BD patients showed decreased functional connectivity between Heschl’s gyrus and planum temporale and the left superior and middle temporal gyrus. Additionally, fronto-temporal functional connectivity with the right inferior frontal/precentral gyrus and the insula was increased in patients. Verbal episodic memory deficits in the investigated sample of BD patients and language-related symptoms might therefore be associated with a diminished FC within the auditory/temporal gyrus and a compensatory fronto-temporal pathway.
Aim: The aim of this study was to measure cortico-cortical connectivity in multiple sclerosis (MS) patients by TMS-evoked potential (TEP) latencies in EEG evoked by transcranial magnetic stimulation (TMS) of the hand area of the primary motor cortex of one hemisphere. TEPs were recorded on the stimulated- and at the homologue site in the non-stimulated contralateral hemisphere. Both interhemispheric directions were tested. Interhemispheric latencies of the two main reproducible TEPs, the positive component at 60 ms and the negative component at 100 ms (P60 and N100, respectively), were expected to be significantly prolonged in MS-patients compared to healthy volunteers.
Material and methods: The study compared interhemispheric propagation of P60 and N100 in groups of 12 patients with early-stage relapsing-remitting MS (RRMS) and 16 age- and gender-matched healthy controls. The study was approved by the Ethics Committee of the Medical Faculty of the Goethe-University of Frankfurt/Main and conformed to the latest revision of the Declaration of Helsinki of 2008. TEPs were recorded by means of EEG and their latencies were statistically evaluated in 10 channels around the stimulation site and in 10 corresponding electrodes in the non-stimulated contralateral hemisphere. Interhemispheric conduction time was calculated by the difference of TEP latency in non-stimulated vs. stimulated hemisphere.
Results: An ANOVA on interhemispheric conduction time showed a significant prolongation for the N100 from left to right hemisphere in MS compared to controls, while no group differences were found for the P60 and the N100 from right to left hemisphere.
Conclusion: The results provide first evidence that the N100 may constitute an interesting marker to measure interhemispheric conduction delays in early-stage RRMS. The specificity of the present finding and its relation to fiber tract pathology should be examined in further correlative analyses with diffusion tensor imaging and other structural MRI data.
Poster presentation: Twenty Second Annual Computational Neuroscience Meeting: CNS*2013. Paris, France. 13-18 July 2013.
Neuronal death and subsequent denervation of target areas is a major feature of several neurological conditions such as brain trauma, ischemia or neurodegeneration. The denervation-induced axonal loss results in reorganization of the dendritic tree of denervated neurons. Dendritic reorganization of denervated neurons has been previously studied using entorhinal cortex lesion (ECL).
ECL leads to shortening and loss of dendritic segments in the denervated outer molecular layer of the dentate gyrus [1]. However, the functional importance of these long-term dendritic alterations is not yet understood and their impact on neuronal electrical properties remains unclear. Therefore, in this study we analyzed what happens to the electrotonic structure and excitability of dentate granule cells after denervation-induced alterations of their dendritic morphology, assuming all other parameters remain equal.
To perform comparative electrotonic analysis we used computer simulations in anatomically and biophysically realistic compartmental models of 3D-reconstructed healthy and denervated granule cells. Our results show that somatofugal and somatopetal voltage attenuation due to passive cable properties was strongly reduced in denervated granule cells. In line with these predictions, the attenuation of simulated backpropagating action potentials and forward propagating EPSPs was significantly reduced in dendrites of denervated neurons. In addition, simulations of somatic and dendritic frequency-current (f-I) curves revealed increased excitability in deafferentated granule cells.
Taken together, our results indicate that unless counterbalanced by a compensatory adjustment of passive and/or active membrane properties, the plastic remodeling of dendrites following lesion of entorhinal cortex inputs to granule cells will boost their electrotonic compactness and excitability.
When studying real world complex networks, one rarely has full access to all their components. As an example, the central nervous system of the human consists of 1011 neurons which are each connected to thousands of other neurons. Of these 100 billion neurons, at most a few hundred can be recorded in parallel. Thus observations are hampered by immense subsampling. While subsampling does not affect the observables of single neuron activity, it can heavily distort observables which characterize interactions between pairs or groups of neurons. Without a precise understanding how subsampling affects these observables, inference on neural network dynamics from subsampled neural data remains limited.
We systematically studied subsampling effects in three self-organized critical (SOC) models, since this class of models can reproduce the spatio-temporal activity of spontaneous activity observed in vivo. The models differed in their topology and in their precise interaction rules. The first model consisted of locally connected integrate- and fire units, thereby resembling cortical activity propagation mechanisms. The second model had the same interaction rules but random connectivity. The third model had local connectivity but different activity propagation rules. As a measure of network dynamics, we characterized the spatio-temporal waves of activity, called avalanches. Avalanches are characteristic for SOC models and neural tissue. Avalanche measures A (e.g. size, duration, shape) were calculated for the fully sampled and the subsampled models. To mimic subsampling in the models, we considered the activity of a subset of units only, discarding the activity of all the other units.
Under subsampling the avalanche measures A depended on three main factors: First, A depended on the interaction rules of the model and its topology, thus each model showed its own characteristic subsampling effects on A. Second, A depended on the number of sampled sites n. With small and intermediate n, the true A¬ could not be recovered in any of the models. Third, A depended on the distance d between sampled sites. With small d, A was overestimated, while with large d, A was underestimated.
Since under subsampling, the observables depended on the model's topology and interaction mechanisms, we propose that systematic subsampling can be exploited to compare models with neural data: When changing the number and the distance between electrodes in neural tissue and sampled units in a model analogously, the observables in a correct model should behave the same as in the neural tissue. Thereby, incorrect models can easily be discarded. Thus, systematic subsampling offers a promising and unique approach to model selection, even if brain activity was far from being fully sampled.
Neuronal dynamics differs between wakefulness and sleep stages, so does the cognitive state. In contrast, a single attractor state, called self-organized critical (SOC), has been proposed to govern human brain dynamics for its optimal information coding and processing capabilities. Here we address two open questions: First, does the human brain always operate in this computationally optimal state, even during deep sleep? Second, previous evidence for SOC was based on activity within single brain areas, however, the interaction between brain areas may be organized differently. Here we asked whether the interaction between brain areas is SOC. ...
In complex networks such as gene networks, traffic systems or brain circuits it is important to understand how long it takes for the different parts of the network to effectively influence one another. In the brain, for example, axonal delays between brain areas can amount to several tens of milliseconds, adding an intrinsic component to any timing-based processing of information. Inferring neural interaction delays is thus needed to interpret the information transfer revealed by any analysis of directed interactions across brain structures. However, a robust estimation of interaction delays from neural activity faces several challenges if modeling assumptions on interaction mechanisms are wrong or cannot be made. Here, we propose a robust estimator for neuronal interaction delays rooted in an information-theoretic framework, which allows a model-free exploration of interactions. In particular, we extend transfer entropy to account for delayed source-target interactions, while crucially retaining the conditioning on the embedded target state at the immediately previous time step. We prove that this particular extension is indeed guaranteed to identify interaction delays between two coupled systems and is the only relevant option in keeping with Wiener’s principle of causality. We demonstrate the performance of our approach in detecting interaction delays on finite data by numerical simulations of stochastic and deterministic processes, as well as on local field potential recordings. We also show the ability of the extended transfer entropy to detect the presence of multiple delays, as well as feedback loops. While evaluated on neuroscience data, we expect the estimator to be useful in other fields dealing with network dynamics.
The neurophysiological changes associated with Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) include an increase in low frequency activity, as measured with electroencephalography or magnetoencephalography (MEG). A relevant property of spectral measures is the alpha peak, which corresponds to the dominant alpha rhythm. Here we studied the spatial distribution of MEG resting state alpha peak frequency and amplitude values in a sample of 27 MCI patients and 24 age-matched healthy controls. Power spectra were reconstructed in source space with linearly constrained minimum variance beamformer. Then, 88 Regions of Interest (ROIs) were defined and an alpha peak per ROI and subject was identified. Statistical analyses were performed at every ROI, accounting for age, sex and educational level. Peak frequency was significantly decreased (p < 0.05) in MCIs in many posterior ROIs. The average peak frequency over all ROIs was 9.68 ± 0.71 Hz for controls and 9.05 ± 0.90 Hz for MCIs and the average normalized amplitude was (2.57 ± 0.59)·10(-2) for controls and (2.70 ± 0.49)·10(-2) for MCIs. Age and gender were also found to play a role in the alpha peak, since its frequency was higher in females than in males in posterior ROIs and correlated negatively with age in frontal ROIs. Furthermore, we examined the dependence of peak parameters with hippocampal volume, which is a commonly used marker of early structural AD-related damage. Peak frequency was positively correlated with hippocampal volume in many posterior ROIs. Overall, these findings indicate a pathological alpha slowing in MCI.
Network or graph theory has become a popular tool to represent and analyze large-scale interaction patterns in the brain. To derive a functional network representation from experimentally recorded neural time series one has to identify the structure of the interactions between these time series. In neuroscience, this is often done by pairwise bivariate analysis because a fully multivariate treatment is typically not possible due to limited data and excessive computational cost. Furthermore, a true multivariate analysis would consist of the analysis of the combined effects, including information theoretic synergies and redundancies, of all possible subsets of network components. Since the number of these subsets is the power set of the network components, this leads to a combinatorial explosion (i.e. a problem that is computationally intractable). In contrast, a pairwise bivariate analysis of interactions is typically feasible but introduces the possibility of false detection of spurious interactions between network components, especially due to cascade and common drive effects. These spurious connections in a network representation may introduce a bias to subsequently computed graph theoretical measures (e.g. clustering coefficient or centrality) as these measures depend on the reliability of the graph representation from which they are computed. Strictly speaking, graph theoretical measures are meaningful only if the underlying graph structure can be guaranteed to consist of one type of connections only, i.e. connections in the graph are guaranteed to be non-spurious. ...
Neuronal activity differs between wakefulness and sleep states. In contrast, an attractor state, called self-organized critical (SOC), was proposed to govern brain dynamics because it allows for optimal information coding. But is the human brain SOC for each vigilance state despite the variations in neuronal dynamics? We characterized neuronal avalanches – spatiotemporal waves of enhanced activity - from dense intracranial depth recordings in humans. We showed that avalanche distributions closely follow a power law – the hallmark feature of SOC - for each vigilance state. However, avalanches clearly differ with vigilance states: slow wave sleep (SWS) shows large avalanches, wakefulness intermediate, and rapid eye movement (REM) sleep small ones. Our SOC model, together with the data, suggested first that the differences are mediated by global but tiny changes in synaptic strength, and second, that the changes with vigilance states reflect small deviations from criticality to the subcritical regime, implying that the human brain does not operate at criticality proper but close to SOC. Independent of criticality, the analysis confirms that SWS shows increased correlations between cortical areas, and reveals that REM sleep shows more fragmented cortical dynamics.
The overall staining by GS clearly reveals astrocytes, including all cells of the astroglial family (1), i.e., Bergmann glia, Müller cells (2), tanycytes (3), and ependymal cells. The star shaped morphology from classical silver impregnations relates to cortical and hippocampal astrocytes, which display a comparable pattern in material stained for GFAP. However, the dense population of GS stained astrocytes found in all diencephalic and mesencephalic regions, known to display faint GFAP-labeling (unpublished observations) indicated that while apparently all astrocytes contain GS they have GFAP-ir filaments only in a region-dependent pattern. This is complicated by the emerging view that "astrocytes" constitute a heterogeneous population even within a given region. In the rat hippocampus, combined immunostainings have revealed that the "classical" GFAP-ir astrocyte constitutes a subpopulation of GS-ir astrocytes, which can also lack GFAP staining [direct double staining (4)]. In view of several astroglial subtypes and/or glial precursors present in the adult rodent brain, anti-GS appears to be the most general astrocyte marker, covering all subtypes. In addition, GS has been found early on to label exclusively astrocytic cells and no other glial or neuronal cell types in situ or in culture [reviewed by (5)]. GS has, thus, been applied as a reliable astrocyte marker in very many studies since.
"Complex cells" in rat hippocampus, initially assumed to be an astrocyte subtype (6) but now understood to belong to NG2 cells, a fourth glial type in the CNS (7), may display faint GS-ir in the soma but not its fine processes. Oligodendrocyte precursor cells, possibly also related to NG2 cells, were found to be devoid of GS-ir (8). The immunocytochemical profile and possible heterogeneity of NG2 cells is still under debate to date. Disputing the exclusion of non-astrocytic cells in GS staining, some authors have later reported GS+ oligodendrocytes, although this has not been investigated systematically. Reports on non-astrocytic GS will be discussed in detail here.
There is a wide range of important pharmaceuticals used in treatment of cancer. Besides their known effects on tumor cells, there is growing evidence for modulation of the immune system. Immunomodulatory drugs (IMiDs®) play an important role in the treatment of patients with multiple myeloma or myelodysplastic syndrome and have already demonstrated antitumor, anti-angiogenic, and immunostimulating effects, in particular on natural killer (NK) cells. Tyrosine kinase inhibitors are directly targeting different kinases and are known to regulate effector NK cells and expression of NKG2D ligands (NKG2DLs) on tumor cells. Demethylating agents, histone deacetylases, and proteasome inhibitors interfere with the epigenetic regulation and protein degradation of malignant cells. There are first hints that these drugs also sensitize tumor cells to chemotherapy, radiation, and NK cell-mediated cytotoxicity by enhanced expression of TRAIL and NKG2DLs. However, these pharmaceuticals may also impair NK cell function in a dose- and time-dependent manner. In summary, this review provides an update on the effects of different novel molecules on the immune system focusing NK cells.
Delayed wound repair in sepsis is associated with reduced local pro-inflammatory cytokine expression
(2013)
Sepsis is one of the main causes for morbidity and mortality in hospitalized patients. Moreover, sepsis associated complications involving impaired wound healing are common. Septic patients often require surgical interventions that in-turn may lead to further complications caused by impaired wound healing. We established a mouse model to the study delayed wound healing during sepsis distant to the septic focus point. For this reason cecal ligation and puncture (CLP) was combined with the creation of a superficial wound on the mouse ear. Control animals received the same procedure without CPL. Epithelialization was measured every second day by direct microscopic visualization up to complete closure of the wound. As interplay of TNF-α, TGF-β, matrix metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) is important in wound healing in general, TNF-α, TGF-β, MMP7, and TIMP1 were assessed immunohistochemical in samples of wounded ears harvested on days 2, 6, 10 and 16 after wounding. After induction of sepsis, animals showed a significant delay in wound epithelialization from day 2 to 12 compared to control animals. Complete wound healing was attained after mean 12.2± standard deviation (SD) 3.0 days in septic animals compared to 8.7± SD 1.7 days in the control group. Septic animals showed a significant reduction in local pro-inflammatory cytokine level of TNF-α on day 2 and day 6 as well as a reduced expression of TGF-β on day 2 in wounds. A significant lower expression of MMP7 as well as TIMP1 was also observed on day 2 after wounding. The induction of sepsis impairs wound healing distant to the septic focus point. We could demonstrate that expression of important cytokines for wound repair is deregulated after induction of sepsis. Thus restoring normal cytokine response locally in wounds could be a good strategy to enhance wound repair in sepsis.
Natural Killer Gene Complex (NKC)–encoded C-type lectin-like receptors (CTLRs) are expressed on various immune cells including T cells, NK cells and myeloid cells and thereby contribute to the orchestration of cellular immune responses. Some NKC-encoded CTLRs are grouped into the C-type lectin family 2 (CLEC2 family) and interact with genetically linked CTLRs of the NKRP1 family. While many CLEC2 family members are expressed by hematopoietic cells (e.g. CD69 (CLEC2C)), others such as the keratinocyte-associated KACL (CLEC2A) are specifically expressed by other tissues. Here we provide the first characterization of the orphan gene CLEC2L. In contrast to other CLEC2 family members, CLEC2L is conserved among mammals and located outside of the NKC. We show that CLEC2L-encoded CTLRs are expressed as non-glycosylated, disulfide-linked homodimers at the cell surface. CLEC2L expression is fairly tissue-restricted with a predominant expression in the brain. Thus CLEC2L-encoded CTLRs were designated BACL (brain-associated C-type lectin). Combining in situ hybridization and immunohistochemistry, we show that BACL is expressed by neurons in the CNS, with a pronounced expression by Purkinje cells. Notably, the CLEC2L locus is adjacent to another orphan CTLR gene (KLRG2), but reporter cell assays did neither indicate interaction of BACL with the KLRG2 ectodomain nor with human NK cell lines or lymphocytes. Along these lines, growth of BACL-expressing tumor cell lines in immunocompetent mice did not provide evidence for an immune-related function of BACL. Altogether, the CLEC2L gene encodes a homodimeric cell surface CTLR that stands out among CLEC2 family members by its conservation in mammals, its biochemical properties and the predominant expression in the brain. Future studies will have to reveal insights into the functional relevance of BACL in the context of its neuronal expression.
The objective of this systematic review was to assess tooth wear against ceramic crowns in posterior region in vitro and in vivo. An electronic PubMed search was conducted to identify studies on tooth wear against ceramic crowns in posterior region. The selected studies were analyzed in regard to type of crowns, natural antagonist, measuring protocol and outcome. From a yield of 1 000 titles, 43 articles were selected for full-text analysis; finally, no in vitro and only five in vivo studies met the inclusion criteria. As there is heterogeneity in design, used measuring method, ceramics and analysis-form, a meta-analysis was not possible. Results of these studies are very controversial which makes a scientifically valid comparison impossible. This review indicated that some all-ceramic crowns are as wear friendly as metal-ceramic crowns. Up to now, it has been impossible to associate tooth wear with any specific causal agent. The role of ceramic surface treatment that might be responsible for the changing in rate of tooth wear seems undetermined as yet through clinical trials. The literature reveals that studies on this topic are subject to a substantial amount of bias. Therefore, additional clinical studies, properly designed to diminish bias, are warranted.