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Objectives. To assess interreader agreements and a learning curve between three (senior, junior, and beginner) different experienced musculoskeletal ultrasonographers. Senior served as the imaging "gold standard".
Methods. Clinically dominant joints (finger, shoulder, knee, tibiotalar, and talonavicular) of 15 rheumatoid arthritis (RA) patients were examined by three different experienced ultrasonographers (senior 10 years, junior 10 months, and beginner one month). Each patient's ultrasonographic findings were reported unaware of the other investigators' results. coefficients, percentage agreements, sensitivities, and specificities were calculated.
Results. 120 joints of 15 RA patients were evaluated. Comparing junior's and beginner's results each to the senior's findings, the overall for all examined joints was 0.83 (93%) for junior and 0.43 (76%) for beginner. Regarding the different joints, junior's findings correlate very well with the senior's findings (finger joints: ; shoulder: ; knee: ; tibiotalar joint: ; talonavicular joint: ) while beginner's findings just showed fair to moderate agreements (finger joints: ; shoulder: ; knee: ; tibiotalar joint: ; talonavicular joint: ). In total, beginner's results clearly improved from (agreement of 67%) at baseline to (agreement of 89%) at the end of the evaluation period.
Conclusions. Ultrasonographic evaluation of a ten-month-experienced investigator in comparison to a senior ultrasonographer was of substantial agreement. Agreements between a beginner and a highly experienced ultrasonographer were only fair at the beginning, but during the study including ultrasonographical sessions of 15 RA patients, the beginner clearly improved in musculoskeletal ultrasonography.
Since the introduction of radiological examination techniques, such as an angiographic computed tomography (ACT) and a computed tomographic angiography (CTA), the diagnosis and treatment planning for cerebral aneurysms became quicker and safer. Unfortunately, the state of development of these techniques, and their possible indications and benefits are still today restricted to specialized centers. The objective of this update was to analyze the current scientific evidence about their actual interventional and diagnostic use and identify the individual advantages of each through a literature review and personal experience-based data.
Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.
The presynaptic protein alpha-synuclein has received much attention because its gain-of-function is associated with Parkinson’s disease. However, its physiological function is still poorly understood. We studied brain regions of knock-out mice at different ages with regard to consistent upregulations of the transcriptome and focused on glyoxalase I (GLO1). The microarray data were confirmed in qPCR, immunoblot, enzyme activity, and behavior analyses. GLO1 induction is a known protective cellular response to glucose stress, representing efforts to decrease toxic levels of methylglyoxal (MG), glyoxal and advanced glycation endproducts (AGEs). Mass spectrometry quantification demonstrated a ubiquitous increase in MG and fructosyl-lysine as consequences of glucose toxicity, and consistent enhancement of certain AGEs. Thus, GLO1 induction in KO brain seems insufficient to prevent AGE formation. In conclusion, the data demonstrate GLO1 expression and glycation damage to be induced by alpha-synuclein ablation. We propose that wild-type alpha-synuclein modulates brain glucose metabolism.
Understanding causal relationships, or effective connectivity, between parts of the brain is of utmost importance because a large part of the brain’s activity is thought to be internally generated and, hence, quantifying stimulus response relationships alone does not fully describe brain dynamics. Past efforts to determine effective connectivity mostly relied on model based approaches such as Granger causality or dynamic causal modeling. Transfer entropy (TE) is an alternative measure of effective connectivity based on information theory. TE does not require a model of the interaction and is inherently non-linear. We investigated the applicability of TE as a metric in a test for effective connectivity to electrophysiological data based on simulations and magnetoencephalography (MEG) recordings in a simple motor task. In particular, we demonstrate that TE improved the detectability of effective connectivity for non-linear interactions, and for sensor level MEG signals where linear methods are hampered by signal-cross-talk due to volume conduction.
Meeting Abstract : Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie e.V. (GAA). 17. Jahrestagung der Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie. Osnabrück, 25.-26.11.2010.
ntroduction: Several drugs require dose adjustment in patients with impaired renal function, which however, often goes undetected. Serum creatinine may be normal in patients while renal function is already reduced. The estimated GFR (eGFR) allows a more precise evaluation of the renal function. This study was carried out in a group practice for family medicine, in Frankfurt/ Main, Germany. The exploration aimed at investigating if patients with renal insufficiency were recognised and if their prescriptions were appropriate in terms of dose adjustment or contra-indications.
Methods: In patients (>65yrs) with renal insufficiency (creatinine clearance <60 ml/min), their prescribed medication was retrospectively explored (Observation period 1.1.2008 to 1.4.2009). The Cockroft-Gault formula was used as estimate for the eGFR, using a creatinine value from the patient’s charts. In 90 patients, a second eGFR could be estimated from a second creatinine value obtained within 3-6 months. The recommended dose of each prescription in the SmPC (Fachinformation“) was compared to the dose that had been actually prescribed.
Results: Out of 232 consecutively patients >65 yrs, 102 had an eGFR <60 ml/min, 16 of these had an eGFR <30 ml/min. The eGFR was closely correlated (r2=0.81) with an independent second eGFR. Out of these 102 patients, 48 had a serum creatinine level within the normal range. Renal adjustment was required in 263 of a total of 613 prescriptions. 72 prescriptions in a total of 45 patients were not appropriately adjusted (32) or prescribed despite a contraindication (40). For chronic prescriptions, metformin, ramipril, enalapril, HCTZ, and spironolactone accounted for 70% of inappropriate dosing; the magnitude of misdosing was 1.5 to 4 fold (median 2). 9 temporary prescriptions (of a total of 60 prescriptions) in 8 patients were not adjusted (cefuroxim, cefpodoxim, levofloxacin). We could not prove that patients with normal serum creatinine had a higher rate of inappropriate dosing than those with already elevated creatinine.
Discussion and conclusion: In this GP practice, we have demonstrated a considerable prevalence of inappropriate dosing in patients with impaired renal function. It remains to be elucidated whether surveillance of appropriate dosing in renal impairment can be optimized e.g. with CPOE.
The C-type lectin-like receptor CLEC-2 signals via phosphorylation of a single cytoplasmic YXXL sequence known as a hem-immunoreceptor tyrosine-based activation motif (hemITAM). In this study, we show that phosphorylation of CLEC-2 by the snake toxin rhodocytin is abolished in the absence of the tyrosine kinase Syk but is not altered in the absence of the major platelet Src family kinases, Fyn, Lyn, and Src, or the tyrosine phosphatase CD148, which regulates the basal activity of Src family kinases. Further, phosphorylation of CLEC-2 by rhodocytin is not altered in the presence of the Src family kinase inhibitor PP2, even though PLCγ2 phosphorylation and platelet activation are abolished. A similar dependence of phosphorylation of CLEC-2 on Syk is also seen in response to stimulation by an IgG mAb to CLEC-2, although interestingly CLEC-2 phosphorylation is also reduced in the absence of Lyn. These results provide the first definitive evidence that Syk mediates phosphorylation of the CLEC-2 hemITAM receptor with Src family kinases playing a critical role further downstream through the regulation of Syk and other effector proteins, providing a new paradigm in signaling by YXXL-containing receptors.
Background: Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood and has a poor prognosis. Here we assessed the capability of ex vivo expanded cytokine-induced killer cells to lyse both alveolar and embryonic rhabdomyosarcoma cell lines and investigated the mechanisms involved.
Design and Methods: Peripheral blood mononuclear cells from six healthy donors were used to generate and expand cytokine-induced killer cells. The phenotype and composition of these cells were determined by multiparameter flow cytometry, while their cytotoxic effect against rhabdomyosarcoma cells was evaluated by a europium release assay.
Results: Cytokine-induced killer cells efficiently lysed cells from both rhabdomyosarcoma cell lines. Antibody-mediated masking of either NKG2D molecule on cytokine-induced killer cells or its ligands on rhabdomyosarcoma cells (major histocompatibility antigen related chain A and B and UL16 binding protein 2) diminished this effect by 50%, suggesting a major role for the NKG2D molecule in rhabdomyosarcoma cell killing. No effect was observed after blocking CD11a, CD3 or TCRαβ molecules on cytokine-induced killer cells or CD1d on rhabdomyosar-coma cells. Remarkably, cytokine-induced killer cells used tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to activate caspase-3, as the main caspase responsible for the execution of apoptosis. Accordingly, blocking TRAIL receptors on embryonic rhabdomyosarcoma cell lines significantly reduced the anti-tumor effect of cytokine-induced killer cells. About 50% of T cells within the cytokine-induced killer population had an effector memory phenotype, 20% had a naïve phenotype and approximately 30% of the cells had a central memory phenotype. In addition, cytokine-induced killer cells expressed low levels of activation-induced markers CD69 and CD137 and demonstrated a low alloreactive potential.
Conclusions: Our data suggest that cytokine-induced killer cells may be used as a novel adoptive immunotherapy for the treatment of patients with rhabdomyosarcoma after allogeneic stem cell transplantation.
The aim of this study was to investigate the frequency and effects of peer-victimization on mental health problems among adolescents. Parental and school support were assumed as protective factors that might interact with one another in acting as buffers for adolescents against the risk of peer-victimization. Besides these protective factors, age and gender were additionally considered as moderating factors. The Social and Health Assessment survey was conducted among 986 students aged 11-18 years in order to assess peer-victimization, risk and protective factors and mental health problems. For mental health problems, the Strengths and Difficulties Questionnaire (SDQ) was used. Effects of peer-victimization on mental health problems were additionally compared with normative SDQ data in order to obtain information about clinically relevant psychopathology in our study sample. Results of this study show that peer-victimization carries a serious risk for mental health problems in adolescents. School support is effective in both male and female adolescents by acting as a buffer against the effect of victimization, and school support gains increasing importance in more senior students. Parental support seems to be protective against maladjustment, especially in peer-victimized girls entering secondary school. Since the effect of peer-victimization can be reduced by parental and school support, educational interventions are of great importance in cases of peer-victimization.
Research indicates that autism is the extreme end of a continuously distributed trait. The Social Responsiveness Scale (SRS) and the Social and Communication Disorders Checklist (SCDC) aim to assess autistic traits. The objective of this study was to compare their clinical validity. The SRS showed sensitivities of .74 to .80 and specificities of .69 to 1.00 for autism. Sensitivities were .85 to .90 and specificities .28 to.82 for the SCDC. Correlations with the ADI-R, ADOS and SCQ were higher for the SRS than for the SCDC. The SCDC seems superior to the SRS to screen for unspecific social and communicative deficits including autism. The SRS appears more suitable than the SCDC in clinical settings and for specific autism screening.
The impact of shift work induced chronic circadian disruption on IL-6 and TNF-α immune responses
(2010)
Aim: Sleep disturbances induce proinflammatory immune responses, which might increase cardiovascular disease risk. So far the effects of acute sleep deprivation and chronic sleep illnesses on the immune system have been investigated. The particular impact of shift work induced chronic circadian disruption on specific immune responses has not been addressed so far.
Methods: Pittsburgh-Sleep-Quality-Index (PSQI) questionnaire and blood sampling was performed by 225 shift workers and 137 daytime workers. As possible markers the proinflammatory cytokines IL-6 and TNF-alpha and lymphocyte cell count were investigated. A medical examination was performed and biometrical data including age, gender, height, weight, waist and hip circumference and smoking habits were collected by a structured interview.
Results: Shift workers had a significantly higher mean PSQI score than day workers (6.73 vs. 4.66; p < 0.001). Day workers and shift workers had similar serum levels of IL-6 (2.30 vs. 2.67 resp.; p = 0.276), TNF-alpha (5.58 vs. 5.68, resp.; p = 0.841) or lymphocytes count (33.68 vs. 32.99, resp.; p = 0.404). Furthermore there were no differences in cytokine levels (IL-6 p = 0.761; TNF-alpha p = 0.759) or lymphocyte count (p = 0.593) comparing the sleep quality within the cohorts. When this calculation of sleep quality was stratified by shift and day workers irrespective of their sleep quality day workers and shift workers had similar serum levels of IL-6, TNF-alpha or lymphocytes count. Multiple linear regression analysis showed a significant correlation of lymphocytes count and smoking habits.
Conclusion: Shift work induces chronic sleep debt. Our data reveals that chronic sleep debt might not always lead to an activation of the immune system, as we did not observe differences in lymphocyte count or level of IL-6 or TNF-alpha serum concentration between shift workers and day workers. Therefore chronic sleep restriction might be eased by a long-term compensating immune regulation which (in healthy) protects against an overstimulation of proinflammatory immune mechanisms and moderates metabolic changes, as they are known from short-term sleep deprivation or sleep related breathing disorders.
Background: Diseases associated with smoking are a foremost cause of premature death in the world, both in developed and developing countries. Eliminating smoking can do more to improve health and prolong life than any other measure in the field of preventive medicine. Today's medical students will play a prominent role in future efforts to prevent and control tobacco use.
Methods: A cross-sectional, self-administered, anonymous survey of fifth-year medical students in Berlin, Germany was conducted in November 2007. The study explored the prevalence of smoking among medical students. We assessed their current knowledge regarding tobacco dependence and the effectiveness of smoking cessation methods. Students' perceived competence to counsel smokers and promote smoking cessation treatments was also explored. Analyses were based on responses from 258 students (86.6% response rate).
Results: One quarter of the medical students surveyed were current smokers. The smoking rate was 22.1% among women, 32.4% among men. Students underestimated smoking-related mortality and the negative effect of smoking on longevity. A considerable number of subjects erroneously assumed that nicotine causes coronary artery disease. Students' overall knowledge of the effectiveness of smoking cessation methods was inadequate. Only one third of the students indicated that they felt qualified to counsel patients about tobacco dependence.
Conclusions: This study reveals serious deficiencies in knowledge and counseling skills among medical students in our sample. The curriculum of every medical school should include a tobacco module. Thus, by providing comprehensive training in nicotine dependence interventions to medical students, smokers will have access to the professional expertise they need to quit smoking.
Family members provide most of the patient care and administer most of the treatments to patients with Alzheimer’s disease (AD). Family caregivers have an important impact on clinical outcomes, such as quality of life (QoL). As a consequence of this service, family caregivers suffer high rates of psychological and physical illness as well as social and financial burdens. Hence, it is important to involve family caregivers in multimodal treatment settings and provide interventions that are both suitable and specifically tailored to their needs. In recent years, several clinical guidelines have been presented worldwide for evidence-based treatment of AD and other forms of dementia. Most of these guidelines have considered family advice as integral to the optimal clinical management of AD. This article reviews current and internationally relevant guidelines with emphasis on recommendations concerning family advice.
We report on screening tests of 66 extracts obtained from 35 marine sponge species from the Caribbean Sea (Curaçao) and from eight species from the Great Barrier Reef (Lizard Island). Extracts were prepared in aqueous and organic solvents and were tested for hemolytic, hemagglutinating, antibacterial and anti-acetylcholinesterase (AChE) activities, as well as their ability to inhibit or activate cell protein phosphatase 1 (PP1). The most interesting activities were obtained from extracts of Ircinia felix, Pandaros acanthifolium, Topsentia ophiraphidites, Verongula rigida and Neofibularia nolitangere. Aqueous and organic extracts of I. felix and V. rigida showed strong antibacterial activity. Topsentia aqueous and some organic extracts were strongly hemolytic, as were all organic extracts from I. felix. The strongest hemolytic activity was observed in aqueous extracts from P. acanthifolium. Organic extracts of N. nolitangere and I. felix inhibited PP1. The aqueous extract from Myrmekioderma styx possessed the strongest hemagglutinating activity, whilst AChE inhibiting activity was found only in a few sponges and was generally weak, except in the methanolic extract of T. ophiraphidites.
Pancreatic resections for advanced M1-pancreatic carcinoma : the value of synchronous metastasectomy
(2010)
Background: For M1 pancreatic adenocarcinomas pancreatic resection is usually not indicated. However, in highly selected patients synchronous metastasectomy may be appropriate together with pancreatic resection when operative morbidity is low.
Materials and Methods: From January 1, 2004 to December, 2007 a total of 20 patients with pancreatic malignancies were retrospectively evaluated who underwent pancreatic surgery with synchronous resection of hepatic, adjacent organ, or peritoneal metastases for proven UICC stage IV periampullary cancer of the pancreas. Perioperative as well as clinicopathological parameters were evaluated.
Results: There were 20 patients (9 men, 11 women; mean age 58 years) identified. The primary tumor was located in the pancreatic head (n=9, 45%), in pancreatic tail (n=9, 45%), and in the papilla Vateri (n=2, 10%). Metastases were located in the liver (n=14, 70%), peritoneum (n=5, 25%), and omentum majus (n=2, 10%). Lymphnode metastases were present in 16 patients (80%). All patients received resection of their tumors together with metastasectomy. Pylorus preserving duodenopancreatectomy was performed in 8 patients, distal pancreatectomy in 8, duodenopancreatectomy in 2, and total pancreatectomy in 2. Morbidity was 45% and there was no perioperative mortality. Median postoperative survival was 10.7 months (2.6–37.7 months) which was not significantly different from a matched-pair group of patients who underwent pancreatic resection for UICC adenocarcinoma of the pancreas (median survival 15.6 months; =.1).
Conclusion: Pancreatic resection for M1 periampullary cancer of the pancreas can be performed safely in well-selected patients. However, indication for surgery has to be made on an individual basis.
In the past, the genetically diabetic-obese diabetes/diabetes (db/db) and obese/obese (ob/ob) mouse strains were used to investigate mechanisms of diabetes-impaired wound healing. Here we determined patterns of skin repair in genetically normal C57Bl/6J mice that were fed using a high fat diet (HFD) to induce a diabetes-obesity syndrome. Wound closure was markedly delayed in HFD-fed mice compared to mice which had received a standard chow diet (CD). Impaired wound tissue of HFD mice showed a marked prolongation of wound inflammation. Expression of vascular endothelial growth factor (VEGF) was delayed and associated with the disturbed formation of wound margin epithelia and an impaired angiogenesis in the reduced granulation tissue. Normal wound contraction was retarded and disordered. Wound disorders in obese C57Bl/6J mice were paralleled by a prominent degradation of the inhibitor of NFκB (IκB-α) in the absence of an Akt activation. By contrast to impaired wound conditions in ob/ob mice, late wounds of HFD mice did not develop a chronic inflammatory state and were epithelialized after 11 days of repair. Thus, only genetically obese and diabetic ob/ob mice finally developed chronic wounds and therefore represent a better suited experimental model to investigate diabetes-induced wound healing disorders.
Cells can respond to stress in various ways ranging from the activation of survival pathways to the initiation of cell death that eventually eliminates damaged cells. Whether cells mount a protective or destructive stress response depends to a large extent on the nature and duration of the stress as well as the cell type. Also, there is often the interplay between these responses that ultimately determines the fate of the stressed cell. The mechanism by which a cell dies (i.e., apoptosis, necrosis, pyroptosis, or autophagic cell death) depends on various exogenous factors as well as the cell's ability to handle the stress to which it is exposed. The implications of cellular stress responses to human physiology and diseases are manifold and will be discussed in this review in the context of some major world health issues such as diabetes, Parkinson's disease, myocardial infarction, and cancer.
One of the hallmarks of human cancers is the intrinsic or acquired resistance to apoptosis. Evasion of apoptosis can be part of a cellular stress response to ensure the cell's survival upon exposure to stressful stimuli. Apoptosis resistance may contribute to carcinogenesis, tumor progression, and also treatment resistance, since most current anticancer therapies including chemotherapy as well as radio- and immunotherapies primarily act by activating cell death pathways including apoptosis in cancer cells. Hence, a better understanding of the molecular mechanisms regarding how cellular stress stimuli trigger antiapoptotic mechanisms and how this contributes to tumor resistance to apoptotic cell death is expected to provide the basis for a rational approach to overcome apoptosis resistance mechanisms in cancers.