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author:("alff, A")
1.  External Ventricular Drain Infections: Risk Factors and Outcome 
External ventricular drainage (EVD) is frequently used in neurosurgery to drain cerebrospinal fluid in patients with raised intracranial pressure. We performed a retrospective single center study in order to evaluate the incidence of EVD-related infections and to identify underlying risk factors. 246 EVDs were placed in 218 patients over a 30-month period. EVD was continued in median for 7 days (range 1–44). The cumulative incidence of EVD-related infections was 8.3% (95% CI, 5.3–12.7) with a device-associated infection rate of 10.4 per 1000 drainage days (95% CI, 6.2–16.5). The pathogens most commonly identified were coagulase-negative Staphylococcus (62%) followed by Enterococcus spp. (19%). Patients with an EVD-related infection had a significantly longer ICU (11 versus 21 days, P < 0.01) and hospital stay (20 versus 28.5 days, P < 0.01) than patients without. Median total duration of external drainage was twice as long in patients with EVD-related infection (6 versus 12 days, P < 0.01). However, there was no significant difference in the duration between first EVD placement and the occurrence of EVD-related infection and EVD removal in patients without EVD-related infection (6 versus 7 days, P = 0.87), respectively. Interestingly no risk factor for EVD-related infection could be identified in our cohort of patients.
PMCID: PMC4251652  PMID: 25484896
2.  Heterogeneous bone marrow uptake on interim 18F-fluorodeoxyglucose positron emission tomography for lymphoma mimicking disease progression: a case report 
The use of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) scanning for baseline staging and assessment of treatment response for higher grade lymphomas is considered to be the standard of care. Evaluation of lymphomatous bone marrow infiltration on 18F-FDG PET can usually distinguish between normal regenerating marrow following chemotherapy by a characteristic pattern of uptake.
Case presentation
Here we report the case of a 51-year-old Caucasian woman with mixed low- and high-grade lymphoma with biopsy confirmed marrow infiltration. An interim post-three cycle chemotherapy 18F-FDG PET scan revealed apparent progression of marrow disease. Subsequent investigations were performed including bone marrow biopsies, repeat 18F-FDG PET scanning and a white cell scan. These revealed the interim 18F-FDG PET scan appearance was due to a highly unusual pattern of scattered islands of regenerating normal marrow, rather than progressive lymphoma.
Our case report highlights that apparent severe bone marrow abnormalities on 18F-FDG PET scans in lymphoma patients treated with chemotherapy are not always due to disease. Clinicians should retain a high index of suspicion for benign causes when 18F-FDG PET scan results appear incongruent with clinical response.
PMCID: PMC4228820  PMID: 25377897
Lymphoma; FDG; PET; Chemotherapy; Response; False; Positive; Granulocyte colony stimulating factor; Pegfilgrastim
3.  Development of a standardized laparoscopic caecum resection model to simulate laparoscopic appendectomy in rats 
Laparoscopic appendectomy (LA) has become one of the most common surgical procedures to date. To improve and standardize this technique further, cost-effective and reliable animal models are needed.
In a pilot study, 30 Wistar rats underwent laparoscopic caecum resection (as rats do not have an appendix vermiformis), to optimize the instrumental and surgical parameters. A subsequent test study was performed in another 30 rats to compare three different techniques for caecum resection and bowel closure.
Bipolar coagulation led to an insufficiency of caecal stump closure in all operated rats (Group 1, n = 10). Endoloop ligation followed by bipolar coagulation and resection (Group 2, n = 10) or resection with a LigaSure™ device (Group 3, n = 10) resulted in sufficient caecal stump closure.
We developed a LA model enabling us to compare three different caecum resection techniques in rats. In conclusion, only endoloop closure followed by bipolar coagulation proved to be a secure and cost-effective surgical approach.
PMCID: PMC4094547  PMID: 24934381
Laparoscopy; Caecum resection; Rats; Appendectomy; Stump closure; Laparoscopic procedures
5.  CT-navigation versus fluoroscopy-guided placement of pedicle screws at the thoracolumbar spine: single center experience of 4,500 screws 
European Spine Journal  2012;22(3):654-660.
Single center evaluation of the placement accuracy of thoracolumbar pedicle screws implanted either with fluoroscopy or under CT-navigation using 3D-reconstruction and intraoperative computed tomography control of the screw position. There is in fact a huge variation in the reported placement accuracy of pedicle screws, especially concerning the screw placement under conventional fluoroscopy most notably due to the lack of the definition of screw misplacement, combined with a potpourri of postinstrumentation evaluation methods.
The operation data of 1,006 patients operated on in our clinic between 1995 and 2005 is analyzed retrospectively. There were 2,422 screws placed with the help of CT-navigation compared to 2,002 screws placed under fluoroscopy. The postoperative computed tomography images were reviewed by a radiologist and an independent spine surgeon.
In the lumbar spine, the placement accuracy was 96.4 % for CT-navigated screws and 93.9 % for pedicle screws placed under fluoroscopy, respectively. This difference in accuracy was statistically significant (Fishers Exact Test, p = 0.001). The difference in accuracy became more impressing in the thoracic spine, with a placement accuracy of 95.5 % in the CT-navigation group, compared to 79.0 % accuracy in the fluoroscopy group (p < 0.001).
This study underlines the relevance of CT-navigation-guided pedicle screw placement, especially when instrumentation of the middle and upper thoracic spine is carried out.
PMCID: PMC3585623  PMID: 23001415
Pedicle screws; Navigation; Placement accuracy; Computed tomography; Fluoroscopy
6.  Conventional mesh repair of a giant iatrogenic bilateral diaphragmatic hernia with an enterothorax 
Diaphragmatic hernias (DHs) are divided into congenital and acquired hernias, most of which are congenital. Among acquired DHs, up to 80% are left-sided, only a few iatrogenic DHs have been reported, and bilateral hernias are extremely rare. For diagnostic reasons, many DHs are overlooked by ultrasonography or X-ray and are only recognized at a later stage when complications occur.
In 2009, we performed three partial diaphragm replacements in our clinic for repairing DHs using a PERMACOL™ implant.
As all patients had uneventful postoperative courses and the clinical outcomes were very good, we present one special case of a 65-year-old male with a giant iatrogenic bilateral DH with an enterothorax.
We see a good indication for diaphragm replacements by using a PERMACOL™ implant for fixing especially DHs with huge hernial gaps and in cases with fragile tissue.
PMCID: PMC3928060  PMID: 24600251
bilateral diaphragmatic hernia; enterothorax; conventional hernia repair; PERMACOL™; biological implant; diaphragm replacement; mesh repair
7.  Iatrogenic Extracellular Matrix Disruption as a Local Trigger for Postoperative Ileus 
The Journal of surgical research  2012;178(2):632-639.
Active MMP-9 disruption of the extracellular matrix plays an important role in inflammatory disorders. In this study, we investigated the inflammatory role of MMP-9 and the extracellular matrix (ECM) breakdown product hyaluronan as a trigger for the postoperative intestinal inflammatory response of postoperative ileus.
A standardized intestinal surgical manipulation (SM) was performed on rats to produce ileus assessed by the oral non-digestible FITC-dextran transit assay. Isolated intestinal muscularis extracts were studied for mRNA expressions of IL-6, MMP-9 and CD44. Peritoneal MMP-9 activity was quantified using zymography. Peritoneal fluid and serum were quantified for hyaluronan and TIMP-1 levels by ELISA. Peritoneal macrophages were cultured and exposed to peritoneal fluid or synthetic hyaluronan for ELISA analysis of IL-6 and MIP-1α.
Transit was significantly delayed after SM and extracts of the isolated jejunal and colonic muscularis demonstrated a significant induction of IL-6, MMP-9 and CD44 mRNAs compared to controls. Zymography confirmed significant MMP-9 activity in peritoneal fluid compared to controls. ELISA measurements showed a significant upregulation in hyaluronan and TIMP-1 in the peritoneal fluid and serum. Additionally, ELISA and RT-PCR measurements of peritoneal macrophages stimulated with postsurgical peritoneal fluid and synthetic hyaluronan resulted in higher expressions of IL-6 and MIP-1α in the macrophage supernatant.
Our results confirm that MMP-9 disruption in the ECM with hyaluronan release and muscularis CD44 receptor induction has the potential to trigger muscularis proinflammatory cascades which cause postoperative ileus and we suggest that MMP-9 inhibition may be a novel therapeutic approach to limit postoperative ileus.
PMCID: PMC3496029  PMID: 23079570
extracellular matrix; hyaluronan; postoperative ileus; CD44; TIMP-1; MMP-9
8.  Malignant melanoma of the ileo-anal pouch anastomosis after restorative proctocolectomy for ulcerative colitis: report of a case 
A 62 year-old patient with therapy-refractory pouchitis after proctocolectomy for ulcerative colitis was admitted with hematochezia and abdominal discomfort. A malignant melanoma (MM) was found after repeated biopsies of the pouch. Complete staging revealed no evidence for distant metastases and the patient underwent abdominoperineal pouch resection. Six weeks later, the patient was readmitted because of severe general deterioration and diffuse metastatic spread to the liver was found. The patient died of hepatorenal syndrome shortly thereafter.
Patients with inflammatory bowel disease are at increased risk of developing cancer, including rarities such as MM. Our experience stresses the importance of repeated biopsies in therapy-refractory pouchitis.
PMCID: PMC4177136  PMID: 24188588
Bowel; Malignant melanoma; Pouch; Ulcerative colitis
9.  Adaptive Lévy Processes and Area-Restricted Search in Human Foraging 
PLoS ONE  2013;8(4):e60488.
A considerable amount of research has claimed that animals’ foraging behaviors display movement lengths with power-law distributed tails, characteristic of Lévy flights and Lévy walks. Though these claims have recently come into question, the proposal that many animals forage using Lévy processes nonetheless remains. A Lévy process does not consider when or where resources are encountered, and samples movement lengths independently of past experience. However, Lévy processes too have come into question based on the observation that in patchy resource environments resource-sensitive foraging strategies, like area-restricted search, perform better than Lévy flights yet can still generate heavy-tailed distributions of movement lengths. To investigate these questions further, we tracked humans as they searched for hidden resources in an open-field virtual environment, with either patchy or dispersed resource distributions. Supporting previous research, for both conditions logarithmic binning methods were consistent with Lévy flights and rank-frequency methods–comparing alternative distributions using maximum likelihood methods–showed the strongest support for bounded power-law distributions (truncated Lévy flights). However, goodness-of-fit tests found that even bounded power-law distributions only accurately characterized movement behavior for 4 (out of 32) participants. Moreover, paths in the patchy environment (but not the dispersed environment) showed a transition to intensive search following resource encounters, characteristic of area-restricted search. Transferring paths between environments revealed that paths generated in the patchy environment were adapted to that environment. Our results suggest that though power-law distributions do not accurately reflect human search, Lévy processes may still describe movement in dispersed environments, but not in patchy environments–where search was area-restricted. Furthermore, our results indicate that search strategies cannot be inferred without knowing how organisms respond to resources–as both patched and dispersed conditions led to similar Lévy-like movement distributions.
PMCID: PMC3618454  PMID: 23577118
10.  Interventions to improve executive functioning and working memory in school-aged children with AD(H)D: a randomised controlled trial and stepped-care approach 
BMC Psychiatry  2013;13:23.
Deficits in executive functioning are of great significance in attention-deficit/hyperactivity disorder (ADHD). One of these executive functions, working memory, plays an important role in academic performance and is often seen as the core deficit of this disorder. There are indications that working memory problems and academic performance can be improved by school-oriented interventions but this has not yet been studied systematically. In this study we will determine the short- and long-term effects of a working memory - and an executive function training applied in a school situation for children with AD(H)D, taking individual characteristics, the level of impairment and costs (stepped-care approach) into account.
The study consists of two parts: the first part is a randomised controlled trial with school-aged children (8–12 yrs) with AD(H)D. Two groups (each n = 50) will be randomly assigned to a well studied computerized working memory training ‘Cogmed’, or to the ‘Paying attention in class’ intervention which is an experimental school-based executive function training. Children will be selected from regular -and special education primary schools in the region of Amsterdam, the Netherlands. The second part of the study will determine which specific characteristics are related to non-response of the ‘Paying attention in class’ intervention. School-aged children (8–12 yrs) with AD(H)D will follow the experimental school-based executive function training ‘Paying attention in class’ (n = 175). Academic performance and neurocognitive functioning (primary outcomes) are assessed before, directly after and 6 months after training. Secondary outcome measures are: behaviour in class, behaviour problems and quality of life.
So far, there is limited but promising evidence that working memory – and other executive function interventions can improve academic performance. Little is know about the applicability and generalization effects of these interventions in a classroom situation. This study will contribute to this lack of information, especially information related to real classroom and academic situations. By taking into account the costs of both interventions, level of impairment and individual characteristics of the child (stepped-care approach) we will be able to address treatment more adequately for each individual in the future. Trial registration: Nederlands Trial Register NTR3415.
PMCID: PMC3548701  PMID: 23311304
AD(H)D; School-aged children; Working memory training; Executive function training; Academic performance; Randomised controlled trial
12.  The t(4;14) translocation and FGFR3 overexpression in multiple myeloma: prognostic implications and current clinical strategies 
Blood Cancer Journal  2012;2(9):e89-.
Multiple myeloma (MM) is a heterogeneous plasma cell disorder characterized by genetic abnormalities, including chromosomal translocations, deletions, duplications and genetic mutations. Translocations involving the immunoglobulin heavy chain region at chromosome 14q32 are observed in approximately 40% of patients with MM. Translocation of oncogenes into this region may lead to their increased expression, contributing to disease initiation, disease progression and therapeutic resistance. The t(4;14) translocation is associated with upregulation of the fibroblast growth factor receptor 3 (FGFR3) and the myeloma SET domain protein. Patients with t(4;14) demonstrate an overall poor prognosis that is only partially mitigated by the use of the novel agents bortezomib and lenalidomide; as such, an unmet medical need remains for patients with this aberration. Preclinical studies of inhibitors of FGFR3 have shown promise in t(4;14) MM, and these studies have led to the initiation of clinical trials. Data from these trials will help to determine the clinical utility of FGFR3 inhibitors for patients with t(4;14) MM and may pave the way for personalized medicine in patients with this incurable disease.
PMCID: PMC3461707  PMID: 22961061
multiple myeloma; translocation; t(4;14); FGFR3; MMSET
13.  Orthotopic Liver Transplantation in Human-Immunodeficiency-Virus-Positive Patients in Germany 
AIDS Research and Treatment  2012;2012:197501.
Objectives. This summary evaluates the outcomes of orthotopic liver transplantation (OLT) of HIV-positive patients in Germany. Methods. Retrospective chart analysis of HIV-positive patients, who had been liver-transplanted in Germany between July 1997 and July 2011. Results. 38 transplantations were performed in 32 patients at 9 German transplant centres. The reasons for OLT were end-stage liver disease (ESLD) and/or liver failure due to hepatitis C (HCV) (n = 19), hepatitis B (HBV) (n = 10), multiple viral infections of the liver (n = 2) and Budd-Chiari-Syndrome. In July 2011 19/32 (60%) of the transplanted patients were still alive with a median survival of 61 months (IQR (interquartile range): 41–86 months). 6 patients had died in the early post-transplantation period from septicaemia (n = 4), primary graft dysfunction (n = 1), and intrathoracal hemorrhage (n = 1). Later on 7 patients had died from septicaemia (n = 2), delayed graft failure (n = 2), recurrent HCC (n = 2), and renal failure (n = 1). Recurrent HBV infection was efficiently prevented in 11/12 patients; HCV reinfection occurred in all patients and contributed considerably to the overall mortality. Conclusions. Overall OLT is a feasible approach in HIV-infected patients with acceptable survival rates in Germany. Reinfection with HCV still remains a major clinical challenge in HIV/HCV coinfection after OLT.
PMCID: PMC3413997  PMID: 22900154
14.  Anti-Inflammatory Role of Glycine In Reducing Rodent Postoperative Inflammatory Ileus 
Inflammatory events within the intestinal muscularis, including macrophage activation and leukocyte recruitment, have been demonstrated to participate in causing postoperative ileus. Recently, glycine has gained attention due to its beneficial immunomodulatory effects in transplantation, shock and sepsis.
The purpose of this study was to determine if pre-operative glycine administration would attenuate postoperative ileus in rodents.
Muscularis glycine receptors were investigated by immunohistochemistry. Gastrointestinal motility was assessed by in vivo transit distribution histograms with calculated geometric center analysis and jejunal circular smooth muscle contractility in a standard organ bath. The impact of glycine on the muscularis inflammatory responses to surgical manipulation of the intestine were measured by real time PCR, nitric oxide Griess reaction, prostaglandin ELISA, Luminex and histochemistry.
Glycine-gated chloride channels were immunohistochemically localized to muscularis macrophages and postoperative infiltrating leukocytes. Pre-operative glycine treatment significantly improved postoperative gastrointestinal transit and jejunal circular muscle contractility. Pre-operative glycine injection significantly reduced the induction of IL-6, TNF-α, iNOS and ICAM-1 mRNAs, which was associated with the attenuation in postoperative leukocyte recruitment. Nitric oxide and prostanoid release from the postsurgical inflamed muscularis was diminished by glycine. The secretion of the inflammatory proteins IL-6, MCP-1 and MIP-1α were also significantly decreased by glycine pretreatment.
The data indicate that pre-operative glycine reduces postoperative ileus via the early attenuation of primal inflammatory events within the surgically manipulated gut wall. Therapeutic modulation of resident macrophages by glycine is a potential novel pharmacological target for the prevention of postoperative ileus.
PMCID: PMC2999652  PMID: 20939853
Glycine; macrophage; leukocytes; inflammation; postoperative ileus
15.  Accuracy of CT parameters for assessment of tumour size and aggressiveness in lung adenocarcinoma with bronchoalveolar elements 
The British Journal of Radiology  2010;83(994):841-849.
Accurate determination of tumour size in lung adenocarcinoma with bronchoalveolar features (BAC) is important for the determination of TNM (tumour, nodes, metastasis) scores used in staging, prognosis and therapy response assessment. However, tumour sizes derived using lung window (LW) CT or soft-tissue/mediastinal window (MW) CT often give different results. This study examines which measurement correlates best with actual tumour size and which best identifies advanced disease. This retrospective study included 43 BAC patients who underwent surgical resection with mediastinal lymphadenectomy <4 weeks post CT scan. The largest unidimensional tumour diameter on each CT window was compared with actual histopathological tumour size (HP). LW, MW and HP size measurements and a recently described CT parameter – the modified tumour shadow disappearance rate (mTDR) = (1 – [MW/LW]) – were then used to determine which parameter best discriminated between the presence or absence of advanced disease. There was no difference between HP and LW sizes, but MW significantly underestimated HP size (p<0.0001). Unlike MW (p = 0.01) and mTDR (p = 0.001), neither HP (p = 0.14) nor LW (p = 0.10) distinguished between patients with or without advanced disease. On receiver operating characteristic (ROC) analysis at a cut-off of ≤0.13, the sensitivity and specificity of mTDR for detecting advanced disease were 69% and 89%, respectively. In patients with tumours ≤3 cm, only mTDR remained a significant predictor of advanced disease (p = 0.017), with best cut-off at ≤0.20, giving a sensitivity and specificity of 71% and 94%, respectively. MW better predicts advanced disease than LW and might also need to be recorded for RECIST (response evaluation criteria in solid tumours) assessment for T staging of BAC; however, mTDR appears to be an even better predictor and should also be used.
PMCID: PMC3473756  PMID: 20846983
16.  Fatty acid synthase as a novel target for meningioma therapy 
Neuro-Oncology  2010;12(8):844-854.
High levels of fatty acid synthase (FAS) expression have been reported in hormone receptor-positive tumors, including prostate, breast, and ovarian cancers, and its inhibition reduces tumor growth in vitro and in vivo. Similar to other hormone receptor-positive tumor types, meningiomas are progesterone receptor- and estrogen receptor-immunoreactive brain tumors. To define the role of FAS in human meningioma growth control, we first analyzed the FAS expression using a tissue microarray containing 38 meningiomas and showed increased FAS expression in 70% of atypical WHO grade II and anaplastic WHO grade III meningiomas compared with 10% of benign WHO grade I tumors. We next confirmed this finding by real-time PCR and Western blotting. Second, we demonstrated that treatment with the FAS inhibitor, cerulenin (Cer), significantly decreased meningioma cell survival in vitro. Third, we showed that Cer treatment reduced FAS expression by modulating Akt phosphorylation (activation). Fourth, we demonstrated that Cer treatment of mice bearing meningioma xenografts resulted in significantly reduced tumor volumes associated with increased meningioma cell death. Collectively, our data suggest that the increased FAS expression in human meningiomas represents a novel therapeutic target for the treatment of unresectable or malignant meningioma.
PMCID: PMC2940685  PMID: 20511185
fatty acid synthase; meningioma; therapy
17.  PEEK cages as a potential alternative in the treatment of cervical spondylodiscitis: a preliminary report on a patient series 
European Spine Journal  2010;19(6):1004-1009.
The surgical management of cervical spondylodiscitis consists of the resection of the affected disc, the decompression of the cervical spinal cord, followed by the stabilization using an autologous bone graft or a titanium implant combined with a ventral plate fixation. Until now, there were no studies about the practicability and putative safety of PEEK cages in cervical spine infection. Now, we present the history of five patients suffering from neurological deficits and septicemia caused by mono- or bisegmental pyogenic cervical discitis and intraspinal abscess without severe bone destruction. Patients were treated surgically by discectomy, decompression, and ventral spondylodesis. The disc was replaced by a PEEK cage without additional fixation. Progressive bony fusion and complete regression of the inflammatory changes was demonstrated 7–8 months later by a computer assisted tomography and contrast enhanced magnetic resonance imaging, respectively. The vertebral alignment changed minimally; the cages developed only a slight average subsidence. The clinical symptoms improved in all patients significantly. Neck pain or instability was never observed. Nevertheless, prospective investigations of a larger patient series are mandatory. We suppose that the use of PEEK cages represents a potential and safe alternative in the treatment of cervical spondylodiscitis in selected patients.
PMCID: PMC2899978  PMID: 20069319
Cervical spondylodiscitis; Targeted antibiotic therapy; Sepsis; PEEK cage; Stabilization; Decompression
18.  Inhibition of macrophage function prevents intestinal inflammation and postoperative ileus in rodents 
Gut  2006;56(2):176-185.
Abdominal surgery results in a molecular and cellular inflammatory response in the intestine, leading to postoperative ileus. It was hypothesised that resident macrophages within the intestinal muscularis have an important role in this local inflammation.
To investigate whether chemical or genetic depletion of resident muscularis macrophages would lead to a reduction in the local inflammation and smooth‐muscle dysfunction.
Two rodent models were used to deplete and inactivate macrophages: (1) a rat model in which resident macrophages were depleted by chlodronate liposomes; (2) a model of mice with osteopetrosis mice, completely lacking the resident muscularis macrophages, used as an additional genetic approach. Animals with normal or altered intestinal macrophages underwent surgical intestinal manipulation. The inflammatory response was investigated by quantitative reverse transcriptase‐polymerase chain reaction for mRNA of MIP‐1α, interleukin (IL)1β, IL6, intracellular adhesion molecule 1 (ICAM‐1) and monocyte chemotractant protein 1 (MCP)‐1 in the isolated small bowel muscularis. In addition, muscularis whole mounts were used for histochemical and immunohistochemical analysis to quantify leucocyte infiltration and detect cytokine expression. Subsequently, in vitro muscle contractility and in vivo gastrointestinal transit were measured.
Both models resulted in markedly decreased expression of MIP‐1α, IL1β, IL6, ICAM‐1 and MCP‐1 after manipulation compared with controls. In addition to this decrease in inflammatory mediators, recruitment of leucocytes into the muscularis was also diminished. Macrophage‐altered animals had near normal in vitro jejunal circular muscle function and gastrointestinal transit despite surgical manipulation.
Resident intestinal muscularis macrophages are initially involved in inflammatory responses resulting in postoperative ileus. Depletion and inactivation of the muscularis macrophage network prevents postoperative ileus.
PMCID: PMC1856749  PMID: 16809419
19.  Glioblastoma cells express functional cell membrane receptors activated by daily used medical drugs 
Calcium ions are highly versatile spacial and temporal intracellular signals of non-excitable cells and have an important impact on nearly every aspect of cellular life controlling cell growth, metabolism, fluid secretion, information processing, transcription, apoptosis, and motility. Neurons and glia respond to stimuli, including neurotransmitters, neuromodulators, and hormones, which increase the intracellular calcium concentration. The function of intracellular calcium in gliomas is unknown. Lots of daily used drugs may act via receptors that can be linked to the intracellular calcium system and therefore could influence glioma biology.
Glioma cells were loaded with the calcium ion sensitive dye Fura 2-AM. Subsequently, cells were stimulated with 25 different medical drugs for 30 s. The increase of free intracellular calcium ions was measured and calculated by a microscope–camera–computer-unit.
Except for the buffer solution HEPES that served as negative control and for the cortisol derivative dexamethasone, all other 24 tested drugs induced a rise of intracellular calcium ions. The cellular calcium responses were classified into seven functional groups. The tested substances activated several types of calcium channels and receptors.
Our study impressively demonstrates that medical drugs are potent inducers of intracellular calcium signals. Totally unexpected, the results show a high amount of functional cellular receptors and channels on glioma cells, which could be responsible for certain biological effects like migration and cell growth. This calcium imaging study proves the usability of the calcium imaging as a screening system for functional receptors on human glioma cells.
PMCID: PMC2847174  PMID: 19543745
Glioma; Calcium imaging; Drugs; Cell-surface receptors; Tumor proliferation; Tumor invasion
20.  Renal impairment after liver transplantation - a pilot trial of calcineurin inhibitor-free vs. calcineurin inhibitor sparing immunosuppression in patients with mildly impaired renal function after liver transplantation 
Chronic kidney disease is frequent in patients after orthotopic liver transplantation (OLT) and has impact on survival. Patients receiving calcineurin inhibitors (CNI) are at increased risk to develop impaired renal function. Early CNI reduction and concomitant use of mycophenolat mofetil (MMF) has been shown to improve renal function.
The aim of this trial was to compare dose-reduced CNI/MMF versus CNI-free MMF/prednisone-based treatment in stable patients after OLT with respect to glomerular filtration rate (GFR). 21 patients [GFR 44.9 ± 9.9 mL/min/1.73 m2 measured by 99m-Tc-DTPA-clearance, serum creatinine (SCr) 1.5 ± 0.42 mg/dL] were randomized either to exchange CNI for 10 mg prednisone (group 1; n = 8) or to receive CNI at 25% of the initial dose (group 2; n = 13) each in combination with 1000 mg MMF b.i.d.
At month 12 mean SCr (-0.3 ± 0.4 mg/dL, p = 0.031) and GFR improved (8.6 ± 13.1 mL/min/1.73 m2, p = 0.015) in group 2 but remained unchanged in group 1. Main side effects were gastroinstestinal symptoms (14.3%) and infections (4.8%). Two biopsy proven, steroid-responsive rejections occurred. In group 1 mean diastolic blood pressure (BP) increased by 11 ± 22 mmHg (p = 0.03).
Reduced dose CNI in combination with MMF but not CNI-free-immunosuppression leads to improvement of GFR in patients with moderately elevated SCr levels after OLT. Addition of steroids resulted in increased diastolic blood pressure presumably counterbalancing the benefits of CNI withdrawal on renal function.
PMCID: PMC3351980  PMID: 19541578
calcineurin inhibitor; GFR; impaired renal function; liver transplantation; mycophenolate mofetil
21.  Readmission to a surgical intensive care unit: incidence, outcome and risk factors 
Critical Care  2008;12(5):R123.
We investigated the incidence of, outcome from and possible risk factors for readmission to the surgical intensive care unit (ICU) at Friedrich Schiller University Hospital, Jena, Germany.
We conducted an analysis of prospectively collected data from all patients admitted to the postoperative ICU between September 2004 and July 2006.
Of 3169 patients admitted to the ICU during the study period, 2852 were discharged to the hospital floor and these patients made up the study group (1828 male (64.1%), mean patient age 62 years). The readmission rate was 13.4% (n = 381): 314 (82.4%) were readmitted once, 39 (10.2%) were readmitted twice and 28 (7.3%) were readmitted more than twice. The first readmission to the ICU occurred within a median of seven days (range 5 to 14 days). Patients who were readmitted to the ICU had a higher simplified acute physiology II score (37 +/- 16 versus 33 +/- 16; p < 0.001) and sequential organ failure score (6 +/- 3 versus 5 +/- 3; p = 0.001) on initial admission to the ICU than those who were not readmitted. In-hospital mortality was significantly higher in patients readmitted to the ICU (17.1% versus 2.9%; p < 0.001) than in other patients. In a multivariate analysis, age (odds ratio (OR) = 1.13 per 10 years; 95% confidence interval (CI) = 1.03 to 1.24; p = 0.04), maximum sequential organ failure score (OR = 1.04 per point; 95% CI = 1.01 to 1.08; p = 0.04) and C-reactive protein levels on the day of discharge to the hospital floor (OR = 1.02; 95% CI = 1.01 to 1.04; p = 0.035) were independently associated with a higher risk of readmission to the ICU.
In this group of surgical ICU patients, readmission to the ICU was associated with a more than five-fold increase in hospital mortality. Older age, higher maximum sequential organ failure score and higher C-reactive protein levels on the day of discharge to the hospital floor were independently associated with a higher risk of readmission to the ICU.
PMCID: PMC2592757  PMID: 18838006
23.  Neighbourhood level and individual level SES effects on child problem behaviour: a multilevel analysis 
OBJECTIVE—This study examined whether neighbourhood level socioeconomic variables have an independent effect on reported child behaviour problems over and above the effect of individual level measures of socioeconomic status.
DESIGN AND SETTING—Multilevel analysis of cross sectional survey data relating individual level child behavioural problems and parental measures of socioeconomic status with neighbourhood level measures of socioeconomic deprivation in the city of Maastricht, the Netherlands.
PARTICIPANTS—Children born in the years 1990-1991 attending the second grade of normal kindergarten schools in the city of Maastricht, the Netherlands. Out of 1417 eligible 5-7 year olds, the parents of 734 children (51.8%) agreed to participate.
MAIN RESULTS—Child behaviour problems were more frequent in families of low parental occupation and education (F=14.51, df 3, 721, p<0.001; F=12.20, df 3, 721, p<0.001, respectively) and in families living in deprived neighbourhoods (F=13.26, df 2, 722, p<0.001). Multilevel random effects regression analysis showed that the effect of neighbourhood level deprivation remained after adjustment for individual level socioeconomic status (B over three levels of deprivation: 1.36; 95%CI=0.28, 2.45).
CONCLUSIONS—Living in a more deprived neighbourhood is associated with higher levels of child problem behaviour, irrespective of individual level socioeconomic status. The additional effect of the neighbourhood may be attributable to contextual variables such as the level of social cohesion among residents.

Keywords: neighbourhood deprivation; behaviour problems; multilevel regression analysis
PMCID: PMC1731860  PMID: 11238579

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