Who attempts suicide among medical students?

OBJECTIVE: To identify factors associated with a history of suicide attempt in medical students. METHODS: A Web-based survey was sent out to a sample of medical students. A multi-predictor Poisson regression was performed to identify factors associated with a history of suicide attempt. In addition, an elastic net regularization was used to build a risk calculator to identify students at risk for attempted suicide. RESULTS: A total of 4,840 participants were included in the study. Prevalence of suicide attempts in the sample was 8.94%. Risk factors associated with past suicide attempt in the multi-predictor Poisson regression were as follows: female gender (P < 0.001); homosexuality (P < 0.001); low income (P = 0.026); bullying by university peers (P = 0.006); childhood (P = 0.001) or adult (P = 0.001) trauma; family history of suicide (P = 0.005); suicidal ideation within the last month (P < 0.001); daily tobacco use (P = 0.037); and being at severe risk for alcohol abuse (P = 0.023). Our elastic net model performed well with an AUC of 0.83. CONCLUSIONS: This study identifies a number of key factors associated with a history of suicide attempts among medical students. Future longitudinal studies should assess the causal relationship between these factors and suicide attempts. Additionally, these results demonstrate that current available data on suicide attempts among medical students can be used to develop an accurate risk algorithm.

[Intraoperative 3D imaging in spinal surgery]. / Intraoperative 3­D-Bildgebung in der Wirbelsäulenchirurgie.

BACKGROUND: Intraoperative imaging during spinal interventions has experienced significant developments over the last two decades. By the introduction of flat screen detectors, 3D imaging has been made possible and easier and by developing compact and mobile systems computed tomography can even be used in the operating theater. OBJECTIVE: Presentation of modern intraoperative 3D imaging and navigation in spinal surgery. MATERIAL AND METHODS: The techniques of intraoperative 3D imaging and navigation during spinal procedures are presented based on the currently available literature and own experiences at a German national spine and trauma center. RESULTS: The use of flat panel detectors and the possibility of 3D visualization nowadays substantially facilitate the use of navigation and allow certain control of surgical results even during the intervention. Radiation exposure of the whole team in the operating theater can be significantly reduced by the new techniques. CONCLUSION: The advantages of intraoperative 3D imaging with a clear improvement of visualization for spinal surgeons and the certain control of materials at the end of the operation are obvious. Even the use of navigation has been greatly simplified and can therefore lead to an even greater precision and less radiation exposure. There are even more sophisticated developments, such as operation suites and intraoperative computed tomography but these are initially reserved for selected centers.

The hand eczema proteome: imbalance of epidermal barrier proteins.

BACKGROUND: Chronic hand eczema (CHE) is a common skin disease with a high socioeconomic impact. While some light has been shed on the genetic factors that predispose individuals to the disease, little is known about its actual pathogenesis. OBJECTIVES: We aimed to carry out a systematic and comprehensive analysis of the differential protein expression in CHE using modern mass spectrometry. METHODS: We performed liquid chromatography with tandem mass spectrometry analyses and label-free quantification to analyse the proteomic profile of palmar skin from 12 individuals (six patients with hand eczema and six healthy volunteers). Immunohistochemistry of the palmar skin from seven different patients with hand eczema and seven different healthy volunteers was performed in a second step. RESULTS: With this method we were able to identify 185 candidate proteins with a significantly different abundance in the hand eczema samples. Among them we found several barrier proteins: filaggrin (FLG), FLG-2 and hornerin were all downregulated in the hand eczema samples, as were the desquamation-related enzymes kallikrein-related peptidase (KLK)5 and KLK7 and cystatin E/M. The antimicrobial peptides S100A7 and S100A8/A9 and the small proline-rich protein 2B and S100A11 were upregulated in the diseased skin. Immunohistochemistry confirmed these findings. CONCLUSIONS: Our results corroborate the assumption that skin barrier dysfunction plays an essential role in the pathogenesis of CHE.

A rapid ex vivo tissue model for optimising drug detection and ionisation in MALDI imaging studies.

The aim of this study was to establish an ex vivo model for a faster optimisation of sample preparation procedures, for example matrix choice, in matrix-assisted laser desorption/ionisation (MALDI) drug imaging studies. The ionisation properties of four drugs, afatinib, erlotinib, irinotecan and pirfenidone, were determined in an ex vivo tissue experiment by spotting decreasing dilution series onto liver sections. Hereby, the drug signals were distinctly detectable using different matrix compounds, which allowed the selection of the optimal matrix for each drug. The analysis of afatinib and erlotinib yielded high drug signals with α-cyano-4-hydroxycinnamic acid matrix, whereas 2,3-dihydroxybenzoic acid was identified as optimal matrix for irinotecan and pirfenidone detection. Our method was validated by a MALDI drug imaging approach of in vivo treated mouse tissue resulting in corresponding findings, indicating the spotting method as an appropriate approach to determine the matrix of choice. The present study shows the accordance between the detection of ex vivo spotted drugs and in vivo administered drugs by MALDI-TOF and MALDI-FT-ICR imaging, which has not been demonstrated so far. Our data suggest the ex vivo tissue spotting method as an easy and reliable model to optimise MALDI imaging measurements and to predict drug detection in tissue sections derived from treated mice prior to the recruitment of laboratory animals, which helps to save animals, time and costs.

A common atopy-associated variant in the Th2 cytokine locus control region impacts transcriptional regulation and alters SMAD3 and SP1 binding.

BACKGROUND: Type 2 immune responses directed by Th2 cells and characterized by the signature cytokines IL4, IL5, and IL13 play major pathogenic roles in atopic diseases. Single nucleotide polymorphisms in the human Th2 cytokine locus in particular in a locus control region within the DNA repair gene RAD50, containing several RAD50 DNase1-hypersensitive sites (RHS), have been robustly associated with atopic traits in genome-wide association studies (GWAS). Functional variants in IL13 have been intensely studied, whereas no causative variants for the IL13-independent RAD50 signal have been identified yet. This study aimed to characterize the functional impact of the atopy-associated polymorphism rs2240032 located in the human RHS7 on cis-regulatory activity and differential binding of transcription factors. METHODS: Differential transcription factor binding was analyzed by electrophoretic mobility shift assays (EMSAs) with Jurkat T-cell nuclear extracts. Identification of differentially binding factors was performed using mass spectrometry (LC-MS/MS). Reporter vector constructs carrying either the major or minor allele of rs2240032 were tested for regulating transcriptional activity in Jurkat and HeLa cells. RESULTS: The variant rs2240032 impacts transcriptional activity and allele-specific binding of SMAD3, SP1, and additional putative protein complex partners. We further demonstrate that rs2240032 is located in an RHS7 subunit which itself encompasses repressor activity and might be important for the fine-tuning of transcription regulation within this region. CONCLUSION: The human RHS7 critically contributes to the regulation of gene transcription, and the common atopy-associated polymorphism rs2240032 impacts transcriptional activity and transcription factor binding.

True blue: S-opsin is widely expressed in different animal species.

Colour vision in animals is an interesting, fascinating subject. In this study, we examined a wide variety of species for expression of S-opsin (blue sensitive) and M-/L-opsin (green-red sensitive) in retinal cones using two novel monoclonal antibodies specific for peptides from human opsins. Mouse, rat and hare did not express one of the investigated epitopes, but we could clearly prove existence of cones through peanut agglutinin labelling. Retinas of guinea pig, dog, wolf, marten, cat, roe deer, pig and horse were positive for S-opsin, but not for M-/L-opsin. Nevertheless all these species are clearly at least dichromats, because we could detect further S-opsin negative cones by labelling with cone arrestin specific antibody. In contrast, pheasant and char had M-/L-opsin positive cones, but no S-opsin expressing cones. Sheep, cattle, monkey, men, pigeon, duck and chicken were positive for both opsins. Visual acuity analyzed through density of retinal ganglion cells revealed least visual discrimination by horses and highest resolution in pheasant and pigeon. Most mammals studied are dichromats with visual perception similar to red-green blind people.

[Repositioning options with percutaneous dorsal stabilization. For burst fractures of the thoracolumbar junction]. / Repositionsmöglichkeiten mittels perkutaner dorsaler Instrumentierung. Bei Berstungsfrakturen des thorakolumbalen Übergangs.

BACKGROUND: The purpose of this investigation was to evaluate the options of percutaneous systems for reducing relevant posttraumatic kyphosis in spinal burst fractures. Clinical advantages of percutaneous techniques are evident from the literature and a disadvantage can be a lack of repositioning options in reducing the fracture kyphosis. Better results seem to be possible with new techniques and especially monoaxial percutaneous screws. PATIENTS AND METHODS: A total of 70 patients with burst fractures (AO type Magerl A3.1-A3.3) of the thoracolumbar spine were treated with a special percutaneous reduction technique in the Trauma Clinic in Murnau (BGU) Germany between July 2009 and March 2011. Posttraumatic, intraoperative and postoperative kyphosis was measured in computed tomography (CT) scans in monosegmental and bisegmental angles. Two different percutaneous fixation systems were compared for reduction. Statistical analyses were carried out with Student's t-test. RESULTS: We found a highly significant difference between preoperative and postoperative kyphosis angles but no differences in reduction between the two percutaneous systems. In 39 cases additional reconstruction of the anterior column was necessary because of a ventral defect. In comparison to the MCS 2 study of the German Society of Trauma Surgery (DGU) we found no differences in postoperative kyphosis angles (3°). CONCLUSION: A significant reduction of posttraumatic kyphosis of thoracolumbar burst fractures is possible with percutaneous techniques. Prerequisites are percutaneous monoaxial screws and tools and a special percutaneous technique as described.

[Incomplete cranial burst fracture in the thoracolumbar junction. Results 6 years after thoracoscopic monosegmental spondylodesis]. / Kraniale inkomplette Berstungsfraktur im thorakolumbalen Übergang. 6-Jahres-Ergebnisse nach thorakoskopischer monosegmentaler Spondylodese.

INTRODUCTION: Ventral thoracoscopic spondylodesis of the thoracolumbar spine is an elegant treatment strategy. MATERIAL AND METHODS: In the years 2002 and 2003 a total of 16 patients with incomplete cranial burst fractures were treated by ventral thoracoscopic monosegmental spondylodesis and were included in this study prospectively. The data acquisition was done preoperatively, postoperatively and after 3, 6, 12 and 18 months. After 6 years a follow-up examination was performed in 13 of these patients (5 men and 8 women, average age 36.3 years, follow-up rate 81%) and 8 patients were treated ventrally only whereas 5 patients were treated dorsoventrally. RESULTS: The operative reduction of the kyphotic malalignment was superior in the dorsoventrally treated patients. The persistent gain of monosegmental correction after 6 years seemed to be higher in the patient group treated dorsoventrally. The average physical component summary (PSC) scores were comparable to a control group of the same age and revision surgery was performed in two patients both related to the iliac crest bone graft. CONCLUSIONS: The ventral and dorsoventral therapy strategies showed good and very good functional outcomes, respectively. The dorsoventral treatment concept secured a persistent gain of monosegmental correction which seemed to be superior compared to a ventral only therapy strategy.

Feasibility and quality development of biomaterials in the pretest studies of the German National Cohort.

BACKGROUND: The German National Cohort (GNC) is designed to address research questions concerning a wide range of possible causes of major chronic diseases (e.g. cancer, diabetes, infectious, allergic, neurologic and cardiovascular diseases) as well as to identify risk factors and prognostic biomarkers for early diagnosis and prevention of these diseases. The collection of biomaterials in combination with extensive information from questionnaires and medical examinations represents one of the central study components. OBJECTIVES: In two pretest studies of the German National Cohort conducted between 2011 and 2013, a range of biomaterials from a defined number of participants was collected. Ten study centres were involved in pretest 1 and 18 study centres were involved in pretest 2. Standard operation procedures (SOP) were developed and evaluated to minimize pre-analytical artefacts during biosample collection. Within the pretest studies different aspects concerning feasibility of sample collection/preparation [pretest 1 (a)] and quality control of biomarkers and proteome analyses were investigated [pretest 1 (b), (c)]. Additionally, recruitment of study participants for specific projects and examination procedures of all study centres in a defined time period according to common standards as well as transportation and decentralized storage of biological samples were tested (pretest 2). These analyses will serve as the basis for the biomaterial collection in the main study of the GNC starting in 2014. MATERIALS AND METHODS: Participants, randomly chosen from the population (n = 1000 subjects recruited at ten study sites in pretest 1) were asked to donate blood, urine, saliva and stool samples. Additionally, nasal and oropharyngeal swabs were collected at the study sites and nasal swabs were collected by the participants at home. SOPs for sample collection, preparation, storage and transportation were developed and adopted for pretest 2. In pretest 2, 18 study sites (n = 599 subjects) collected biomaterials mostly identical to pretest 1. Biomarker analyses to test the quality of the biomaterials were performed. RESULTS: In pretest 1 and 2, it was feasible to collect all biomaterials from nearly all invited participants without major problems. The mean response rate of the subjects was 95 %. As one important result we found for example that after blood draw the cellular fraction should be separated from the plasma and serum fractions during the first hour with no significant variation for up to 6 h at 4 ℃ for all analysed biomarkers. Moreover, quality control of samples using a proteomics approach showed no significant clustering of proteins according to different storage conditions. All developed SOPs were validated for use in the main study after some adaptation and modification. Additionally, electronic and paper documentation sheets were developed and tested to record time stamps, volumes, freezing times, and aliquot numbers of the collected biomaterials. DISCUSSION: The collection of the biomaterials was feasible without major problems at all participating study sites. However, the processing times were in some cases too long. To avoid pre-analytical artefacts in sample collection, appropriate standardisation among the study sites is necessary. To achieve this, blood and urine collection will have to be adapted to specific conditions of usage of liquid handling robots, which will be available at all participating study centres in the main study of the GNC. Strict compliance with the SOPs, thorough training of the staff and accurate documentation are mandatory to obtain high sample quality for later analyses. The so obtained biomaterials represent a valuable resource for research on infectious and other common complex diseases in the GNC.

FPGA-Based Pulse Pile-Up Correction With Energy and Timing Recovery.

Modern field programmable gate arrays (FPGAs) are capable of performing complex discrete signal processing algorithms with clock rates well above 100 MHz. This, combined with FPGA's low expense, ease of use, and selected dedicated hardware make them an ideal technology for a data acquisition system for a positron emission tomography (PET) scanner. The University of Washington is producing a high-resolution, small-animal PET scanner that utilizes FPGAs as the core of the front-end electronics. For this scanner, functions that are typically performed in dedicated circuits, or offline, are being migrated to the FPGA. This will not only simplify the electronics, but the features of modern FPGAs can be utilized to add significant signal processing power to produce higher quality images. In this paper we report on an all-digital pulse pile-up correction algorithm that has been developed for the FPGA. The pile-up mitigation algorithm will allow the scanner to run at higher count rates without incurring large data losses due to the overlapping of scintillation signals. This correction technique utilizes a reference pulse to extract timing and energy information for most pile-up events. Using pulses acquired from a Zecotech Photonics MAPD-N with an LFS-3 scintillator, we show that good timing and energy information can be achieved in the presence of pile-up utilizing a moderate amount of FPGA resources.

Isolation, characterization and establishment of an equine retinal glial cell line: a prerequisite to investigate the physiological function of Müller cells in the retina.

Retinal Müller glial cells are of vital importance for maintaining a physiological environment within the retina. To this end, they provide highly specialized physiological properties to support neurons in structure, nutrition and metabolism. The purpose of this study was to isolate Müller cells from the equine retina, determine their characteristics and subsequently establish a stable equine Müller cell line (eqMC) that will provide a prerequisite for investigations on their physiological properties. Dissociated retinal cells were obtained from equine retinas by a papain digestion technique followed by trituration and a cell attachment method by which pure Müller cell cultures were achieved. Morphological examination was performed using phase-contrast microscopy, and further characterization of different subcultures was accomplished by immunocytochemistry. Cells of passage 1 showed distinct signals for glutamine synthetase and vimentin, whereas glial fibrillary acidic protein expression was almost absent. Characteristic expression patterns remained unaltered in all subcultures. Furthermore, cultured Müller cells stably expressed the microfilament alpha-smooth muscle actin, the proliferation marker Ki67 and the membrane channels Kir4.1 and aquaporin 4. The present study introduces the eqMC-7 that will facilitate studies investigating the physiological role of Müller cells within the equine retina.

[Reconstruction after spinal fractures in the thoracolumbar region]. / Rekonstruktion der ventralen Säule nach thorakolumbalen Wirbelsäulenverletzungen.

The morbidity of anterior approaches has significantly influenced the development of therapeutic concepts for the treatment of thoracolumbar spine fractures. Minimally-invasive techniques such as mini-open and endoscopic have enlarged the numbers of anterior reconstruction after spinal fractures in the thoracolumbar region. These minimally-invasive approaches have been facilitated by the development of special implants adapted to the new technique and to the local anatomical requirements.Two multi center studies in Germany (MCSI and II) showed the trend towards minimal invasive procedures and anterior approaches in the German speaking spine centers. Since the first report on thoracoscopic anterior procedures in Germany in 1997 a growing number of spine centers established this method. There is still no evidence based high level literature to substantiate a significant benefit for the patients by anatomical reduction and reconstruction of the anterior spinal column. However, there are some reports on better short outcomes in radiological parameters as well as better clinical results in 5 to 8 year follow-ups.The minimal invasive anterior approach seems to be advantageous for the patients by reducing significantly additive operation morbidity. It has become more important over the last two decades for anterior reconstruction after trauma and posttraumatic malalignment of the thoracolumbar spine.

[Recommendations for the treatment of thoracolumbar and lumbar spine injuries]. / Therapieempfehlungen zur Versorgung von Verletzungen der Brust- und Lendenwirbelsäule.

This paper gives recommendations for treatment of thoracolumbar and lumbar spine injuries. The recommendations are based on the experience of the involved spine surgeons, who are part of a study group of the "Deutsche Gesellschaft für Unfallchirurgie" and a review of the current literature. Basics of diagnostic, conservative, and operative therapy are demonstrated. Fractures are evaluated by using morphologic criteria like destruction of the vertebral body, fragment dislocation, narrowing of the spinal canal, and deviation from the individual physiologic profile. Deviations from the individual sagittal profile are described by using the monosegmental or bisegmental end plate angle. The recommendations are developed for acute traumatic fractures in patients without severe osteoporotic disease.

The global topography of Mars and implications for surface evolution.

Elevations measured by the Mars Orbiter Laser Altimeter have yielded a high-accuracy global map of the topography of Mars. Dominant features include the low northern hemisphere, the Tharsis province, and the Hellas impact basin. The northern hemisphere depression is primarily a long-wavelength effect that has been shaped by an internal mechanism. The topography of Tharsis consists of two broad rises. Material excavated from Hellas contributes to the high elevation of the southern hemisphere and to the scarp along the hemispheric boundary. The present topography has three major drainage centers, with the northern lowlands being the largest. The two polar cap volumes yield an upper limit of the present surface water inventory of 3.2 to 4.7 million cubic kilometers.

Value of MRI imaging prior to a kyphoplasty for osteoporotic insufficiency fractures.

Previous studies have shown the safety and effectiveness of balloon kyphoplasty in the treatment of osteoporotic vertebral compression fractures (OVCFs). MRI and particularly the short tau inversion recovery (STIR) sequence are very sensitive for detecting vertebral edema as a result of fresh fractures or micro-fractures. Therefore, it has a great therapeutic relevance in differentiating vertebral deformities seen by conventional X-ray and CT scans. Although an MRI scan is expensive, to my knowledge no study has evaluated the benefits of preoperative MRI in evaluating a therapeutic plan for kyphoplasty. This is a prospective study evaluating the benefit of a preoperative MRI scan regarding changes of kyphoplasty therapy. Twenty-eight patients were included in this study. Twenty-four patients were treated by balloon kyphoplasty, in a total of 40 vertebral bodies. The mean age was 73 years. All patients suffered from OVCFs. As a first step, all patients got a CT scan. The individual therapeutic plan was then defined by the patients' history, complaints and the results of the CT scan. As far as all criteria for kyphoplasty were fulfilled, an MRI examination including the STIR sequences was performed preoperatively. The number of times a change was made in therapy as a result from the additional information from the MRI was then evaluated. By performing a preoperatively MRI examination, the therapy plan was changed in 16 out of 28 (57%) patients. Eight patients underwent additional levels of kyphoplasty at the same procedure. In five patients, lesions were found to be old fractures and therefore were not treated operatively. Two of these patients received no kyphoplasty at all. Another patient only a part of the originally intended levels was treated. The other two cases received a kyphoplasty at different vertebral levels, as these vertebral bodies showed signs of an acute fracture in the MRI scan. Additionally, an incidental diagnosis of carcinoma of the kidney was made in two patients. Kyphoplasty was deferred and they were referred for further evaluation. One patient was found to have an aortic aneurysm. Kyphoplasty was performed and after that the patient was referred in order to treat the aneurysm. This study confirms the diagnostic benefits of an MRI scan before performing a kyphoplasty. For 16 out of 28 patients, the therapeutic plan was changed because of the information obtained by preoperative MRI. Preoperative MRI helped to generate the correct surgical strategy, by demonstrating the correct location of injury and by detecting concomitant diseases.

Percutaneous vertebral augmentation in fragility fractures-indications and limitations.

INTRODUCTION: There is still no general consensus about the management of osteoporotic vertebral fractures. Recommendations depend on type of fracture, grade of instability, bone quality, and general conditions of the patient. Spontaneous fractures may be considered to be treated different compared to cases with high-velocity trauma. METHODS: According to the DVO, patients without trauma should first be treated conservatively. However, there is no more strict time protocol of 3 or 6 week conservative treatment before operations may be indicated. Surgical criteria are not yet distinctly defined. For highly unstable fractures (type B and C according to the AO Spine Classification), posterior instrumentation with cement augmented screws and as long construct, respectively, is adequate. Current literature has been analysed for diagnostic and therapeutic protocols. RESULTS: There is no clear operative concept for burst fractures and classic osteoporotic fractures with dynamic ongoing sintering. Percutaneous vertebral augmentation showed to prevent the fractures from ongoing kyphotic deformity and the patients from painful immobilization. Indications and results of classical vertebroplasty and kyphoplasty have been discussed intensively in the literature. Further development included special injection techniques, cements with different viscosities and stenting systems to reach more stable constructs and avoid typical complications, such as cement extrusion. CONCLUSIONS: This review reports upon indications and limitations of percutaneous vertebral augmentation and the potential development of classifications and therapeutic algorithms.

Investigation of corneal autoantibodies in horses with immune mediated keratitis (IMMK).

Immune mediated keratitis (IMMK) is primarily a non-ulcerative keratitis in horses causing intermittent ocular pain, eventually resulting in visual impairment. Affected horses typically respond to immunomodulatory treatment. However, the underlying cause of the disease remains enigmatic. The current study was undertaken to investigate the presence of autoantibodies in horses with immune mediated keratitis. Using 28 horses with IMMK and 27 healthy controls screening for serum autoantibodies against the corneal proteome using indirect immunofluorescence, one-dimensional (1DE) and two-dimensional electrophoresis (2DE) with subsequent western blot analysis was performed followed by mass spectrometric identification of bands or spots of interest. Indirect immunofluorescence did not reveal a difference in immune response towards corneal proteins between healthy horses and those with IMMK. Using western blot analysis some horses affected by IMMK (4/28) showed a single band (1D) or a single spot (2DE) (5/28) not detected in healthy controls. The corresponding spot was identified as maspin (SERPINB5), a protein responsible for the inhibition of corneal vascularisation, cell migration and cell adhesion to the extracellular matrix. Tests with a recombinant human protein commercially available did not verify blot findings, but the human protein may not be fully cross-reactive. Still, maspin might play a role in some cases of equine IMMK. Further research is needed to clarify the etiology of this disease.

Oncogenic CARMA1 couples NF-κB and ß-catenin signaling in diffuse large B-cell lymphomas.

Constitutive activation of the antiapoptotic nuclear factor-κB (NF-κB) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of ß-catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3ß to oncogenic CARMA1. Recruitment of the ß-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-κB activation and promoted the stabilization of ß-catenin. The ß-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated ß-catenin expression. In line, ß-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased ß-catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, ß-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that ß-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and ß-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-κB target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.

Sixty-minute alteplase protocol: a new accelerated recombinant tissue-type plasminogen activator regimen for thrombolysis in acute myocardial infarction.

OBJECTIVES: Our aim was to design and evaluate a new and easily administered recombinant tissue-type plasminogen activator (rt-PA) regimen for thrombolysis in acute myocardial infarction (AMI) based on established pharmacokinetic data that improve the reperfusion success rate. BACKGROUND: Rapid restoration of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow is a primary predictor of mortality after thrombolysis in AMI. However, TIMI grade 3 patency rates 90 min into thrombolysis of only 50% to 60% indicate an obvious need for improved thrombolytic regimens. METHODS: Pharmacokinetic simulations were performed to design a new rt-PA regimen. We aimed for a plateau tissue-type plasminogen activator (t-PA) plasma level similar to that of the first plateau of the Neuhaus regimen. These aims were achieved with a 20-mg rt-PA intravenous (i.v.) bolus followed by an 80-mg i.v. infusion over 60 min (regimen A). This regimen was tested in a consecutive comparative trial in 80 patients versus 2.25 10(6) IU of streptokinase/60 min (B), and 70 mg (C) or 100 mg (D) of rt-PA over 90 min. Subsequently, a confirmation trial of regimen A in 254 consecutive patients was performed with angiographic assessment by independent investigators of patency at 90 min. RESULTS: The comparative phase of the trial yielded, respectively, TIMI grade 3 and total patency (TIMI grades 2 and 3) of 80% and 85% (regimen A), 35% and 50% (B), 50% and 55% (C) and 60% and 70% (D). In the confirmation phase of the trial, regimen A yielded 81.1% TIMI grade 3 and 87.0% total patency. At follow-up angiography 7 (4.1%) of 169 vessels had reoccluded. In-hospital mortality rate was 1.2%. Nadir levels of fibrinogen, plasminogen and alpha2-antiplasmin were 3.6 +/- 0.8 mg/ml, 60 +/- 21% and 42 +/- 16%, respectively (mean +/- SD). Fifty-seven patients (22.4%) suffered from bleeding; 3.5% needed blood transfusions. CONCLUSIONS: The 60-min alteplase thrombolysis in AMI protocol achieved a TIMI grade 3 patency rate of 81.1% at 90 min with no indication of an increased bleeding hazard; it was associated with a 1.2% overall mortality rate. These results are substantially better than those reported from all currently utilized regimens. Head to head comparison with established thrombolytic regimens in a large-scale randomized trial is warranted.

[Fractures of the thoracic and lumbar spine]. / Frakturen der Brust- und Lendenwirbelsäule.

Fractures of the thoracic and lumbar spine result from high velocity trauma, assuming bone density is normal. The main location of fractures is the thoracolumbar junction. Most injuries can be treated conservatively; however, patients transferred to hospitals and spine centers represent a preselection with more severe trauma and a higher incidence of operative treatment. There is a large variety of operative techniques that can be used, which can be principally differentiated by the approach: posterior or anterior. Dorsal approaches are differentiated by the instrumentation for spondylodesis as open or percutaneous techniques. Minimally invasive options are favored more and more. For osteoporotic bone, cement augmented solutions may be used. Correct reduction of mainly kyphotic malalignment is crucial for the long-term outcome. Biomechanically stable reconstruction of the anterior spinal column is important mainly for the thoracolumbar junction.