Orthopaedic Hand Patient Support Systems Have Valuable Insight to Patient Function and Pain.

Patient-reported outcome measures (PROs) are increasingly used in clinical assessment. Research on how patient support systems contribute to physician understanding of patient condition is limited. Thus, insights from significant others may provide value, especially when concerns exist regarding patient response validity. Patients recruited from the pre-operative environment undergoing orthopaedic hand procedures responded to PROMIS-Pain Interference (PI), PROMIS-Upper Extremity (UE), PROMIS-Depression (D), and QuickDASH. They then selected a significant other (SO) to do the same. Patients and SOs were also asked to complete the West Haven-Yale Multidimensional Pain Inventory (WHYMPI) as a measure of support-related responses. Patient and SO responses were compared, and support-related responses were added in subsequent analyses to examine their effect on SO PRO assessment.

Enhanced RBE of Particle Radiation Depends on Beam Size in the Micrometer Range.

High-linear energy transfer (LET) radiation, such as heavy ions is associated with a higher relative biological effectiveness (RBE) than low-LET radiation, such as photons. Irradiation with low- and high-LET particles differ in the interaction with the cellular matter and therefore in the spatial dose distribution. When a single high-LET particle interacts with matter, it results in doses of up to thousands of gray (Gy) locally concentrated around the ion trajectory, whereas the mean dose averaged over the target, such as a cell nucleus is only in the range of a Gy. DNA damage therefore accumulates in this small volume. In contrast, up to hundreds of low-LET particle hits are required to achieve the same mean dose, resulting in a quasi-homogeneous damage distribution throughout the cell nucleus. In this study, we investigated the dependence of RBE from different spatial dose depositions using different focused beam spot sizes of proton radiation with respect to the induction of chromosome aberrations and clonogenic cell survival. Human-hamster hybrid (AL) as well as Chinese hamster ovary cells (CHO-K1) were irradiated with focused low LET protons of 20 MeV (LET = 2.6 keV/µm) beam energy with a mean dose of 1.7 Gy in a quadratic matrix pattern with point spacing of 5.4 × 5.4 µm2 and 117 protons per matrix point at the ion microbeam SNAKE using different beam spot sizes between 0.8 µm and 2.8 µm (full width at half maximum). The dose-response curves of X-ray reference radiation were used to determine the RBE after a 1.7 Gy dose of radiation. The RBE for the induction of dicentric chromosomes and cell inactivation was increased after irradiation with the smallest beam spot diameter (0.8 µm for chromosome aberration experiments and 1.0 µm for cell survival experiments) compared to homogeneous proton radiation but was still below the RBE of a corresponding high LET single ion hit. By increasing the spot size to 1.6-1.8 µm, the RBE decreased but was still higher than for homogeneously distributed protons. By further increasing the spot size to 2.7-2.8 µm, the RBE was no longer different from the homogeneous radiation. Our experiments demonstrate that varying spot size of low-LET radiation gradually modifies the RBE. This underlines that a substantial fraction of enhanced RBE originates from inhomogeneous energy concentrations on the µm scale (mean intertrack distances of low-LET particles below 0.1 µm) and quantifies the link between such energy concentration and RBE. The missing fraction of RBE enhancement when comparing with high-LET ions is attributed to the high inner track energy deposition on the nanometer scale. The results are compared with model results of PARTRAC and LEM for chromosomal aberration and cell survival, respectively, which suggest mechanistic interpretations of the observed radiation effects.

Biomarkers Apo10 and TKTL1: Epitope-detection in monocytes (EDIM) as a new diagnostic approach for cholangiocellular, pancreatic and colorectal carcinoma.

OBJECTIVE: The EDIM (Epitope detection in monocytes) blood test is based on two biomarkers Apo10 and TKTL1. Apo10 is responsible for cell proliferation and resistance to apoptosis. TKTL1 plays a major role in anaerobic glycolysis of tumor cells, leading to destruction of the basal membrane and metastasis as well as in controlling cell cycle. For the first time we analyzed Apo10 and TKLT1 in patients with cholangiocellular (CCC), pancreatic (PC), and colorectal carcinoma (CRC). METHODS: Blood samples of 62 patients with CCC, PC, and CRC were measured and compared to 29 control patients. We also investigated 13 patients with inflammatory conditions, because elevated TKTL1 and Apo10 have been previously described in affected individuals. Flow cytometry was used to detect surface antigens CD14+/CD16+ (activated monocytes/macrophages). Percentages of macrophages harboring TKTL1 and Apo10 were determined. A combined EDIM score (EDIM-CS: TKTL1 plus Apo10) was calculated. Results were correlated with serum tumor markers CEA and CA19-9. RESULTS: Patients with CCC had 100% positive EDIM-CS but CEA and CA19-9 were positive in only 22.2% and 70%, respectively. Patients with PC had 100% positive EDIM-CS but positive tumor markers in only 37.5% (CEA) and 72.7% (CA19-9). Patients with CRC had 100% positive EDIM-CS but only 50% positive CEA. EDIM-CS was positive in 100% (62/62) of all cancer patients and in 0% of healthy individuals. Of the individuals with inflammation, 7.7% had a positive EDIM-CS. CONCLUSION: The sensitivity of the EDIM blood test and the comparison with traditional tumor markers indicate that this new test might improve the detection of carcinomas (CCC, PC and, CRC) and might be relevant for the diagnosis of all tumor entities.

Detection of MET mRNA in gastric cancer in situ. Comparison with immunohistochemistry and sandwich immunoassays.

Determination of predictive biomarkers by immunohistochemistry (IHC) relies on antibodies with high selectivity. RNA in situ hybridization (RNA ISH) may be used to confirm IHC and may potentially replace it if suitable antibodies are not available or are insufficiently selective to discriminate closely related protein isoforms. We validated RNA ISH as specificity control for IHC and as a potential alternative method for selecting patients for treatment with MET inhibitors. MET, the HGF receptor, is encoded by the MET proto-oncogene that may be activated by mutation or amplification. MET expression and activity were tested in a panel of control cell lines. MET could be detected in formalin fixed paraffin, embedded (FFPE) samples by IHC and RNA ISH, and this was confirmed by sandwich immunoassays of fresh frozen samples. Gastric cancer cell lines with high MET expression and phosphorylation of tyrosine-1349 respond to the MET inhibitor, BAY-853474. High expression and phosphorylation of MET is a predictive biomarker for response to MET inhibitors. We then analyzed MET expression and activity in a matched set of FFPE vs. fresh frozen tumor samples consisting of 20 cases of gastric cancer. Two of 20 clinical samples investigated exhibited high MET expression with RNA ISH and IHC. Both cases were shown by sandwich immunoassays to exhibits strong functional activity. Expression levels and functional activity in these two cases were in a range that predicted response to treatment. Our findings indicate that owing to its high selectivity, RNA ISH can be used to confirm findings obtained by IHC and potentially may replace IHC for certain targets if no suitable antibodies are available. RNA ISH is a valid platform for testing predictive biomarkers for patient selection.

The influence of reference radiation photon energy on high-LET RBE: comparison of human peripheral lymphocytes and human-hamster hybrid AL cells.

The relative biological effectiveness (RBE) based on the induction of dicentrics in any cell type is principally an important information for the increasing application of high-LET radiation in cancer therapy. Since the standard system of human lymphocytes for measuring dicentrics are not compatible with our microbeam irradiation setup where attaching cells are essential, we used human-hamster hybrid AL cells which do attach on foils and fulfil the special experimental requirement for microbeam irradiations. In this work, the dose-response of AL cells to photons of different energy, 70 and 200 kV X-rays and 60Co γ-rays, is characterized and compared to human lymphocytes. The total number of induced dicentrics in AL cells is approximately one order of magnitude smaller. Despite the smaller α and ß parameters of the measured linear-quadratic dose-response relationship, the α/ß-ratio versus photon energy dependence is identical within the accuracy of measurement for AL cells and human lymphocytes. Thus, the influence of the reference radiation used for RBE determination is the same. For therapy relevant doses of 2 Gy (60Co equivalent), the difference in RBE is around 20% only. These findings indicate that the biological effectiveness in AL cells can give important information for human cells, especially for studies where attaching cells are essential.

Stent Retriever Thrombectomy of Small Caliber Intracranial Vessels Using pREset LITE: Safety and Efficacy.

PURPOSE: Few devices are approved for thrombectomy of distal vessel branches, and clinical experience is limited. Here we report our experience with pREset LITE for thrombectomy of small intracranial vessels. METHODS: From an institutional database we selected consecutive patients treated with pREset LITE for an occlusion of small (≤ 2 mm), intracranial target vessels. Recanalization success was measured by applying the modified Thrombolysis In Cerebral Infarction (mTICI) score. To assess safety, we recorded device-related procedural events and potentially device-related hemorrhages on follow-up imaging. Infarcts in the dependent territory served as a measure for efficacy. RESULTS: Of 536 patients treated between August 2013 and March 2015, 76 met the inclusion criteria. pREset LITE was used in 90 branches with an average diameter of 1.6 mm (1.3-2.0 mm). An mTICI score ≥ 2b was achieved in 70.0 %. Procedural events consisted of 5.6 % significant vasospasm, 2.2 % suspected dissections, 2.2 % downstream emboli, and 1.1 % self-limiting extravasations. On posttreatment imaging 2.2 % parenchymal hemorrhages type I (PHI) and 13.3 % focal subarachnoid hemorrhage (SAH) were potentially device related, but all of these events remained asymptomatic. After successful recanalization, 33.3 % developed no ischemia in the dependent territory while 41.7 % developed a partial infarct, and 25 % developed a complete infarct. Successful recanalization significantly increased the chance to develop no or only partial infarct compared with a complete infarction (p = 0.003, p = 0.013). CONCLUSIONS: Thrombectomy of small vessels with pREset LITE is feasible with good recanalization and reasonable safety margins. Successful recanalization significantly reduces the risk of infarction in the dependent territory. The impact on the overall clinical outcome remains to be determined.

Overnight switching from oxcarbazepine to eslicarbazepine acetate: an observational study.

OBJECTIVES: There are clinical situations where it might be appropriate to switch patients from immediate-release oxcarbazepine (OXC) to eslicarbazepine acetate (ESL). We investigated the effects of transitioning patients overnight from OXC to ESL. MATERIALS AND METHODS: A retrospective, single-center study was conducted in which patients with drug-resistant focal epilepsy on a stable dose of immediate-release OXC for at least 4 weeks were switched overnight to ESL. Patients were switched because they experienced persistent seizures with OXC but were unable to tolerate increased OXC dosing due to adverse events. Tolerability was assessed using the Adverse Events Profile (AEP), quality of life was assessed using the Quality of Life in Epilepsy Inventory 10 (QOLIE-10), and alertness was assessed as reaction time using a subtest of the Test Battery for Attention Performance version 2.3. Assessments were performed immediately prior to and 5 days after switching from OXC to ESL (days 0 and 5, respectively). RESULTS: The analysis included 21 patients (12 women, 9 men; mean age 36 years). After switching from OXC to ESL, there were significant improvements in mean scores for AEP (P<.001), QOLIE-10 (P=.001), and alertness (P<.05). Adverse Events Profile total scores improved for 21/21 (100.0%) patients, QOLIE-10 total scores improved for 17/21 (81.0%) patients, and alertness scores improved for 16/21 (76.2%) patients. CONCLUSIONS: In this short-term, single-center study, an overnight switch from twice-daily OXC to once-daily ESL in patients with drug-resistant focal epilepsies resulted in improvements in side effects, quality of life, and alertness.

Climate analogues suggest limited potential for intensification of production on current croplands under climate change.

Climate change could pose a major challenge to efforts towards strongly increase food production over the coming decades. However, model simulations of future climate-impacts on crop yields differ substantially in the magnitude and even direction of the projected change. Combining observations of current maximum-attainable yield with climate analogues, we provide a complementary method of assessing the effect of climate change on crop yields. Strong reductions in attainable yields of major cereal crops are found across a large fraction of current cropland by 2050. These areas are vulnerable to climate change and have greatly reduced opportunity for agricultural intensification. However, the total land area, including regions not currently used for crops, climatically suitable for high attainable yields of maize, wheat and rice is similar by 2050 to the present-day. Large shifts in land-use patterns and crop choice will likely be necessary to sustain production growth rates and keep pace with demand.

Allogeneic Blood Product Usage in Coronary Artery Bypass Grafting (CABG) with minimalized Extracorporeal Circulation System (MECC) Versus Standard On-Pump Coronary Artery Bypass Grafting.

AIM: Intraoperative allogeneic blood product transfusion (ABPT) in cardiac surgery is associated with worse overall outcome, including mortality. The objective of this study was to evaluate the ABPTs in minimalized extracorporeal cardiopulmonary (MECC(TM)) compared with standard open system on-pump coronary revascularization. METHODS: Data of 156 patients undergoing myocardial revascularization between September 2008 and September 2010 were reviewed. 83 patients were operated by the MECC technique and 73 were treated by standard extracorporeal circulation (sECC). ABPT and overall early postoperative complications were analyzed. RESULTS: Operative mortality and morbidity were similar in both groups. ABPT in the MECC group was significantly lower than in the sECC group both intraoperatively (7.2 vs. 60.3% of patients p<0.001) and during the first five postoperative days (19.3 vs. 57.5%; p<0.001). "Skin to skin"- (214 ± 45 vs. 232 ± 45 min; p=0.012), cardiopulmonary bypass (CPB) - (82 ± 25 vs. 95 ± 26 min; p=0.014), and X-clamp- times (50 ± 16 vs. 56 ± 17 min; p=0.024) were significantly lower in the MECC group than in the sECC group. Length of ICU (intensive care unit) - and hospital stay were also significantly lower in the MECC group vs. the sECC group (26.7 ± 20.2 vs. 54.5 ± 68.9 h; p<0.001, and 12.0 ± 4.1 vs. 14.5 ± 4.6 days; p<0.001). CONCLUSION: Application of MECC as on-pump coronary artery bypass graft (CABG) results in significantly lower ABPT as well as shorter ICU and in-hospital stay. In order to achieve these benefits of MECC autologous retrograde priming, Bispectral index (BIS) monitoring, intraoperative cell salvage, meticulous hemostasis and strict peri- and postoperative volume management are crucial.

[What are the Prerequisites for a Successful Cooperation between Nursing Homes and Physicians? - Results of a Mixed-methods Cross-Sectional Study in Bavarian Nursing Homes]. / Was sind die Voraussetzungen für eine erfolgreiche Zusammenarbeit zwischen Pflegeeinrichtung und Ärzten? ­ Ergebnisse einer Mixed Methods Querschnittserhebung in bayerischen Pflegeeinrichtungen.

Aim: This mixed-methods cross-sectional study examined the cooperation between nursing home staff and physicians in Bavarian nursing homes in order to understand which organisational and communication measures are resulting in satisfying teamwork among professional groups in nursing homes. Methods: In 3 interview rounds nursing home staff, general practitioners, medical specialists, dentists, nursing home residents, and relatives in 52 nursing homes were interviewed using a questionnaire that was enhanced after every round. Additionally, focus group interviews have been performed in 2 nursing homes. Results: 443 persons involved in patient care, 50 residents and 47 relatives participated in the structured interviews. 22 persons attended the focus group interviews. 65% of the nursing homes required regular visits of general practitioners and 36% or, respectively, 27% required regular or on demand visits of specialists. 47% of the nursing home staff that was asked about this issue stated that it would make their work easier if only a small number of physicians were in charge of their institution. Measures for improvement of medical care in nursing homes most frequently suggested by interview partners responsible for patient care were: better communication (9%), better remuneration of physicians' nursing home visits (7%, nurses and physicians) and less bureaucracy and regular physicians' visits (5% in each question). Conclusion: Because of the composition of our study sample it cannot be assumed that the results are representative for all Bavarian nursing homes. Confidence in one another, low number of persons in charge, binding agreements and regular physicians' nursing home visits are essential for a successful cooperation between providing physicians and nursing home staff.

Differences between intrinsic and extrinsic ureteropelvic junction obstruction related to crossing vessels: histology and functional analyses.

PURPOSE: In children, ureteropelvic junction obstruction (UPJO) is mostly caused by intrinsic factors (IUPJO); extrinsic UPJO are rare and often due to crossing vessels (CVs). METHODS: We retrospectively reviewed all data of children with UPJO that underwent surgery in our institution from 2004 to 2011. Analyses included age at surgery, gender, preoperative and postoperative results of ultrasound and renal scans [differential renal function (DRF); signs of obstruction], and pathology reports. Available histological specimens of cases with CV were compared to a random selection of intrinsic cases in a blinded fashion. After additional Masson's trichrome staining, the specimens were scored for fibrosis, muscular hypertrophy, and chronic inflammation. RESULTS: Out of 139 patients with UPJO, 39 cases were associated with CV. Median age at surgery was 68 months (range 2-194) in the CV group and 11.5 months (range 0-188) in IUPJO group. Laparoscopic dismembered pyeloplasty (LDMP) was carried out in 134 and open DMP in five patients. Preoperative ultrasound identified 28/39 cases with CV. DRF below 40 % was more frequently seen in CV patients (p = 0.020). Histological analyses revealed no differences between the CV and IUPJO specimens in total. CV patients with higher grades of muscular hypertrophy had lower preoperative DRF, compared to those with higher preoperative DRF (p = 0.026). Functional recovery after (L)DMP was excellent in both groups. CONCLUSION: We could not find any significant histological differences between CV and IUPJO in children. To obtain excellent functional recovery, surgical procedures with a definite correction of the UPJ should be preferred in paediatric patients with CV.

Sub-micrometer 20MeV protons or 45MeV lithium spot irradiation enhances yields of dicentric chromosomes due to clustering of DNA double-strand breaks.

In conventional experiments on biological effects of radiation types of diverse quality, micrometer-scale double-strand break (DSB) clustering is inherently interlinked with clustering of energy deposition events on nanometer scale relevant for DSB induction. Due to this limitation, the role of the micrometer and nanometer scales in diverse biological endpoints cannot be fully separated. To address this issue, hybrid human-hamster AL cells have been irradiated with 45MeV (60keV/µm) lithium ions or 20MeV (2.6keV/µm) protons quasi-homogeneously distributed or focused to 0.5×1µm(2) spots on regular matrix patterns (point distances up to 10.6×10.6µm), with pre-defined particle numbers per spot to provide the same mean dose of 1.7Gy. The yields of dicentrics and their distribution among cells have been scored. In parallel, track-structure based simulations of DSB induction and chromosome aberration formation with PARTRAC have been performed. The results show that the sub-micrometer beam focusing does not enhance DSB yields, but significantly affects the DSB distribution within the nucleus and increases the chance to form DSB pairs in close proximity, which may lead to increased yields of chromosome aberrations. Indeed, the experiments show that focusing 20 lithium ions or 451 protons per spot on a 10.6µm grid induces two or three times more dicentrics, respectively, than a quasi-homogenous irradiation. The simulations reproduce the data in part, but in part suggest more complex behavior such as saturation or overkill not seen in the experiments. The direct experimental demonstration that sub-micrometer clustering of DSB plays a critical role in the induction of dicentrics improves the knowledge on the mechanisms by which these lethal lesions arise, and indicates how the assumptions of the biophysical model could be improved. It also provides a better understanding of the increased biological effectiveness of high-LET radiation.

[Sudden cardiac death during a city marathon run]. / Plötzlicher Herztod beim Stadtmarathon.

Sudden cardiac death (SCD) in young athletes during physical stress is a rare event with an incidence of 1-3 deaths per 100,000 athletes per year. A coronary anomaly is the second most common cause of death following hypertrophic cardiomyopathy. Symptomatic prodromes occur in 20% of cases prior to the SCD event. This case report describes a 35-year-old male who collapsed near the finishing line of a half marathon run. Despite immediate resuscitation attempts and initial return of spontaneous circulation (ROSC), a pulseless electrical activity (PEA) followed and the patient died 1 h after arrival in the resuscitation unit. The autopsy revealed an anomalous left coronary artery (ALCA), which can lead to ischemia of the respective heart muscles under severe stress.

Impact of the serum- and glucocorticoid-inducible kinase 1 on platelet dense granule biogenesis and secretion.

BACKGROUND: Platelet secretion is critical to development of acute thrombotic occlusion. Platelet dense granules contain a variety of important hemostatically active substances. Nevertheless, biogenesis of platelet granules is poorly understood. OBJECTIVES: Serum- and glucocorticoid-inducible kinase 1 (SGK1) has been shown to be highly expressed in platelets and megakaryocytes, but its role in the regulation of platelet granule biogenesis and its impact on thrombosis has not been investigated so far. METHODS AND RESULTS: Electron microscopy analysis of the platelet ultrastructure revealed a significant reduction in the number and packing of dense granules in platelets lacking SGK1 (sgk1(-/-) ). In sgk1(-/-) platelets serotonin content was significantly reduced and activation-dependent secretion of ATP, serotonin and CD63 significantly impaired. In vivo adhesion after carotis ligation was significantly decreased in platelets lacking SGK1 and occlusive thrombus formation after FeCl3 -induced vascular injury was significantly diminished in sgk1(-/-) mice. Transcript levels and protein abundance of dense granule biogenesis regulating GTPase Rab27b were significantly reduced in sgk1(-/-) platelets without affecting Rab27b mRNA stability. In MEG-01 cells transfection with constitutively active (S422) (D) SGK1 but not with inactive (K127) (N) SGK1 significantly enhanced Rab27b mRNA levels. Sgk1(-/-) megakaryocytes show significantly reduced expression of Rab27b and serotonin/CD63 levels compared with sgk1(+/+) megakaryocytes. Proteome analysis identified nine further vesicular transport proteins regulated by SGK1, which may have an impact on impaired platelet granule biogenesis in sgk1(-/-) platelets independent of Rab27b. CONCLUSIONS: The present observations identify SGK1 as a novel powerful regulator of platelet dense granule biogenesis, platelet secretion and thrombus formation. SGK1 is at least partially effective because it regulates transcription of Rab27b in megakaryocytes.

The effectiveness of the high-LET radiations from the boron neutron capture [10B(n,α) 7Li] reaction determined for induction of chromosome aberrations and apoptosis in lymphocytes of human blood samples.

Provided that a selective accumulation of (10)B-containing compounds is introduced in tumor cells, following irradiation by thermal neutrons produces high-LET alpha-particles ((4)He) and recoiling lithium-7 ((7)Li) nuclei emitted during the capture of thermalized neutrons (0.025 eV) from (10)B. To estimate the biological effectiveness of this boron neutron capture [(10)B(n,α)(7)Li] reaction, the chromosome aberration assay and the flow cytometry apoptosis assay were applied. At the presence of the clinically used compounds BSH (sodium borocaptate) and BPA (p-boronophenylalanine), human lymphocytes were irradiated by sub-thermal neutrons. For analyzing chromosome aberrations, human lymphocytes were exposed to thermally equivalent neutron fluences of 1.82 × 10(11) cm(-2) or 7.30 × 10(11) cm(-2) (corresponding to thermal neutron doses of 0.062 and 0.248 Gy, respectively) in the presence of 0, 10, 20, and 30 ppm of BSH or BPA. Since the kerma coefficient of blood increased by 0.864 × 10(-12) Gy cm(2) per 10 ppm of (10)B, the kerma coefficients in blood increase from 0.34 × 10(-12) cm(2) (blood without BSH or BPA) up to 2.93 × 10(-12) Gy cm(2) in the presence of 30 ppm of (10)B. For the (10)B(n, α)(7)Li reaction, linear dose-response relations for dicentrics with coefficients α = 0.0546 ± 0.0081 Gy(-1) for BSH and α = 0.0654 ± 0.0075 Gy(-1) for BPA were obtained at 0.062 Gy as well as α = 0.0985 ± 0.0284 Gy(-1) for BSH and α = 0.1293 ± 0.0419 Gy(-1) for BPA at 0.248 Gy. At both doses, the corresponding (10)B(n, α)(7)Li reactions from BSH and BPA are not significantly different. A linear dose-response relation for dicentrics also was obtained for the induction of apoptosis by the (10)B(n, α)(7)Li reaction at 0.248 Gy. The linear coefficients α = 0.0249 ± 0.0119 Gy(-1) for BSH and α = 0.0334 ± 0.0064 Gy(-1) for BPA are not significantly different. Independently of the applied thermal neutron doses of 0.062 Gy or 0.248 Gy, the (10)B(n, α)(7)Li reaction from 30 ppm BSH or BPA induced an apparent RBE of about 2.2 for the production of dicentrics as compared to exposure to thermal neutrons alone. Since the apparent RBE value is defined as the product of the RBE of a thermal neutron dose alone times a boron localization factor which depends on the concentration of a (10)B-containing compound, this localization factor determines the biological effectiveness of the (10)B(n, α)(7)Li reaction.

Coronary sinus lead extraction in CRT patients with CIED-related infection: risks, implications and outcomes.

AIM: The aim of the study was to examine risks, implications and outcomes of coronary sinus (CS) lead extraction in patients with infections of cardiac resynchronization therapy (CRT) systems. METHODS: The study included 40 (65.5 ± 11.1 years; 80% male) transvenous CS lead extraction procedures performed between 2000-2011. Nine (22.5%) patients suffered from infection and included one sepsis (11.1%), two (22.2%) of lead and valve endocarditis, and four (44.4%) cases of pocket infection. CS lead extraction in the infection subgroup was performed between 14 days and more than five years after the last CIED-related surgical procedure. RESULTS: Totally 42 CS and 35 non-CS leads were extracted. Leads extracted in the infection subgroup were significantly longer in situ (49.7 ± 30.7 months) compared to the non-infection subgroup (19.2 ± 28.6 months). Extraction in infected patients required more aggressive methods and longer exposure to radiation than non-infected. Procedural success without major complications was achieved in all patients. Minor post-procedural complications occurred in four (44.4%) of the infected and one (3.2%) of the non-infected patients and were surgical-related in three cases. Overall hospitalization times were significantly longer for the infection than for the non-infection subgroup (21.4 ± 15 versus 9.6 ± 6.9 days). CONCLUSION: Our results support the concept of complete CIED-system removal in CIED-associated infection, regardless of whether or not infection appears to be limited to the generator pocket site, despite risk of heart failure, patient frailty and a high level of comorbidity. An interdisciplinary approach encompassing appropriate diagnostic, procedural and safety standards allows CS lead extraction in this high-risk subpopulation to be performed with excellent outcomes and low complication rates.

Role of acid sphingomyelinase in the regulation of mast cell function.

BACKGROUND: Degranulation of mast cells is stimulated by store-operated Ca(2+) -entry (SOCE). In other cell types, Ca(2+) -entry is modified by ceramide. Exogenously added ceramide has been shown to trigger mast cell apoptosis. Effects of endogenously produced ceramide in mast cells remained, however, elusive. Ceramide may be produced from sphingomyelin by acid sphingomyelinase (Asm). OBJECTIVE: This study explored the impact of Asm on mast cell functions. METHODS: Mast cells were isolated from bone marrow (BMMCs) or peritoneal lavage of gene-targeted mice lacking Asm (asm(-/-)) and their wild-type littermates (asm(+/+)). BMMC maturation and apoptosis-associated annexin V binding were determined by flow cytometry. Asm activity was assessed enzymatically, cytosolic Ca(2+) activity ([Ca(2+)]i) utilizing Fura-2 fluorescence, current across the cell membrane by whole-cell patch clamp, degranulation from hexosaminidase-release and migration utilizing a transwell chamber. In vivo anaphylaxis was derived from decrease in body temperature. RESULTS: Peritoneal mast cell number, BMMC phenotype, spontaneous BMMC apoptosis as well as BMMC CD117, CD34 and FcεRI expression were similar in both genotypes. In asm(+/+) BMMCs, stimulation with antigen resulted in a fast ~2.5-fold increase in Asm activity. Release of Ca(2+) from internal stores and hence several Ca(2+) -dependent functions were strongly impaired in asm(-/-) BMMCs. Thus, antigen-induced increase in [Ca(2+)]i in IgE-sensitized cells, antigen- but not ionomycin-induced currents through Ca(2+) -activated K(+) -channels (KCa 3.1), IgE/antigen-triggered ß-hexosaminidase release, and antigen-induced migration were all lower in asm(-/-) BMMCs than in asm(+/+) BMMCs. Pharmacological inhibition of Asm by amitriptyline (500 nm, 3 h) in asm(+/+) BMMCs similarly decreased antigen-induced increase in [Ca(2+)]i , KCa 3.1 currents, ß-hexosaminidase release and migration. The decrease in body temperature upon the induction of systemic anaphylaxis was significantly less pronounced in asm(-/-) mice than in asm(+/+) mice, an observation pointing to in vivo significance of Asm. CONCLUSIONS AND CLINICAL RELEVANCE: Asm is a novel, powerful regulator of mast cell function and thus a potential target in the treatment of allergic reactions.

TGFß1 and SGK1-sensitive store-operated Ca2+ entry and Orai1 expression in endometrial Ishikawa cells.

The serum-and-glucocorticoid-inducible-kinase-1 (SGK1) is ubiquitously expressed and under genomic control by cell stress, hormones and further mediators. A most powerful stimulator of SGK1 expression is transforming growth factor TGFß1. SGK1 is activated by insulin and growth factors via phosphatidylinositol-3-kinase and the 3-phosphoinositide-dependent kinase PDK1. As shown recently, SGK1 increases the store-operated Ca(2+) entry (SOCE), which is accomplished by the pore-forming ion channel unit Orai. Most recent observations further revealed that SGK1 plays a critical role in the regulation of fertility. SGK1 is up-regulated in the luminal epithelium of women with unexplained infertility but down-regulated in decidualizing stromal cells of patients with recurrent pregnancy loss. The present study explored whether Orai1 is expressed in endometrium and sensitive to regulation by SGK1 and/or TGFß1. To this end, Orai1 protein abundance was determined by western blotting and SOCE by fura-2 fluorescence. As a result, Orai1 was expressed in human endometrium and in human endometrial Ishikawa cells. Orai1 expression and SOCE in Ishikawa cells were increased by transfection with constitutively active (S422D)SGK1 but not by transfection with inactive (K127N)SGK1. The difference of SOCE between (S422D)SGK1 and (K127N)SGK1-transfected cells was virtually abrogated in the presence of Orai1 inhibitor 2-aminoethoxydiphenyl borate (2-APB, 50 µM). Similar to (S422D)SGK1 transfection TGFß1 treatment up-regulated both Orai1 protein abundance and SOCE. In conclusion, Orai1 is expressed in the human endometrium and is up-regulated by SGK1 and TGFß1. The present observations thus uncover a novel element in SGK1-sensitive regulation of endometrial cells.

[Effectiveness of initial antibiotic therapy for treatment of contact lens-related bacterial keratitis]. / Effektivität antibiotischer Initialtherapie in der Behandlung der kontaktlinsenassoziierten bakteriellen Keratitis.

BACKGROUND: Contact lens-related microbial keratitis is a cause of potentially sight-threatening corneal opacification. Effective initial antimicrobial therapy is crucial to prevent long-term complications. This investigation was undertaken to test the effectiveness of current routine empirical antibiotic treatment regimens. METHODS/PATIENTS: All consecutive cases of contact lens-related keratitis presenting in the outpatient clinic of the Department of Ophthalmology at the Medical University of Innsbruck between January 2010 and April 2012 were retrospectively analyzed. RESULTS: Cultures were positive in 69 out of the 123 cases included in the study. Culture results identified 59.4 % Gram positive strains, 50.7 % Gram negative strains and 7.2 % fungal strains. Mixed infections accounted for 29 % of cases. The combination of an aminoglycoside and a second generation quinolone antibiotic was the most common initial treatment regimen (87.8 %). In vitro this regimen was less effective compared to combinations of moxifloxacin and ciprofloxacin or moxifloxacin and gentamicin. CONCLUSION: Empirical combined regimens remain an effective treatment of contact lens-related keratitis. Fluoroquinolones proved to be inadequate for monotherapy.

Frequency and relevance of anterior cerebral artery embolism caused by mechanical thrombectomy of middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: Spread of thrombus material in previously unaffected vessels is a potential hazard of mechanical thrombectomy, but it has not yet been investigated in detail, to our knowledge. Our purpose was to evaluate the frequency and relevance of these events in mTE of M1 occlusions. MATERIALS AND METHODS: We retrospectively reviewed all patients treated for isolated M1 occlusion between January 2008 and July 2012. Angiographic images were analyzed to assess emboli in anterior cerebral artery branches induced by mTE and associated devices. Recanalization attempts in the ACA were reported as well as technical success and adverse events of rescue therapies. ACA infarcts on follow-up imaging served as a surrogate for clinical relevance. ACA infarcts were quantified volumetrically and assessed visually for involvement of motor or supplementary motor areas. RESULTS: New ACA emboli occurred in 12 of 105 (11.4%) M1 recanalization procedures and were caused by a stent-retriever in 11 intances. Attempts to recanalize the ACA were made in 6 patients and were deemed technically successful in 5 with no adverse events. We detected 6 (5.7%) new infarcts on follow-up imaging with an average volume of 26.9 cm(3). Involvement of motor or supplementary motor areas was seen in 4 (3.8%) cases. Three patients developed ACA infarcts despite successful endovascular ACA recanalization. CONCLUSIONS: The frequency of ACA emboli in mTE of M1 occlusions is relevant, causing ACA infarcts in 5.7% of patients; 3.8% of emboli were likely to hamper motor-function recovery. Endovascular recanalization of major ACA branches reduced the incidence of infarcts with no adverse events.