In idiopathic scoliosis distances of spinal cord to thoracic pedicle are within 2 mm in a large region of the thoracic apex.

Despite a 15% misplacement rate of screws in idiopathic scoliosis surgery, little is known about the relationship between pedicles and nerve structures in the entire thoracic curve. This study aimed to explore the spinal cord's proximity to the pedicle wall at each thoracic vertebra in the entire thoracic curve, while considering different anatomical changes. Spinal cord to medial pedicle distances were measured on magnetic resonance imaging in 73 patients who underwent posterior spinal fusion with pedicle screw instrumentation. Associations with different variables were examined. A total of 51 patients (69.9%) showed a distance within 2 mm at the apex vertebra on the concave side, more than 50% had a distance within 2 mm in the next thoracic vertebra level above and below, and more than 25% two levels above and below. Weak correlations were found between proximity of the spinal cord at the apex vertebra and vertebra's level and Cobb angle on the concave side (r = - 0.310, P = 0.008, r = 0.380, P = 0.001, respectively). These results emphasize the importance of thorough assessment when placing thoracic pedicle screws in idiopathic scoliosis patients. Further research is warranted to develop surgical strategies aimed at preventing potentially neurological complications resulting from screw misplacement.

A noninvasive method to quantify the impairment of spinal motion ability in Parkinson's disease.

PURPOSE: There is a high demand on spinal surgery in patients with Parkinson's disease (PD) but the results are sobering. Although detailed clinical and radiological diagnostics were carried out with great effort and expense, the biodynamic properties of the spine of PD patients have never been considered. We propose a noninvasive method to quantify the impairment of motion abilities in patients with PD. METHODS: We present an analytical cross-sectional study of 21 patients with severe PD. All patients underwent a biodynamic assessment during a standardized movement-choreography. Thus, individual spinal motion profiles of each patient were objectively assessed and compared with a large comparative cohort of individuals without PD. Moreover, clinical scores to quantify motor function and lumbar back pain were collected and X-ray scans of the spine in standing position were taken and analysed. RESULTS: Biodynamic measurement showed that 36.9% of the assessed motions of all PD patients were severely impaired. Men were generally more functionally impaired than women, in 52% of all motion parameters. The neurological and radiological diagnostics recorded pathological values, of which UPDRS-III ON correlated with findings of the biodynamics assessment (R = 0.52, p = 0.02). CONCLUSIONS: The decision to operate on a PD patient's spine is far-reaching and requires careful consideration. Neurological and radiological scores did not correlate with the biodynamics of the spine. The resulting motion profile could be used as individual predictive factor to estimate whether patients are eligible for spinal surgery or alternative therapies.

Comparison of three validated systems to analyse spinal shape and motion.

The assessment of spinal shape and mobility is of great importance for long-term therapy evaluation. As frequent radiation should be avoided, especially in children, non-invasive measurements have gained increasing importance. Their comparability between each other however stays elusive. Three non-invasive measurement tools have been compared to each other: Idiag M360, raster stereography and Epionics SPINE. 30 volunteers (15 females/15 males) have each been assessed by each system, investigating lumbar lordosis, thoracic kyphosis and spinal range-of-motion in the sagittal plane. Lumbar lordosis differed significantly (p < 0.001) between measurement devices but correlated significant to each other (Pearson's r 0.5-0.6). Regarding thoracic kyphosis no significant difference and a high correlation (r = 0.8) could be shown between Idiag M360 and raster stereography. For lumbar mobility resulting measurements differed significantly and correlated only moderate between Idiag M360 and Epionics SPINE. Although the different measurement systems are moderate to high correlated to each other, their absolute agreement is limited. This might be explained by differences in their angle definition for lordotic and kyphotic angle, their measurement placement, or their capturing of mobility (static vs. dynamic assessment). Therefore, for long-term evaluation of the back profile, inter-modal comparison of values between different non-invasive devices should be avoided.

Activation of the stress response among the cardiac surgical residents: comparison of teaching procedures and other (daily) medical activities.

BACKGROUND: The aim of this Pilot study was to investigate the cardiac surgical residents' workload during different surgical teaching interventions and to compare their stress levels with other working time spent in the intensive care unit or normal ward. METHODS: The objective stress was assessed using two cardiac surgical residents' heart rate variability (HRV) both during surgical activities (32 selected teaching operations (coronary artery bypass graft n = 26 and transcatheter aortic valve implantation n = 6), and during non-surgical periods. Heart rate, time and frequency domains as well as non-linear parameters were analyzed using the Wilcoxon test. RESULTS: The parasympathetic activity was significantly reduced during the surgical phase, compared to the non-surgical phase: Mean RR (675.7 ms vs. 777.3 ms), RMSSD (23.1 ms vs. 34.0 ms) and pNN50 (4.7% vs. 10.6%). This indicates that the residents had a higher stress level during surgical activities in comparison to the non-surgical times. The evaluation of the Stress Index during the operations and outside the operating room (8.07 vs. 10.6) and the parasympathetic nervous system index (- 1.75 to - 0.91) as well as the sympathetic nervous system index (1.84 vs. 0.65) confirm the higher stress level during surgery. This can be seen too used the FFT Analysis with higher intraoperative LF/HF ratio (6.7 vs. 3.8). CONCLUSION: HRV proved to be a good, objective method of identifying stress among physicians both in and outside the operating room. Our results show that residents are exposed to high psychological workloads during surgical activities, especially as the operating surgeon.

Does Total Hip Arthroplasty Affect Spinopelvic and Spinal Alignment?: A Prospective Observational Investigation.

STUDY DESIGN: A prospective observational study, level of evidence 3. OBJECTIVES: The study with patients undergoing unilateral total hip arthroplasty (THA) aimed to evaluate the following hypotheses: (1) the spinal sagittal and coronal alignment alters due to THA, (2) the spinopelvic parameter changes after THA, (3) the spinopelvic alignment differs between sagittal balanced and imbalanced patients. SUMMARY OF BACKGROUND DATA: Surgical correction of spinal sagittal misalignment affects the spinopelvic alignment and pelvic tilt. It is not yet known to what extent THA affects spinopelvic, spinal sagittal, and coronal alignment. MATERIALS AND METHODS: A total of 153 patients undergoing THA were assessed with biplanar stereoradiography in standing position preoperatively and postoperatively. Two independent investigators examined C7-sagittal vertical axis (C7-SVA), pelvic incidence-lumbar lordosis (PI-LL) mismatch, lumbar lordosis (LL), C7-central sacral vertical line, pelvic oblique angle lumbosacral, intra-pelvic oblique angle, pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), anterior plane pelvic tilt (APPT), and pelvic femoral angle (PFA). An analysis of the sagittal misaligned subgroups of C7-SVA and PI-LL on the influence of the spinopelvic alignment was performed. RESULTS: A significant difference in spinopelvic parameters was detected in the preoperative to postoperative comparison (SS, PT, APPT, and PFA; P <0.000) ( d =-0.394; d =0.609; d =-0.481; d =0.431). The coronal alignment and pelvic obliquity revealed no significant differences. The misaligned groups (C7-SVA; PI-LL) demonstrated significant increases in PI and PT and decreased in LL compared with the groups with normal sagittal alignment. Preoperatively, 66/153 (C7-SVA) and 46/153 (PI-LL) of the THA patients presented sagittal misalignment, respectively. CONCLUSIONS: The results suggest an effect of THA on sagittal spinal and spinopelvic alignment, with a significant reduction of PT postoperatively and no effect on coronal alignment. Particularly striking are the significant differences in the misaligned groups, which may be classified as risk population and potentially can contribute biomechanically to a higher risk of posterior impingement and anterior THA dislocation. The substantial proportion of sagittal misaligned patients in the THA collective illustrates the crucial need for interdisciplinary collaboration.

Evaluation of Stress Levels of Trainee Cardiac Surgery Residents during Training Interventions Using Physiological Stress Parameters.

BACKGROUND: This study analysed the psychological and psycho-emotional stress in cardiac surgery. Using heart rate variability (HRV) analysis, it is possible to record intraoperative objective stress responses in surgeons. The aim of the study was to assess with the help of HRV parameters the postulated increased stress levels of cardiac surgeons in training compared to experienced senior cardiothoracic surgeons in exactly the same work situation in order to make qualification-differentiated statements about physiological stress during surgical interventions. METHODS: During surgical teaching procedures, long-term ECG data (n = 15 each) for two operating residents and their assisting senior physicians were recorded. Time and frequency domain HRV parameters were analysed. RESULTS: The time-related parasympathetic-dominated HRV parameters RMSSD (19.5 ms vs. 28.1 ms), NN50 (297.67 vs. 693.40), and cardiac interval mean RR (692.8 ms vs. 737.3 ms) indicate a higher stress level in the operating residents compared to the experienced surgeons. The higher stress index (11.61 vs. 8.86) confirms this. CONCLUSION: Compared to experienced surgeons, operating residents showed lower parasympathetic activity and higher stress levels during cardiac surgery training procedures.

Numerical simulations of bone remodelling and formation following nucleotomy.

Nucleotomy is the gold standard treatment for disc herniation and has proven ability to restore stability by creating a bony bridge without any additional fixation. However, the evolution of mineral density in the extant and new bone after nucleotomy and fixation techniques has to date not been investigated in detail. The main goal of this study is to determine possible mechanisms that may trigger the bone remodelling and formation processes. With that purpose, a finite element model of the L4-L5 spinal segment was used. Bone mineral density (BMD), new tissue composition, and endplate deflection were determined as indicators of lumbar fusion. A bone-remodelling algorithm and a tissue-healing algorithm, both mechanically driven, were implemented to predict vertebral bone alterations and fusion patterns after nucleotomy, internal fixation, and anterior plate placement. When considering an intact disc height, neither nucleotomy nor internal fixation were able to provide the necessary stability to promote bony fusion. However, when 75% of the disc height was considered, bone fusion was predicted for both techniques. By contrast, an anterior plate allowed bone fusion at all disc heights. A 50% disc-height reduction led to osteophyte formation in all cases. Changes in the intervertebral disc tissue caused BMD alterations in the endplates. From this observations it can be drawn that fusion may be self-induced by controlling the mechanical stabilisation without the need of additional fixation. The amount of tissue to be removed to achieve this stabilisation remains to be determined.

Spinal Deformity Surgery: A Critical Review of Alignment and Balance.

Correction of the overall coronal and/or sagittal plane deformities is one of the main predictors of successful spinal surgery. In routine clinical practice, spinal alignment is assessed using several spinal and pelvic parameters, such as pelvic incidence and tilt, sacral slope, lumbar lordosis, thoracic kyphosis, and sagittal vertical axis. Standard values have been defined for all these parameters, and the formulas of correction have been set for determining the surgical strategy. However, several factors can potentially bias these formulas. First, all standard values are measured using conventional plain radiographs and are, therefore, prone to bias. The radiologist, measuring surgeon, and patient are possible confounding influencing factors. Second, spino-pelvic compensatory effects and biomechanically relevant structures for the patient's posture, including ligaments, tendons, and muscles, have received minimal consideration in the literature. Therefore, even in cases of appropriately planned deformity correction surgeries, complications, revision rates, and surgical outcomes significantly vary. This study aimed to illustrate the current clinical weaknesses of the assessment of spinal alignment and the importance of holistically approaching the musculoskeletal system for any spinal deformity surgery. We believe that our detailed insights regarding spinal, sagittal, and coronal alignments as well as the considerations of an individual's spinal balance will contribute toward improvement in routine patient care.

Separate the Sheep from the Goats: Use and Limitations of Large Animal Models in Intervertebral Disc Research.

Approximately 5,168 large animals (pigs, sheep, goats, and cattle) were used for intervertebral disc research in identified studies published between 1985 and 2016. Most of the reviewed studies revealed a low scientific impact, a lack of sound justifications for the animal models, and a number of deficiencies in the documentation of the animal experimentation. The scientific community should take suitable measures to investigate the presumption that animal models have translational value in intervertebral disc research. Recommendations for future investigations are provided to improve the quality, validity, and usefulness of animal studies for intervertebral disc research. More in vivo studies are warranted to comprehensively evaluate the suitability of animal models in various applications and help place animal models as an integral, complementary part of intervertebral disc research.

Spinal fusion without instrumentation - Experimental animal study.

BACKGROUND: The number and cost of instrumented spinal fusion surgeries have increased rapidly, primarily for the treatment of lumbar segmental instabilities. However, what if the organism itself is able to restore segmental stability over time? This large-animal study using sheep aimed to investigate whether the reparative response after destabilization via facetectomy and nucleotomy without instrumentation can effectively fuse the spinal segment comparable to instrumented standard fusion surgery. METHODS: The following four surgical interventions were investigated: dorsal fixation via internal fixator, ventral fixation via cage as well as facetectomy and nucleotomy without additional instrumentation. Six months postoperatively, the animals were sacrificed, and the lumbar spines were used for biomechanical tests. FINDINGS: Spinal stability was restored to the destabilized spinal segments at six months postoperatively and was comparable to the results of conventional surgery via screws and cages. Iatrogenic hypomobilization caused significant reductions in facet joint space and intervertebral disc height of segments at index and adjacent level. Restabilized segments after iatrogenic hypermobilzation also significantly decreased facet joint space and disc height at index level, but revealed no influence on adjacent segments. INTERPRETATION: These findings in the sheep model question the necessity of costly instrumentation and suggest the alternative possibility of stimulating the reparative capacity of the body in human lumbar spine fusion surgery.

Psychometric properties of the St George's Respiratory Questionnaire in patients with idiopathic pulmonary fibrosis.

The St George's Respiratory Questionnaire (SGRQ) has been used to measure health-related quality of life (HRQoL) in patients with idiopathic pulmonary fibrosis (IPF).This analysis evaluated the psychometric properties of the SGRQ using data from 428 patients with IPF who participated in a 12-month, randomised, placebo-controlled phase II trial of nintedanib.Internal consistency (Cronbach's α) was 0.91 for SGRQ total and >0.70 for domain scores. Test-retest reliability (intraclass correlation coefficients) was 0.77, 0.77, 0.69 and 0.66 for SGRQ total, activity, impact and symptoms scores, respectively. Construct validity of SGRQ total and domain scores was supported by weak to moderate cross-sectional correlations with the Medical Research Council dyspnoea scale (0.32-0.55), 6-min walk test distance (-0.25- -0.34), percentage predicted forced vital capacity (-0.11- -0.15) and measures of gas exchange (-0.26-0.03). There was some evidence that the SGRQ total score was sensitive to detecting change.The reliability, construct validity and responsiveness of the SGRQ in patients with IPF suggest that this is an acceptable measure of HRQoL in patients with IPF.

Growth of Murine Splenic Tissue Is Suppressed by Lymphotoxin ß-Receptor Signaling (LTßR) Originating from Splenic and Non-Splenic Tissues.

Development and maintenance of secondary lymphoid organs such as lymph nodes and spleen essentially depend on lymphotoxin ß-receptor (LTßR) signaling. It is unclear, however, by which molecular mechanism their size is limited. Here, we investigate whether the LTßR pathway is also growth suppressing. By using splenic tissue transplantation it is possible to analyze a potential contribution of LTßR signaling inside and outside of the implanted tissue. We show that LTßR signaling within the endogenous spleen and within non-splenic tissues both significantly suppressed the regeneration of implanted splenic tissue. The suppressive activity positively correlated with the total number of LTßR expressing cells in the animal (regenerate weights of 115 ± 8 mg in LTßR deficient recipients and of 12 ± 9 mg in wild-type recipients), affected also developed splenic tissue, and was induced but not executed via LTßR signaling. Two-dimensional differential gel electrophoresis and subsequent mass spectrometry of stromal splenic tissue was applied to screen for potential factors mediating the LTßR dependent suppressive activity. Thus, LTßR dependent growth suppression is involved in regulating the size of secondary lymphoid organs, and might be therapeutically used to eradicate tertiary lymphoid tissues during autoimmune diseases.

Tiotropium improves lung function, exacerbation rate, and asthma control, independent of baseline characteristics including age, degree of airway obstruction, and allergic status.

BACKGROUND: Many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS) with or without long-acting ß2-agonists (LABAs). Tiotropium add-on to ICS plus a LABA has been shown to improve lung function and reduce exacerbation risk in patients with symptomatic asthma. OBJECTIVE: To determine whether the efficacy of tiotropium add-on therapy is dependent on patients' baseline characteristics. METHODS: Two randomized, double-blind, parallel-group, twin trials (NCT00772538 and NCT00776984) of once-daily tiotropium Respimat(®) 5 µg add-on to ICS plus a LABA were performed in parallel in patients with severe symptomatic asthma. Exploratory subgroup analyses of peak forced expiratory volume in 1 s (FEV1), trough FEV1, time to first severe exacerbation, time to first episode of asthma worsening, and seven-question Asthma Control Questionnaire responder rate were performed to determine whether results were influenced by baseline characteristics. RESULTS: 912 patients were randomized: 456 received tiotropium and 456 received placebo. Tiotropium improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, compared with placebo, independent of baseline characteristics including gender, age, body mass index, disease duration, age at asthma onset, and FEV1 % predicted at screening and reversibility. CONCLUSION: Once-daily tiotropium 5 µg compared with placebo improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, independent of a broad range of baseline characteristics, as add-on to ICS plus LABAs in patients with severe symptomatic asthma. TRIAL REGISTRY: ClinicalTrials.gov; numbers NCT00772538 and NCT00776984 URL: www.clinicaltrials.gov.

Biomechanics of the L5-S1 motion segment after total disc replacement - Influence of iatrogenic distraction, implant positioning and preoperative disc height on the range of motion and loading of facet joints.

Total disc replacement has been introduced to overcome negative side effects of spinal fusion. The amount of iatrogenic distraction, preoperative disc height and implant positioning have been considered important for surgical success. However, their effect on the postoperative range of motion (RoM) and loading of the facets merits further discussion. A validated osteoligamentous finite element model of the lumbosacral spine was employed and extended with four additional models to account for different disc heights. An artificial disc with a fixed center of rotation (CoR) was implemented in L5-S1. In 4000 simulations, the influence of distraction and the CoR's location on the RoM, facet joint forces (FJFs) and facet capsule ligament forces (FCLFs) was investigated. Distraction substantially altered segmental kinematics in the sagittal plane by decreasing range of flexion (0.5° per 1mm of distraction), increasing range of extension (0.7°/mm) and slightly affecting complete sagittal RoM (0.2°/mm). The distraction already strongly increased the FCLFs during surgery (up to 230N) and in flexion (~12N/mm), with higher values in models with larger preoperative disc heights, and increased FJFs in extension. A more anterior implant location decreased the RoM in all planes. In most loading cases, a more posterior location of the implant's CoR increased the FJFs and FCLFs, whereas a more caudal location increased the FCLFs but decreased the FJFs. The results of this study may explain the worse clinical results in patients with overdistraction after TDR. The complete RoM in the sagittal plane appears to be insensitive to detecting surgery-related biomechanical changes.

Spinal loads during cycling on an ergometer.

Cycling on an ergometer is an effective exercise for improving fitness. However, people with back problems or previous spinal surgery are often not aware of whether cycling could be harmful for them. To date, little information exists about spinal loads during cycling. A telemeterized vertebral body replacement allows in vivo measurement of implant loads during the activities of daily living. Five patients with a severe compression fracture of a lumbar vertebral body received these implants. During one measurement session, four of the participants exercised on a bicycle ergometer at various power levels. As the power level increased, the maximum resultant force and the difference between the maximum and minimum force (force range) during each pedal revolution increased. The average maximum-force increases between the two power levels 25 and 85 W were 73, 84, 225 and 75 N for the four patients. The corresponding increases in the force range during a pedal revolution were 84, 98, 166 and 101 N. There were large variations in the measured forces between the patients and also within the same patient, especially for high power levels. In two patients, the maximum forces during high-power cycling were higher than the forces during walking measured on the same day. Therefore, the authors conclude that patients with back problems should not cycle at high power levels shortly after surgery as a precaution.

Nuclear death receptor TRAIL-R2 inhibits maturation of let-7 and promotes proliferation of pancreatic and other tumor cells.

BACKGROUND & AIMS: Tumor necrosis factor-related apoptosis inducing ligand (TRAIL-R1) (TNFRSF10A) and TRAIL-R2 (TNFRSF10B) on the plasma membrane bind ligands that activate apoptotic and other signaling pathways. Cancer cells also might have TRAIL-R2 in the cytoplasm or nucleus, although little is known about its activities in these locations. We investigated the functions of nuclear TRAIL-R2 in cancer cell lines. METHODS: Proteins that interact with TRAIL-R2 initially were identified in pancreatic cancer cells by immunoprecipitation, mass spectrometry, and immunofluorescence analyses. Findings were validated in colon, renal, lung, and breast cancer cells. Functions of TRAIL-R2 were determined from small interfering RNA knockdown, real-time polymerase chain reaction, Drosha-activity, microRNA array, proliferation, differentiation, and immunoblot experiments. We assessed the effects of TRAIL-R2 overexpression or knockdown in human pancreatic ductal adenocarcinoma (PDAC) cells and their ability to form tumors in mice. We also analyzed levels of TRAIL-R2 in sections of PDACs and non-neoplastic peritumoral ducts from patients. RESULTS: TRAIL-R2 was found to interact with the core microprocessor components Drosha and DGCR8 and the associated regulatory proteins p68, hnRNPA1, NF45, and NF90 in nuclei of PDAC and other tumor cells. Knockdown of TRAIL-R2 increased Drosha-mediated processing of the let-7 microRNA precursor primary let-7 (resulting in increased levels of mature let-7), reduced levels of the let-7 targets (LIN28B and HMGA2), and inhibited cell proliferation. PDAC tissues from patients had higher levels of nuclear TRAIL-R2 than non-neoplastic pancreatic tissue, which correlated with increased nuclear levels of HMGA2 and poor outcomes. Knockdown of TRAIL-R2 in PDAC cells slowed their growth as orthotopic tumors in mice. Reduced nuclear levels of TRAIL-R2 in cultured pancreatic epithelial cells promoted their differentiation. CONCLUSIONS: Nuclear TRAIL-R2 inhibits maturation of the microRNA let-7 in pancreatic cancer cell lines and increases their proliferation. Pancreatic tumor samples have increased levels of nuclear TRAIL-R2, which correlate with poor outcome of patients. These findings indicate that in the nucleus, death receptors can function as tumor promoters and might be therapeutic targets.

Characterisation of exacerbation risk and exacerbator phenotypes in the POET-COPD trial.

BACKGROUND: Data examining the characteristics of patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD) and associated hospitalisations and mortality are scarce. METHODS: Post-hoc analysis of the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, targeting exacerbations as the primary endpoint. Patients were classified as non-, infrequent, and frequent exacerbators (0, 1, or ≥ 2 exacerbations during study treatment), irrespective of study treatment. A multivariate Cox regression model assessed the effect of covariates on time to first exacerbation. RESULTS: In total, 7376 patients were included in the analysis: 63.5% non-exacerbators, 22.9% infrequent, 13.6% frequent exacerbators. Factors significantly associated with exacerbation risk were age, sex, body mass index, COPD duration and severity, smoking history, baseline inhaled corticosteroid use, and preceding antibiotic or systemic corticosteroid courses. Frequent exacerbators had greater severity and duration of COPD, received more pulmonary medication, and ≥ 2 systemic corticosteroid or antibiotic courses in the preceding year, and were more likely to be female and ex-smokers. The small proportion of frequent exacerbators (13.6%) accounted for 56.6% of exacerbation-related hospitalisations, which, overall, were associated with a three-fold increase in mortality. CONCLUSION: The frequent exacerbator phenotype was closely associated with exacerbation-related hospitalisations, and exacerbation-related hospitalisations were associated with poorer survival. TRIAL REGISTRATION: NCT00563381; Study identifier: BI 205.389.

Surface CD107a/LAMP-1 protects natural killer cells from degranulation-associated damage.

Cytotoxic lymphocytes are important for immune responses against viral infections and cancer. They are able to kill target cells through the release of cytotoxic granules (CGs) without being harmed in the process. Because the lysosomal-associated membrane proteins (LAMPs) appear on the cell surface after CG exocytosis, we hypothesized that some of these proteins might be involved in transiently protecting cytotoxic lymphocytes from self-destruction. Intracellular expression of CD107a/LAMP-1, and to a lesser extent that of CD107b/LAMP-2, correlated with lymphocyte CG content. Engineered surface expression of CD107a/LAMP-1, but not of CD107b/LAMP-2, reduced the granule-mediated killing of transfected target cells. This was dependent on glycosylation of the CD107a/LAMP-1 hinge. Moreover, surface expression of CD107a/LAMP-1 reduced binding of perforin to cells. Importantly, knockdown of CD107a/LAMP-1 in primary human natural killer (NK) cells and deficiency of CD107a/LAMP-1 in mice resulted in increased NK cell apoptosis upon target cell-induced degranulation. Thus, our data support a novel role of CD107a/LAMP-1 in the protection of NK cells from degranulation-associated suicide, which may represent a general mechanism to transiently limit self-destruction by cytotoxic lymphocytes upon target cell killing.

Seasonal distribution of COPD exacerbations in the Prevention of Exacerbations with Tiotropium in COPD trial.

BACKGROUND: There is still a lack of data on the seasonality of exacerbations of COPD based on large randomized studies using COPD exacerbations as primary end points. The objective of this study was to assess the seasonal pattern of moderate and severe exacerbations and analyze the influence of associated baseline factors. We also determined the timing of second exacerbations and the potential impact of the 2009 influenza A(H1N1) pandemic on exacerbations. METHODS: Analyses of exacerbation rates across treatment groups were adjusted for differing times on treatment by means of descriptive statistics based on the 1-year Prevention of Exacerbations with Tiotropium in COPD (POET-COPD) trial, in which exacerbations were the primary end point. RESULTS: Of the 7,376 patients who were randomized, a total of 4,411 exacerbations were reported in 2,691 patients. Mean monthly exacerbation rates during winter were 2.16-fold higher than during summer, regardless of baseline characteristics (age, sex, COPD severity, smoking status, BMI, inhaled corticosteroid use, cardiovascular comorbidity, concomitant cardiovascular medication). Second exacerbations after a previous event in October to March occurred 1 month earlier than during the warmer half of the season. The portion of exacerbation-related hospitalizations remained constant throughout the year. Most exacerbations were treated with antibiotics and reached a peak in the colder season. All-cause mortality showed a seasonal pattern similar to exacerbations. The 2009 A(H1N1) pandemic was not associated with an increase in exacerbation rates or deaths. CONCLUSIONS: This analysis presented a marked impact of season on exacerbation outcomes, antibiotic treatment, timing of second exacerbations, and all-cause mortality.

The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2.

Rocaglamides are potent natural anticancer products that inhibit proliferation of various cancer cells at nanomolar concentrations. We have recently shown that these compounds prevent tumor growth and sensitize resistant cancer cells to apoptosis by blocking the MEK-ERK-eIF4 pathway. However, their direct molecular target(s) remain(s) unknown. In this study, using an affinity chromatography approach we discovered that prohibitin (PHB) 1 and 2 are the direct targets of rocaglamides. Binding of rocaglamides to PHB prevents interaction between PHB and CRaf and, thereby, inhibits CRaf activation and subsequently CRaf-MEK-ERK signaling. Moreover, knockdown of PHB mimicked the effects of rocaglamides on the CRaf-MEK-ERK pathway and cell cycle progression. Thus, our finding suggests that rocaglamides are a new type of anticancer agent and that they may serve as a small-molecular tool for studying PHB-mediated cellular processes.