Increased vaccine tolerability and protection via NF-κB modulation.

Improving adjuvant responses is a promising pathway to develop vaccines against some pathogens (e.g., HIV or dengue). One challenge in adjuvant development is modulating the inflammatory response, which can cause excess side effects, while maintaining immune activation and protection. No approved adjuvants yet have the capability to independently modulate inflammation and protection. Here, we demonstrate a method to limit inflammation while retaining and often increasing the protective responses. To accomplish this goal, we combined a partial selective nuclear factor kappa B (NF-kB) inhibitor with several current adjuvants. The resulting vaccines reduce systemic inflammation and boost protective responses. In an influenza challenge model, we demonstrate that this approach enhances protection. This method was tested across a broad range of adjuvants and antigens. We anticipate these studies will lead to an alternative approach to vaccine formulation design that may prove broadly applicable to a wide range of adjuvants and vaccines.

Can the Charlson Comorbidity Index be used to predict the ASA grade in patients undergoing spine surgery?

BACKGROUND: The American Society of Anaesthesiologists' Physical Status Score (ASA) is a key variable in predictor models of surgical outcome and "appropriate use criteria". However, at the time when such tools are being used in decision-making, the ASA rating is typically unknown. We evaluated whether the ASA class could be predicted statistically from Charlson Comorbidy Index (CCI) scores and simple demographic variables. METHODS: Using established algorithms, the CCI was calculated from the ICD-10 comorbidity codes of 11'523 spine surgery patients (62.3 ± 14.6y) who also had anaesthetist-assigned ASA scores. These were randomly split into training (N = 8078) and test (N = 3445) samples. A logistic regression model was built based on the training sample and used to predict ASA scores for the test sample and for temporal (N = 341) and external validation (N = 171) samples. RESULTS: In a simple model with just CCI predicting ASA, receiver operating characteristics (ROC) analysis revealed a cut-off of CCI ≥ 1 discriminated best between being ASA ≥ 3 versus < 3 (area under the curve (AUC), 0.70 ± 0.01, 95%CI,0.82-0.84). Multiple logistic regression analyses including age, sex, smoking, and BMI in addition to CCI gave better predictions of ASA (Nagelkerke's pseudo-R2 for predicting ASA class 1 to 4, 46.6%; for predicting ASA ≥ 3 vs. < 3, 37.5%). AUCs for discriminating ASA ≥ 3 versus < 3 from multiple logistic regression were 0.83 ± 0.01 (95%CI, 0.82-0.84) for the training sample and 0.82 ± 0.01 (95%CI, 0.81-0.84), 0.85 ± 0.02 (95%CI, 0.80-0.89), and 0.77 ± 0.04 (95%CI,0.69-0.84) for the test, temporal and external validation samples, respectively. Calibration was adequate in all validation samples. CONCLUSIONS: It was possible to predict ASA from CCI. In a simple model, CCI ≥ 1 best distinguished between ASA ≥ 3 and < 3. For a more precise prediction, regression algorithms were created based on CCI and simple demographic variables obtainable from patient interview. The availability of such algorithms may widen the utility of decision aids that rely on the ASA, where the latter is not readily available.

Soil net nitrogen mineralisation across global grasslands.

Soil nitrogen mineralisation (Nmin), the conversion of organic into inorganic N, is important for productivity and nutrient cycling. The balance between mineralisation and immobilisation (net Nmin) varies with soil properties and climate. However, because most global-scale assessments of net Nmin are laboratory-based, its regulation under field-conditions and implications for real-world soil functioning remain uncertain. Here, we explore the drivers of realised (field) and potential (laboratory) soil net Nmin across 30 grasslands worldwide. We find that realised Nmin is largely explained by temperature of the wettest quarter, microbial biomass, clay content and bulk density. Potential Nmin only weakly correlates with realised Nmin, but contributes to explain realised net Nmin when combined with soil and climatic variables. We provide novel insights of global realised soil net Nmin and show that potential soil net Nmin data available in the literature could be parameterised with soil and climate data to better predict realised Nmin.

Photon upconversion for the enhancement of microfluidic photochemical synthesis.

Photochemical transformations are greatly improved in yield by fluidic reactor technology. However, the delivery of synthetically-active light to the reactants is a challenge. Here, we use upconversion in a bio-inspired microreactor to augment the flux of critical wavelengths of light. This new technology increased of a model reaction by converting a greater portion of sunlight to photochemically-available photons.

Androgen receptor dampens tissue factor expression via nuclear factor-κB and early growth response protein 1.

Essentials Androgen deprivation increases the rate of venous thromboembolism in prostate cancer patients. We characterized androgen receptor-mediated tissue factor regulation in prostate epithelial cells. Androgen receptor is dampening tissue factor expression in prostate epithelial cells. Androgen deprivation could enhance tissue factor expression and raise venous thromboembolism rates. SUMMARY: Background Prostate cancer is one of the leading causes of cancer death in men. Advanced prostate cancer is usually treated by androgen deprivation therapy (ADT), which is aimed at reducing circulating testosterone levels to reduce cancer growth. There is growing evidence that ADT can increase the rate of venous thromboembolism (VTE) in prostate cancer patients. The tissue factor (TF) gene is one of the most important mediators of coagulation and VTE, but, so far, there are limited data on androgen receptor (AR)-mediated TF gene expression. Objectives To characterize AR-mediated TF regulation in vitro and in vivo. Methods We used the androgen-dependent prostate cancer cell lines LNCaP and MyC-CaP to test whether TF expression is regulated by AR. Furthermore, we cloned the TF gene promoter into a luciferase reporter vector to identify the transcription factor-binding sites that mediate TF regulation downstream of AR. Finally, we used castration experiments in mice to characterize AR-mediated TF regulation in vivo. Results TF is directly regulated by AR. In LNCaP cells, nuclear factor-κB signaling and EGR1 mediate TF expression. By using castration experiments in mice, we could detect upregulation of TF and early growth response protein 1 mRNA and protein expression in prostate epithelial cells. Conclusion AR is crucial for dampening TF expression, which could be important for increased TF expression and TF-positive microvesicle release in androgen-deprived prostate cancer patients.

Multiple Supersonic Phase Fronts Launched at a Complex-Oxide Heterointerface.

Selective optical excitation of a substrate lattice can drive phase changes across heterointerfaces. This phenomenon is a nonequilibrium analogue of static strain control in heterostructures and may lead to new applications in optically controlled phase change devices. Here, we make use of time-resolved nonresonant and resonant x-ray diffraction to clarify the underlying physics and to separate different microscopic degrees of freedom in space and time. We measure the dynamics of the lattice and that of the charge disproportionation in NdNiO_{3}, when an insulator-metal transition is driven by coherent lattice distortions in the LaAlO_{3} substrate. We find that charge redistribution propagates at supersonic speeds from the interface into the NdNiO_{3} film, followed by a sonic lattice wave. When combined with measurements of magnetic disordering and of the metal-insulator transition, these results establish a hierarchy of events for ultrafast control at complex-oxide heterointerfaces.

HSP27 and 70 expression in thymic epithelial tumors and benign thymic alterations: diagnostic, prognostic and physiologic implications.

Thymic Epithelial Tumors (TETs), the most common tumors in the anterior mediastinum in adults, show a unique association with autoimmune Myasthenia Gravis (MG) and represent a multidisciplinary diagnostic and therapeutic challenge. Neither risk factors nor established biomarkers for TETs exist. Predictive and diagnostic markers are urgently needed. Heat shock proteins (HSPs) are upregulated in several malignancies promoting tumor cell survival and metastases. We performed immunohistochemical staining of HSP27 and 70 in patients with TETs (n = 101) and patients with benign thymic alterations (n = 24). Further, serum HSP27 and 70 concentrations were determined in patients with TETs (n = 46), patients with benign thymic alterations (n = 33) and volunteers (n = 49) by using ELISA. HSPs were differentially expressed in histologic types and pathological tumor stages of TETs. Weak HSP tumor expression correlated with worse freedom from recurrence. Serum HSP concentrations were elevated in TETs and MG, correlated with clinical tumor stage and histologic subtype and decreased significantly after complete tumor resection. To conclude, we found HSP expression in the vast majority of TETs, in physiologic thymus and staining intensities in patients with TETs have been associated with prognosis. However, although interesting and promising the role of HSPs in TETs as diagnostic and prognostic or even therapeutic markers need to be further evaluated.

[Bone defect adjusted strategy in revision arthroplasty of the hip : Wich implant in wich situation? Innovations and approved methods]. / Defektadaptierte Rekonstruktionsstrategien in der Hüftrevisionsendoprothetik : Welches Implantat in welcher Situation? Innovationen und Bewährtes.

BACKGROUND: Revision total hip arthroplasty is of rising importance, with 35,000 procedures a year in Germany. OBJECTIVES: Primary stability of the revision implant, reconstruction of the anatomical hip center, reconstruction of bone stock, and permanent secondary integration are the main priorities. METHODS: Current literature and examples from our own experience are presented. RESULTS AND CONCLUSIONS: Novel developments from basic research and industrial partners extend the possibilities for treating affected patients. For an integrated therapy concept in implant selection criteria, such as situation and structure of the defect, combination with any remaining implants, causes of loosening and failure, implant allergy, and patient-specific parameters should be taken into consideration.

Diffuse multiple scattering.

A new form of diffraction lines has been identified, similar to Rutherford, Kikuchi and Kossel lines. This paper highlights some of the properties of these lines and shows how they can be used to eliminate the need for sample/source matching in Lonsdale's triple convergent line method in lattice-parameter determination.

The effect of CYP2C19 gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease.

CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC[0-tlast]), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC(0-tlast) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [CI]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiving clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, p<0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VN-PRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures p<0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons p<0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all p<0.001), and comparable effects in EMs (all p≥0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg.

Serial position effects in patients with mild cognitive impairment and early and moderate Alzheimer's disease compared with healthy comparison subjects.

BACKGROUND/AIMS: This study aimed to investigate whether the serial position effects in memory can differentiate patients with different subtypes of mild cognitive impairment (MCI) from healthy controls and patients with different stages of Alzheimer's disease (AD). METHODS: The serial position effects was tested with the CERAD word list task in 184 persons (39 healthy control subjects, 15 amnestic MCI single domain subjects, 23 amnestic MCI multiple domain subjects, 31 nonamnestic MCI subjects, 45 early or mild AD patients, and 31 moderate AD patients). RESULTS: With progression of dementia, memory deficits increased and the impairment in the primacy effect during the learning trials advanced, whereas the recall of recent items was less impaired. The serial position profile of nonamnestic MCI patients resembled that of healthy control subjects, whereas amnestic MCI patients showed poorer performance in all 3 positions but no significant difference as a function of serial word position. CONCLUSION: Analyses of the serial position effect may be a useful complement to clinical neuropsychological measures for distinguishing amnestic MCI patients from normal aging and patients with different stages of dementia.

Irradiated cultured apoptotic peripheral blood mononuclear cells regenerate infarcted myocardium.

BACKGROUND: Acute myocardial infarction (AMI) is followed by post AMI cardiac remodelling, often leading to congestive heart failure. Homing of c-kit+ endothelial progenitor cells (EPC) has been thought to be the optimal source for regenerating infarcted myocardium. METHODS: Immune function of viable peripheral blood mononuclear cells (PBMC) was evaluated after co-culture with irradiated apoptotic PBMC (IA-PBMC) in vitro. Viable PBMC, IA-PBMC and culture supernatants (SN) thereof were obtained after 24 h. Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were utilized to quantify interleukin-8 (IL-8), vascular endothelial growth factor, matrix metalloproteinase-9 (MMP9) in PBMC, SN and SN exposed fibroblasts. Cell suspensions of viable- and IA-PBMC were infused in an experimental rat AMI model. Immunohistological analysis was performed to detect inflammatory and pro-angiogenic cells within 72 h post-infarction. Functional data and determination of infarction size were quantified by echocardiography and Elastica van Gieson staining. RESULTS: The IA-PBMC attenuated immune reactivity and resulted in secretion of pro-angiogenic IL-8 and MMP9 in vitro. Fibroblasts exposed to viable and IA-PBMC derived SN caused RNA increment of IL-8 and MMP9. AMI rats that were infused with IA-PBMC cell suspension evidenced enhanced homing of endothelial progenitor cells within 72 h as compared to control (medium alone, viable-PBMC). Echocardiography showed a significant reduction in infarction size and improvement in post AMI remodelling as evidenced by an attenuated loss of ejection fraction. CONCLUSION: These data indicate that infusion of IA-PBMC cell suspension in experimental AMI circumvented inflammation, caused preferential homing of regenerative EPC and replaced infarcted myocardium.

Myocardial lipofuscin-laden lysosomes contain the apoptosis marker caspase-cleaved cytokeratin-18.

BACKGROUND: Acute coronary syndrome is related to increased circulatory concentration of soluble apoptosis specific caspase-cleaved cytokeratin-18 (ccCK-18). Potential cardiac sources of this intermediate filament derivative have not been investigated to date. MATERIALS AND METHODS: Paraffin embedded tissue of normal myocardium, and chronically damaged samples of ischaemic, congestive and hypertrophic cardiomyopathy were analysed by histology and by CK-8, CK-18, ccCK-18 immunohistochemistry (each group, n = 15). Antibody specificity of the ccCK-18 antibody M30 was checked by immunoblotting on lysed myocardium and enriched myocardial lysosomes. RESULTS: ccCK-18 and CK-18 but not CK-8 were present in all forms of cardiomyopathy, most prominently in ischaemic cardiomyopathy while only traces were detectable immunohistochemically in normal myocardium. Weak CK-18 and strong ccCK-18 staining co-localized to lysosomes with cardiac age pigment lipofuscin. Weak staining of CK-18 was detected in the cytoplasm of coronary endothelia. CONCLUSION: Our study reveals that cardiac lipofuscin-laden lysosomes contain ccCK-18, a marker of apoptosis and its precursor CK-18. This ccCK-18 pool might contribute to increased systemic levels of ccCK-18 in acute coronary syndrome thus monitoring myocardial damage.

Elevated levels of interleukin-1beta-converting enzyme and caspase-cleaved cytokeratin-18 in acute myocardial infarction.

BACKGROUND: Systemic inflammation and apoptosis-specific immune activation play a major role in acute coronary syndromes (ACS) including acute myocardial infarction (AMI). The role of systemic and coronary obtained inflammatory plasma protein interleukin-1beta precursor (IL-1betap), IL-1beta-converting enzyme (ICE) and the apoptosis-specific caspase-cleaved cytokeratin-18 (ccCK-18) are not known in ACS. MATERIALS AND METHODS: Plasma samples were obtained from stable angina (SA, n = 34), unstable angina (UA, n = 37) and patients with AMI (n = 39). Coronary blood was acquired by means of thrombectomy devices (X-sizer) in AMI patients. IL-1betap, ICE and ccCK-18 were determined by enzyme-linked immunosorbent assay (ELISA). Group comparisons were evaluated by parametric Tukey test. Multivariate logistic regression analysis was performed to determine predictive values of IL-1betap, ICE and ccCK-18 as compared to creatine kinase (CK) and troponin T (TnT) in order to relate these markers with the occurrence of myocardial damage. RESULTS: IL-1betap, ICE and ccCK-18 were identified to be significantly altered in the peripheral blood of patients suffering from AMI as compared to SA and UA. ROC curves were plotted and revealed that ccCK-18 is a novel sensitive marker for the detection of myocardial damage as compared to TnT or CK. (AUC ccCK-18 0.925, TnT AUC 0.62 and CK AUC 0.858.) Moreover, ICE and ccCK-18 were significantly increased at the site of coronary occlusion as compared to peripheral blood samples in AMI patients (both P < 0.001). CONCLUSION: Our data suggest that ACS is related to increased concentration of systemic soluble ICE and ccCK-18. Moreover, soluble ccCK-18 was identified to be a superior marker as compared to TnT or CK, for detection of myocardial damage.

Blockade of RAGE suppresses alloimmune reactions in vitro and delays allograft rejection in murine heart transplantation.

The receptor for advanced glycation endproducts (RAGE), a multiligand member of the immunoglobulin superfamily, interacts with proinflammatory AGEs, the products of nonenzymatic glycation and oxidation of proteins; high-mobility group box 1 (HMGB1), also known as amphoterin and S100/calgranulins to amplify inflammation and tissue injury. Previous studies showed that blockade of RAGE suppressed recruitment of proinflammatory mechanisms in murine models. We tested the hypothesis that RAGE contributes to alloimmune responses and report that in vivo, acute rejection of fully allogeneic cardiac allografts in a murine model of heterotopic cardiac transplantation is significantly delayed by pharmacological antagonism of RAGE. In parallel, allogeneic T-cell proliferation in the mixed lymphocyte reaction is, at least in part, RAGE-dependent. These data provide the first insights into key roles for RAGE in allorecognition responses and suggest that antagonism of this receptor may exert beneficial effects in allogeneic organ transplantation.