Indian Ocean response to anomalous conditions in 2006

[1] The equatorial Indian Ocean (EIO) exhibited anomalous conditions characteristic of an Indian Ocean dipole (IOD) during 2006. The eastern EIO had cold sea surface temperature anomalies (SSTA), lower sea level, shallow thermocline and higher chlorophyll than normal. The anomalies in the east, restricted to the south of the equator, were highest off Sumatra. The western pole of the IOD was marked by warm SSTA and deeper thermocline with maxima on either side of the equator. An ocean general circulation model of the Indian Ocean forced by QuikSCAT winds reproduces the IOD of 2006 remarkably well. The switch over to cooling in the east and warming in the west happened during May and July respectively. In the east, airsea heat flux initiated cold SSTA in the model which were sustained later by oceanic processes. In the west, surface heat fluxes and horizontal advection caused warm SSTA and contribution by the latter decreased after August. Citation: Vinayachandran, P. N., J. Kurian, and C. P. Neema (2007), Indian Ocean response to anomalous conditions in 2006, Geophys. Res. Lett., 34, L15602, doi:10.1029/2007GL030194.

Processing Response of Boron Modified Ti-6Al-4V Alloy In (alpha plus beta) Working Regime

Titanium alloys like Ti-6A-4V are the backbone materials for aerospace, energy and chemical industries. Hypoeutectic boron addition to Ti-6Al-4V alloy produces a reduction in as-cast grain size by roughly an order of magnitude resulting in the possibility of avoiding ingot breakdown step and thereby reducing the processing cost. In the present study, ISM processed as-cast boron added Ti-6Al-4V alloy is deformed in (alpha+beta)-phase field, where alpha-lath bending seemed to be the dominating deformation mechanism.

Enhanced dielectric response of ZrO2 upon Ti doping and introduction of O vacancies

We determine the electronic properties and dielectric response of zirconia (ZrO2) with oxygen vacancies (O vacancies) and Ti doping using first-principles density functional theory calculations based on pseudopotentials and a plane wave basis. We find significantly enhanced static dielectric response in zirconia with Ti doping and introduction of oxygen vacancies. Softening of phonon modes are responsible for the enhanced dielectric response of doped samples compared to pure zirconia.

Chlamydial infertility in women: Diagnosis, epidemiology and immune response

This project primarily focused on the development of a novel, non-invasive peptide-based ELISA to diagnose C. trachomatis-related infertility in women. In this study, an in silico approach was applied to identify and design novel peptide antigens that are specific to women with C. trachomatis-related infertility. The serological assay was developed such that it could potentially replace invasive techniques for early infertility investigation. The thesis further investigated the sero-prevalence of chlamydial infertility in women from a low-resource, high prevalence setting. In addition, the thesis also identified immune markers that were associated with the C. trachomatis-related infertility in women.

Indian Ocean response to anomalous conditions in 2006

The equatorial Indian Ocean (EIO) exhibited anomalous conditions characteristic of an Indian Ocean dipole (IOD) during 2006. The eastern EIO had cold sea surface temperature anomalies (SSTA), lower sea level, shallow thermocline and higher chlorophyll than normal. The anomalies in the east, restricted to the south of the equator, were highest off Sumatra. The western pole of the IOD was marked by warm SSTA and deeper thermocline with maxima on either side of the equator. An ocean general circulation model of the Indian Ocean forced by QuikSCAT winds reproduces the IOD of 2006 remarkably well. The switch over to cooling in the east and warming in the west happened during May and July respectively. In the east, air-sea heat flux initiated cold SSTA in the model which were sustained later by oceanic processes. In the west, surface heat fluxes and horizontal advection caused warm SSTA and contribution by the latter decreased after August.

Cyclosporine A in the treatment of Interstitial Cystitis

Painful bladder syndrome/interstitial cystitis (PBS/IC) is a chronic urinary bladder disorder of unknown etiology characterized by symptoms of bladder pain and urinary frequency. PBS/IC is a chronic disease in which drug therapy has not led to significant success over the course of time. If the symptoms of PBS/IC are refractory to standard treatments, a possible cure might demand surgical intervention involving cystectomy. The eventual autoimmune etiology in mind, immunosuppressive drug therapy with cyclosporine A (CyA) was started to patients with refractory PBS/IC. CyA is a potent anti-inflammatory drug, a calcineurin inhibitor which inhibits T lymphocyte IL-2 produc-tion. T cells are present in abundance in inflammation of the bladder in PBS/IC. On the basis of a pilot, short-term study with CyA on PBS/IC, use of CyA was continued empirically over the long term. We conducted a prospective, randomized, six-month study in 64 patients comparing the effect of CyA with the FDA approved treatment, pentosan polysulfate sodium (PPS). We measured the drug effect on patient s symptoms, the potassium sensitivity test, and on urinary biomarkers. We further tested the impact of CyA, PPS, DMSO and BCG therapy on a health-related quality of life questionnaire and evaluated the response rate to treatment with these therapies. Long-term use of CyA was safe and effective in PBS/IC patients. The good clinical effect matured individually during the years in which CyA was continued. Cessation of medication led to the reappearance of symptoms, and restarting CyA to renewed alleviation, so that CyA was administered as continuous medication. The response rate to CyA increased during the study period, comprising 75% of CyA patients at six months. 19% of patients responded to PPS therapy. Adverse effects were more common in the CyA group, underlining the importance of monitoring the drug safety and appropriate titration of the dose. The potassium sensitivity test is positive in the majority of PBS/IC patients. Successful therapy of PBS/IC can alter nerve sensitivity to external potassium. This effect was seen more often after CyA therapy. Successful treatment of PBS/IC with CyA resulted to decreasing urinary levels of EGF. IL-6 levels in urine were higher among older patient with a longer history of PBS/IC. In these patients, reduced levels of urinary IL-6 were measured after CyA therapy. Patients who experience the best treatment response have improved quality of life according to the post-treatment health-related quality of life (HRQOL) questionnaire. CyA had more impact on the ma-jority of the aspects of QoL than PPS. Despite DMSO therapy being more successful than BCG in the count of responders, DMSO and BCG had equal effects on the HRQOL questionnaire.

Microscopic Frictional Response of Sodium Oleate Self-Assembled on Steel

The article peruses the frictional response of an important metal working lubricant additive, sodium oleate. Frictional force microscopy is used to track the response of molecules self-assembled on a steel substrate of 3–4 nm roughness at 0% relative humidity. The friction-normal load characteristic emerges as bell-shaped, where the peak friction and normal load at peak friction are both sensitive to substrate roughness. The frictional response at loads lower than that associated with the peak friction is path reversible while at higher loads the loading and unloading paths are different. We suggest that a new low-friction interface material is created when the normal loads are high.

Cow's milk allergy and the development of tolerance

Aims: To gain insight on the immunological processes behind cow’s milk allergy (CMA) and the development of oral tolerance. To furthermore investigate the associations of HLA II and filaggrin genotypes with humoral responses to early oral antigens. Methods: The study population was from a cohort of 6209 healthy, full-term infants who in a double-blind randomized trial received supplementary feeding at maternity hospitals (mean duration 4 days): cow’s milk (CM) formula, extensively hydrolyzed whey formula or donor breast milk. Infants who developed CM associated symptoms that subsided during elimination diet (n=223) underwent an open oral CM challenge (at mean age 7 months). The challenge was negative in 112, and in 111 it confirmed CMA, which was IgE-mediated in 83. Patients with CMA were followed until recovery, and 94 of them participated in a follow-up study at age 8-9 years. We investigated serum samples at diagnosis (mean age 7 months, n=111), one year later (19 months, n=101) and at follow-up (8.6 years, n=85). At follow-up, also 76 children randomly selected from the original cohort and without CM associated symptoms were included. We measured CM specific IgE levels with UniCAP (Phadia, Uppsala, Sweden), and β-lactoglobulin, α-casein and ovalbumin specific IgA, IgG1, IgG4 and IgG levels with enzyme-linked immunosorbent assay in sera. We applied a microarray based immunoassay to measure the binding of IgE, IgG4 and IgA serum antibodies to sequential epitopes derived from five major CM proteins at the three time points in 11 patients with active IgE-mediated CMA at age 8-9 years and in 12 patients who had recovered from IgE-mediated CMA by age 3 years. We used bioinformatic methods to analyze the microarray data. We studied T cell expression profile in peripheral blood mononuclear cell (PBMC) samples from 57 children aged 5-12 years (median 8.3): 16 with active CMA, 20 who had recovered from CMA by age 3 years, 21 non-atopic control subjects. Following in vitro β-lactoglobulin stimulation, we measured the mRNA expression in PBMCs of 12 T-cell markers (T-bet, GATA-3, IFN-γ, CTLA4, IL-10, IL-16, TGF-β, FOXP3, Nfat-C2, TIM3, TIM4, STIM-1) with quantitative real time polymerase chain reaction, and the protein expression of CD4, CD25, CD127, FoxP3 with flow cytometry. To optimally distinguish the three study groups, we performed artificial neural networks with exhaustive search for all marker combinations. For genetic associations with specific humoral responses, we analyzed 14 HLA class II haplotypes, the PTPN22 1858 SNP (R620W allele) and 5 known filaggrin null mutations from blood samples of 87 patients with CMA and 76 control subjects (age 8.0-9.3 years). Results: High IgG and IgG4 levels to β-lactoglobulin and α-casein were associated with the HLA (DR15)-DQB1*0602 haplotype in patients with CMA, but not in control subjects. Conversely, (DR1/10)-DQB1*0501 was associated with lower IgG and IgG4 levels to these CM antigens, and to ovalbumin, most significantly among control subjects. Infants with IgE-mediated CMA had lower β -lactoglobulin and α-casein specific IgG1, IgG4 and IgG levels (p<0.05) at diagnosis than infants with non-IgE-mediated CMA or control subjects. When CMA persisted beyond age 8 years, CM specific IgE levels were higher at all three time points investigated and IgE epitope binding pattern remained stable (p<0.001) compared with recovery from CMA by age 3 years. Patients with persisting CMA at 8-9 years had lower serum IgA levels to β-lactoglobulin at diagnosis (p=0.01), and lower IgG4 levels to β-lactoglobulin (p=0.04) and α-casein (p=0.05) at follow-up compared with patients who recovered by age 3 years. In early recovery, signal of IgG4 epitope binding increased while that of IgE decreased over time, and binding patterns of IgE and IgG4 overlapped. In T cell expression profile in response to β –lactoglobulin, the combination of markers FoxP3, Nfat-C2, IL-16, GATA-3 distinguished patients with persisting CMA most accurately from patients who had become tolerant and from non-atopic subjects. FoxP3 expression at both RNA and protein level was higher in children with CMA compared with non-atopic children. Conclusions: Genetic factors (the HLA II genotype) are associated with humoral responses to early food allergens. High CM specific IgE levels predict persistence of CMA. Development of tolerance is associated with higher specific IgA and IgG4 levels and lower specific IgE levels, with decreased CM epitope binding by IgE and concurrent increase in corresponding epitope binding by IgG4. Both Th2 and Treg pathways are activated upon CM antigen stimulation in patients with CMA. In the clinical management of CMA, HLA II or filaggrin genotyping are not applicable, whereas the measurement of CM specific antibodies may assist in estimating the prognosis.

Slim P‐E hysteresis loop and anomalous dielectric response in sol-gel derived antiferroelectric PbZrO3 thin films

Sol-gel derived PbZrO3 (PZ) thin films have been deposited on Pt(111)/Ti/SiO2/Si substrate and according to the pseudotetragonal symmetry of PZ, the relatively preferred (110)t oriented phase formation has been noticed. The room temperature P‐E hysteresis loops have been observed to be slim by nature. The slim hysteresis loops are attributed to the [110]t directional antiparallel lattice motion of Pb ions and by the directionality of the applied electric field. Pure PZ formation has been characterized by the dielectric phase transition at 235 °C and antiferroelectric P‐E hysteresis loops at room temperature. Dielectric response has been characterized within a frequency domain of 100 Hz–1 MHz at various temperatures ranging from 40 to 350 °C. Though frequency dispersion of dielectric behaves like a Maxwell–Wagner type of relaxation, ω2 dependency of ac conductivity indicates that there must be G‐C equivalent circuit dominance at high frequency. The presence of trap charges in PZ has been determined by Arrhenius plots of ac conductivity. The temperature dependent n (calculated from the universal power law of ac conductivity) values indicate an anomalous behavior of the trapped charges. This anomaly has been explained by strongly and weakly correlated potential wells of trapped charges and their behavior on thermal activation. The dominance of circuit∕circuits resembling Maxwell–Wagner type has been investigated by logarithmic Nyquist plots at various temperatures and it has been justified that the dielectric dispersion is not from the actual Maxwell–Wagner-type response.

Seismic response of reinforced soil retaining wall models: Influence of backfill relative density

This paper presents the results of shaking table tests on model reinforced soil retaining walls in the laboratory. The influence of backfill relative density on the seismic response was studied through a series of laboratory model tests on retaining walls. Construction of model retaining walls in the laminar box mounted on shaking table, instrumentation and results from the shaking table tests are described in detail. Three types of walls: wrap- and rigid-faced reinforced soil walls and unreinforced rigid-faced walls constructed to different densities were tested for a relatively small excitation. Wrap-faced walls are further tested for higher base excitation at different frequencies and relative densities. It is observed from these tests that the effect of backfill density on the seismic performance of reinforced retaining walls is pronounced only at very low relative density and at the higher base excitation. The walls constructed with higher backfill relative density showed lesser face deformations and more acceleration amplifications compared to the walls constructed with lower densities when tested at higher base excitation. The response of wrap- and rigid-faced retaining walls is not much affected by the backfill relative density when tested at smaller base excitation. The effects of facing rigidity were evaluated to a limited extent. Displacements in wrap-faced walls are many times higher compared to rigid-faced walls. The results obtained from this study are helpful in understanding the relative performance of reinforced soil retaining walls constructed to when subjected to smaller and higher base excitation for the range of relative density employed in the testing program. (C) 2007 Elsevier Ltd. All rights reserved.

Author response: "Missed opportunity related to statistical methods"

"We thank MrGilder for his considered comments and suggestions for alternative analyses of our data. We also appreciate Mr Gilder’s support of our call for larger studies to contribute to the evidence base for preoperative loading with high-carbohydrate fluids..."

First-Line afatinib versus chemotherapy in patients with non–small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases

Introduction Metastatic spread to the brain is common in patients with non–small cell lung cancer (NSCLC), but these patients are generally excluded from prospective clinical trials. The studies, phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations (LUX-Lung 3) and a randomized, open-label, phase III study of BIBW 2992 versus chemotherapy as first-line treatment for patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation (LUX-Lung 6) investigated first-line afatinib versus platinum-based chemotherapy in epidermal growth factor receptor gene (EGFR) mutation-positive patients with NSCLC and included patients with brain metastases; prespecified subgroup analyses are assessed in this article. Methods For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n = 35 and n = 46, respectively). Post hoc analyses of clinical outcomes was undertaken in the combined data set (n = 81). Results In both studies, there was a trend toward improved PFS with afatinib versus chemotherapy in patients with brain metastases (LUX-Lung 3: 11.1 versus 5.4 months, hazard ratio [HR] = 0.54, p = 0.1378; LUX-Lung 6: 8.2 versus 4.7 months, HR = 0.47, p = 0.1060). The magnitude of PFS improvement with afatinib was similar to that observed in patients without brain metastases. In combined analysis, PFS was significantly improved with afatinib versus with chemotherapy in patients with brain metastases (8.2 versus 5.4 months; HR, 0.50; p = 0.0297). Afatinib significantly improved the objective response rate versus chemotherapy in patients with brain metastases. Safety findings were consistent with previous reports. Conclusions These findings lend support to the clinical activity of afatinib in EGFR mutation–positive patients with NSCLC and asymptomatic brain metastases.

Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: Results of an open-label, randomized, controlled phase II study (CERTO)

Background: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. Results: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvβ3 and αvβ5 expression was neither a predictive nor a prognostic indicator. Conclusions: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment.

Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): Pooled subset analyses from two randomized trials

Background: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. Methods: The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib. Results: One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0–18.2] with dacomitinib and 9.6 months (95% CI 7.4–12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458–1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6–41.5) with dacomitinib versus 23.2 months (95% CI 16.0–31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431–1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. Conclusions: Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721). Clinical trials number: ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).

Replication of Japanese encephalitis virus in mouse brain induces alterations in lymphocyte response

The experimental model using intracerebral (i.c.) challenge was employed in many studies evaluating the protection against disease induced by Japanese encephalitis virus (JEV). We investigated alterations in peripheral lymphocyte response caused by i.c. infection of mice with JEV. Splenocytes from the i.c.-infected mice showed suppressed proliferative response to concanavalin A (con A) and anti-CD3 antibody stimulation. At the same time, the expression of CD25 (IL-2R) and production of IL-2 was inhibited. Addition of anti-CD28 antibody restored the decreased anti-CD3 antibody-mediated proliferation in the splenocytes. Moreover, the number of con A-stimulated cells secreting IL-4 was significantly reduced in splenocytes from i.c.-infected mice. These studies suggested that the i.c. infection with JEV might involve additional immune modulation effects due to massive virus replication in the brain.