Contribution of elevation and residential proximity to the coast in explaining geographic variations in hip fracture incidence. A Norwegian Epidemiologic Osteoporosis Studies (NOREPOS) study.

A higher risk of hip fracture was found in areas of Norway at higher elevation and farther from the coast. However, the previously seen county variations could not be explained by these geographical factors. INTRODUCTION: Norway is an elongated country extending north of the Arctic Circle with substantial coast-inland variation in topography and climate. Differences in hip fracture incidence between counties and a distinct seasonal variation have previously been shown. The aim of the current study was to explore these variations further by considering associations of height above sea level (elevation) and distance to the coast with hip fracture incidence. METHODS: All patients with hip fractures admitted to Norwegian hospitals in the period 2009-2018 were included. Individual residential elevation and distance to the coast was calculated in Geographic Information Systems and combined with individual-level population data on all Norwegians 50 years of age or older during the observation period, including hospital information on fractures. Age-standardized incidences rate and incidence rate ratios with 95% confidence intervals (IRR, 95% CI) according to elevation and coastal proximity were estimated. The associations were tested using Poisson models adjusting for sex, urban/rural location of residency, country of birth, and season of hip fracture occurrence. RESULTS: From 2009 to 2018, there were 85,776 first hip fractures. There was an increasing risk with higher residential elevation (above versus below mean) for women: IRR = 1.04, 95% CI: 1.02, 1.05), but not for men (IRR = 1.00, 95% CI: 0.97, 1.02). Incidence of hip fracture increased with distance from the coast. Women residing the farthest away from the coast (above versus below mean distance) had a higher age-adjusted incidence of hip fracture compared to those living closer to the coast (IRR = 1.04 (95% CI: 1.02, 1.06), whereas no association was found in men (IRR = 1.00 (95% CI: 1.00, 1.01). Combining elevation and distance to coast showed a higher incidence in women living at high elevation far from the coast compared with women living at low elevation near the coast (IRR = 1.07, 95% CI: 1.04, 1.10). A similar result was found in men but only for hip fractures occurring during March-May (IRR = 1.07, 95% CI: 1.00, 1.15). The previously shown patterns of county differences and seasonal variations were unchanged when considering geography. CONCLUSION: We found a somewhat higher incidence of hip fracture in inland residents living in areas of high elevation, as compared to those living in more coastal proximity; however, the geographic variation did not explain county and seasonal differences in fracture incidence in Norway. More in-depth analyses on temperature and climate factors may give further clues.

Contribution of remnant cholesterol to cardiovascular risk.

BACKGROUND: Remnant cholesterol in triglyceride-rich lipoproteins is associated observationally and genetic, causally with increased risk of atherosclerotic cardiovascular disease in healthy individuals. OBJECTIVES: We tested the hypothesis that an unmet medical need exists in individuals with high nonfasting remnant cholesterol and prior atherosclerotic cardiovascular disease. METHODS: From amongst 109 574 individuals in a prospective cohort study of the Danish general population, we included 2973 individuals aged 20-80 with baseline diagnoses of myocardial infarction/ischaemic stroke ascertained from national Danish health registries. RESULTS: The recurrent major cardiovascular event (MACE) incidence rates per 1000 person-years were 39 (95% confidence interval: 30-50) for individuals with remnant cholesterol levels ≥ 1.5 mmol L-1 (≥58 mg dL-1 ), 31 (26-37) for 1-1.49 mmol L-1 (39-57 mg dL-1 ), 27 (24-31) for 0.5-0.99 mmol L-1 (19-38 mg dL-1 ) and 23 (19-27) for individuals with remnant cholesterol < 0.5 mmol L-1 (<19 mg dL-1 ). Compared to individuals with remnant cholesterol < 0.5 mmol L-1 (<19 mg dL-1 ), the subhazard ratio for recurrent MACE was 1.23 (95% CI: 0.98-1.55) for individuals with remnant cholesterol levels of 0.5-0.99 mmol L-1 (19-38 mg dL-1 ), 1.48 (1.14-1.92) for 1-1.49 mmol L-1 (39-57 mg dL-1 ) and 1.79 (1.28-2.49) for ≥ 1.5 mmol L-1 (≥58 mg dL-1 ). The recurrent MACE incidence rates per 1000 person-years for individuals with remnant cholesterol levels < 0.5 mmol L-1 (<19 mg dL-1 ) and ≥ 1.5 mmol L-1 (≥58 mg dL-1 ) were 10 (6.6-15) and 31 (21-47) for those below age 65 and correspondingly 25 (21-30) and 43 (32-59) for those with LDL cholesterol levels < 3 mmol L-1 (<116 mg dL-1 ), respectively. For a 20% recurrent MACE risk reduction in secondary prevention, an estimated remnant cholesterol lowering of 0.83 mmol L-1 (32 mg dL-1 ) would be needed. CONCLUSIONS: In individuals with a diagnosis of myocardial infarction/ischaemic stroke, a lower remnant cholesterol of 0.8 mmol L-1 (32 mg dL-1 ) was estimated to reduce recurrent MACE by 20% in secondary prevention. Our data indicate an unmet medical need for secondary prevention in individuals with high nonfasting remnant cholesterol levels.

History of cardiovascular disease and cardiovascular biomarkers are associated with 30-day mortality in patients with hip fracture.

Hip fractures are associated with increased mortality and it is important to identify risk factors. This study demonstrates that preexisting cardiovascular disease as well as cardiovascular biomarkers that are associated with increased 30-day mortality. These findings can be used to identify high-risk patients who might benefit from specialized care. INTRODUCTION: This study investigates the association between cardiovascular disease (CVD), cardiovascular biomarkers, and 30-day mortality following a hip fracture. METHODS: The Danish National Patient Registry was used to investigate the association between CVD and mortality following hip fracture in a nationwide population-based cohort study. In a subset of the included patients (n = 355), blood samples were available from a local biobank. These samples were used for analyzing the association between specific biochemical markers and mortality. The primary outcome was 30-day mortality. RESULTS: A total of 113,211 patients were included in the population-based cohort study. Among these, heart failure was present in 9.4%, ischemic heart disease in 15.9%, and ischemic stroke in 12.0%. Within 30 days after the hip fracture, 11,488 patients died, resulting in an overall 30-day mortality of 10.1%. The 30-day mortality was significantly increased in individuals with preexisting CVD with multivariably adjusted odds ratios of 1.69 (95% confidence interval, 1.60-1.78) for heart failure, 1.23 (1.17-1.29) for ischemic heart disease, and 1.06 (1.00-1.12) for ischemic stroke. In the local database including 355 patients, 41 (11.5%) died within 30 days. The multivariably adjusted odds ratio for 30-day mortality increased with increasing NT-proBNP (2.36 [1.53-3.64] per quartile) and decreased with increasing HDL cholesterol (0.58 [0.41-0.82] per quartile). On this basis, we established a model for predicting the probability of death based on the biochemical markers. CONCLUSION: Preexisting CVD was associated with increased 30-day mortality after a hip fracture. Furthermore, high levels of NT-proBNP and low levels of HDL cholesterol were associated with increased 30-day mortality.

Acute endovascular reperfusion treatment in patients with ischaemic stroke and large-vessel occlusion (Denmark 2011-2017).

BACKGROUND AND PURPOSE: Acute endovascular reperfusion treatment (aERT) of stroke patients with large-vessel occlusions is efficacious and safe according to several clinical trials. Data on outcome and safety of aERT in daily clinical routine are warranted and, in this study, we present national data from Denmark during 2011-2017. METHODS: National data for Denmark from 2011 to 2017 on all aERT procedures in patients with acute ischaemic stroke and computed tomography angiography/magnetic resonance angiography-verified large-vessel occlusion were derived from the Danish Stroke Registry, a national clinical quality registry to which reporting is mandatory for all hospitals treating stroke patients. Outcome (modified Rankin Scale score) after 3 months, including time of death, was assessed prospectively based on clinical examination or the Danish Civil Registration System. RESULTS: During the 7 years of observation, a total of 1720 patients were treated with aERT. The annual number of procedures increased from 128 in 2011 to 409 in 2017. The median age was 70 years, 58% were males and median National Institutes of Health Stroke Scale score at baseline was 16. Median time from symptom onset to groin puncture was 238 min with a decreasing trend during the years. Successful recanalization was reported in 1306 (76%) patients. At 3-month follow-up, an modified Rankin Scale score of 0-2 was reported in 46% of patients, whereas 14% of patients had died. CONCLUSION: Routine data on aERT in acute ischaemic stroke in Denmark from 2011 to 2017 suggest that the procedure is safe and efficacious.

Variation in expenditure for common, high cost surgical procedures in a working age population: implications for reimbursement reform.

BACKGROUND: In the move toward value-based care, bundled payments are believed to reduce waste and improve coordination. Some commercial insurers have addressed this through the use of bundled payment, the provision of one fee for all care associated with a given index procedure. This system was pioneered by Medicare, using a population generally over 65 years of age, and despite its adoption by mainstream insurers, little is known of bundled payments' ability to reduce variation or cost in a working-age population. This study uses a universally-insured, nationally-representative population of adults aged 18-65 to examine the effect of bundled payments for five high-cost surgical procedures which are known to vary widely in Medicare reimbursement: hip replacement, knee replacement, coronary artery bypass grafting (CABG), lumbar spinal fusion, and colectomy. METHODS: Five procedures conducted on adults aged 18-65 were identified from the TRICARE database from 2011 to 2014. A 90-day period from index procedure was used to determine episodes of associated post-acute care. Data was sorted by Zip code into hospital referral regions (HRR). Payments were determined from TRICARE reimbursement records, they were subsequently price standardized and adjusted for patient and surgical characteristics. Variation was assessed by stratifying the HRR into quintiles by spending for each index procedure. RESULTS: After adjusting for case mix, significant inter-quintile variation was observed for all procedures, with knee replacement showing the greatest variation in both index surgery (107%) and total cost of care (75%). Readmission was a driver of variation for colectomy and CABG, with absolute cost variation of $17,257 and $13,289 respectively. Other post-acute care spending was low overall (≤$1606, for CABG). CONCLUSIONS: This study demonstrates significant regional variation in total spending for these procedures, but much lower spending for post-acute care than previously demonstrated by similar procedures in Medicare. Targeting post-acute care spending, a common approach taken by providers in bundled payment arrangements with Medicare, may be less fruitful in working aged populations.

Instrument Calibration of the Interface Region Imaging Spectrograph (IRIS) Mission.

The Interface Region Imaging Spectrograph (IRIS) is a NASA small explorer mission that provides high-resolution spectra and images of the Sun in the 133 - 141 nm and 278 - 283 nm wavelength bands. The IRIS data are archived in calibrated form and made available to the public within seven days of observing. The calibrations applied to the data include dark correction, scattered light and background correction, flat fielding, geometric distortion correction, and wavelength calibration. In addition, the IRIS team has calibrated the IRIS absolute throughput as a function of wavelength and has been tracking throughput changes over the course of the mission. As a resource for the IRIS data user, this article describes the details of these calibrations as they have evolved over the first few years of the mission. References to online documentation provide access to additional information and future updates.

Hyponatremia and hypernatremia are associated with increased 30-day mortality in hip fracture patients.

UNLABELLED: Using data from the Danish national registries on 7317 patients, this study shows that abnormal plasma sodium levels, in the form of hyponatremia and hypernatremia, are prevalent and associated with increased 30-day mortality in hip fracture patients. INTRODUCTION: The aim of this study was to examine the prevalence of hyponatremia and hypernatremia in patients admitted with a fractured hip as well as the association with 30-day in mortality in these patients. METHODS: A total of 7317 hip fracture patients (aged 60 years or above) with admission plasma sodium measurements were included. Data on comorbidity, medication, and death was retrieved from Danish national registries. The association between plasma sodium and mortality was examined using Cox proportional hazard models. RESULTS: The prevalence of hyponatremia and hypernatremia on admission was 19.0 and 1.7 %, respectively. Thirty-day mortality was increased for patients with hyponatremia (12.2 %, p = 0.005) and hypernatremia (15.5 %, p = 0.03) compared to normonatremic patients (9.6 %). After adjustment for possible confounding factors, hyponatremia (1.38 [1.16-1.64], p = 0.0003) and hypernatremia (1.71 [1.08-2.70], p = 0.02) were still associated with increased risk of death by 30 days. Looking at the association between changes in plasma sodium during admission and mortality, there was no difference between patients with normalized and persistent hyponatremia (10.4 vs 11.3 %, p = 0.6) while a lower mortality was found for normalized hypernatremia compared to persistent hypernatremia (12.4 vs 33.3 %, p = 0.03). CONCLUSIONS: This study shows that abnormal plasma sodium levels are prevalent in patients admitted with a fractured hip and that both hyponatremia and hypernatremia are associated with increased risk of death within 30 days of admission.

Assessment of acute oxaliplatin-induced cold allodynia: a pilot study.

BACKGROUND: Following oxaliplatin treatment, acute neurotoxicity symptoms are suggested to be correlated with both the development and degree of chronic neuropathy. AIMS: The aim of this clinical commentary was to examine different methods to assess acute cold allodynia and dysesthesia in patients treated with adjuvant oxaliplatin. METHODS: Nine patients over the age of 18 years scheduled for standard adjuvant treatment with capecitabine and oxaliplatin were included. Patients were asked to come for two visits: a baseline visit before and a follow-up visit within 5 days after treatment. Patients were examined with questionnaires, thermal tests, and the thermal grill. RESULTS: All patients reported neurotoxicity, and they all had abnormal cold sensitivity. The only significant changes observed were increased ratings of pain, unpleasantness, and pricking sensations to holding a ~8°C metal cylinder for 10 s and an increased intensity of unpleasantness and pricking sensation to the 20-s contact with the 10°C plates of the thermal grill on the palmar hand. CONCLUSIONS: he results showed that the palm of the hand is the most sensitive part of the body when detecting oxaliplatin-induced cold allodynia, and the use of a cold metal cylinder seems as a promising sensitive method.

Outcome determinants for transformed indolent lymphomas treated with or without autologous stem-cell transplantation.

BACKGROUND: Transformation of indolent lymphomas (IL) to an aggressive histology (TIL) often results in a rapid clinical course, treatment refractoriness and shortened survival. Although rituximab-containing regimens (R-chemo) have become standard of care in CD20-positive TIL, the role of autologous stem-cell transplantation (ASCT) is still debated. The purpose of this study was to determine whether the outcome of TIL patients improved if they, at transformation, also received ASCT. Furthermore, we investigated the outcome of cases with histologically low- and high-grade components diagnosed either simultaneously or after a period of overt indolent disease. We also analyzed, whether prior rituximab treatment during the indolent course of the disease affected outcome after transformation. PATIENTS AND METHODS: Eighty-five patients (≤68 years) with histologically confirmed TIL were included. Five-year overall (OS) and progression-free survival (PFS) were calculated. Selected parameters were tested in a multivariate analysis. All analyses were conducted on three cohorts: (i) whole cohort (all TIL), (ii) patients with co-existing evidence of both indolent and aggressive histology at diagnosis (Composite/discordant TIL) and (iii) patients transformed after prolonged prior indolent disease (sequential TIL). RESULTS: Fifty-four patients (64%) received ASCT consolidation and 31 (36%) did not. Within the 'all TIL' cohort, the 5-year OS and PFS for R-chemo + ASCT versus R-chemo alone, were 67% versus 48% (P = 0.11) and 60% versus 30% (P = 0.02), respectively. Furthermore, in 'Composite/discordant TIL' R-chemo + ASCT showed no impact on OS (76% versus 67%; P = 0.66) or PFS (71% versus 62%; P = 0.54). Conversely, R-chemo + ASCT improved the outcome of 'sequential TIL' (OS 62% versus 36%; P = 0.07; PFS 53% versus 6%; P = 0.002), regardless of prior rituximab therapy. The beneficial effect of ASCT was significantly higher in patients who had not received rituximab at IL stage. CONCLUSIONS: ASCT improved the outcome in sequential, but not composite/discordant TIL. The beneficial impact of ASCT was greater in patients, who were rituximab-naïve at transformation.

Characterization of the Immunogenicity and Allergenicity of Two Cow's Milk Hydrolysates--A Study in Brown Norway Rats.

Hypoallergenic infant formulas based on hydrolysed milk proteins are used in the diet for cow's milk allergic infants. For a preclinical evaluation of the immunogenicity and allergenicity of new protein ingredients for such hypoallergenic infant formulas as well as for the investigation of which characteristics of hydrolysates that contribute to allergenicity, in vivo models are valuable tools. In this study, we examine the immunogenicity and allergenicity of two hydrolysates in a Brown Norway (BN) rat model, using i.p. dosing, which allows for the use of small quantities. Intact BLG, hydrolysed BLG and a hydrolysed whey product suitable for use in extensively hydrolysed formulas were thoroughly characterized for protein chemical features and administered to BN rats by i.p. immunization with or without adjuvant. Sera were analysed for specific IgG and IgE for evaluation of sensitizing capacity, immunogenicity and antibody-binding capacity. For evaluation of eliciting capacity a skin test was performed. The study showed that the hydrolysates had no residual allergenicity, lacking the capacity to sensitize and elicit reactions in the BN rats. Dosing with or without adjuvant induced a large difference in immunogenicity. Only antibodies from rats sensitized to intact BLG with adjuvant were able to bind the hydrolysates, and the whey-based hydrolysate only showed immunogenicity when dosed with adjuvant. This study showed that hydrolysates can be evaluated by an i.p. animal model, but that the choice of in vitro tests used for evaluation of antibody responses may greatly influence the result as well as may the use of adjuvant.

Precautionary allergen labelling: perspectives from key stakeholder groups.

Precautionary allergen labelling (PAL) was introduced by the food industry to help manage and communicate the possibility of reaction from the unintended presence of allergens in foods. However, in its current form, PAL is counterproductive for consumers with food allergies. This review aims to summarize the perspectives of all the key stakeholders (including clinicians, patients, food industry and regulators), with the aim of defining common health protection and risk minimization goals. The lack of agreed reference doses has resulted in inconsistent application of PAL by the food industry and in levels of contamination that prompt withdrawal action by enforcement officers. So there is a poor relationship between the presence or absence of PAL and actual reaction risk. This has led to a loss of trust in PAL, reducing the ability of consumers with food allergies to make informed choices. The result has been reduced avoidance, reduced quality of life and increased risk-taking by consumers who often ignore PAL. All contributing stakeholders agree that PAL must reflect actual risk. PAL should be transparent and consistent with rules underpinning decision-making process being communicated clearly to all stakeholders. The use of PAL should indicate the possible, unintended presence of an allergen in a consumed portion of a food product at or above any proposed action level. This will require combined work by all stakeholders to ensure everyone understands the approach and its limitations. Consumers with food allergy then need to be educated to undertake individualized risk assessments in relation to any PAL present.

Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect.

BACKGROUND: An observational study has suggested that relapsing-remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients. OBJECTIVE: To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS. METHODS: The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24-55) years, disease duration 9 (4-34) years, Expanded Disability Status Scale score 2.5 (1-5.0), and number of relapses within the last two years 3 (2-5). Four patients received no disease modifying therapy, while six patients received IFN-ß. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes. RESULTS: Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change. CONCLUSIONS: In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect.

Induction of Bcl-xL-specific cytotoxic T lymphocytes in mice.

The induction of active immunity against tumour-associated antigens to prevent relapse of cancer is a promising approach but has so far shown only low efficacy. This low efficacy may in part be due to clonal escape of tumour cell variants by the downregulation of antigen expression or inflammation-induced dedifferentiation. Identification of novel tumour-associated antigens that at the same time are essential for continued tumour cell survival is thus critical for the development of active cancer vaccinations. At the same time, identification of novel endogenous murine tumour antigens will help improve preclinical development of cancer immunotherapy. The anti-apoptotic protein Bcl-xL has been suggested to be such an essential tumour antigen, but the lack of well-defined murine epitopes have delayed preclinical studies of Bcl-xL-targeting cancer vaccines. Here, we report the identification of two novel murine tumour-associated epitopes TAYQSFEQV and AFFSFGGAL derived from mouse Bcl-xL. Dendritic cell (DC)-based vaccination induced CD8(+) T cells capable of producing IFN-γ upon restimulation with these epitopes. Thus, our data may benefit the design of future immunotherapy strategies by providing a preclinical model for cancer vaccination with an endogenous tumour antigen that can be combined with other cancer treatments.

Electron-nuclear energy sharing in above-threshold multiphoton dissociative ionization of H2.

We report experimental observation of the energy sharing between electron and nuclei in above-threshold multiphoton dissociative ionization of H2 by strong laser fields. The absorbed photon energy is shared between the ejected electron and nuclei in a correlated fashion, resulting in multiple diagonal lines in their joint energy spectrum governed by the energy conservation of all fragment particles.

Natural killer cell activity in metastatic castration resistant prostate cancer patients treated with enzalutamide.

Metastatic castration resistant prostate cancer (mCRPC) is still the lethal stage for the whole spectrum of prostate cancer disease. Even though different treatment options have been introduced in the last decade with a significant survival improvement for this population, a lack of more reliable prognostic and predictive markers is still one of the main clinical challenges in management of mCRPC. The aim of this study was to investigate the correlation between Natural Killer cell activity (NKA) and both treatment effect and outcomes in patients with mCRPC treated with enzalutamide. A total of 87 patients with mCRPC treated with enzalutamide as the first line treatment were enrolled. NKA was estimated at baseline and prior to each treatment cycle. Endpoints included both treatment effect with biochemical response (BR), biochemical progression (BP) and radiological progression (RP), as well as outcome data with overall survival (OS), radiologic progression free survival (rPFS), and time to next treatment (TTT). At the time of BR, interferon-gamma (IFNγ) decreased significantly compared to levels detected at baseline (z-score = 2.33, p = 0.019). Regarding outcome data, the whole cohort was divided into four groups according to the change of IFNγ level during the first 3 cycles of enzalutamide treatment. In group 1 (n = 42) the IFNγ level remained within a normal range (≥ 250 pg/mL),while in group 2 (n = 7) it increased from an abnormal (< 250 pg/mL) to a normal level. In group 3 (n = 13) it dropped to an abnormal level, and it remained at an abnormal level during treatment in group 4 (n = 17). Patients in group 2 showed the worst prognosis with shorter both rPFS and TTT (HR 4.30, p = 0.037; and HR 6.82, p = 0.011, respectively). In this study inverse correlations between NKA and both treatment response and outcomes was observed in mCRPC patients receiving enzalutamide, suggesting an unfavourable role of NK cells in the late stage of PCa.

On the role of TRPC1 in control of Ca2+ influx, cell volume, and cell cycle.

Ca(+) signaling plays a crucial role in control of cell cycle progression, but the understanding of the dynamics of Ca(2+) influx and release of Ca(2+) from intracellular stores during the cell cycle is far from complete. The aim of the present study was to investigate the role of the free extracellular Ca(2+) concentration ([Ca(2+)](o)) in cell proliferation, the pattern of changes in the free intracellular Ca(2+) concentration ([Ca(2+)](i)) during cell cycle progression, and the role of the transient receptor potential (TRP)C1 in these changes as well as in cell cycle progression and cell volume regulation. In Ehrlich Lettré Ascites (ELA) cells, [Ca(2+)](i) decreased significantly, and the thapsigargin-releasable Ca(2+) pool in the intracellular stores increased in G(1) as compared with G(0). Store-depletion-operated Ca(2+) entry (SOCE) and TRPC1 protein expression level were both higher in G(1) than in G(0) and S phase, in parallel with a more effective volume regulation after swelling [regulatory volume decrease (RVD)] in G(1) as compared with S phase. Furthermore, reduction of [Ca(2+)](o), as well as two unspecific SOCE inhibitors, 2-APB (2-aminoethyldiphenyl borinate) and SKF96365 (1-(ß-[3-(4-methoxy-phenyl)propoxyl-4-methoxyphenethyl)1H-imidazole-hydrochloride), inhibited ELA cell proliferation. Finally, Madin-Darby canine kidney cells in which TRPC1 was stably silenced [TRPC1 knockdown (TRPC1-KD) MDCK] exhibited reduced SOCE, slower RVD, and reduced cell proliferation compared with mock controls. In conclusion, in ELA cells, SOCE and TRPC1 both seem to be upregulated in G(1) as compared with S phase, concomitant with an increased rate of RVD. Furthermore, TRPC1-KD MDCK cells exhibit decreased SOCE, decreased RVD, and decreased proliferation, suggesting that, at least in certain cell types, TRPC1 is regulated during cell cycle progression and is involved in SOCE, RVD, and cell proliferation.

Can we define a tolerable level of risk in food allergy? Report from a EuroPrevall/UK Food Standards Agency workshop.

BACKGROUND: There is an emerging consensus that, as with other risks in society, zero risk for food-allergic people is not a realistic or attainable option. Food allergy challenge data and new risk assessment methods offer the opportunity to develop quantitative limits for unintended allergenic ingredients which can be used in risk-based approaches. However, a prerequisite to their application is defining a tolerable level of risk. This requires a value judgement and is ultimately a 'societal' decision that has to involve all relevant stakeholders. OBJECTIVE: The aim of the workshop was to bring together key representatives from the stakeholders (regulators, food industry, clinical researchers and patients), and for the first time ever discuss the definition of a tolerable level of risk with regard to allergic reactions to food. RESULTS: The discussions revealed a consensus that zero risk was not a realistic option and that it is essential to address the current lack of agreed action levels for cross-contamination with allergens if food allergen management practice is to be improved. The discussions also indicated that it was difficult to define and quantify a tolerable level of risk, although both the clinical and the industry groups tried to do so. A consensus emerged that doing nothing was not a viable option, and there was a strong desire to take action to improve the current situation. CONCLUSIONS AND CLINICAL RELEVANCE: Two concrete actions were suggested: (1) Action levels should be derived from the data currently available. Different scenarios should be examined and further developed in an iterative process. On the basis of this work, a tolerable level of risk should be proposed. (2) 'One-dose' clinical trial with a low challenge dose should be performed in multiple centres to provide additional information about the general applicability of dose-distribution models and help validate the threshold levels derived.

Multiphoton above threshold effects in strong-field fragmentation.

We present a study of multiphoton dissociative ionization from molecules. By solving the time-dependent Schrödinger equation for H(2)(+) and projecting the solution onto double continuum scattering states, we observe the correlated electron-nuclear ionization dynamics in detail. We show-for the first time-how multiphoton structure prevails as long as one accounts for the energies of all the fragments. Our current work provides a new avenue to analyze strong-field fragmentation that leads to a deeper understanding of the correlated molecular dynamics.

NLFM waveform generation using tunable integrated optical ring resonators: simulation and proof of concept experiment.

The NLFM waveform resulting from a tunable integrated optical ring resonator is simulated. The metrics of interest are the first sidelobe levels and FWHM times of the autocorrelation, as these directly relate to the long-range performance and fine range resolution of a LADAR system, and should ideally be as small as possible. Through simulation, the maximum sidelobe level of the autocorrelation of an NLFM waveform generated by a series of tunable integrated optical ring resonators is shown to be -20 to -30 dB or lower. A proof of concept experiment employing an off-the-shelf thermally tunable silicon-nitride optical ring resonator is shown to generate NLFM chirped waveforms with a bandwidth of 28 kHz.