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.

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.

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.

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.

Up-front rituximab maintenance improves outcome in patients with follicular lymphoma: a collaborative Nordic study.

The introduction of the anti-CD20 antibody rituximab in combination with chemotherapy (R-chemo) has improved the prognosis of patients with follicular lymphoma (FL). During the last decade, the addition of a maintenance treatment with rituximab (MR) after R-chemo has been tested with the hope of further improving the outcome of these patients. Using 2 independent population-based cohorts, we investigated the effect of up-front MR on time related end points as well as the risk of histological transformation (HT). FL patients were included if they: (1) completed first-line induction treatment with R-chemo, (2) were alive after induction treatment and eligible for MR, and (3) had no evidence of HT at this time point. The training cohort consisted of 733 Danish patients of whom 364 were consolidated with MR; 369 were not. Patients receiving MR more often had advanced clinical stage (90% vs 78%), high Follicular Lymphoma International Prognostic Index (FLIPI) score (64% vs 55%), and bone marrow infiltration (49% vs 40%). Those consolidated with MR had an improved 5-year overall survival (OS; 89% vs 81%; P = .001) and progression-free survival (PFS; 72% vs 60%; P < .001). In the training cohort, MR was associated with a reduction of HT risk (P = .049). Analyses of an independent validation cohort of 190 Finnish patients confirmed the favorable impact of MR on 5-year OS (89% vs 81%; P = .046) and PFS (70% vs 57%; P = .005) but did not find a reduced risk of HT. The present population-based data suggest that the outcome of patients with FL has improved after consolidation of R-chemo with MR.

Role of progesterone concentrations during early follicular development in beef cattle: II. Ovulatory follicle growth and pregnancy rates.

Two experiments were conducted to investigate the role of relatively lesser and greater progesterone (P4) concentrations during early follicular development on ovulatory follicle growth and pregnancy rate in beef cattle. In Experiment 1, time of ovulation was synchronized with the 5 d CO-Synch + CIDR (Controlled Internal Drug Release) program in multiparous cows (n = 241). Six days after the 2nd GnRH injection of the pre-synchronization program (d 0), ablation of follicles ≥ 5 mm in the ovaries was performed and cows were assigned to receive either a previously used CIDR and 2x-25 mg PGF2α doses 8 h apart (LoP4), or a new CIDR (HiP4). On d 5, CIDR were removed from all cows, 2x-25 mg PGF2α were administered, and estrous detection tail paint was applied. Timed artificial insemination (TAI) was performed on d 8. On d 5, P4 concentrations were greater (P <  0.01) in the HiP4 (4.9 ± 0.13 ng/mL) than LoP4 (1.0 ± 0.06 ng/mL) treatment group. Conversely, d 5 estradiol (E2) concentrations and follicular diameter were greater (P <  0.01) in the LoP4 (5.0 ± 0.23 pg/mL and 8.9 ± 0.20 mm) than HiP4 (1.5 ± 0.12 pg/mL and 7.4 ± 0.15 mm) treatment group. Follicular diameter at TAI (12.0 ± 0.12 mm, Table 1) and TAI pregnancy rate did not differ (P >  0.10) between treatment groups. In Experiment 2, a new follicular wave was induced with estradiol benzoate on d -7, and cows (n = 275) were assigned on d 0 to receive 25 mg PGF2α and either have the CIDR replaced with a new CIDR (HiP4) or the used CIDR was left in place (LoP4).Furthermore, all cows received GnRH on d 0. The CIDRs were removed from all cows on d 5 and two doses of -25 mg PGF2α were administered. Estrous detection combined with AI 12 h later (Estrus-AI) was performed for 60 h after CIDR removal with TAI coupled with GnRH administration at 72 h if estrus was not detected. The concentrations of P4 on d 5 were greater (P <  0.01) in the HiP4 (2.8 ± 0.10 ng/ml) than LoP4 (1.7 ± 0.05 ng/mL) treatment group. For cows that were detected in estrus after PGF2α administration, estrous response (83.5%) and interval to estrus (55.0 ± 0.5 h) did not differ between treatment groups. Pregnancy rate (combined Estrus-AI and TAI) that resulted from breeding at the time of the synchronized time of estrus was similar between treatment groups (HiP4: 77.1%; LoP4: 82.3%). In conclusion, differences in P4 concentrations during early follicular development do not effect pregnancy rate in beef cows when the cows are inseminated at the time of a synchronized estrus if the cows have similar intervals of proestrus.

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.

Approaches to assess IgE mediated allergy risks (sensitization and cross-reactivity) from new or modified dietary proteins.

The development and introduction of new dietary protein sources has the potential to improve food supply sustainability. Understanding the potential allergenicity of these new or modified proteins is crucial to ensure protection of public health. Exposure to new proteins may result in de novo sensitization, with or without clinical allergy, or clinical reactions through cross-reactivity. In this paper we review the potential of current methodologies (in silico, in vitro degradation, in vitro IgE binding, animal models and clinical studies) to address these outcomes for risk assessment purposes for new proteins, and especially to identify and characterise the risk of sensitization for IgE mediated allergy from oral exposure. Existing tools and tests are capable of assessing potential crossreactivity. However, there are few possibilities to assess the hazard due to de novo sensitization. The only methods available are in vivo models, but many limitations exist to use them for assessing risk. We conclude that there is a need to understand which criteria adequately define allergenicity for risk assessment purposes, and from these criteria develop a more suitable battery of tests to distinguish between proteins of high and low allergenicity, which can then be applied to assess new proteins with unknown risks.

Insulin resistance in vascular endothelial cells promotes intestinal tumour formation.

The risk of several cancers, including colorectal cancer, is increased in patients with obesity and type 2 diabetes, conditions characterised by hyperinsulinaemia and insulin resistance. Because hyperinsulinaemia itself is an independent risk factor for cancer development, we examined tissue-specific insulin action in intestinal tumour formation. In vitro, insulin increased proliferation of intestinal tumour epithelial cells by almost two-fold in primary culture of tumour cells from ApcMin/+ mice. Surprisingly, targeted deletion of insulin receptors in intestinal epithelial cells in ApcMin/+ mice did not change intestinal tumour number or size distribution on either a low or high-fat diet. We therefore asked whether cells in the tumour stroma might explain the association between tumour formation and insulin resistance. To this end, we generated ApcMin/+ mice with loss of insulin receptors in vascular endothelial cells. Strikingly, these mice had 42% more intestinal tumours than controls, no change in tumour angiogenesis, but increased expression of vascular cell adhesion molecule-1 (VCAM-1) in primary culture of tumour endothelial cells. Insulin decreased VCAM-1 expression and leukocyte adhesion in quiescent tumour endothelial cells with intact insulin receptors and partly prevented increases in VCAM-1 and leukocyte adhesion after treatment with tumour necrosis factor-α. Knockout of insulin receptors in endothelial cells also increased leukocyte adhesion in mesenteric venules and increased the frequency of neutrophils in tumours. We conclude that although insulin is mitogenic for intestinal tumour cells in vitro, impaired insulin action in the tumour microenvironment may be more important in conditions where hyperinsulinaemia is secondary to insulin resistance. Insulin resistance in tumour endothelial cells produces an activated, proinflammatory state that promotes tumorigenesis. Improvement of endothelial dysfunction may reduce colorectal cancer risk in patients with obesity and type 2 diabetes.

P and Ca digestibility is increased in broiler diets supplemented with the high-phytase HIGHPHY wheat.

Around 70% of total seed phosphorus is represented by phytate which must be hydrolysed to be bioavailable in non-ruminant diets. The limited endogenous phytase activity in non-ruminant animals make it common practice to add an exogenous phytase source to most poultry and pig feeds. The mature grain phytase activity (MGPA) of cereal seeds provides a route for the seeds themselves to contribute to phytate digestion, but MGPA varies considerably between species and most varieties in current use make negligible contributions. Currently, all phytases used for feed supplementation and transgenic improvement of MGPA are derived from microbial enzymes belonging to the group of histidine acid phosphatases (HAP). Cereals contain HAP phytases, but the bulk of MGPA can be attributed to phytases belonging to a completely different group of phosphatases, the purple acid phosphatases (PAPhy). In recent years, increased MGPAs were achieved in cisgenic barley holding extra copies of barley PAPhy and in the wheat HIGHPHY mutant, where MGPA was increased to ~6200 FTU/kg. In the present study, the effect of replacing 33%, 66% and 100% of a standard wheat with HIGHPHY wheat was compared with a control diet with and without 500 FTU of supplemental phytase. Diets were compared by evaluating broiler performance, ileal Ca and P digestibility and tibia development, using nine replicate pens of four birds per diet over 3 weeks from hatch. There were no differences between treatments in any tibia or bird performance parameters, indicating the control diet did not contain sufficiently low levels of phosphorus to distinguish effect of phytase addition. However, in a comparison of the two wheats, the ileal Ca and P digestibility coefficients for the 100% HIGHPHY wheat diets are 22.9% and 35.6% higher, respectively, than for the control diet, indicating the wheat PAPhy is functional in the broiler digestive tract. Furthermore, 33% HIGHPHY replacement of conventional wheat, significantly improved Ca and P digestibility over the diet-supplemented exogenous phytase, probably due to the higher phytase activity in the HIGHPHY diet (1804 v. 1150 FTU). Full replacement by HIGHPHY gave 14.6% and 22.8% higher ileal digestibility coefficients for Ca and P, respectively, than for feed supplemented with exogenous HAP phytase at 500 FTU. This indicates that in planta wheat PAPhys has promising potential for improving P and mineral digestibility in animal feed.

Functional and structural assessment of patients with and without persistent pain after thoracotomy.

BACKGROUND: Persistent pain is frequent after thoracotomy, with a reported prevalence of up to 60%. It remains unclear why some patients develop pain, whereas others do not. We therefore examined patients with and without pain after thoracotomy to identify pathophysiological contributors to persistent pain. METHODS: Twenty patients with persistent pain, 12 patients without pain and 20 healthy controls underwent detailed functional and structural assessment including psychometric and neuropathic pain questionnaires, bedside examination for pinprick hyperalgesia and brush allodynia, quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain, measurement of capsaicin-evoked flare response, intradermal nerve density as determined by skin biopsies and laser- and heat-evoked potentials. RESULTS: Bedside testing revealed evoked pain in 16 of 20 patients with pain, but only in 2 of 12 patients without pain (p < 0.001). Quantitative sensory testing showed increased mechanical pain sensitivity (p = 0.018) on the operated side in patients with pain, but there were no differences between the two patient groups with regard to intradermal nerve fibre density, area and flux following capsaicin application and laser- and heat-evoked potentials. CONCLUSION: Different and individual pathophysiological mechanisms of pain may obscure the clinical picture and thus preclude identification of a specific pain profile in patients with persistent post-thoracotomy pain. SIGNIFICANCE: Evoked pain is more frequent in patients with pain. Assessment of intradermal nerve density, capsaicin-induced flare response and contact and laser heat-evoked potentials revealed no differences between pain patients and pain-free patients.

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.

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.

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.