Individually dosed omalizumab facilitates peanut oral immunotherapy in peanut allergic adolescents.

BACKGROUND: Peanut oral immunotherapy (pOIT) has showed good short-term outcomes, but allergic reactions may prevent effective up-dosing and is a major cause of stopping OIT. In placebo-controlled trials, omalizumab has been shown to facilitate allergen immunotherapy and increase tolerance to peanut. OBJECTIVE: We hypothesized that by combining omalizumab with pOIT, and monitor treatment effects with basophil allergen threshold sensitivity tests (CD-sens), peanut allergic patients could safely initiate pOIT and thereafter slowly withdraw omalizumab. METHODS: This is the 2nd part of a one-armed open phase-2 study where peanut allergic adolescents (n = 23) started pOIT after an individualized omalizumab treatment. The pOIT dose was increased from 280 to 2800 mg peanut protein in 8 weeks followed by an individualized step-wise withdrawal of omalizumab, based on clinical symptoms and CD-sens levels. pOIT continued for 12 weeks followed by an open peanut challenge. Peanut CD-sens and allergen-binding activity (ABA) and IgE-ab, IgG-ab and IgG4-ab to peanut and its components were measured during the study. RESULTS: All 23 patients successfully reached the 2800 mg maintenance dose. Moderate/systemic allergic reactions were rare while receiving full-dose omalizumab. Eleven of 23 (48%) successfully continued with pOIT after omalizumab was stopped. Compared to treatment failures, median baseline IgE-ab to peanut components Ara h 1-3 and CD-sens to peanut were significantly lower among successfully treated patients and IgG4-ab to peanut, Ara h 2 and 6 increased significantly more during treatment. CONCLUSIONS AND CLINICAL RELEVANCE: This study indicates that omalizumab is an effective adjunctive therapy for initiation and rapid up-dosing of pOIT; however, adverse events from pOIT become more frequent as omalizumab doses are decreased. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov; NCT02402231. EudraCT; 2012-005625-78.

Non-cardioembolic TIA and ischemic stroke: Implications of severity.

OBJECTIVES: Our purpose was to explore major vascular and bleeding outcomes in relation to risk and severity scores (ABCD2 or NIHSS) in patients with transient ischemic attack (TIA) or acute ischemic stroke (AIS). METHODS: This nationwide observational study was based on data from 4 national registries. Outcomes were assessed by Kaplan-Meier and Cox regression analyses. RESULTS: The total cohort comprised 21 268 patients (median age 73 years, 47.6% females). Based on ABCD2-score, the TIA-population (n = 10 174) was divided into low-risk (0-3 p, n = 3463) and high-risk (4-7 p, n = 6711). Based on NIHSS-score, the AIS-population (n = 11 454) was divided into minor (0-5 p, n = 8596), moderate (6-10 p, n = 1630) and severe (≥11 p, n = 1228). During follow-up (mean 1.7 years), the composite endpoint of stroke, myocardial infarction or death occurred in 3572 (16.5%) of all the patients, and major bleeding in 668 (3.1%) patients. Using low-risk TIA as reference, the adjusted hazard ratios (HR, 95% CI) of the composite endpoint were 1.41 (1.23-1.62) for high-risk TIA, 1.94 (1.70-2.22) for minor, 2.86 (2.45-3.34) for moderate and 4.18 (3.57-4.90) for severe stroke. When analyzed separately, the association with increased risk remained significant for stroke and death, but not for myocardial infarction. The HR of major bleeding were 1.31 (0.99-1.73) for high-risk TIA, 1.49 (1.13-1.95) for minor, 1.54 (1.08-2.21) for moderate and 2.10 (1.44-3.05) for severe stroke. CONCLUSIONS: This study confirms the association between severity of the index ischemic stroke and risk of future major vascular and bleeding events, and highlights the increased risk also for patients with high-risk TIA.

Individually dosed omalizumab: an effective treatment for severe peanut allergy.

BACKGROUND: Treatment with omalizumab has shown a positive effect on food allergies, but no dosages are established. Basophil allergen threshold sensitivity (CD-sens) can be used to objectively measure omalizumab treatment efficacy and correlates with the outcome of double-blind placebo-controlled food challenge to peanut. OBJECTIVE: To evaluate whether individualized omalizumab treatment monitored by CD-sens could be an effective intervention for suppression of allergic reactions to peanut. METHODS: Severely peanut allergic adolescents (n = 23) were treated with omalizumab for 8 weeks, and CD-sens was analysed before and after. Based on whether CD-sens was suppressed after 8 weeks, the patients either were subject to a peanut challenge or received eight more weeks with increased dose of omalizumab, followed by peanut challenge or another 8-week cycle of omalizumab. IgE and IgE-antibodies to peanut and its components were analysed before treatment. RESULTS: After individualized omalizumab treatment (8-24 weeks), all patients continued with an open peanut challenge with no (n = 18) or mild (n = 5) objective allergic symptoms. Patients (n = 15) needing an elevated omalizumab dose (ED) to suppress CD-sens had significantly higher CD-sens values at baseline 1.49 (0.44-20.5) compared to those (n = 8) who managed with normal dose (ND) 0.32 (0.24-5.5) (P < 0.01). Median ratios for Ara h 2 IgE-ab/IgE were significantly higher in the ED group (17%) compared to the ND group (11%). CONCLUSIONS AND CLINICAL RELEVANCE: Individually dosed omalizumab, monitored by CD-sens, is an effective and safe treatment for severe peanut allergy. The ratio of IgE-ab to storage protein Ara h 2/IgE as well as CD-sens to peanut may predict the need of a higher omalizumab dose. Clinical trials numbers: EudraCT; 2012-005625-78, ClinicalTrials.gov; NCT02402231.

Gait speed and one-leg standing time each add to the predictive ability of FRAX.

Gait speed or one-leg standing time (OLST) as additional predictors in FRAX. Population 351 elderly women followed 10 years. Both could improve predictions. The area under curve (AUC) for FRAX is 0.59, OLST is 0.69 and gait speed is 0.71. The net reclassification index (NRI) for classification to highest risk quartile or lowest three quartiles was 0.24 for gait speed and non-significant for OLST. INTRODUCTION: The risk of falls and bone strength are two main determinants of hip fracture risk. The fracture risk assessment tool FRAX, however, lacks direct measures of fall risk1. A short OLST and a slow gait speed are both fall-related risk factors for hip fractures. The aim of this study was to investigate whether the addition to FRAX of either gait speed or OLST could improve the predictive ability for hip fractures, compared to FRAX alone. METHODS: A population-based sample of 351 women aged between 69 and 79 years were tested for one-leg standing time with eyes open and mean gait speed over a 15 + 15-m walk. Fracture and mortality data were obtained from health care registers. RESULTS: The AUC for the receiver operating characteristic (ROC) increased from 0.61 to 0.71 when gait speed was added to FRAX. The AUC was 0.69 for OLST added to FRAX. The highest quartile of hip fracture risks according to FRAX had an absolute 10-year risk of ≥15%. The population was divided into one group with a hip fracture risk of ≥15% and one group with a fracture risk of <15%. NRI for addition of gait speed to FRAX was 0.24 (p = 0.023), while NRI was 0.08 (p = 0.544) for addition of OLST to FRAX. CONCLUSION: Gait speed tended to improve the predictive ability of FRAX more than OLST, but they both added value to FRAX.

Six years without pholcodine; Norwegians are significantly less IgE-sensitized and clinically more tolerant to neuromuscular blocking agents.

BACKGROUND: As a strong inducer of IgE antibodies to substituted ammonium ion epitopes (QAI), pholcodine (PHO) is a postulated cause of allergic anaphylaxis to neuromuscular blocking agents (NMBAs). Three years after withdrawal of PHO in Norway, a significant reduction in IgE sensitization and anaphylaxis reporting was seen. OBJECTIVE: Six-year follow-up study on the effects of PHO withdrawal on IgE sensitization and anaphylaxis reporting. METHODS: From 650 acute consecutive reports (2005-2013) to the Norwegian Network for Anaphylaxis under Anaesthesia (NARA), total number of reports on suspected anaphylactic reactions, number of reactions where NMBAs were administered, number of reactions where serum IgE antibodies (≥0.35 kUA /l) to suxamethonium (SUX) and PHO were present at time of reaction and anaphylaxis severity grades were retrieved. In addition, NMBA sales and prevalence of IgE sensitization to PHO and SUX among 'allergics' were monitored. RESULTS: From baseline period P0 (PHO on the market) through the first (P1) and second (P2), three-year periods after withdrawal, significant falls in total reports (P < 0.001) and reports with IgE antibodies to PHO (P = 0.008) and SUX (P = 0.001) at time of reaction were found. Total NMBA sales in P2 were 83% of P0, and SUX and rocuronium (ROC) together made up 86% of sales throughout the study. Five NMBA-related anaphylactic deaths occurred during P0 and P1 and, however, none during P2. Prevalence of IgE sensitization to SUX in 'allergics' fell to 0% at 4 and 5 years after withdrawal. CONCLUSIONS: Six years after PHO withdrawal, the Norwegian population has become significantly less IgE-sensitized and clinically more tolerant to NMBAs.

Amputation Rates, Mortality, and Pre-operative Comorbidities in Patients Revascularised for Intermittent Claudication or Critical Limb Ischaemia: A Population Based Study.

OBJECTIVES: The aims of this population based study were to describe mid- to long-term amputation risk, cumulative incidence of death or amputation, and differences in pre-operative comorbidities in patients revascularised for lower limb peripheral artery disease (PAD). METHODS: This was an observational cohort study. Data from the Swedish National Quality Registry for Vascular Surgery (Swedvasc) were combined with mandatory national health care registries and patient medical records. All patients who underwent revascularisation in Sweden between May 2008 and May 2013 for intermittent claudication (IC) or critical limb ischaemia (CLI), aged 50 years and older, were identified through the Swedvasc database. The mandatory national health care registries and medical records provided data on comorbidities, mortality, and major amputations. RESULTS: A total of 16,889 patients with PAD (IC, n = 6272; CLI, n = 10,617) were studied. The incidence of amputations in IC patients was 0.4% (range 0.3%-0.5%) per year. Among CLI patients, the amputation rate during the first 6 months following revascularisation was 12.0% (95% CI 11.3-12.6). Thereafter, the incidence declined to approximately 2% per year. The cumulative combined incidence of death or amputation 3 years after revascularisation was 12.9% (95% CI 12.0-13.9) in IC patients and 48.8% (95% CI 47.7-49.8) in CLI patients. Among CLI patients, compared with IC patients, the prevalence of diabetes, ischaemic stroke, heart failure, and atrial fibrillation was approximately doubled and renal failure was nearly tripled, even after age standardisation. CONCLUSION: The risk of amputation is particularly high during the first 6 months following revascularisation for CLI. IC patients have a benign course in terms of limb loss. Mortality in both IC and CLI patients is substantial. Revascularised CLI patients have different comorbidities from IC patients.

A policy of routine umbilical cord blood gas analysis decreased missing samples from high-risk births.

AIM: This study compared obstetric units practicing routine or selective umbilical cord blood gas analysis, with respect to the risk of missing samples in high-risk deliveries and in infants with birth asphyxia. METHODS: This was a Swedish population-based cohort study that used register data for 155 235 deliveries of live singleton infants between 2008 and 2014. Risk ratios and 95% confidence intervals were calculated to estimate the association between routine and selective umbilical cord blood gas sampling strategies and the risk of missing samples. RESULTS: Selective sampling increased the risk ratios when routine sampling was used as the reference, with a value of 1.0, and these were significant in high-risk deliveries and birth asphyxia. The risk ratios for selective sampling were large-for-gestational age (9.07), preterm delivery at up to 36 weeks of gestation (8.24), small-for-gestational age (7.94), two or more foetal scalp blood samples (5.96), an Apgar score of less than seven at one minute (2.36), emergency Caesarean section (1.67) and instrumental vaginal delivery (1.24). CONCLUSION: Compared with routine sampling, selective umbilical cord blood gas sampling significantly increased the risks of missing samples in high-risk deliveries and in infants with birth asphyxia.

The discovery of IgE.

In 1919, the search began for the factor, later called reagin, that could mediate an allergy, such as allergic asthma, in sera of allergic subjects. In 1967, the fifth class of immunoglobulins, IgE, was discovered and found to be able to carry reagin activity. This discovery has had immense importance for the understanding, diagnosis, and treatment of allergic diseases.

ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: a POLG mimic?

BACKGROUND AND PURPOSE: Defects of coenzyme Q10 (CoQ10) metabolism cause a variety of disorders ranging from isolated myopathy to multisystem involvement. ADCK3 is one of several genes associated with CoQ10 deficiency that presents with progressive cerebellar ataxia, epilepsy, migraine and psychiatric disorders. Diagnosis is challenging due to the wide clinical spectrum and overlap with other mitochondrial disorders. METHODS: A detailed description of three new patients and one previously reported patient from three Norwegian families with novel and known ADCK3 mutations is provided focusing on the epileptic semiology and response to treatment. Mutations were identified by whole exome sequencing and in two measurement of skeletal muscle CoQ10 was performed. RESULTS: All four patients presented with childhood-onset epilepsy and progressive cerebellar ataxia. Three patients had epilepsia partialis continua and stroke-like episodes affecting the posterior brain. Electroencephalography showed focal epileptic activity in the occipital and temporal lobes. Genetic investigation revealed ADCK3 mutations in all patients including a novel change in exon 15: c.T1732G, p.F578V. There was no apparent genotype-phenotype correlation. CONCLUSION: ADCK3 mutations can cause a combination of progressive ataxia and acute epileptic encephalopathy with stroke-like episodes. The clinical, radiological and electrophysiological features of this disorder mimic the phenotype of polymerase gamma (POLG) related encephalopathy and it is therefore suggested that ADCK3 mutations be considered in the differential diagnosis of mitochondrial encephalopathy with POLG-like features.

B vitamin treatments modify the risk of myocardial infarction associated with a MTHFD1 polymorphism in patients with stable angina pectoris.

BACKGROUND: Methylenetetrahydrofolate dehydrogenase (MTHFD1) catalyzes three sequential reactions that metabolize derivatives of tetrahydrofolate (THF) in folate-dependent one-carbon metabolism. Impaired MTHFD1 flux has been linked to disturbed lipid metabolism and oxidative stress. However, limited information is available on its relation to the development of atherothrombotic cardiovascular disease. METHODS AND RESULTS: We explored the association between a MTHFD1 polymorphism (rs1076991 C > T) and acute myocardial infarction (AMI), and potential effect modifications by folic acid/B12 and/or vitamin B6 treatment in suspected stable angina pectoris patients (n = 2381) participating in the randomized Western Norway B Vitamin Intervention Trial (WENBIT). During the median follow-up of 4.9 years 204 participants (8.6%) suffered an AMI. After adjusting for established CVD risk factors, the MTHFD1 polymorphism was significantly associated with AMI (HR: 1.49; 95% CI, 1.23-1.81). A similar association was observed among patients allocated to treatment with vitamin B6 alone (HR: 1.53; 95% CI, 1.01-2.31), and an even stronger relationship was seen in patients treated with both vitamin B6 and folic acid/B12 (HR: 2.35; 95% CI, 1.55-3.57). However, no risk association between the MTHFD1 polymorphism and AMI was seen in patients treated with placebo (HR: 1.29; 95% CI, 0.86-1.93) or folic acid/B12 (1.17; 95% CI, 0.83-1.65). CONCLUSION: A common and functional MTHFD1 polymorphism is associated with increased risk of AMI, although the risk seems to be dependent on specific B vitamin treatment. Further studies are warranted to elucidate the possible mechanisms, also in order to explore potential effect modifications by nutritional factors.

High respiratory rate is associated with early reduction of lung edema clearance in an experimental model of ARDS.

BACKGROUND: The independent impact of respiratory rate on ventilator-induced lung injury has not been fully elucidated. The aim of this study was to investigate the effects of two clinically relevant respiratory rates on early ventilator-induced lung injury evolution and lung edema during the protective ARDSNet strategy. We hypothesized that the use of a higher respiratory rate during a protective ARDSNet ventilation strategy increases lung inflammation and, in addition, lung edema associated to strain-induced activation of transforming growth factor beta (TGF-ß) in the lung epithelium. METHODS: Twelve healthy piglets were submitted to a two-hit lung injury model and randomized into two groups: LRR (20 breaths/min) and HRR (40 breaths/min). They were mechanically ventilated during 6 h according to the ARDSNet strategy. We assessed respiratory mechanics, hemodynamics, and extravascular lung water (EVLW). At the end of the experiment, the lungs were excised and wet/dry ratio, TGF-ß pathway markers, regional histology, and cytokines were evaluated. RESULTS: No differences in oxygenation, PaCO2 levels, systemic and pulmonary arterial pressures were observed during the study. Respiratory system compliance and mean airway pressure were lower in LRR group. A decrease in EVLW over time occurred only in the LRR group (P < 0.05). Wet/dry ratio was higher in the HRR group (P < 0.05), as well as TGF-ß pathway activation. Histological findings suggestive of inflammation and inflammatory tissue cytokines were higher in LRR. CONCLUSION: HRR was associated with more pulmonary edema and higher activation of the TGF-ß pathway. In contrast with our hypothesis, HRR was associated with less lung inflammation.

Individual Face-to-Face Cognitive Behavioural Therapy in Multiple Sclerosis: A Qualitative Study.

OBJECTIVE: To investigate how people with multiple sclerosis (MS) experience their participation in individual, face-to-face cognitive behavioural therapy (CBT) aimed at alleviating depressive symptoms. METHOD: Semistructured interviews with 12 participants were conducted after CBT and analyzed using qualitative content analysis. RESULTS: Two main themes emerged: CBT as a demanding process and confronting everyday life after CBT with self-knowledge and well-being. The participants had gained strategies for handling feelings of depression and anxiety. The therapist was considered important for guiding them through the demanding therapy. CONCLUSION: It is important to inform the participants of what CBT entails so that they are mentally prepared for the demanding process and can make the necessary adjustments in their daily life. Knowledge of MS among the therapists as well as collaboration with the multidisciplinary MS care may facilitate participation in CBT.

Basophil allergen threshold sensitivity and component-resolved diagnostics improve hazelnut allergy diagnosis.

BACKGROUND: IgE sensitization to hazelnut is common, especially in birch endemic areas. However, its clinical significance often needs to be confirmed by a food challenge. OBJECTIVE: To evaluate the clinical significance of IgE antibodies to hazelnut components and basophil allergen threshold sensitivity (CD-sens) to hazelnut, in relation to double-blind placebo-controlled food challenge (DBPCFC) in children with a suspected hazelnut allergy. METHODS: Forty children underwent a DBPCFC. CD-sens to hazelnut as well as IgE antibodies to hazelnut and its components Cor a 1, Cor a 8, Cor a 9 and Cor a 14 were analysed. Serum tryptase was measured before, during and after DBPCFC. RESULTS: Eight children had a positive DBPCFC, and all of them had a high CD-sens value to hazelnut. Of the 32 children that passed the DBPCFC, 31 were very low or negative in CD-sens. A positive DBPCFC corresponded with significantly higher CD-sens values (median 8.9, range 3.3-281) compared to children negative in challenge (median 0.05, range 0-34.7, P < 0.0001). Children positive in challenge also had higher levels of IgE-ab to Cor a 9 and Cor a 14 (P < 0.01 and P < 0.001, respectively) compared with those with a negative challenge. In relation to the results from DBPCFC, the sensitivity of CD-sens and IgE-ab to Cor a 14 was excellent (100%) and the specificity was very high (> 97% and > 94%, respectively). Five of the eight patients positive at challenge showed an increase in tryptase > 20% compared to tryptase baseline levels. CONCLUSIONS AND CLINICAL RELEVANCE: CD-sens and component-resolved diagnostics to hazelnut, used separately or in combination, may improve the diagnostic accuracy and safety and reduce overdiagnosis of hazelnut allergy.

Evaluation of basophil allergen threshold sensitivity (CD-sens) to peanut and Ara h 8 in children IgE-sensitized to Ara h 8.

BACKGROUND: Diagnosing peanut allergy properly is important and can be achieved by combining clinical history with various diagnostic methods such as IgE-antibody (IgE-ab) measurements, skin-prick test, basophil allergen threshold sensitivity (CD-sens) and food challenge. We aimed to evaluate CD-sens to peanut, Ara h 8 and Gly m 4 in relation to an oral peanut challenge in children IgE-sensitized to birch, peanut and Ara h 8 avoiding peanuts. METHODS: Twenty children IgE-sensitized to birch pollen and Ara h 8, but not to Ara h 1, Ara h 2 or Ara h 3 were challenged orally with roasted peanuts. Blood samples were drawn for IgE-ab and CD-sens analysis. To measure CD-sens, basophils were stimulated in vitro with decreasing doses of allergens until threshold sensitivity was reached. RESULTS: All children passed challenge without objective symptoms, but mild oral allergy syndrome (OAS) symptoms were reported in 6/20 children. Nineteen of twenty children were negative in CD-sens to peanut but 17/20 were positive to rAra h 8. Eleven of twenty children were positive in CD-sens to rGly m 4. CONCLUSION: Positive CD-sens to rAra h 8 show that the Ara h 8 IgE-ab sensitized basophils can be activated by a rAra h 8 allergen and initiate an allergic inflammation despite a negative challenge. Hence, children sensitized to Ara h 8 but not to peanut storage proteins may be at risk for systemic allergic reaction when eating larger amounts of peanuts but most likely don't have to fear smaller amounts.

Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation.

BACKGROUND: Despite its promise as a highly useful therapy for pancreatic cancer (PC), the addition of external beam radiation therapy to PC treatment has shown varying success in clinical trials. Understanding PC radioresistance and discovery of methods to sensitise PC to radiation will increase patient survival and improve quality of life. In this study, we identified PC radioresistance-associated pathways using global, unbiased techniques. METHODS: Radioresistant cells were generated by sequential irradiation and recovery, and global genome cDNA microarray analysis was performed to identify differentially expressed genes in radiosensitive and radioresistant cells. Ingenuity pathway analysis was performed to discover cellular pathways and functions associated with differential radioresponse and identify potential small-molecule inhibitors for radiosensitisation. The expression of FDPS, one of the most differentially expressed genes, was determined in human PC tissues by IHC and the impact of its pharmacological inhibition with zoledronic acid (ZOL, Zometa) on radiosensitivity was determined by colony-forming assays. The radiosensitising effect of Zol in vivo was determined using allograft transplantation mouse model. RESULTS: Microarray analysis indicated that 11 genes (FDPS, ACAT2, AG2, CLDN7, DHCR7, ELFN2, FASN, SC4MOL, SIX6, SLC12A2, and SQLE) were consistently associated with radioresistance in the cell lines, a majority of which are involved in cholesterol biosynthesis. We demonstrated that knockdown of farnesyl diphosphate synthase (FDPS), a branchpoint enzyme of the cholesterol synthesis pathway, radiosensitised PC cells. FDPS was significantly overexpressed in human PC tumour tissues compared with healthy pancreas samples. Also, pharmacologic inhibition of FDPS by ZOL radiosensitised PC cell lines, with a radiation enhancement ratio between 1.26 and 1.5. Further, ZOL treatment resulted in radiosensitisation of PC tumours in an allograft mouse model. CONCLUSIONS: Unbiased pathway analysis of radioresistance allowed for the discovery of novel pathways associated with resistance to ionising radiation in PC. Specifically, our analysis indicates the importance of the cholesterol synthesis pathway in PC radioresistance. Further, a novel radiosensitiser, ZOL, showed promising results and warrants further study into the universality of these findings in PC, as well as the true potential of this drug as a clinical radiosensitiser.

Peripheral and site-specific CD4(+) CD28(null) T cells from rheumatoid arthritis patients show distinct characteristics.

Proinflammatory CD4(+) CD28(null) T cells are frequently found in the circulation of patients with rheumatoid arthritis (RA), but are less common in the rheumatic joint. In the present study, we sought to identify functional differences between CD4(+) CD28(null) T cells from blood and synovial fluid in comparison with conventional CD28-expressing CD4(+) T cells. Forty-four patients with RA, displaying a distinct CD4(+) CD28(null) T cell population in blood, were recruited for this study; the methylation status of the IFNG locus was examined in isolated T cell subsets, and intracellular cytokine production (IFN-γ, TNF, IL-17) and chemokine receptor expression (CXCR3, CCR6 and CCR7) were assessed by flow cytometry on T cells from the two compartments. Circulating CD4(+) CD28(null) T cells were significantly more hypomethylated in the CNS-1 region of the IFNG locus than conventional CD4(+) CD28(+) T cells and produced higher levels of both IFN-γ and TNF after TCR cross-linking. CD4(+) CD28(null) T cells from the site of inflammation expressed significantly more CXCR3 and CCR6 compared to their counterparts in blood. While IL-17A production could hardly be detected in CD4(+) CD28(null) cells from the blood, a significant production was observed in CD4(+) CD28(null) T cells from synovial fluid. CD4(+) CD28(null) T cells were not only found to differ from conventional CD4(+) CD28(+) T cells in the circulation, but we could also demonstrate that synovial CD4(+) CD28(null) T cells showed additional effector functions (IL-17 coproduction) as compared to the same subset in peripheral blood, suggesting an active role for these cells in the perpetuation of inflammation in the subset of patients having a CD28(null) population.

One-leg standing time and hip-fracture prediction.

UNLABELLED: A hip fracture results in a lower quality of life and a cost of £30,000. In this study, one-leg standing time (OLST) had a negative linear relationship to the risk of a hip fracture. OLST could be a useful tool to assess the need for fracture-preventive interventions. INTRODUCTION: A hip fracture immobilizes, restricts autonomy, shortens life expectancy, and results in a cost of £30,000 in the UK health care system. However, effective preventive treatments can be offered to high-risk individuals. Impaired postural balance is an important risk factor for hip fractures, and the aim of this study was to evaluate whether OLST can predict hip fractures in elderly women. FRAX is the most established fracture risk assessment tool worldwide and a secondary aim was to relate the predictive ability of OLST to that of FRAX in this population. METHODS: Three hundred fifty-one women aged between 69 and 79 years were timed standing on one leg up to 30 s with eyes open and assessed with FRAX. Fracture data was obtained from registers. RESULTS: The main outcome, a hip fracture, occurred in 40 of the 351 participants (11.4%). The age-adjusted risk of a hip fracture was 5% lower with 1 s longer OLST (Hazard ratio 0.95, 95% CI 0.927-0.978). The relation between OLST and hip fracture risk was linear. Harrell's c was 0.60 for FRAX and 0.68 for OLST adjusted for age. CONCLUSION: With 1 s longer OLST, the risk of a hip fracture decreased significantly by 5%. This risk reduction was not explained by differences in the classic fracture risk factors included in FRAX. OLST had a predictive ability similar to FRAX. OLST is an easily performed balance test which may prove to be valuable in the assessment of hip fracture risk.

Differences in exosome populations in human breast milk in relation to allergic sensitization and lifestyle.

BACKGROUND: Breast-feeding has many beneficial effects on the developing immune system of the newborn. Breast milk contains immunoregulatory factors, such as nano-sized vesicles named exosomes. This study aimed at characterizing breast milk exosomes from human early milk and mature milk and to investigate whether allergic sensitization and an anthroposophic lifestyle could influence the exosome profile. METHODS: Breast milk was collected from 22 mothers at day 3-8 and from 61 mothers at 2 months postpartum, all part of the ALADDIN birth cohort. Isolated exosomes were captured on anti-MHC-class II- or anti-CD63 beads and analyzed by flow cytometry. Exosomal phenotype was related to lifestyle and allergic sensitization of the mothers, and sensitization of the child at 2 years of age. RESULTS: We found a higher content of exosomes in early milk compared with mature milk. Early milk exosomes were enriched in HLA-DR molecules and displayed significantly lower levels of HLA-ABC compared with those in mature milk. Phenotypically different subpopulations of exosomes were found in mature milk. Significantly lower levels of MUC1 were detected on CD63-enriched exosomes from sensitized mothers compared with nonsensitized. Furthermore, women with an anthroposophic lifestyle had significantly lower MUC1 expression on their HLA-DR-enriched milk exosomes and up-regulated levels of CD63 on CD63-enriched exosomes compared with nonanthroposophic mothers. Notably, mothers whose children developed sensitization had an increased amount of HLA-ABC on their milk exosomes enriched for CD63. CONCLUSIONS: The phenotype of exosomes in breast milk varies with maternal sensitization and lifestyle, which might influence allergy development in the child.

Incidence rates and trends of hip/femur fractures in five European countries: comparison using e-healthcare records databases.

Hip fractures represent a major public health challenge worldwide. Multinational studies using a common methodology are scarce. We aimed to estimate the incidence rates (IRs) and trends of hip/femur fractures over the period 2003-2009 in five European countries. The study was performed using seven electronic health-care records databases (DBs) from Denmark, The Netherlands, Germany, Spain, and the United Kingdom, based on the same protocol. Yearly IRs of hip/femur fractures were calculated for the general population and for those aged ≥50 years. Trends over time were evaluated using linear regression analysis for both crude and standardized IRs. Sex- and age-standardized IRs for the UK, Netherlands, and Spanish DBs varied from 9 to 11 per 10,000 person-years for the general population and from 22 to 26 for those ≥50 years old; the German DB showed slightly higher IRs (about 13 and 30, respectively), whereas the Danish DB yielded IRs twofold higher (19 and 52, respectively). IRs increased exponentially with age in both sexes. The ratio of females to males was ≥2 for patients aged ≥70-79 years in most DBs. Statistically significant trends over time were only shown for the UK DB (CPRD) (+0.7% per year, P < 0.01) and the Danish DB (-1.4% per year, P < 0.01). IRs of hip/femur fractures varied greatly across European countries. With the exception of Denmark, no decreasing trend was observed over the study period.

Marked improvement of cytotoxic effects induced by docetaxel on highly metastatic and androgen-independent prostate cancer cells by downregulating macrophage inhibitory cytokine-1.

BACKGROUND: Overexpression of macrophage inhibitory cytokine-1 (MIC-1) frequently occurs during the progression of prostate cancer (PC) to androgen-independent (AI) and metastatic disease states and is associated with a poor outcome of patients. METHODS: The gain- and loss-of-function analyses of MIC-1 were performed to establish its implications for aggressive and chemoresistant phenotypes of metastatic and AI PC cells and the benefit of its downregulation for reversing docetaxel resistance. RESULTS: The results have indicated that an enhanced level of secreted MIC-1 protein in PC3 cells is associated with their acquisition of epithelial-mesenchymal transition features and higher invasive capacity and docetaxel resistance. Importantly, the downregulation of MIC-1 in LNCaP-LN3 and PC3M-LN4 cells significantly decreased their invasive capacity and promoted the antiproliferative, anti-invasive and mitochrondrial- and caspase-dependent apoptotic effects induced by docetaxel. The downregulation of MIC-1 in PC3M-LN4 cells was also effective in promoting the cytotoxic effects induced by docetaxel on the side population (SP) endowed with stem cell-like properties and the non-SP cell fraction from PC3M-LN4 cells. CONCLUSION: These data suggest that the downregulation of MIC-1 may constitute a potential therapeutic strategy for improving the efficacy of current docetaxel-based chemotherapies, eradicating the total mass of PC cells and thereby preventing disease relapse and the death of PC patients.