Population-based register study of children born in Sweden from 1997 to 2014 showed an increase in rickets during infancy

Abstract Aim This population-based study assessed the incidence of rickets in infants up to age of one born in Sweden from 1997-2014. We also examined maternal and perinatal factors and co-morbidity. Methods We used Swedish National Board of Health and Welfare registers and data from Statistics Sweden. The outcome measure was an International Classification of Diseases, Tenth Revision, code for rickets. Results There were 273 cases of rickets, with an incidence of 14.7 per 100,000 and a 10-fold incidence increase between 1997-2014. The majority (78.4%) were born preterm, half were small-for-gestational age (SGA) (birthweightPeer reviewe

Hypoxia upregulates neutrophil degranulation and potential for tissue injury.

BACKGROUND: The inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as COPD and cystic fibrosis, but the effects of hypoxia on potentially harmful neutrophil functional responses such as degranulation are unknown. METHODS AND RESULTS: Following exposure to hypoxia (0.8% oxygen, 3 kPa for 4 h), neutrophils stimulated with inflammatory agonists (granulocyte-macrophage colony stimulating factor or platelet-activating factor and formylated peptide) displayed a markedly augmented (twofold to sixfold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by coincubation with the antiprotease α-1 antitrypsin; both normoxic and hypoxic supernatants impaired ciliary function. Surprisingly, the hypoxic upregulation of neutrophil degranulation was not dependent on hypoxia-inducible factor (HIF), nor was it fully reversed by inhibition of phospholipase C signalling. Hypoxia augmented the resting and cytokine-stimulated phosphorylation of AKT, and inhibition of phosphoinositide 3-kinase (PI3K)γ (but not other PI3K isoforms) prevented the hypoxic upregulation of neutrophil elastase release. CONCLUSION: Hypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion.Supported by the British Lung Foundation, Papworth Hospital NHS Foundation Trust, BBSRC and the Cambridge NIHR-Biomedical Research Centre. CS was funded by Wellcome Trust Early Postdoctoral Research Fellowship for Clinician Scientists (WT101692MA).This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by BMJ Publishing Group

Safety assessment of inhaled xylitol in mice and healthy volunteers

BACKGROUND: Xylitol is a 5-carbon sugar that can lower the airway surface salt concentration, thus enhancing innate immunity. We tested the safety and tolerability of aerosolized iso-osmotic xylitol in mice and human volunteers. METHODS: This was a prospective cohort study of C57Bl/6 mice in an animal laboratory and healthy human volunteers at the clinical research center of a university hospital. Mice underwent a baseline methacholine challenge, exposure to either aerosolized saline or xylitol (5% solution) for 150 minutes and then a follow-up methacholine challenge. The saline and xylitol exposures were repeated after eosinophilic airway inflammation was induced by sensitization and inhalational challenge to ovalbumin. Normal human volunteers underwent exposures to aerosolized saline (10 ml) and xylitol, with spirometry performed at baseline and after inhalation of 1, 5, and 10 ml. Serum osmolarity and electrolytes were measured at baseline and after the last exposure. A respiratory symptom questionnaire was administered at baseline, after the last exposure, and five days after exposure. In another group of normal volunteers, bronchoalveolar lavage (BAL) was done 20 minutes and 3 hours after aerosolized xylitol exposure for levels of inflammatory markers. RESULTS: In naïve mice, methacholine responsiveness was unchanged after exposures to xylitol compared to inhaled saline (p = 0.49). There was no significant increase in Penh in antigen-challenged mice after xylitol exposure (p = 0.38). There was no change in airway cellular response after xylitol exposure in naïve and antigen-challenged mice. In normal volunteers, there was no change in FEV1 after xylitol exposures compared with baseline as well as normal saline exposure (p = 0.19). Safety laboratory values were also unchanged. The only adverse effect reported was stuffy nose by half of the subjects during the 10 ml xylitol exposure, which promptly resolved after exposure completion. BAL cytokine levels were below the detection limits after xylitol exposure in normal volunteers. CONCLUSIONS: Inhalation of aerosolized iso-osmotic xylitol was well-tolerated by naïve and atopic mice, and by healthy human volunteers

Dietary and other lifestyle correlates of serum folate concentrations in a healthy adult population in Crete, Greece: a cross-sectional study

BACKGROUND: Folate has emerged as a key nutrient for optimising health. Impaired folate status has been identified as a risk factor for cardiovascular disease, various types of cancers, and neurocognitive disorders. The study aimed at examining the distribution and determinants of serum folate concentrations in a healthy adult population in Crete, Greece. METHODS: A cross-sectional sample of 486 healthy adults (250 men, 236 women) aged 39 ± 14 years, personnel of the Medical School and the University Hospital of Crete in Greece, was examined. Serum folate and vitamin B(12 )concentrations were measured by microbiological assay, and total homocysteine was determined fluorometrically and by high-pressure liquid chromatography. Lifestyle questionnaires were completed, and nutrient intakes and food consumption were assessed by 24-h dietary recalls. Multivariate analyses were performed using SPSS v10.1. RESULTS: The geometric mean (95% confidence interval) concentrations of serum folate were 15.6 μmol/l (14.6–16.8) in men and 19.2 μmol/l (17.9–20.7) in women (p < 0.001). Inadequate folate levels (≤7 nmol/l) were present in 6.8% of men and 2.1% of women (p < 0.001). Approximately 76% of men and 87% of women did not meet the reference dietary intake for folate (400 μg/day). Serum folate was inversely related to total homocysteine levels (p < 0.001). Increased tobacco and coffee consumption were associated with lower folate concentrations (p < 0.05 for both) but these associations disappeared after controlling for nutrient intakes. In multivariate analysis, intakes of MUFA, fibre, calcium, magnesium, folate, and vitamins A, E, C, B(1), and B(6 )were positively associated with serum folate. Consumption of potatoes, legumes, fruits, and vegetables were favourably related to the serum folate status. CONCLUSION: Serum folate concentrations were associated with various demographic, lifestyle and dietary factors in healthy Cretan adults. Large-scale epidemiological studies should be conducted within the general Greek adult population to assess the prevalence of impaired folate status and further examine associations with dietary patterns and chronic disease risk. Considering the importance of folate in health maintenance, it is important to increase the public's awareness of modifiable lifestyle patterns and diet and tobacco use in particular, which may be associated with improved folate status

Long Term Running Biphasically Improves Methylglyoxal-Related Metabolism, Redox Homeostasis and Neurotrophic Support within Adult Mouse Brain Cortex

Oxidative stress and neurotrophic support decline seem to be crucially involved in brain aging. Emerging evidences indicate the pro-oxidant methylglyoxal (MG) as a key player in the age-related dicarbonyl stress and molecular damage within the central nervous system. Although exercise promotes the overproduction of reactive oxygen species, habitual exercise may retard cellular aging and reduce the age-dependent cognitive decline through hormetic adaptations, yet molecular mechanisms underlying beneficial effects of exercise are still largely unclear. In particular, whereas adaptive responses induced by exercise initiated in youth have been broadly investigated, the effects of chronic and moderate exercise begun in adult age on biochemical hallmarks of very early senescence in mammal brains have not been extensively studied. This research investigated whether a long-term, forced and moderate running initiated in adult age may affect the interplay between the redox-related profile and the oxidative-/MG-dependent molecular damage patterns in CD1 female mice cortices; as well, we investigated possible exercise-induced effects on the activity of the brain derived neurotrophic factor (BDNF)-dependent pathway. Our findings suggested that after a transient imbalance in almost all parameters investigated, the lately-initiated exercise regimen strongly reduced molecular damage profiles in brains of adult mice, by enhancing activities of the main ROS- and MG-targeting scavenging systems, as well as by preserving the BDNF-dependent signaling through the transition from adult to middle age

Floating-Harbor syndrome and polycystic kidneys associated with SRCAP mutation.

Floating-Harbor syndrome (FHS) is a rare genetic disorder recently shown to be caused by mutations in the Snf2-related CREB-binding protein activator protein gene (SRCAP). It comprises three key clinical features of characteristic facies, expressive and receptive speech impairment and short stature. We report on a patient with this syndrome associated with early adult-onset hypertension and bilateral polycystic kidneys. Family screening for polycystic kidney disease was negative and mutations in polycystic kidney disease 1 and 2 genes (PKD1 and PKD2) were absent. Sequencing of the SRCAP gene demonstrated a de novo mutation matching one of the known FHS-associated mutations. The patient required treatment with anti-hypertensives and will require lifelong renal monitoring. We suggest this patient's presentation may be due to the pleiotropic effects of SRCAP mutations. Further, the protein encoded by SRCAP is known to interact with CREB-binding protein, the product of the gene mutated in Rubinstein-Taybi syndrome, which is associated with renal abnormalities. A literature review of the renal findings in patients with Floating-Harbor syndrome identified another patient with possible polycystic kidneys, two patients with early onset hypertension, and a young patient with a ruptured intracranial aneurysm, which can be a feature of classic adult polycystic kidney disease. Collectively, these findings suggest that all patients with Floating-Harbor syndrome should undergo regular blood pressure monitoring and screening for polycystic kidneys by ultrasound at the time of the FHS diagnosis with imaging to be repeated during adulthood if a childhood ultrasound was negative