Comparison of four-times-a-day and twice-a-day dosing regimens in subjects requiring 1200 μg or less of budesonide to control mild to moderate asthma

AbstractThe aim of this study was to compare the efficacy, compliance and side-effects of budesonide administered twice daily (b.d.) and four times a day (q.d.) with a Turbuhaler® device in asthmatic subjects requiring ≤ 1200 μg daily. The randomized, parallel group study design included a 2-week baseline period followed by a 6–12-month treatment period. Subjects were assessed at regular intervals in hospital through FEV1, PC20 methacholine, adrenal function and throat swabs. They were asked to record their symptoms and PEF values morning and evening at home. An asthmatic flare-up, which was the main outcome resulting in a patient's termination of the study, was defined beforehand as (a) 25% or greater diurnal variability in PEF for 2 consecutive days, and/or (b) nocturnal awakenings due to asthma symptoms 2 days or more in the same week and/or (c) an increase (doubling or more) in the need for inhaled bronchodilator 2 days in the same week.Fifty-eight adult asthmatic subjects (20 males and 38 females) entered the study, one-half being randomly assigned to the b.d. regimen and one-half to the q.d. regimen. Fourteen subjects were on 400 μg, 15 subjects on 800 μg and 29 subjects on 1200 μg of budesonide daily. Seventeen flare-ups were recorded in the b.d. regimen group as opposed to 11 in the q.d. regimen (P=0·05), significant differences being found in the 800 and 1200 μg groups (a total of 13 flare-ups in the b.d. group and eight flare-ups in the q.d. group for the two doses, P=0·01). Kaplan-Meier survival analysis yielded similar results. There was no significant difference in FEV1, PC20 or cortisol levels during the study on either regimen. Throat symptoms and growth of Candida albicans were more common in the q.d. group. Compliance assessed by the number of times the Turbuhaler® device was actuated was significantly better in the b.d. group (95%) as compared with the q.d. group (83%). To conclude, administering inhaled budesonide with a Turbuhaler® device on a q.d. basis results in fewer flare-ups in spite of less satisfactory compliance and more common, local side-effects than on a b.d. regimen at daily doses of 800 and 1200 μg

Na+, K+-ATPase activity in children with autism spectrum disorder: Searching for the reason(s) of its decrease in blood cells

Na+, K+-ATPase (NKA) activity, which establishes the sodium and potassium gradient across the cell membrane and is instrumental in the propagation of the nerve impulses, is altered in a number of neurological and neuropsychiatric disorders, including autism spectrum disorders (ASD). In the present work, we examined a wide range of biochemical and cellular parameters in the attempt to understand the reason(s) for the severe decrease in NKA activity in erythrocytes of ASD children that we reported previously. NKA activity in leukocytes was found to be decreased independently from alteration in plasma membrane fluidity. The different subunits were evaluated for gene expression in leukocytes and for protein expression in erythrocytes: small differences in gene expression between ASD and typically developing children were not apparently paralleled by differences in protein expression. Moreover, no gross difference in erythrocyte plasma membrane oxidative modifications was detectable, although oxidative stress in blood samples from ASD children was confirmed by increased expression of NRF2 mRNA. Interestingly, gene expression of some NKA subunits correlated with clinical features. Excess inhibitory metals or ouabain-like activities, which might account for NKA activity decrease, were ruled out. Plasma membrane cholesterol, but not phosphatidylcholine and phosphatidlserine, was slighty decreased in erythrocytes from ASD children. Although no compelling results were obtained, our data suggest that alteration in the erytrocyte lipid moiety or subtle oxidative modifications in NKA structure are likely candidates for the observed decrease in NKA activity. These findings are discussed in the light of the relevance of NKA in ASD. Autism Research 2018. \ua9 2018 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. Lay Summary: The activity of the cell membrane enzyme NKA, which is instrumental in the propagation of the nerve impulses, is severely decreased in erythrocytes from ASD children and in other brain disorders, yet no explanation has been provided for this observation. We strived to find a biological/biochemical cause of such alteration, but most queries went unsolved because of the complexity of NKA regulation. As NKA activity is altered in many brain disorders, we stress the relevance of studies aimed at understanding its regulation in ASD

N-terminal probrain natriuretic peptide is a stronger predictor of cardiovascular mortality than C-reactive protein and albumin excretion rate in elderly patients with type 2 diabetes: the Casale Monferrato population-based study.

OBJECTIVE: To study whether N-terminal probrain natriuretic peptide (NT-proBNP) is a short-term independent predictor of both all-cause and cardiovascular (CV) mortality in type 2 diabetic patients and to establish whether albuminuria and C-reactive protein (CRP) affect this relationship. RESEARCH DESIGN AND METHODS: The prospective study included 1,825 type 2 diabetic patients from the population-based cohort of the Casale Monferrato study. CV risk factors, preexisting CVD, and NT-proBNP levels were evaluated at baseline. All-cause and CV mortality were assessed 5.5 years after baseline examination. Multivariate Cox proportional hazards modeling was used to estimate mortality hazard ratios (HRs). RESULTS: During the follow-up period, 390 people died (175 for CVD) out of 9,101 person-years of observations. A significantly increased mortality risk by quartiles of NT-proBNP was observed (test for trend, P < 0.001). NT-proBN P values >91 pg/mL conferred HRs of 2.05 (95% CI 1.47–2.86) for all-cause and 4.47 (2.38–8.39) for CV mortality, independently of CV risk factors, including CRP and albumin excretion rate (AER). The association was also significant for modest rises in NT-proBNP levels and in patients without microalbuminuria and CVD at baseline (upper quartiles HRs 3.82 [95% CI 1.24–13.75]) and 3.14 [1.00–9.94]). Albuminuria and NT-proBNP had an additive effect on mortality, though the association was stronger for NT-proBNP. CONCLUSIONS: NT-proBNP is a strong independent predictor of short-term CV mortality risk in elderly people with type 2 diabetes, including those without preexisting CVD. This association is evident even in people with slightly increased values, is not modified by CRP, and is additive to that provided by AER

Cdkn2a inactivation promotes malignant transformation of mouse immature thymocytes before the β-selection checkpoint

CDKN2A deletion is the most frequent genetic alteration in T-cell acute lymphoblastic leukemia (T-ALL), occurring across all molecular and immunophenotypic subtypes. CDKN2A encodes two functionally unrelated tumor suppressor proteins, ARF and INK4a, which are critical regulators of cell cycle and proliferation. Arf has been reported to suppress T-ALL development in post−b-selection thymocytes, but whether CDKN2A acts as a tumor suppressor gene in immature, pre−b-selection thymocytes remains to be elucidated. Resorting to a Rag2-deficient model of T-ALL, driven by the ETV6:: JAK2 fusion, we report that Cdkn2a haploinsufficiency at early stages of T-cell development facilitates leukemia developmentPPBI-POCI-01-0145-FEDER-022122; POCI-01-0145-FEDER-007274; NORTE01-0145-FEDER-000029info:eu-repo/semantics/publishedVersio

Oxidative stress and erythrocyte membrane alterations in children with autism: correlation with clinical features

It has been suggested that oxidative stress may play a role in the pathogenesis of Autism Spectrum Disorders (ASD), but the literature reports somewhat contradictory results. To further investigate the issue, we evaluated a high number of peripheral oxidative stress parameters, and some related issues such as erythrocyte membrane functional features and lipid composition. Twenty-one autistic children (Au) aged 5 to 12 years, were gender and age-matched with 20 typically developing children (TD). Erythrocyte thiobarbituric acid reactive substances, urinary isoprostane and hexanoyl-lysine adduct levels were elevated in Au, thus confirming the occurrence of an imbalance of the redox status of Au, whilst other oxidative stress markers or associated parameters (urinary 8-oxo-dG, plasma radical absorbance capacity and carbonyl groups, erythrocyte superoxide dismutase and catalase activities) were unchanged. A very significant reduction of Na+/K+-ATPase activity (-66%, p<0.0001), a reduction of erythrocyte membrane fluidity and alteration in erythrocyte fatty acid membrane profile (increase in monounsaturated fatty acids, decrease in EPA and DHA-\u3c93 with a consequent increase in \u3c96/\u3c93 ratio) were found in Au compared to TD, without change in membrane sialic acid content. Some Au clinical features appear to be correlated with these findings; in particular, hyperactivity score appears to be related with some parameters of the lipidomic profile and membrane fluidity. Oxidative stress and erythrocyte membrane alterations may play a role in the pathogenesis of ASD and prompt the development of palliative therapeutic protocols. Moreover, the marked decrease in NKA could be potentially utilized as a peripheral biomarker of ASD

Optimising calcium phosphate cement formulations to widen clinical applications

The demand for reconstructive orthopaedic implants continues expanding at a reasonable pace as the incidence of fracture injuries and infectious diseases rises. There has been an increase in the clinical need for more effective synthetic bone graft materials due to the drawbacks of autogenous grafts. Since the 1980’s calcium phosphate cements (CPC’s) have attracted a great deal of interest due to their chemical similarities to natural bone; chemical, physical and mechanical characteristics have been investigated and manipulated to maximise osteoconductivity and osteointegration of these CPC’s since the start of their commercialisation. Here in this thesis, a series of investigation are complied to demonstrate novel and inventive approaches to expand the application of CPC’s: (1) limiting the liquid phase in the setting reaction of a brushite cement to produce monetite (dehydrated brushite) based cement, with increased solubility to overcome the problems faced by long term stability of hydroxyapatite (HA) cements; (2) manipulating the cement formulation to produce a cement that can set on a change in temperature, upon implantation, increasing handling time during surgeries; (3) incorporating therapeutic molecules to eliminate secondary surgeries following infectious diseases; (4) to enhance osteointegration of CPC’s by synchronising the degradation to natural bone formation. Results exhibit compressive strength appropriate for the application of cranioplasty; long term ageing studies demonstrates that the novel cement formulations do not hydrolyse to HA, eliminating the risk of catastrophic brittle failure that is commonly associated with CPC’s.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Association between SNAP-25 gene polymorphisms and cognition in autism: functional consequences and potential therapeutic strategies.

Synaptosomal-associated protein of 25 kDa (SNAP-25) is involved in different neuropsychiatric disorders, including schizophrenia and attention-deficit/hyperactivity disorder. Consistently, SNAP-25 polymorphisms in humans are associated with hyperactivity and/or with low cognitive scores. We analysed five SNAP-25 gene polymorphisms (rs363050, rs363039, rs363043, rs3746544 and rs1051312) in 46 autistic children trying to correlate them with Childhood Autism Rating Scale and electroencephalogram (EEG) abnormalities. The functional effects of rs363050 single-nucleotide polymorphism (SNP) on the gene transcriptional activity, by means of the luciferase reporter gene, were evaluated. To investigate the functional consequences that SNAP-25 reduction may have in children, the behaviour and EEG of SNAP-25(+/-) adolescent mice (SNAP-25(+/+)) were studied. Significant association of SNAP-25 polymorphism with decreasing cognitive scores was observed. Analysis of transcriptional activity revealed that SNP rs363050 encompasses a regulatory element, leading to protein expression decrease. Reduction of SNAP-25 levels in adolescent mice was associated with hyperactivity, cognitive and social impairment and an abnormal EEG, characterized by the occurrence of frequent spikes. Both EEG abnormalities and behavioural deficits were rescued by repeated exposure for 21 days to sodium salt valproate (VLP). A partial recovery of SNAP-25 expression content in SNAP-25(+/-) hippocampi was also observed by means of western blotting. A reduced expression of SNAP-25 is responsible for the cognitive deficits in children affected by autism spectrum disorders, as presumably occurring in the presence of rs363050(G) allele, and for behavioural and EEG alterations in adolescent mice. VLP treatment could result in novel therapeutic strategies

Assessing Specific Cognitive Deficits Associated with Dementia in Older Adults with Down Syndrome: Use and Validity of the Arizona Cognitive Test Battery (ACTB)

BACKGROUND: Down syndrome is associated with specific cognitive deficits. Alongside this, older adults with Down syndrome are a high risk group for dementia. The Arizona Cognitive Test Battery (ACTB), a cognitive assessment battery specifically developed for use with individuals with Down syndrome, has been proposed for use as outcome measures for clinical trials in this population. It has not been validated in older adults with Down syndrome. This study aims to assess the use and validity of the ACTB in older adults with Down syndrome. METHODS: Participants with Down syndrome aged 45 and over were assessed using the ACTB, standard tabletop tests and informant ratings. RESULTS: Assessment outcomes of 49 participants were analysed. Of these, 19 (39%) had a diagnosis of dementia or possible dementia. Most participants were able to attempt most of the tasks, although some tasks had high floor effects (including CANTAB Intra-Extra Dimensional shift stages completed and Modified Dots Task). Of the ACTB tasks, statistically significant differences were observed between the dementia and no dementia groups on CANTAB Simple Reaction Time median latency, NEPSY Visuomotor Precision-Car and Motorbike and CANTAB Paired Associates Learning stages completed. No significant differences were observed for CANTAB Intra-Extra Dimensional Shift, Modified Dots Task, Finger Sequencing, NEPSY Visuomotor precision-Train and Car and CANTAB Paired Associates Learning first trial memory score. Several of the tasks in the ACTB can be used in older adults with Down syndrome and have mild to moderate concurrent validity when compared to tabletop tests and informant ratings, although this varies on a test by test basis. CONCLUSIONS: Overall, scores for a number of tests in the ACTB were similar when comparing dementia and no dementia groups of older adults with Down syndrome, suggesting that it would not be an appropriate outcome measure of cognitive function for clinical trials of dementia treatments without further modification and validation