238 research outputs found

    Idiopathic intracranial hypertension: the association between weight loss and the requirement for systemic treatment

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    <p>Abstract</p> <p>Background</p> <p>To determine whether weight loss is significantly associated with a discontinuation of treatment for idiopathic intracranial hypertension</p> <p>Methods</p> <p>The notes of 36 patients with idiopathic intracranial hypertension under regular review for at least 12 months by a single neuro-ophthalmologist were retrospectively reviewed. Weight was recorded at each assessment and weight loss recommended. Treatment was adjusted according to symptoms, visual function including visual fields and optic disc appearance only. Patients were divided according to duration of continuous follow-up, and then sub-divided as to whether they were on or not on treatment at most recent review and whether weight loss had been achieved compared to presentation. Survival analysis was performed to assess the probability of remaining on treatment having lost weight.</p> <p>Results</p> <p>Considering the patients as 3 groups, those with at least 12 months follow-up (n = 36), those with at least 18 months follow-up (n = 24) and those with 24 months or more follow-up (n = 19), only the group with 24 months or more follow-up demonstrated a significant association between weight loss and stopping systemic treatment (Fisher's exact test, p = 0.04). Survival analysis demonstrated that the probability of being on treatment at 5 years having gained weight was 0.63 and having lost weight was 0.38 (log rank test, p = 0.04). The results suggest that final absolute body mass index is more important than the change in body mass index for patients who stop treatment (Mann Whitney U, p = 0.05).</p> <p>Conclusion</p> <p>This is the first study to demonstrate that weight loss is associated with discontinuation of treatment. Unlike previous studies, our results suggest that final absolute body mass index is more important for stopping treatment than a proportional reduction in weight.</p

    Activation of mammalian skeletal-muscle carbonic anhydrase III by arginine modification

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    Purified carbonic anhydrase isozymes I, II, and III (CA I, CA II, CA III) from various sources were treated with 2,3-butanedione and their bicarbonate dehydration reactions followed. The specific activities of human and bovine CA I and CA II and chicken CA III were not affected by the butanedione treatment, whereas the activities of human, gorilla, and bovine CA III were rapidly activated. These findings suggest that one, or both, of the two arginyl residues which appear to be unique to the active sites of the mammalian CA III isozymes are modified by butanedione.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44191/1/10540_2005_Article_BF01121914.pd

    Increased plasma membrane cholesterol in cystic fibrosis cells correlates with CFTR genotype and depends on de novo cholesterol synthesis

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    <p>Abstract</p> <p>Background</p> <p>Previous observations demonstrate that <it>Cftr</it>-null cells and tissues exhibit alterations in cholesterol processing including perinuclear cholesterol accumulation, increased <it>de novo </it>synthesis, and an increase in plasma membrane cholesterol accessibility compared to wild type controls. The hypothesis of this study is that membrane cholesterol accessibility correlates with CFTR genotype and is in part influenced by <it>de novo </it>cholesterol synthesis.</p> <p>Methods</p> <p>Electrochemical detection of cholesterol at the plasma membrane is achieved with capillary microelectrodes with a modified platinum coil that accepts covalent attachment of cholesterol oxidase. Modified electrodes absent cholesterol oxidase serves as a baseline control. Cholesterol synthesis is determined by deuterium incorporation into lipids over time. Incorporation into cholesterol specifically is determined by mass spectrometry analysis. All mice used in the study are on a C57Bl/6 background and are between 6 and 8 weeks of age.</p> <p>Results</p> <p>Membrane cholesterol measurements are elevated in both R117H and ΔF508 mouse nasal epithelium compared to age-matched sibling wt controls demonstrating a genotype correlation to membrane cholesterol detection. Expression of wt CFTR in CF epithelial cells reverts membrane cholesterol to WT levels further demonstrating the impact of CFTR on these processes. In wt epithelial cell, the addition of the CFTR inhibitors, Gly H101 or CFTR<sub>inh</sub>-172, for 24 h surprisingly results in an initial drop in membrane cholesterol measurement followed by a rebound at 72 h suggesting a feedback mechanism may be driving the increase in membrane cholesterol. <it>De novo </it>cholesterol synthesis contributes to membrane cholesterol accessibility.</p> <p>Conclusions</p> <p>The data in this study suggest that CFTR influences cholesterol trafficking to the plasma membrane, which when depleted, leads to an increase in <it>de novo </it>cholesterol synthesis to restore membrane content.</p

    Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing.

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    Funder: Fondazione Fibrosi Cistica - FFC#1/2017Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. The 3272-26A>G and 3849+10kbC>T CFTR mutations alter the correct splicing of the CFTR gene, generating new acceptor and donor splice sites respectively. Here we develop a genome editing approach to permanently correct these genetic defects, using a single crRNA and the Acidaminococcus sp. BV3L6, AsCas12a. This genetic repair strategy is highly precise, showing very strong discrimination between the wild-type and mutant sequence and a complete absence of detectable off-targets. The efficacy of this gene correction strategy is verified in intestinal organoids and airway epithelial cells derived from CF patients carrying the 3272-26A>G or 3849+10kbC>T mutations, showing efficient repair and complete functional recovery of the CFTR channel. These results demonstrate that allele-specific genome editing with AsCas12a can correct aberrant CFTR splicing mutations, paving the way for a permanent splicing correction in genetic diseases

    Azithromycin reduces spontaneous and induced inflammation in ΔF508 cystic fibrosis mice

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    BACKGROUND: Inflammation plays a critical role in lung disease development and progression in cystic fibrosis. Azithromycin is used for the treatment of cystic fibrosis lung disease, although its mechanisms of action are poorly understood. We tested the hypothesis that azithromycin modulates lung inflammation in cystic fibrosis mice. METHODS: We monitored cellular and molecular inflammatory markers in lungs of cystic fibrosis mutant mice homozygous for the ΔF508 mutation and their littermate controls, either in baseline conditions or after induction of acute inflammation by intratracheal instillation of lipopolysaccharide from Pseudomonas aeruginosa, which would be independent of interactions of bacteria with epithelial cells. The effect of azithromycin pretreatment (10 mg/kg/day) given by oral administration for 4 weeks was evaluated. RESULTS: In naive cystic fibrosis mice, a spontaneous lung inflammation was observed, characterized by macrophage and neutrophil infiltration, and increased intra-luminal content of the pro-inflammatory cytokine macrophage inflammatory protein-2. After induced inflammation, cystic fibrosis mice combined exaggerated cellular infiltration and lower anti-inflammatory interleukin-10 production. In cystic fibrosis mice, azithromycin attenuated cellular infiltration in both baseline and induced inflammatory condition, and inhibited cytokine (tumor necrosis factor-α and macrophage inflammatory protein-2) release in lipopolysaccharide-induced inflammation. CONCLUSION: Our findings further support the concept that inflammatory responses are upregulated in cystic fibrosis. Azithromycin reduces some lung inflammation outcome measures in cystic fibrosis mice. We postulate that some of the benefits of azithromycin treatment in cystic fibrosis patients are due to modulation of lung inflammation
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