We report a case of bilateral mitochondrial optic neuropathies secondary to long-term linezolid treatment, show the nature of recovery, review the findings in the literature and propose a potential ...mitochondrial mechanism for linezolid-induced mitochondrial optic neuropathy. This is an observational case report and literature review with presentation of the clinical course of linezolid mitochondrial optic neuropathies through clinical and psychophysical documentation. Main outcome measures included: visual acuity, funduscopical examinations and peripapillary retinal nerve fibre layer (PRNFL) optical coherence tomography (OCT). A 6-year-old boy presented with bilateral optic neuropathies secondary to 1 year of linezolid treatment for osteomyelitis of the mandible. On presentation, visual acuities were 20/400 in both eyes, with considerable optic disc oedema, hyperaemia and PRNFL swelling confirmed by OCT. 2 weeks after the discontinuation of linezolid, visual acuities returned to 20/25 in both eyes, with reduction in the optic disc oedema, hyperaemia and PRNFL swelling. 3 months after the discontinuation of linezolid treatment, visual acuities were stable at 20/20 in both eyes, with a marked decrease in PRNFL swelling confirmed by OCT, and the development of mild temporal optic disc pallor in both eyes. Doctors should be aware of impairments of vision among patients on long-term linezolid treatment and promptly discontinue treatment to prevent irreversible vision loss. The development and resolution of bilateral optic neuropathies with considerable PRNFL swelling in this patient provide insight into the more general rubric of mitochondrial optic neuropathies.
Asthma phenotypes in inner-city children Zoratti, Edward M., MD; Krouse, Rebecca Z., MS; Babineau, Denise C., PhD, MS ...
Journal of allergy and clinical immunology,
10/2016, Letnik:
138, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Background Children with asthma in low-income urban areas have high morbidity. Phenotypic analysis in these children is lacking, but may identify characteristics to inform successful tailored ...management approaches. Objective We sought to identify distinct asthma phenotypes among inner-city children receiving guidelines-based management. Methods Nine inner-city asthma consortium centers enrolled 717 children aged 6 to 17 years. Data were collected at baseline and prospectively every 2 months for 1 year. Participants' asthma and rhinitis were optimally managed by study physicians on the basis of guidelines. Cluster analysis using 50 baseline and 12 longitudinal variables was performed in 616 participants completing 4 or more follow-up visits. Results Five clusters (designated A through E) were distinguished by indicators of asthma and rhinitis severity, pulmonary physiology, allergy (sensitization and total serum IgE), and allergic inflammation. In comparison to other clusters, cluster A was distinguished by lower allergy/inflammation, minimally symptomatic asthma and rhinitis, and normal pulmonary physiology. Cluster B had highly symptomatic asthma despite high step-level treatment, lower allergy and inflammation, and mildly altered pulmonary physiology. Cluster C had minimally symptomatic asthma and rhinitis, intermediate allergy and inflammation, and mildly impaired pulmonary physiology. Clusters D and E exhibited progressively higher asthma and rhinitis symptoms and allergy/inflammation. Cluster E had the most symptomatic asthma while receiving high step-level treatment and had the highest total serum IgE level (median, 733 kU/L), blood eosinophil count (median, 400 cells/mm3 ), and allergen sensitizations (15 of 22 tested). Conclusions Allergy distinguishes asthma phenotypes in urban children. Severe asthma often coclusters with highly allergic children. However, a symptomatic phenotype with little allergy or allergic inflammation was identified.
To determine the incidence of endophthalmitis following 25-gauge and standard 20-gauge vitrectomy.
In this single-centre retrospective interventional case series, we evaluated the incidence of acute ...endophthalmitis occurring within the 14-day postoperative period in all patients who underwent pars plana vitrectomy between 1 November 2002 and 31 December 2006. A total of 3477 consecutive patients were identified. Of them, 3046 patients underwent 20-gauge vitrectomy and 431 underwent 25-gauge vitrectomy.
The event rates of postoperative endophthalmitis were 0.03% (1 of 3046) after 20-gauge vitrectomy and 0.23% (1 of 431) after 25-gauge vitrectomy (P=0.23). In the endophthalmitis case that occurred after 25-gauge vitrectomy, a combined phacoemulsification cataract surgery was performed with the 25-gauge vitrectomy. Analyses of event rates of postoperative endophthalmitis after combining phacoemulsification cataract surgery and vitrectomy were 0% (0 of 170) for 20-gauge vitrectomy and 2.17% (1 of 46) for 25-gauge surgery vitrectomy (P=0.21).
The incidence of postoperative endophthalmitis following 25-gauge vitrectomy and 20-gauge surgery is low. Although there is a trend suggesting an increased risk of endophthalmitis with the 25-gauge system, this difference was not statistically significant given the low number of measured outcomes.
Acute liver injury is frequently associated with oxidative stress. Here, we investigated the therapeutic potential of carbon monoxide releasing molecule A-1 (CORM A-1) in oxidative stress-mediated ...liver injury. Overnight-fasted mice were injected with acetaminophen (APAP; 300 mg/kg; intraperitoneally) and were sacrificed at 4 and 12 h. They showed elevated levels of serum transaminases, depleted hepatic glutathione (GSH) and hepatocyte necrosis. Mice injected with CORM A-1 (20 mg/kg) 1 h after APAP administration, had reduced serum transaminases, preserved hepatic GSH and reduced hepatocyte necrosis. Mice that received a lethal dose of APAP (600 mg/kg), died by 10 h; but those co-treated with CORM A-1 showed a 50% survival. Compared to APAP-treated mice, livers from those co-treated with CORM A-1, had upregulation of Nrf2 and ARE genes (HO-1, GCLM and NQO-1). APAP-treated mice had elevated hepatic mRNA levels of inflammatory genes (Nf-κB, TNF-α, IL1-β and IL-6), an effect blunted in those co-treated with CORM A-1. In tert-butyl hydroperoxide (t-BHP)-treated HepG2 cells, CORM A-1 augmented cell viability, reduced oxidative stress, activated the nuclear factor erythroid 2–related factor 2 (Nrf2) and anti-oxidant response element (ARE) genes. The molecular docking profile of CO in the kelch domain of Keap1 protein suggested that CO released from CORM A-1 mediated Nrf2 activation. Collectively, these data indicate that CORM A-1 reduces oxidative stress by upregulating Nrf2 and related genes, and restoring hepatic GSH, to reduce hepatocyte necrosis and thus minimize liver injury that contributes to an overall improved survival rate.
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•CORM A-1 treatment improved cell viability and intracellular oxidative stress.•CORM A-1 induced Nrf2 translocation in HepG2 cells and APAP induced hepatotoxicity.•CORM A-1 prevented APAP induced hepatic necrosis and improved survival rate.•CO docks with Keap1 protein as evidenced by docking studies.
Summary Background Thrombophilias are common disorders that increase the risk of pregnancy-associated venous thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated ...pregnancy complications (severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia. Methods In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks' gestation, and twice daily thereafter until at least 37 weeks' gestation) or to no antepartum dalteparin (control group). Randomisation was done by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous thromboembolism. We did intention-to-treat and on-treatment analyses. This trial is registered with ClinicalTrials.gov , number NCT00967382 , and with Current Controlled Trials, number ISRCTN87441504. Findings Between Feb 28, 2000, and Sept 14, 2012, 292 women consented to participate and were randomly assigned to the two groups. Three women were excluded after randomisation because of ineligibility (two in the antepartum dalteparin group and one in the control group), leaving 146 women assigned to antepartum dalteparin and 143 assigned to no antepartum dalteparin. Some patients crossed over to the other group during treatment, and therefore for on-treatment and safety analysis there were 143 patients in the dalteparin group and 141 in the no dalteparin group. Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (dalteparin 25/146 17·1%; 95% CI 11·4–24·2% vs no dalteparin 27/143 18·9%; 95% CI 12·8–26·3%; risk difference −1·8% 95% CI −10·6% to 7·1%)) and on-treatment analysis (dalteparin 28/143 19·6% vs no dalteparin 24/141 17·0%; risk difference +2·6% 95% CI −6·4 to 11·6%). In safety analysis, the occurrence of major bleeding did not differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 19·6%) than in the no dalteparin group (13/141 9·2%; risk difference 10·4%, 95% CI 2·3–18·4; p=0·01). Interpretation Antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high risk of these complications and is associated with an increased risk of minor bleeding. Funding Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.
We tested all samples from patients with ocular toxoplasmosis sent to the Palo Alto Medical Foundation Toxoplasma Reference Laboratory from June 2004 through August 2010 for serologic evidence of ...recent Toxoplasma gondii infection. Of 205 patients aged 10–96 years, 11.7% had recent infection. Many people develop ocular disease soon after T. gondii infection.
To evaluate the impact of modifying the abicipar pegol (abicipar) manufacturing process on the safety and treatment effect of abicipar in patients with neovascular age-related macular degeneration ...(nAMD).
A new process for manufacturing abicipar was developed to reduce host cell impurities. In a prospective, Phase 2, multicenter, open-label, 28-week clinical trial, patients (n=123) with active nAMD received intravitreal injections of abicipar 2 mg at baseline (day 1) and weeks 4, 8, 16, and 24. Outcome measures included proportion of patients with stable vision (<15-letter loss from baseline; primary endpoint), change from baseline in best-corrected visual acuity (BCVA) and central retinal thickness (CRT), and adverse events.
Overall, 8.9% (11/123) of patients experienced intraocular inflammation (IOI) and discontinued treatment. IOI cases were assessed as mild (2.4% 3/123), moderate (4.9% 6/123), or severe (1.6% 2/123) and resolved with steroid treatment. Visual acuity in most patients with IOI (8 of 11) recovered to baseline BCVA or better by study end. No cases of endophthalmitis or retinal vasculitis were reported. Stable vision was maintained for ≥95.9% (≥118/123) of patients at all study visits. At week 28, treatment-naïve patients showed a greater mean improvement from baseline in BCVA compared with previously treated patients (4.4 vs 1.8 letters) and a larger mean CRT reduction from baseline (98.5 vs 45.5 μm).
Abicipar produced using a modified manufacturing process showed a moderately lower incidence and severity of IOI compared with Phase 3 abicipar studies. Beneficial effects of treatment were demonstrated.
Copy number variants affect both disease and normal phenotypic variation, but those lying within heavily duplicated, highly identical sequence have been difficult to assay. By analyzing short-read ...mapping depth for 159 human genomes, we demonstrated accurate estimation of absolute copy number for duplications as small as 1.9 kilobase pairs, ranging from 0 to 48 copies. We identified 4.1 million "singly unique nucleotide" positions informative in distinguishing specific copies and used them to genotype the copy and content of specific paralogs within highly duplicated gene families. These data identify human-specific expansions in genes associated with brain development, reveal extensive population genetic diversity, and detect signatures consistent with gene conversion in the human species. Our approach makes ~1000 genes accessible to genetic studies of disease association.
Background Treatment levels required to control asthma vary greatly across a population with asthma. The factors that contribute to variability in treatment requirements of inner-city children have ...not been fully elucidated. Objective We sought to identify the clinical characteristics that distinguish difficult-to-control asthma from easy-to-control asthma. Methods Asthmatic children aged 6 to 17 years underwent baseline assessment and bimonthly guideline-based management visits over 1 year. Difficult-to-control and easy-to-control asthma were defined as daily therapy with 500 μg of fluticasone or greater with or without a long-acting β-agonist versus 100 μg or less assigned on at least 4 visits. Forty-four baseline variables were used to compare the 2 groups by using univariate analyses and to identify the most relevant features of difficult-to-control asthma by using a variable selection algorithm. Nonlinear seasonal variation in longitudinal measures (symptoms, pulmonary physiology, and exacerbations) was examined by using generalized additive mixed-effects models. Results Among 619 recruited participants, 40.9% had difficult-to-control asthma, 37.5% had easy-to-control asthma, and 21.6% fell into neither group. At baseline, FEV1 bronchodilator responsiveness was the most important characteristic distinguishing difficult-to-control asthma from easy-to-control asthma. Markers of rhinitis severity and atopy were among the other major discriminating features. Over time, difficult-to-control asthma was characterized by high exacerbation rates, particularly in spring and fall; greater daytime and nighttime symptoms, especially in fall and winter; and compromised pulmonary physiology despite ongoing high-dose controller therapy. Conclusions Despite good adherence, difficult-to-control asthma showed little improvement in symptoms, exacerbations, or pulmonary physiology over the year. In addition to pulmonary physiology measures, rhinitis severity and atopy were associated with high-dose asthma controller therapy requirement.
Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide ...resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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