Effect of Erdosteine on COPD Exacerbations in COPD Patients with Moderate Airflow Limitation

Background: The RESTORE study, a multi-national randomized, placebo-controlled study, showed that erdosteine - a muco-active antioxidant that modulates bacterial adhesiveness - reduced the rate and duration of exacerbations in moderate and severe COPD with a history of exacerbations. How much benefit patients with less severe disease experience when taking this drug remains unclear. Methods: This post hoc analysis of the 254 RESTORE participants with spirometrically-defined moderate COPD (post-bronchodilator forced expiratory volume in 1 second [FEV1] 50\u201279% predicted) examined exacerbation rate and duration, time to first exacerbation, and exacerbation-free time. Data were analyzed using descriptive statistics and comparisons between treatment groups used Wilcoxon rank-sum tests, Mann-Whitney U-tests, or log rank tests. Results: Patients with moderate COPD received erdosteine 300 mg twice daily (n=126) or placebo (n=128) added to usual COPD therapy for 12 months. During this time, there were 53 exacerbations in the erdosteine group and 74 in the placebo group, with 42.1% and 57.8% of patients, respectively, experiencing an exacerbation. There was a 47% reduction in the mean exacerbation rate with erdosteine compared to placebo (0.27 vs 0.51 exacerbations per-patient per-year, respectively, P=0.003), and a 58.3% reduction in the mild exacerbation rate (0.23 vs 0.53 mild exacerbations per-patient per-year, P=0.001). Mean duration of exacerbations was 26% shorter in erdosteine-treated patients (9.1 vs 12.3 days for placebo, P=0.022), with significant reductions in the duration of mild and moderate-to-severe exacerbations. Mean time to first exacerbation was prolonged by 7.7% (182 days for erdosteine vs 169 days for placebo, P<0.001) and the mean exacerbation-free time was increased by 51 days (279 days for erdosteine vs 228 days for placebo; P<0.001). Conclusion: These results indicate that adding erdosteine to usual COPD maintenance therapy reduces the number of mild, and duration of all, exacerbations in patients with moderate COPD and a history of exacerbations

Emergency endovascular treatment of cavernous internal carotid artery acute bleeding with flow diverter stent: a single-center experience

Background and objective To describe our single-center experience in the treatment of cavernous internal carotid artery (ICA) acute bleeding with flow diverter stent (FDS), as a single endovascular procedure or combined with an endoscopic endonasal approach. Methods We analyze a case series of 5 patients with cavernous ICA acute bleeding, i.e., 3 iatrogenic, 1 post-traumatic, and 1 erosive neoplastic. After an immediate nasal packing to temporarily bleeding control, patients underwent digital subtraction angiography (DSA) to identify the site of the ICA injury. A concomitant balloon occlusion test (BOT) was performed, to exclude post-occlusive ischemic neurological damage. An FDS was placed with parallel intravenous infusion of abciximab in 3 cases and tirofiban in 2 cases. In two patients, an innovative "sandwich technique" combining the endovascular reconstruction with an extracranial intrasphenoidal cavernous ICA resurfacing with autologous flaps or grafts by endoscopic endonasal approach was performed. Results No patient had periprocedural ischemic-hemorrhagic complications. All patients had a regular clinical evolution, without general complications or new onset of focal neurological deficits. No further bleeding occurred in 3 patients, while 2 cases experienced a mild rebleeding in a period ranging from 5 to 15 days after the endovascular procedure. In these two cases, we proceeded with an endoscopic endonasal procedure to resurface the exposed ICA wall in the sphenoid sinus. Conclusions Although the treatment of choice for cavernous ICA acute bleeding remains the occlusion of the injured vessel, in cases of poor hemodynamic compensation at the BTO, the endovascular FDS emergency placement can be effective. A combined endoscopic endonasal technique to support the extracranial side of the vessel using autologous flaps or grafts can be performed to prevent the risk of rebleeding

Value of systolic pulmonary arterial pressure as a prognostic factor of death in the systemic sclerosis EUSTAR population.

The aim of this study was to assess the prognostic value of systolic pulmonary artery pressure (sPAP) estimated by echocardiography in the multinational European League Against Rheumatism Scleroderma Trial and Research (EUSTAR) cohort.Data for patients with echocardiography documented between 1 January 2005 and 31 December 2011 were extracted from the EUSTAR database. Stepwise forward multivariable statistical Cox pulmonary hypertension analysis was used to examine the independent effect on survival of selected variables.Based on our selection criteria, 1476 patients were included in the analysis; 87\% of patients were female, with a mean age of 56.3 years (s.d. 13.5) and 31\% had diffuse SSc. The mean duration of follow-up was 2.0 years (s.d. 1.2, median 1.9). Taking index sPAP of 50 mmHg. In a multivariable Cox model, sPAP and the diffusing capacity for carbon monoxide (DLCO) were independently associated with the risk of death [HR 1.833 (95\% CI 1.035, 3.247) and HR 0.973 (95\% CI 0.955, 0.991), respectively]. sPAP was an independent risk factor for death with a HR of 3.02 (95\% CI 1.91, 4.78) for sPAP ≥36 mmHg.An estimated sPAP >36 mmHg at baseline echocardiography was significantly and independently associated with reduced survival, regardless of the presence of pulmonary hypertension based on right heart catheterization

A novel GRN mutation in an Italian patient with non-fluent variant of primary progressive aphasia at onset: a longitudinal case report

ObjectivesWe report the clinical presentation and evolution of a case with a novel Progranulin gene (GRN) mutation and non-fluent language disturbances at onset.Materials and methodsA 60 year-old, white patient was followed due to a history of language disturbances. Eighteen months after onset, the patient underwent FDG positron emission tomography (PET), and at month 24 was hospitalized to perform neuropsychological evaluation, brain 3 T MRI, lumbar puncture for cerebrospinal fluid (CSF) analysis, and genotyping. At month 31, the patient repeated the neuropsychological evaluation and brain MRI.ResultsAt onset the patient complained prominent language production difficulties, such as effortful speech and anomia. At month 18, FDG-PET showed left fronto-temporal and striatal hypometabolism. At month 24, the neuropsychological evaluation reported prevalent speech and comprehension deficits. Brain MRI reported left fronto-opercular and striatal atrophy, and left frontal periventricular white matter hyperintensities (WMHs). Increased CSF total tau level was observed. Genotyping revealed a new GRN c.1018delC (p.H340TfsX21) mutation. The patient received a diagnosis of non-fluent variant of primary progressive aphasia (nfvPPA). At month 31, language deficits worsened, together with attention and executive functions. The patient presented also with behavioral disturbances, and a progressive atrophy in the left frontal-opercular and temporo-mesial region.Discussion and conclusionThe new GRN p.H340TfsX21 mutation resulted in a case of nfvPPA characterized by fronto-temporal and striatal alterations, typical frontal asymmetric WMHs, and a fast progression toward a widespread cognitive and behavioral impairment, which reflects a frontotemporal lobar degeneration. Our findings extend the current knowledge of the phenotypic heterogeneity among GRN mutation carriers

Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort.

Objectives To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc). Methods We evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression. Results Of 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p<0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09). Conclusions Progressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality