Retinal ischemia gives rise to a complex spectrum in which the cumulative profile of ischemia of the middle and inner retina can be highly variable. We reviewed the current knowledge on paracentral ...acute middle maculopathy (PAMM) pathophysiology and accompanying risk factors, the middle and inner retinal vasculature and blood flow, and the vulnerability of the middle retina in vaso-occlusive disorders. The inner nuclear layer (INL) is easily affected by slight degrees of retinal hypoperfusion and ischemia. INL infarction starts at perivenular sites, manifesting as skip PAMM lesions and a fern-like appearance in cross-sectional and en face views, respectively. With horizontal progression, INL infarction may develop into diffuse globular PAMM. If vertical progression occurs, the entire middle and inner portions of the retina can be affected. Transmural infarction of the middle and inner retina would be at the end of this spectrum. This gradient of ischemic progression resembles an ischemic cascade. We review the evidence supporting the term “retinal ischemic cascade,” which encompasses a broad continuum of manifestations with roots in middle retinal infarction. With this terminology, variations in spatial and temporal progression and resolution of ischemia can also be delivered; it further enables addressing the possible associations between the middle and inner retinal ischemic patterns.
Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides ...novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider "young" patients with COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in
) young adults with COPD and
) those with pre-COPD at any age.
Acute exacerbations of idiopathic pulmonary fibrosis Collard, Harold R; Moore, Bethany B; Flaherty, Kevin R ...
American journal of respiratory and critical care medicine,
10/2007, Letnik:
176, Številka:
7
Journal Article
Recenzirano
Odprti dostop
The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may ...experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.
We previously described the contributions of increased total airway mucin concentrations to the pathogenesis and diagnosis of the chronic bronchitic component of chronic obstructive pulmonary disease ...(COPD). Here, we investigated the relative contribution of each of the major airway gel-forming mucins, MUC5AC and MUC5B, to the initiation, progression, and early diagnosis of airways disease in COPD.
SPIROMICS was a multicentre, observational study in patients aged 40-80 years recruited from six clinical sites and additional subsites in the USA. In this analysis, MUC5AC and MUC5B were quantitated by stable isotope-labelled mass spectrometry in induced sputum samples from healthy never-smokers, ever-smokers at risk for COPD, and ever-smokers with COPD. Participants were extensively characterised using results from questionnaires, such as the COPD assessment test (CAT) and St George's Respiratory Questionnaire; quantitative CT, such as residual volume/total lung capacity ratio (RV/TLC) and parametric response mapping-functional small airway disease (PRM-fSAD); and pulmonary function tests, such as FEV
, forced vital capacity (FVC), and forced expiratory flow, midexpiratory phase (FEF
). Absolute concentrations of both MUC5AC and MUC5B were related to cross-sectional (baseline, initial visit) and 3-year follow-up longitudinal data, including lung function, small airways obstruction, prospective acute exacerbations, and smoking status as primary outcomes. This study is registered with ClinicalTrials.gov (NCT01969344).
This analysis included 331 participants (mean age 63 years SEM 9·40), of whom 40 were healthy never-smokers, 90 were at-risk ever-smokers, and 201 were ever-smokers with COPD. Increased MUC5AC concentrations were more reliably associated with manifestations of COPD than were MUC5B concentrations, including decreased FEV
and FEF
, and increased prospective exacerbation frequency, RV/TLC, PRM-fSAD, and COPD assessment scores. MUC5AC concentrations were more reactive to cigarette smoke exposure than were MUC5B concentrations. Longitudinal data from 3-year follow-up visits generated a multivariate-adjusted odds ratio for two or more exacerbations of 1·24 (95% CI 1·04-1·47, p=0·015) for individuals with high baseline MUC5AC concentration. Increased MUC5AC, but not MUC5B, concentration at baseline was a significant predictor of FEV
, FEV
/FVC, FEF
, and CAT score decline during the 3-year follow-up. Moreover, current smokers in the at-risk group showed raised MUC5AC concentrations at initial visits and decreased lung function over 3 years. By contrast, former smokers in the at-risk group showed normal MUC5AC concentrations at the initial visit and preserved lung function over 3 years.
These data indicate that increased MUC5AC concentration in the airways might contribute to COPD initiation, progression, exacerbation risk, and overall pathogenesis. Compared with MUC5B, greater relative changes in MUC5AC concentrations were observed as a function of COPD severity, and MUC5AC concentration seems to be an objective biomarker to detect disease in at-risk and pre-COPD individuals. These data suggest that MUC5AC-producing pathways could be potential targets for future therapeutic strategies. Thus, MUC5AC could be a novel biomarker for COPD prognosis and for testing the efficacy of therapeutic agents.
National Institutes of Health; National Heart, Lung, and Blood Institute.
The role of stem cells in tissue maintenance is appreciated and hierarchical models of stem cell self-renewal and differentiation often proposed. Stem cell activity in the male germline is restricted ...to undifferentiated A-type spermatogonia (A
); however, only a fraction of this population act as stem cells in undisturbed testis and A
hierarchy remains contentious. Through newly developed compound reporter mice, here we define molecular signatures of self-renewing and differentiation-primed adult A
fractions and dissect A
heterogeneity by single-cell analysis. We uncover an unappreciated population within the self-renewing A
fraction marked by expression of embryonic patterning genes and homeodomain transcription factor PDX1. Importantly, we find that PDX1 marks a population with potent stem cell capacity unique to mature, homeostatic testis and demonstrate dynamic interconversion between PDX1+ and PDX1- A
states upon transplant and culture. We conclude that A
exist in a series of dynamic cell states with distinct function and provide evidence that stability of such states is dictated by niche-derived cues.
Geographic atrophy (GA) is a progressive degenerative disease that significantly contributes to visual impairment in individuals aged 50 years and older. The development of GA is influenced by ...various modifiable and non-modifiable risk factors, including age, smoking, and specific genetic variants, particularly those related to the complement system regulators. Given the multifactorial and complex nature of GA, several treatment approaches have been explored, such as complement inhibition, gene therapy, and cell therapy. The recent approval by the Food and Drug Administration of pegcetacoplan, a complement C3 inhibitor, marks a significant breakthrough as the first approved treatment for GA. Furthermore, numerous interventions are currently in phase II or III trials, alongside this groundbreaking development. In light of these advancements, this review provides a comprehensive overview of GA, encompassing risk factors, prevalence, genetic associations, and imaging characteristics. Additionally, it delves into the current landscape of GA treatment, emphasizing the latest progress and future considerations. The goal of starting this discussion is to ultimately identify the most suitable candidates for each therapy, highlight the importance of tailoring treatments to individual cases, and continue monitoring the long-term implications of these emerging interventions.
The spatial and temporal variability of extreme wave climate along the Central-South American continent is analyzed. The study evaluates changes in the intensity of extreme significant wave height ...(SWH) throughout the year over the 1980–2008 period, using a calibrated long-term wave reanalysis database forced with NCEP/NCAR reanalysis. A non-stationary extreme value model, based on monthly maxima with a new approach for long-term trends, has been applied. Results show a common positive trend in the Pacific basin throughout all seasons and a significant decreasing trend pattern in the area of Surinam and north of Brazil, on the Atlantic border (up to −1.5 cm/year in March–April–May). A higher increase of the extreme wave heights is found in the austral summer (December–January–February) at Tierra de Fuego and the Falkland Islands, reaching 6.5 cm/year (which means 1.82 m for the 28 years studied). Furthermore, the complete reanalysis period (1948–2008) is analyzed in order to compare results with the assimilation data period (1980–2008), resulting in some discrepancies, especially in the Atlantic basin.
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