Abstract Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).
Although Frontotemporal dementia (FTD) is generally indicated as the second most common form of dementia after Alzheimer's Disease (AD), epidemiological specific studies aimed to measure the prevalence are rarely conducted. Specifically, no data exist in Italian population. Aim of the study was to calculate the prevalence rate of FTD in a rural population of southern Italy where a large FTD family with a PGRN mutation has been described (Bruni et al, Neurology 2007). The whole population of all residents who were aged ≥ 50 y (702 subjects mean age 71.9 ± 11.2) was selected for a door to door study. Screening instruments were: 1) a questionnaire containing demographic characteristics; 2) a form collecting data on health and vascular risk factors filled out by the family physician; 3) MMSE, ADL, IADL, phonological and categorical verbal fluency. Subjects presenting with MMSE score ≤ 21and/or behavioural disturbances and/or altered verbal fluency performed a complete neurological/neuropsychological evaluation by using a Mental Deterioration Battery (Carlesimo et al. Eur Neurol, 1996).A venous blood sample was taken for biochemistry and APOE genotype. 509 individuals (72%, mean age 71.6 ± 11.1; 55.4% of females) accepted to participate. 18.1% (92 persons) performed the second step. 29 patients showed dementia: three patients (10.3%) were diagnosed as having AD, three patients (10.3%) had VaD, 16 (55.2%) had FTD, one person had Parkinson dementia (3.5%), six patients (20.7%) showed other forms of dementia. Overall prevalence of dementia was 5.7 (95% CI 3.8 to 8.2) per 100. FTD prevalence was 3.1 (95% CI 1.8 to 5.1) per 100.Mean age at onset in FTD patients resulted 77.3 years, there was a female preponderance (11:5) and APOEϵ4 allele frequency in FTD patients was 12.5% (NS). Overall prevalence rate of dementia is in agreement with the Italian Longitudinal study on Aging (International Journal Epidemiology, 1997). Prevalence rate of FTD is however, higher and showing a later onset than previously reported. APOEe4 allele is not statistically associated with FTD. Higher FTD prevalence could be explained by a founder effect probably present in this isolated population.
Abstract The distribution of glucose 6-phosphate dehydrogenase and D-glyceraldehyde 3-phosphate: NADP reductase activities in maize leaf blades was investigated by differential tissue fractionation. The reliability of this technique was verified on the basis of distribution of several marker enzymes (NADP-malate dehydrogenase and phosphoenolpyruvate carboxylase for mesophyll cells, NADP-malic enzyme and fructose 1,6-bisphosphate aldolase for bundle-sheath cells). Glucose 6-phosphate dehydrogenase is found mainly (70%) in the mesophyll, similar to the triose phosphate dehydrogenases, both NAD- and NAD(P)-dependent. D-glyceraldehyde 3-phosphate: NADP reductase occurs 75% in the mesophyll. Neither enzyme is found in chloroplasts. Specific activities of nine leaf enzymes were followed for up to 7 days after exposure of 4-day-old dark-grown seedlings to the light. While several activities related to C4 photosynthesis (aldolase, phosphoenolpyruvate carboxylase, NADP-glyceraldehyde 3-phosphate dehydrogenase, NADP-malic enzyme, NADP-malate dehydrogenase) increase with time as expected, D-glyceraldehyde 3-phosphate: NADP reductase shows a limited increase after illumination to final levels of 7-10 nmol min−1 mg−1 protein. NAD-malate dehydrogenase activity decreases first, to recover later. NAD-glyceraldehyde 3-phosphate dehydrogenase and glucose 6-phosphate dehydrogenase drop to low activities in the greening leaf, the latter enzyme to rates comparable to D-glyceraldehyde 3-phosphate: NADP reductase and concomitant with the appearance of a new isozyme (Valenti et al., 1984). The function of glucose 6-phosphate dehydrogenase and D-glyceraldehyde 3-phosphate: NADP reductase in the green maize mesophyll is discussed in the context of C4 metabolism.
The airway epithelium stretches and relaxes during the normal respiratory cycle, and hyperventilation exaggerates this effect, resulting in changes in lung physiology. In fact, stretching of the airways influences lung function and the secretion of airway mediators, which in turn may cause a potentially injurious inflammatory response. This aim of the present narrative review was to illustrate the current evidence on the importance of mechanical stress in the pathophysiology of lung diseases with a particular focus on chronic obstructive pulmonary disease (COPD) and to discuss how this may influence pharmacological treatment strategies. Overall, treatment selection should be tailored to counterpart the effects of mechanical stress, which influences inflammation both in asthma and COPD. The most suitable treatment approach between a long-acting β 2-agonists/long-acting antimuscarinic-agonist (LABA/LAMA) alone or with the addition of inhaled corticosteroids should be determined based on the underlying mechanism of inflammation. Noteworthy, the anti-inflammatory effects of the glycopyrronium/indacaterol combination on hyperinflation and mucociliary clearance may decrease the rate of COPD exacerbations, and it may synergistically improve bronchodilation with a double action on both the cyclic adenosine monophosphate (cAMP) and the acetylcholine pathways.
Abstract: In the upcoming years, the proportion of elderly patients with chronic obstructive pulmonary disease (COPD) will increase, according to the progressively aging population and the increased efficacy of the pharmacological treatments, especially considering the management of chronic comorbidities. The issue to prescribe an appropriate inhalation therapy to COPD patients with significant handling or coordination difficulties represents a common clinical experience; in the latter case, the choice of an inadequate inhalation device may jeopardize the adherence to the treatment and eventually lead to its ineffectiveness. Treatment options that do not require particular timing for coordination between activation and/or inhalation or require high flow thresholds to be activated should represent the best treatment option for these patients. Nebulized bronchodilators, usually used only in acute conditions such as COPD exacerbations, could fulfill this gap, enabling an adequate drug administration during tidal breathing and without the need for patients’ cooperation. However, so far, only short-acting muscarinic antagonists have been available for nebulization. Recently, a nebulized formulation of the inhaled long-acting muscarinic antagonist glycopyrrolate, delivered by means of a novel proprietary vibrating mesh nebulizer closed system (SUN-101/eFlow ® ), has progressed to Phase III trials and is currently in late-stage development as an option for maintenance treatment in COPD. The present critical review describes the current knowledge about the novel nebulizer technology, the efficacy, safety, and critical role of nebulized glycopyrrolate in patients with COPD. To this end, PubMed, ClinicalTrials.gov, Embase, and Cochrane Library have been searched for relevant papers. According to the available results, the efficacy and tolerability profile of nebulized glycopyrrolate may represent a valuable and dynamic treatment option for the chronic pharmacological management of patients with COPD. Keywords: glycopyrrolate, glycopyrronium, nebulizer, COPD, antimuscarinic, device
The leaves of maize seedlings contain two principal isozymes of fructose 1,6-bisphosphate aldolase (E.C. 4.1.2.13), one chloroplastic and one cytosolic (Gasperini and Pupillo, 1982). Mesophyll protoplasts were separated from bundle sheath (BS) strands of both light-grown and dark-grown maize leaves. Aldolase isozymes were separated from extracts of chloroplasts, etioplasts, protoplasts and BS strands by column isoelectric focusing. The major isozyme of green leaves (pI 4.2) was exclusively in BS chloroplasts, and there was no evidence of other isozymes occurring in BS tissue. The cytosolic isozyme (pI 6.7) was present in protoplasts of mesophyll cells, where it may limit the synthesis of hexose-phosphates (estimated activity of 9.4 μmol h−1 g−1 fr. wt.) together with lower activities of an acidic form (pI 4.6). Etiolated leaves contained significant amounts of the pI 6.7 isozyme in both mesophyll and BS cells, but also minor activities of one or more acidic forms with pI values of 4.4–4.7 (average pI 4.6) which appear to be located partly in BS etioplasts. The main developmental events for maize leaf aldolase after illumination were a moderate decrease of cytosolic isozyme (pI 6.7) which disappears from the BS within hours and a large, gradual increase of the BS plastid isozyme (pI 4.2). The isoform with a pI 4.6 also increased rapidly to a low, steady activity in greening mesophyll protoplasts.
