Методика неинвазивного мониторинга дыхательного паттерна у больных бронхиальной астмой

Impedance pneumography (IP) system for breathing pattern monitoring was developed. IP system was calibrated volumetrically using integrated pneumotachigraphy. We studied mean breathing pattern parameters in 39 healthy subjects, patients with mild (n=39), moderate (n=25) and severe (n=17) bronchial asthma (BA) in sitting posture during 10 min. interval. Mean breathing rate was significantly (p<0.05) higher in all BA groups (18.0±0.6, 18.0±0.6, 20.4±1.2 /min., M±m) than in controls (16,2±0,6 /min.). Patients with severe BA demonstrated significantly higher mean partial expiratory time (58.2±0.8%) and lower mean tidal volume (0.35±0.04 I) than healthy subjects (55.8±0.5% and 0.47±0.02 I, respectively). We concluded that developed noninvasive breathing pattern monitoring method is informative in patients with BA.Разработана методика автоматизированного неинвазивного мониторинга дыхательного паттерна методом импедансной пневмографии, калиброванной в единицах объема вентиляции, с помощью интегрированной пневмотахограммы. Проведено сравнительное исследование средних величин параметров дыхательного паттерна у 39 здоровых лиц и больных бронхиальной астмой (БА) с легким (л=39), среднетяжелым (п=25) и тяжелым (л=17) течением заболевания в положении сидя за 10 мин. Во всех группах больных БА средняя частота дыхания (18,0±0,6, 18,0±0,6, 20,4±1,2 в 1 мин, М ±т) была достоверно (р<0,05) выше, чем в контроле (16,2±0,6 в 1 мин). В группе с тяжелым течением БА наблюдалось достоверное увеличение среднего относительного времени выдоха в дыхательном цикле (58,2±0,8%) и уменьшение среднего дыхательного объема (0,35±0,04 л) относительно контроля (55,8±0,5% и 0,47±0,02 л соответственно). Сделан вывод о информативности разработанной методики для мониторинга вентиляции легких у больных БА

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo.

Synapses are an early pathological target in many neurodegenerative diseases ranging from well-known adult onset conditions such as Alzheimer and Parkinson disease to neurodegenerative conditions of childhood such as spinal muscular atrophy (SMA) and neuronal ceroid lipofuscinosis (NCLs). However, the reasons why synapses are particularly vulnerable to such a broad range of neurodegeneration inducing stimuli remains unknown. To identify molecular modulators of synaptic stability and degeneration, we have used the Cln3-/- 33 mouse model of a juvenile form of NCL. We profiled and compared the molecular composition of anatomically-distinct, differentially-affected pre-synaptic populations from the Cln3-/- 35 mouse brain using proteomics followed by bioinformatic analyses. Identified protein candidates were then tested using a Drosophila CLN3 model to study their ability to modify the CLN3-neurodegenerative phenotype in vivo. We identified differential perturbations in a range of molecular cascades correlating with synaptic vulnerability, including valine catabolism and rho signalling pathways. Genetic and pharmacological targeting of key ‘hub’ proteins in such pathways was sufficient to modulate phenotypic presentation in a Drosophila CLN3 model. We propose that such a workflow provides a target rich method for the identification of novel disease regulators which could be applicable to the study of other conditions where appropriate models exist

PROTECTION OF BRAIN MITOCHONDRIA AGAINST MICRO STROKE-INDUCED INJURY: A STUDY OF ETHYLMETHYLHYDROXYPYRIDINE SUCCINATE IN EXPERIMENTAL MODEL USING TWO PHOTON LASER FLUORESCENT MICROSCOPY

Objective. Mitochondrial injury plays a central role in neuronal death following ischemic stroke. In the present study, we investigated effects of ethylmethylhydroxypyridine succinate on a microstroke-induced mitochondria swelling, a hallmark of mitochondrial injury.Materials and Methods. Ischemic microstroke was induced in Thy1-CFP-MitoS mice expressing cyano fluorescent protein (CFP) in brain mitochondria by impulse infrared laser. Ethylmethylhydroxypyridine succinate 25 mg/kg or saline (control) were administered i.p. at 30 min after the stroke onset. A period of observation was 48 h. Brain images were obtained by two photon laser fluorescent microscopy and analyzed using a software developed in Neurotar Ltd (Finland). Nonparametric Mann-Whitney-Wilcoxon test was used for te statistical analysis of results.Results. Microstroke resulted in mitochondria swelling, i.e. injury, in the zone surrounding the thrombus. The most profound changes of mitochondrial morphology were observed at 2 h from the stroke onset. Ethylmethylhydroxypyridine succinate significantly reduces the stroke-induced swelling at 1 h (p<0.05) and 2 h (p<0.05), as compared to the control.Conclusion. These results suggest that ethylmethylhydroxypyridine succinate significantly protects brain mitochondria against microstroke-induced injury

KCC2 interacts with the dendritic cytoskeleton to promote spine development.

The neuron-specific K-Cl cotransporter, KCC2, induces a developmental shift to render GABAergic transmission from depolarizing to hyperpolarizing. Now we demonstrate that KCC2, independently of its Cl− transport function, is a key factor in the maturation of dendritic spines. This morphogenic role of KCC2 in the development of excitatory synapses is mediated by structural interactions between KCC2 and the spine cytoskeleton. Here, the binding of KCC2 C-terminal domain to the cytoskeleton-associated protein 4.1N may play an important role. A more general conclusion based on our data is that KCC2 acts as a synchronizing factor in the functional development of glutamatergic and GABAergic synapses in cortical neurons and networks

Antiinflammatory therapy with canakinumab for atherosclerotic disease

BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. Copyright © 2017 Massachusetts Medical Society