A 72-hour study to test the efficacy and safety of the "Mucus Slurper" in mechanically ventilated sheep

OBJECTIVE: In patients intubated with endotracheal tubes (ETTs), suctioning is routinely performed to remove mucus from within the ETT and trachea. The Mucus Slurper is a novel ETT with built-in suction ports arranged radially at its tip. We evaluated the safety and efficacy of the Mucus Slurper, compared with conventional tracheal suction, to prevent airway obstruction in sheep with the ETT and trachea oriented below horizontal. DESIGN: Prospective randomized animal study. SETTING: Animal research facility at the National Institutes of Health. SUBJECTS: Twelve healthy sheep. INTERVENTIONS: Sheep were randomized to be intubated with either the Mucus Slurper (study group) or a Hi-Lo Tracheal Tube (Mallinckrodt, St. Louis, MO) (control group) and mechanically ventilated for 72 hrs. In the study group, automatic, timed tracheal aspiration lasted 0.3 secs, was repeated every 2 mins, and was synchronized with the early expiratory phase. In the control group, tracheal suction was performed every 6 hrs or as required. MEASUREMENTS AND MAIN RESULTS: In the control group, tracheal secretions accumulated progressively within the ETT and the trachea. In the study group, all mucus that reached the tip of the Mucus Slurper was aspirated, keeping the lumen of the ETT, and proximal trachea, free from secretions. In the study group, expiratory water trap protein concentration, a crude index to measure mucus drainage through the ETT, was consistently less than the control group (p < .001). At autopsy, no macroscopic injury to the tracheal mucosa was found in either group. In the study group, the respiratory circuit was less colonized than in the control group. There were no statistically significant differences between the two groups in bacterial colonization of the lungs/bronchi. CONCLUSIONS: The Mucus Slurper, combined with orientation of the trachea below horizontal, prevents accumulation of secretions within the lumen of the ETT and trachea, without need for conventional tracheal suctioning.     

A one-to-one telestroke network: the first Italian study of a web-based telemedicine system for thrombolysis delivery and patient monitoring

Over 10 years after European approval, thrombolysis is still limited by a restricted time window and non-optimal territorial coverage. Implementation of telestroke can give a growing number of patients access to treatment. We hereby present the first Italian telemedicine study applied to both the acute and the monitoring phase of stroke care. From January 2011 to December 2013, we tested a web-based, drip, and treat interaction model, connecting the cerebrovascular specialist of one hub center to the Emergency Department of a Spoke center. We then compared thrombolysis delivered using the telestroke model with thrombolysis provided at the Hub Stroke Unit at the time when the telemedicine program was activated. Telethrombolysis data were then compared with data from the two main international telestroke projects (TEMPiS and REACH), and other European telestroke studies performed at the time of writing. We collected a total of 131 thrombolysis procedures (25 telethrombolysis and 106 thrombolysis patients at the Stroke Unit). Statistical analysis with the t test yielded no statistically significant differences between the two populations in door-to-scan, door-to-needle (DTN), and onset-to-treatment times (OTT). Our OTT and DTN pathway times were longer than the TEMPiS and REACH studies but comparable with other European telemedicine trials, despite different models of interaction and number of centers. Our study in a northeastern province of Italy confirms the potential of applying telemedicine to a cerebrovascular pathology.     

Long‐term preclinical magnetic resonance imaging alterations in sporadic Creutzfeldt–Jakob disease

An asymptomatic 74‐year‐old woman, on follow‐up for a carotid body tumor, showed magnetic resonance imaging (MRI) focal restricted diffusion confined to the left temporal and occipital cortices. Thirteen months later, diffusion‐weighted images revealed a bilateral cortical ribbon sign involving all lobes. After 1 month, the patient developed gait instability and cognitive decline rapidly evolving to severe dementia and death within 3 months. Prion protein gene sequence, molecular, and neuropathological studies confirmed the diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) MM1 subtype. Here we show the kinetics of MRI changes and prion spreading in preclinical sCJD MM1. Ann Neurol 2016;80:629–632     

Investigation of the electrophysiological correlates of negative BOLD response during intermittent photic stimulation: An EEG‐fMRI study

Although the occurrence of concomitant positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to visual stimuli is increasingly investigated in neuroscience, it still lacks a definite explanation. Multimodal imaging represents a powerful tool to study the determinants of negative BOLD responses: the integration of functional Magnetic Resonance Imaging (fMRI) and electroencephalographic (EEG) recordings is especially useful, since it can give information on the neurovascular coupling underlying this complex phenomenon. In the present study, the brain response to intermittent photic stimulation (IPS) was investigated in a group of healthy subjects using simultaneous EEG‐fMRI, with the main objective to study the electrophysiological mechanisms associated with the intense NBRs elicited by IPS in extra‐striate visual cortex. The EEG analysis showed that IPS induced a desynchronization of the basal rhythm, followed by the instauration of a novel rhythm driven by the visual stimulation. The most interesting results emerged from the EEG‐informed fMRI analysis, which suggested a relationship between the neuronal rhythms at 10 and 12 Hz and the BOLD dynamics in extra‐striate visual cortex. These findings support the hypothesis that NBRs to visual stimuli may be neuronal in origin rather than reflecting pure vascular phenomena. Hum Brain Mapp 37:2247–2262, 2016. © 2016 Wiley Periodicals, Inc.     

Association between serum values of C-reactive protein and cytokine production in whole blood of patients with type 2 diabetes

Diabetes mellitus accelerates atherosclerotic processes, and it is known that inflammation plays a key role in atherosclerosis. The aim of the present study was to evaluate in patients with Type 2 diabetes whether serum levels of CRP (C-reactive protein) are associated with cytokine production in whole blood. A total of 89 outpatients with Type 2 diabetes were enrolled, and blood pressure, body mass index, fasting blood glucose, glycated haemoglobin, cholesterol, triacylglycerols (triglycerides) and hs-CRP (high-sensitivity CRP) were measured. IL-6 (interleukin-6), IL-1beta (interleukin-1beta) and TNF-alpha (tumour necrosis factor-alpha) were measured before and after 24 h of incubation of whole blood with LPS (lipopolysaccharide) or saline. The basal values of IL-1beta, IL-6 and TNF-alpha were low and were not significantly related to hs-CRP levels. A univariate analysis showed that the level of IL-1beta and IL-6, obtained after 24 h of incubation of whole blood with LPS, increased significantly with increasing levels of hs-CRP and, after adjusting for potential confounders, IL-1beta still remained statistically significant. In our sample of patients with Type 2 diabetes, there was no association between serum hs-CRP levels and basal levels of IL-6, IL-1beta and TNF-alpha. Conversely, a significant association was observed between serum hs-CRP levels and IL-1beta and IL-6 production after 24 h of incubation of whole blood with LPS. In conclusion, our data suggest that patients with Type 2 diabetes and high hs-CRP levels may have an enhanced reactivity in response to specific stimuli that produce different interleukins, with possible implications in inflammatory atherosclerotic processes.     

Therapeutic approaches to prion diseases

Prion diseases are unique in that they comprise sporadic, genetic, and iatrogenically or environmentally acquired forms. When disease is acquired by peripheral route, neuroinvasion occurs via at least two different neural pathways (vague and splanchnic nerves) and is usually preceded by prion propagation in secondary lymphoid organs. Conversely, in the other etiologic forms, PrPSc formation occurs within, and is apparently limited to, the CNS. Longitudinal studies on experimental scrapie indicate that substantial neuropathologic changes (i.e., glial activation and nerve cell degeneration) already are present before the onset of symptoms and are topographically related to PrPSc deposits. Accordingly, any effective intervention should start during the preclinical stage of disease, and be aimed at preventing neuroinvasion or PrPSc propagation in the CNS. Unfortunately, no tests are available currently to detect presymptomatic individuals, except for carriers of pathogenic mutations of the PRNP gene. Inhibition of PrPSc formation can be achieved through (1) abrogation of PrPC synthesis or prevention of its transport to the cell surface; (2) stabilization of the PrPC structure to make its conformational change unfavorable; (3) sequestration of PrPSc; (4) reversion of PrPSc to a protease-sensitive form; or (5) interference with the interaction between PrPC, PrPSc, and other macromolecules that feature in the conversion process. The compounds that have some effectiveness in in vitro, cell culture, or animal models of prion disease seem to operate through one of these mechanisms (see Table 1); however, even the most effective drugs only work when administered at the time of infection or very short thereafter, and these conditions are incurable at present. The heterogeneity and complexity of the etiopathogenesis of prion diseases suggest that various strategies and a combination of several compounds with different modes of actions are likely necessary for prevention and treatment. Major efforts should be focused on the development of preclinical diagnostic tests in conjunction with immunization strategies for diseases acquired by peripheral route and identification of more effective compounds for the other etiological forms.     

ESPRESSO: A novel device for laser-assisted surgery of the anterior eye segment

Introduction: Merging robotics with laser eye surgery could enhance precision, repeatability and automation. During some eye laser procedures the patient is awake, thus eye stabilization is desired to avoid movements that could affect the treatment. Material and methods: The ESPRESSO platform has a two-stage actuation system to position a stabilization tool on the eye, a proximity sensing unit to monitor the stabilization tool position, and a sensing unit to monitor the pressure exerted on the eye. The platform is tested in-vitro and ex-vivo with clinicians. A maximum pressure to be exerted on the eye is defined with expert ophthalmic surgeons to be 22?mmHg: physiological intraocular pressure (IOP) range is 10-21?mmHg. This pressure corresponds to a force of 0.3 N. Results: The necessary contact force to have eye fixation (according to the clinicians' feedback) is evaluated: maximum values resulted always below 0.3 N. A maximum IOP increase of 4.67?mmHg is observed, that is a slight variation with respect to the performance of other platforms (IOP elevations up to 328?mmHg). Conclusion: Design and initial assessment of the platform is presented. Eye stabilization is performed without exceeding the critical contact force value and causing large/sudden IOP increases.     

Tolerability of high cumulative doses of the HFA modulite beclomethasone dipropionate/formoterol combination inhaler in asthmatic patients

The corticosteroid beclomethasone dipropionate (BDP) has been formulated with the long acting beta agonist formoterol (BDP/formoterol 100 microg/6 microg, Foster) in a single inhaler using Modulite technology. We have investigated the acute tolerability of high, cumulative doses of BDP/formoterol compared to formoterol alone and placebo. This was a double blind, 3-way cross-over comparison of 10 puffs of BDP/formoterol 100 microg/6 microg or formoterol 6 microg or placebo during maintenance treatment with BDP/formoterol two puffs per day. Pharmacokinetics over 12h during maintenance treatment was measured on day 7. High cumulative doses were then administered on three separated days. Eighteen patients with asthma were recruited (mean FEV(1) 65% predicted). The primary endpoint was serum potassium over the 12h period after high doses. QTc, blood pressure and heart rate over 12h, and plasma lactate and glucose over 3h following dosing were assessed. Formoterol caused a significantly greater decrease in serum potassium than BDP/formoterol or placebo (difference in mean minimum concentrations; 0.11 and -0.15 mmol/l, respectively, p<0.05 for both comparisons). No significant differences in serum potassium parameters were found between BDP/formoterol and placebo. QTc, plasma lactate and vital signs values observed with the combination were not statistically different from those with formoterol alone. For glucose, the mean maximum increase after formoterol treatment was 0.4 mmol/l (p<0.01 compared to placebo), while BDP/formoterol treatment caused a maximum increase of 0.7 mmol/l (p<0.01 compared to formoterol and placebo). The active metabolite of BDP is beclomethasone-17-monopropriate (B17MP), which reached Cmax at 0.25 h, with an elimination half-life of 3.7 h. Formoterol also reached Cmax at 0.25 h, and concentrations were measurable up to 12 h. High doses of BDP/formoterol did not significantly reduce serum potassium, while formoterol alone did to a greater extent. The BDP/formoterol combination was well tolerated, and exhibited a safety profile generally similar to formoterol alone when administered in high doses to stable asthmatic patients.     

Dynamic Left Ventricular Outflow Tract Obstruction During Myocardial Ischemia in Mitral Valve Prolapse Syndrome

Systolic anterior motion of the mitral valve (MV) with dynamic left ventricular (LV) outflow tract obstruction is a well known phenomenon in hypertrophic cardiomyopathy, or other forms of hyper-dynamic LV function associated with hypovolemic states, or LV hypertrophy. We report three patients with MV prolapse in the absence of the above predisposing factors, who developed an LV outflow dynamic gradient during acute transient myocardial ischemia. An interaction between structural abnormalities of the mitral apparatus and ischemia-dependent LV shape deformity most likely accounted for the outflow gradient.     

Molecular determinants of the physiological adaptation to stress in the cardiomyocyte: a focus on AKT

Cardiomyocytes (CMCs) adapt to physiological or pathological stimuli by undergoing molecular changes which differentiate according to the specificity of the stimulus and eventually generate a phenotype with peculiar molecular characteristics. Here, we review the literature on the molecular mechanisms activated in the CMC during physiologic adaptation to stress, as opposed to maladaptation. The critical role of the IGF-1 receptor/PI3K/Akt signaling pathway during this process is described, including effector targets regulating inotropism and cell size.