Noninvasive ventilation for patients with acute lung injury or acute respiratory distress syndrome

Few studies have been performed on noninvasive ventilation (NIV) to treat hypoxic acute respiratory failure in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). The outcomes of these patients, for whom endotracheal intubation is not mandatory, depend on the degree of hypoxia, the presence of comorbidities and complications, and their illness severity. The use of NIV as an alternative to invasive ventilation in severely hypoxemic patients with ARDS (ie, P(aO(2))/F(IO(2)) < 200) is not generally advisable and should be limited to hemodynamically stable patients who can be closely monitored in an intensive care unit by highly skilled staff. Early NIV application may be extremely helpful in immunocompromised patients with pulmonary infiltrates, in whom intubation dramatically increases the risk of infection, pneumonia, and death. The use of NIV in patients with severe acute respiratory syndrome and other airborne diseases has generated debate, despite encouraging clinical results, mainly because of safety issues. Overall, the high rate of NIV failure suggests a cautious approach to NIV use in patients with ALI/ARDS, including early initiation, intensive monitoring, and prompt intubation if signs of NIV failure emerge.     

Stress-induced reduction in reward-related prefrontal cortex function

Acute psychological stress can trigger normal and abnormal motivated behaviors such as reward seeking, habitual behavior, and drug craving. Animal research suggests that such effects may result from actions of catecholamines and glucocorticoids that converge in brain regions that regulate motivated behaviors and incentive processing. At present, however, little is known about the acute effects of stress on these circuits in humans. During functional magnetic resonance imaging (fMRI), twenty-seven healthy young women performed a modified version of the monetary incentive delay (MID) task, which is known to robustly engage ventral striatal and medial prefrontal regions. To induce psychological stress, strongly aversive movie clips (versus neutral movie clips) were shown with the instruction to imagine being an eyewitness. Physiological (cortisol levels, heart rate frequency, and heart rate variability) and subjective measurements confirmed successful induction of moderate levels of acute psychological stress. Brain imaging data revealed that stress induction resulted in a significant decrease in reward-related responses in the medial prefrontal cortex (PFC) without affecting ventral striatal responses. Our results thus show that acute psychological stress induces regionally specific changes in functioning of incentive processing circuits. This regional specificity is in line with animal data showing inverted U-shaped relations between levels of stress-related neuromodulators and functioning of the PFC, a structure that is believed to be critical for coordinating behavior in accordance with higher order internal goals. Our findings thus suggest that stress-related increases in habitual and reward-seeking behaviors may be triggered primarily by an impairment of such PFC-dependent cognitive control mechanisms.     

Intrapulmonary percussive ventilation improves the outcome of patients with acute exacerbation of chronic obstructive pulmonary disease using a helmet

OBJECTIVE: To evaluate the effect of intrapulmonary percussive ventilation (IPV) by mouthpiece during noninvasive positive-pressure ventilation with helmet in patients with exacerbation of chronic obstructive pulmonary disease (COPD). DESIGN: Randomized clinical trial. SETTING: General intensive care unit, university hospital. PATIENTS: Forty patients with exacerbation of COPD ventilated with noninvasive positive-pressure ventilation by helmet were randomized to two different mucus clearance strategies: IPV (IPV group) vs. respiratory physiotherapy (Phys group). As historical control group, 40 patients receiving noninvasive positive pressure and ventilated by face mask treated with respiratory physiotherapy were studied. INTERVENTIONS: Two daily sessions of IPV (IPV group) or conventional respiratory physiotherapy (Phys group). MEASUREMENTS AND MAIN RESULTS: Physiologic variables were measured at entry in the intensive care unit, before and after the first session of IPV, and at discharge from the intensive care unit. Outcome variables (need for intubation, ventilatory assistance, length of intensive care unit stay, and complications) were also measured. All physiologic variables improved after IPV. At discharge from the intensive care unit, Paco2 was lower in the IPV group compared with the Phys and control groups (mean +/- sd, 58 +/- 5.4 vs. 64 +/- 5.2 mm Hg, 67.4 +/- 4.2 mm Hg, p < .01). Pao2/Fio2 was higher in IPV (274 +/- 15) than the other groups (Phys, 218 +/- 34; control, 237 +/- 20; p < .01). In the IPV group, time of noninvasive ventilation (hrs) (median, 25th-75th percentile: 61, 60-71) and length of stay in the intensive care unit (days) (7, 6-8) were lower than other groups (Phys, 89, 82-96; control, 87, 75-91; p < .01; and Phys, 9, 8-9; control, 10, 9-11; p < .01). CONCLUSIONS: IPV treatment was feasible for all patients. Noninvasive positive-pressure ventilation by helmet associated with IPV reduces the duration of ventilatory treatment and intensive care unit stay and improves gas exchange at discharge from intensive care unit in patients with severe exacerbation of COPD.     

Lower anticoagulation for mechanical heart valves: experience with the ATS bileaflet valve

Background: The design of the bileaflet ATS (ATS Medical Inc., Minneapolis, USA) mechanical valve incorporates an open pivot at the hinge mechanism. Total washout of the blood at the pivot area was observed using 3-D computational fluid dynamics modelling. This phenomenon could make the valve less vulnerable to clot formation in patients without major thromboembolic risk factors.

Methods: From January 1993 to June 1999, 286 consecutive patients had the ATS valve inserted in the aortic position. Patients were divided into two groups. Group 1 comprised all patients in regular sinus rhythm with good left ventricular function (144 patients). Group 2 included patients in non-sinus rhythm and/or with large hypocontractile left ventricles (142 patients). The anticoagulation regime in group 1 was used to obtain an international normalised ratio (INR) between 1.5 and 2.5. This contrasts with our regular aim to maintain the INR strictly between 2.5 and 3.5 for all mechanical valves, as achieved in group 2.

Results: The follow-up period (99% completeness) ranged from 18 to 84 months. Survival (Kaplan-Meier) was 97 and 98% and 92 and 81% at 1 and 5 years in group 1 and group 2, respectively (P = 0.12). Log rank analysis failed to detect a statistical difference in thromboembolism or bleeding between both groups (P > 0.05). However, trends were in favour of group 1. Univariate analysis selected poor ventricular function and an ‘erratic’ INR value (P = 0.002) as risk factors for death. The sole independent risk factor for bleeding was the use of aspirin (P = 0.025).

Conclusions: The excellent group 1 data and outcome encouraged us to continue our low intensive anticoagulation regime and perhaps should be regarded as a new concept for treatment of selected mechanical valve patients.     

The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition of Mycobacterium tuberculosis viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against M. tuberculosis in vitro, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition of M. tuberculosis growth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistant M. tuberculosis strains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target against M. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development.     

Resveratrol protects against homocysteine‐induced cell damage via cell stress response in neuroblastoma cells

Recent findings underscore that some natural compounds are responsible for specific biochemical effects, i.e., the activation of redox‐sensitive intracellular pathways and modulation of different stress proteins, such as heat shock proteins and sirtuins. Resveratrol, a natural polyphenol widely present in plants, has been shown to display various beneficial effects, including neuroprotection, in several pathological conditions. In the present study, by using differentiated SH‐SY5Y neuroblastoma cells, we investigated the potential protective effects of resveratrol against homocysteine‐induced neurotoxicity. We observed that homocysteine (100 µM) decreased cell viability while at the same time significantly increasing intracellular reactive oxygen species and DNA fragmentation. Cell pretreatment with resveratrol concentrations ranging from 1 to 5 µM elicited protective effects through the reduction of oxidative stress and genotoxic damage. In addition, we observed that resveratrol produced significant changes in the expression of both Hsp70 and sirtuin 1 (SIRT1). After homocysteine treatment in the presence of resveratrol, SIRT1 protein was found abundantly not only in the cytosol but also in the nucleus, as demonstrated by confocal laser scanning microscopy. The results of this study suggest that resveratrol is a potential protective agent against homocysteine‐induced neurotoxicity and that beneficial effects are accompanied by changes in cell stress response. Taken together, these features contribute to our knowledge of underlying mechanisms involved in resveratrol‐induced cell survival. © 2014 Wiley Periodicals, Inc.     

CD28 superagonist-mediated boost of regulatory T cells increases thrombo-inflammation and ischemic neurodegeneration during the acute phase of experimental stroke

While the detrimental role of non-regulatory T cells in ischemic stroke is meanwhile unequivocally recognized, there are controversies about the properties of regulatory T cells (T_reg). The aim of this study was to elucidate the role of T_reg by applying superagonistic anti-CD28 antibody expansion of T_reg. Stroke outcome, thrombus formation, and brain-infiltrating cells were determined on day 1 after transient middle cerebral artery occlusion. Antibody-mediated expansion of T_reg enhanced stroke size and worsened functional outcome. Mechanistically, T_reg increased thrombus formation in the cerebral microvasculature. These findings confirm that T_reg promote thrombo-inflammatory lesion growth during the acute stage of ischemic stroke.     

Differential contribution of Ih to the integration of excitatory synaptic inputs in substantia nigra pars compacta and ventral tegmental area dopaminergic neurons

The selective vulnerability of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is an enigmatic trait of Parkinson's disease (PD), especially if compared to the remarkable resistance of closely related DA neurons in the neighboring ventral tegmental area (VTA). Overall evidence indicates that specific electrophysiological, metabolic and molecular factors underlie SNc vulnerability, although many pieces of the puzzle are still missing. In this respect, we recently demonstrated that 1‐methyl‐4‐phenylpyridinium (MPP+), the active metabolite of the parkinsonizing toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), alters the electrophysiological properties of SNc DA neurons in vitro by inhibiting the hyperpolarization‐activated current (Ih). Here, we present an electrophysiological investigation of the functional role of Ih in the integration of synaptic inputs in identified SNc and VTA DA neurons, comparatively, in acute midbrain slices from TH‐GFP mice. We show that pharmacological suppression of Ih increases the amplitude and decay time of excitatory postsynaptic potentials, leading to temporal summation of multiple excitatory potentials at somatic level. Importantly, these effects are quantitatively more evident in SNc DA neurons. We conclude that Ih regulates the responsiveness to excitatory synaptic transmission in SNc and VTA DA neurons differentially. Finally, we present the hypothesis that Ih loss of function may be linked to PD trigger mechanisms, such as mitochondrial failure and ATP depletion, and act in concert with SNc‐specific synaptic connectivity to promote selective vulnerability.