The use of non-invasive ventilation in very old patients with hypercapnic acute respiratory failure because of COPD exacerbation.

AIMS: We prospectively enrolled 207 patients (121 were 75 or older and 86 younger than 75) who were admitted to three Respiratory Monitoring Units. The primary outcomes were intubation and mortality rates; the secondary outcomes were changes in arterial blood gases analysis, non-invasive ventilation (NIV) duration and length of hospital stay. RESULTS: Hospital mortality was similar in the two groups, as were intubation rates. The proportion who died in the very old patient group was 19.8% (24/121) vs. 10.4% (9/86) in the younger group. Intubation rate was 10.7% (13/121) in the very old patient group and 11.6% (10/86) in the younger group. The presence of comorbidities, the severity of illness (SAPS II), the level of consciousness, NIV failure (intubation), absolute value of pH prior to NIV, as well as the changes in pH and paCO2 and PaO2 /FiO2 after 2 h of NIV, were the variables associated with higher mortality. Very old patients had significantly higher NIV duration than younger patients (69.0 ± 47.0 vs. 57.0 ± 27.0 h) (p ≤ 0.03) and hospital stays (11.6 ± 3.8 vs. 8.4 ± 1.4) (p ≤ 0.02). CONCLUSIONS: The use of NIV in very old patients was effective in many cases. Endotracheal intubation after NIV failure was not efficacious in either group.

Mechanism of block of single protopores of the Torpedo chloride channel ClC-0 by 2-(p-chlorophenoxy)butyric acid (CPB).

We investigated in detail the mechanism of inhibition by the S(-) enantiomer of 2-(p-chlorophenoxy)butyric acid (CPB) of the Torpedo Cl(-)channel, ClC-0. The substance has been previously shown to inhibit the homologous skeletal muscle channel, CLC-1. ClC-0 is a homodimer with probably two independently gated protopores that are conductive only if an additional common gate is open. As a simplification, we used a mutant of ClC-0 (C212S) that has the common gate "locked open" (Lin, Y.W., C.W. Lin, and T.Y. Chen. 1999. J. Gen. Physiol. 114:1-12). CPB inhibits C212S currents only when applied to the cytoplasmic side, and single-channel recordings at voltages (V) between -120 and -80 mV demonstrate that it acts independently on individual protopores by introducing a long-lived nonconductive state with no effect on the conductance and little effect on the lifetime of the open state. Steady-state macroscopic currents at -140 mV are half-inhibited by approximately 0.5 mM CPB, but the inhibition decreases with V and vanishes for V > or = 40 mV. Relaxations of CPB inhibition after voltage steps are seen in the current responses as an additional exponential component that is much slower than the gating of drug-free protopores. For V = 60 mV) with an IC50 of approximately 30-40 mM. Altogether, these findings support a model for the mechanism of CPB inhibition in which the drug competes with Cl(-) for binding to a site of the pore where it blocks permeation. CPB binds preferentially to closed channels, and thereby also strongly alters the gating of the single protopore. Since the affinity of CPB for open WT pores is extremely low, we cannot decide in this case if it acts also as an open pore blocker. However, the experiments with the mutant K519E strongly support this interpretation. CPB block may become a useful tool to study the pore of ClC channels. As a first application, our results provide additional evidence for a double-barreled structure of ClC-0 and ClC-1.

Chest radiological findings of influenza A H1N1 pneumonia.

OBJECTIVE: The objective of this study was to review chest radiographs (CXR) and chest computer tomography (CT) findings in patients with influenza A H1N1 virus pneumonia. MATERIALS AND METHODS: Of ninety-eight patients with influenza A H1N1 infections seen in the General Hospitals of Villa Scassi, Genoa, and Sestri Levante from September 2009 to December 2009, twenty-eight developed pneumonia. The initial CXR were evaluated for radiological patterns: (ground-glass, consolidation, nodules, reticulation), distribution, and extent of the disease. Chest CT scans were reviewed for the same findings. A new radiographic score (CXR score) was used to evaluate the severity of the illness. RESULTS: The predominant radiological findings on chest CT in the patients at presentation were unilateral or bilateral multifocal ground glass opacities (84.5% of the patients). Consolidation areas had a peribronchovascular and subpleural predominance and were found mainly in the middle and upper zones of the lung. Reticular opacities were found in about 20% of the cases. The most outstanding CXR and chest CT features of the disease were basal and axial alveolar consolidation and ground-glass opacities. The severity of disease as determinate by need for mechanical ventilation was greater in patients with a greater number of lobes involved and a higher CXR score. CONCLUSION: Bilateral ground-glass opacities and areas of consolidation were the predominant radiological findings of influenza A (H1N1) virus pneumonia. Multifocal bilateral opacities and CXR score are strictly correlated with the severity of the illness.

Drastic reduction of the slow gate of human muscle chloride channel (ClC-1) by mutation C277S.

1. Single channel measurements suggest that the human muscle chloride channel ClC-1 presumably has a double barrelled structure, with a fast single protopore gate and a slow common pore gate similar to that of ClC-0, the chloride channel from Torpedo. The single point mutation C212S has been shown to abolish the slow gating of ClC-0 locking the slow gate in the open state. In order to test the hypothesis that the slow gating process found in ClC-1 corresponds to the well characterised slow gate found in ClC-0 we investigated the gating effects in ClC-1 of the homologous mutation corresponding to C212S, C277S. 2. We found that the mutation C277S strongly reduced the slow component of macroscopic gating relaxations at negative and at positive voltages. 3. Time constants of the fast gating relaxations were not affected by the mutation but the minimal open probability of the fast gate at negative voltages was slightly reduced to 0.08 compared with the WT value of 0.22. 4. Additionally, we characterised the block of WT ClC-1 and mutant C277S by the S(-) enantiomer of CPB (2-(p-chlorophenoxy) butyric acid), and found that the block is practically unaffected by the mutation suggesting that CPB does not interact with the slow gate of ClC-1. 5. We conclude that the slow and fast gating processes of ClC-1, respectively, reflect the slow common pore gate and the single protopore gate of the double-barrelled ClC-1 channel.

Two open states and rate-limiting gating steps revealed by intracellular Na+ block of human KCNQ1 and KCNQ1/KCNE1 K+ channels.

KCNQ1, the first member of a new K+ channel family, associates with the small KCNE1 subunit to form the slow cardiac delayed rectifier current, IKs. Mutations in both genes encoding these channels lead to cardiac arrhythmia. We studied the block by intracellular Na+ of human homomeric KCNQ1 (homomers) and heteromeric KCNQ1/KCNE1 (heteromers) expressed in CHO cells (Chinese hamster ovary cell line) using whole-cell patch recording. In the nominal absence of extracellular K+ and with 65 mM intracellular K+, the replacement of 65 mM intracellular N-methyl-D-glucamine (NMDG+) by 65 mM Na+ induced a decay of outward (K+) currents through homomers after maximal activation reminiscent of an inactivation process. The decay had a time constant in the hundreds of milliseconds range. The inactivation process of homomers was, however, not directly dependent on [Na+]i, as evidenced by unaltered biphasic deactivation at negative voltages. An instantaneous voltage-dependent Na+ block of homomers was revealed using tail current protocols with activating prepulses that saturated the gating processes of the channel. The instantaneous block was partially relieved at very large positive voltages (> or = 60 mV) and in 20 mM extracellular K+. The instantaneous block of homomers was much less pronounced if the tail currents were measured after short activating prepulses, demonstrating the presence of (at least) two open states: a first, relatively [Na+]i-insensitive and a subsequent [Na+]i-sensitive open state; the current decay reflects the transition between the two open states. Heteromers exhibited a very similar instantaneous block by Na+i independently of the prepulse duration. Heteromers did not show a Na+i-induced current decay. Our results demonstrate the presence of two open states of KCNQ1 channels with different [Na+]i sensitivities. The rate-limiting step of homomeric KCNQ1 gating at positive voltages is the transition between these two open states. The rate-limiting step of the gating of KCNQ1/KCNE1 channels appears to be the entry into the first open state.