Hypoalbuminemia in COVID-19: assessing the hypothesis for underlying pulmonary capillary leakage.

BACKGROUND: Since the first observations of patients with COVID-19, significant hypoalbuminaemia was detected. Its causes have not been investigated yet. OBJECTIVE: We hypothesized that pulmonary capillary leakage affects the severity of respiratory failure, causing a shift of fluids and proteins through the epithelial-endothelial barrier. METHODS: One hundred seventy-four COVID-19 patients with respiratory symptoms, 92 admitted to the intermediate medicine ward (IMW) and 82 to the intensive care unit (ICU) at Luigi Sacco Hospital in Milan, were studied. RESULTS: Baseline characteristics at admission were considered. Proteins, interleukin 8 (IL-8) and interleukin 10 (IL-10) in bronchoalveolar lavage fluid (BALF) were analysed in 26 ICU patients. In addition, ten autopsy ultrastructural lung studies were performed in patients with COVID-19 and compared with postmortem findings in a control group (bacterial pneumonia-ARDS and H1N1-ARDS). ICU patients had lower serum albumin than IMW patients [20 (18-23) vs 28 (24-33) g L-1 , P < 0.001]. Serum albumin was lower in more compromised groups (lower PaO2 -to-FiO2 ratio and worst chest X-ray findings) and was associated with 30 days of probability of survival. Protein concentration was correlated with IL-8 and IL-10 levels in BALF. Electron microscopy examinations of eight out of ten COVID-19 lung tissues showed loosening of junctional complexes, quantitatively more pronounced than in controls, and direct viral infection of type 2 pneumocytes and endothelial cells. CONCLUSION: Hypoalbuminaemia may serve as severity marker of epithelial-endothelial damage in patients with COVID-19. There are clues that pulmonary capillary leak syndrome plays a key role in the pathogenesis of COVID-19 and might be a potential therapeutic target.

Extended transsphenoidal microsurgical approach for diaphragma sellae and tuberculum meningiomas.

Diaphragma sellae meningiomas represent a difficult challenge for neurosurgeons; they are generally operated on by a transcranial approach. Some authors reported transsphenoidal surgery in selected cases, but without accurately focusing the surgical technique that should be necessary for removing the typical hard fibrous tissue of the meningioma, that is not aspirable, by this approach. We present the surgical technique and the useful instrumentarium for removing a diaphragma sellae meningioma through an extended microsurgical transsphenoidal approach.

Echocardiography and cardiac assist devices.

Mechanical circulatory support is, nowadays, a well established treatment modality for end stage heart failure. Patients candidate for cardiac transplantation who decompensate while awaiting graft can be supported by long-term left ventricular assist devices (long-term LVAD). These devices are intracorporeal pumps, expensive and complicated to install, but offer the advantages of a high cardiac output and a good patient mobility. Echocardiography is usually applied to any kind of LVAD to accomplish: preoperative evaluation to exclude contraindications, intraoperative when circulatory support starts to assess left ventricular (LV) filling and unloading, postoperative evaluation during intensive care unit course to prevent hypovolemia, cardiac tamponade and right ventricular failure, controls during assistance for suspected device malfunction. Short-term devices are utilized as acute support after the initial resuscitation of the patient. These devices are bedside extracorporeal pumps, less expensive and less complicated to install. They provide a brief but sufficient time to wait patient recovery (''bridge to recovery'') or to evaluate further therapies (''bridge to long-term device'' or ''bridge to transplantation''). Echocardiography has an important role during implantation to guide cannulae positioning, to prevent insufficient LV unloading, to detect echo contrast enhancement with blood stagnation and intracardiac clot formation, to titrate pharmacologic support, and to assess myocardial recovery.

Impella recover 100 microaxial left ventricular assist device: the Niguarda experience.

BACKGROUND: The Impella Recover 100 (IR100) is an intravascular microaxial blood pump used to support blood circulation for a maximum of 7 days in cases of reduced left ventricular function, for example in postcardiotomy low output syndrome or in cardiogenic shock after acute myocardial infarction. MATERIALS AND METHODS: We supported five patients with the IR100. The mean age, cardiac index (CI), and ejection fraction (EF) of our population were 42 years, 1.83 L/min/m(2), and 20%, respectively. Two patients (group A) with ischemic dilated cardiomyopathy were bridged to heart transplant. Two patients (group B) with fulminan myocarditis and septic shock were bridged to recovery. One patient, with severe valvular cardiomyopathy who underwent aortic valve replacement and mitral valve annuloplasty, was supported to weaning from ECC. RESULTS: Mean support time was 9.8 +/- 2.3 days. Only one acute myocarditis patient died from a severe vasoplegic syndrome despite maximal inotropic and vasoactive support. Both group A patients were successfully transplanted. Among group B, the second patient resolved the septic status and was slowly weaned from the device and discharged home with moderate improvement of LV function (EF = 40%). Patient C was weaned from the IR100 and electively placed on the heart transplant recipient list. CONCLUSIONS: IR100 is a device that in our experience can be utilized for various indications for short-term support. In compromised patients where a traditional LVAD is contraindicated, the IR100 showed good results, for it is minimally invasive and does not need ECC or systemic anticoagulation.

Time-course phosphorylation of the mitogen activated protein (MAP) kinase group of signalling proteins and related molecules following middle cerebral artery occlusion (MCAO) in rats.

Recovery from the debilitating effects of ischaemic stroke is variable and unpredictable. To maximize patient recovery, a greater understanding of the molecular mechanisms involved in regulating both apoptosis and the repair processes affecting neuronal protection, particularly in the penumbra region, is desirable. We have previously shown, in human subjects, the increased expression of several growth factors soon after stroke, together with appearance of tyrosine phosphorylated proteins, in particular mitogen activated protein (MAP) kinase (ERK1/2). In this paper, we demonstrate a relatively short-lasting (< 12 h), but substantial increase in expression of phosphorylated proteins, in particular, p-JNK (phosphorylated c-Jun N-terminal kinase) and p-ERK1/2 in both the grey matter penumbra and infarcted tissue of rats, following permanent middle cerebral artery occlusion. p-ERK1/2 was associated with neurones and endothelial cells in the vicinity of the infarct while p-JNK was mainly expressed in neurones. Expression of both p-MEK3/6 and p-p38 MAP kinase was also increased in neurones and astroglia, within 1 h of infarction, p-p38 remaining elevated and associated with neurones and in particular with astroglia in the penumbra region for > 4 days. Evidence suggests that short-term activation of these proteins may be detrimental to neuronal survival, while their transient nature makes them unlikely to support angiogenesis, revascularization and reperfusion over a period of days and weeks. On the other hand, short-medium-term up-regulation of neuronal p-JNK, p-c-Jun, p-Stat-1 and p-p38 might be a factor in the regulation of apoptosis. Therapeutic manipulation of phosphorylation/activation of these and other important signalling intermediates might form the basis of an appropriate treatment to maximize revascularization and neuronal protection after ischaemic stroke.

Th1/Th2 lymphocyte polarization in asthma.

Asthma is a complex inflammatory disease of the lung characterized by variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Inflammation in asthma consists of airway infiltration by mast cells, lymphocytes, and eosinophils. There is accumulating evidence that CD4+ lymphocytes with a Th2-cytokine pattern play a pivotal role in the pathogenesis of asthma. These cells orchestrate the recruitment and activation of the primary effector cells of the allergic response (mast cells and eosinophils), through the release of cytokines such as IL-4, IL-5, and IL-13. Allergic inflammation is also implicated in airway epithelium changes, although the mechanisms by which inflammatory cells and, in particular, T cells interact with the epithelium are not completely clarified. This paper explores the role of T cells in the allergic inflammation of asthma.

Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma control. On behalf of the Italian Study Group.

OBJECTIVES: This study was designed to compare the effects of a 6-month treatment with budesonide 100 microg bid (low dose) and 400 microg bid (standard reference dose) in controlling symptoms and lung function in a group of asthmatics with moderate asthma (baseline FEV(1) > or = 50% and < or = 90% of predicted values) previously treated with inhaled beclomethasone dipropionate (500 to 1,000 microg/d). Moreover, we investigated whether or not asthma exacerbations could be treated by a short-term increase in the daily dose of budesonide. METHODS: After a 2-week run-in period and 1-month treatment with a high dose of budesonide (800 microg bid), 213 patients with moderate asthma were assigned to randomized treatments. Daily treatment included budesonide (bid) plus an additional treatment in case of exacerbation (qid for 7 days). Treatments were as follows: budesonide 400 microg plus placebo (group 1); budesonide 100 microg plus budesonide 200 microg (group 2); and budesonide 100 microg plus placebo (group 3). Symptoms and a peak expiratory flow (PEF) diary were recorded and lung function was measured each month. An exacerbation was defined as a decrease in PEF > 30% below baseline values on 2 consecutive days. RESULTS: We found that that 1-month treatment with a high budesonide dose remarkably reduced all asthma symptoms. Moreover, symptoms were under control in all treatment groups throughout the study period. Similarly, lung function improved and remained stable, and no relevant differences between groups were observed. In each treatment group, the majority of patients had no exacerbations. In patients treated with the standard budesonide dose (group 1), the number of exacerbations and days with exacerbations were significantly lower than in group 3 (intention-to-treat analysis). Additionally, patients treated with low budesonide dose plus budesonide (group 2) experienced a significantly lower number of exacerbations and days with exacerbations compared to group 3 (per-protocol analysis). CONCLUSIONS: This study demonstrates that when patients with moderate asthma had reached a stable clinical condition with a high dose of budesonide, a low dose of budesonide (200 microg/d) is as effective as the standard dose (800 microg/d) in the control of symptoms and lung function over a period of several months. Furthermore, results showed that the addition of inhaled budesonide (800 microg/d) at onset of an asthmatic exacerbation has a beneficial clinical effect.

Efficacy and tolerability of levodropropizine in adult patients with non-productive cough. Comparison with dextromethorphan.

The results of a double-blind, randomized clinical trial involving 209 adult patients of either sex with moderate non-productive cough are reported. The therapeutic efficacy and the tolerability of levodropropizine syrup (60 mg t.i.d. for 5 days) was evaluated in comparison with dextromethorphan syrup (15 mg t.i.d. for 5 days). Efficacy was assessed by the number of coughing spells in a 6h period, the cough frequency classes, the cough intensity and the night awakenings due to cough. Tolerability was evaluated by laboratory results, vital signs and any adverse event occurred during the clinical trial, including presence or absence of somnolence. Independently from the underlying pathology and from the degree of baseline cough severity, the number of coughing spells was significantly (P < 0.05) reduced by both levodropropizine and dextromethorphan already after the 2nd day of treatment, the effect and its time of onset being similar for both drugs. Cough intensity was significantly (P < 0.01) reduced by both drugs throughout the treatment, at an earlier time with levodropropizine than with dextromethorphan. Concurrently with the relief of cough, the number of night awakenings was decreased remarkably and significantly (P < 0.05), with levodropropizine displaying an improvement significantly higher (P < 0.05) than dextromethorphan. No change in laboratory tests values was considered clinically relevant and vital signs were not clinically affected by the study drugs. The number of patients reporting adverse events was significantly higher (P < 0.05) in the dextromethorphan (12.1%) than in the levodropropizine (3.6%) group. Overall, somnolence was reported for a low percentage of patients with both drugs, with the percentage of patients experiencing this side effect being one half in the group treated with levodropropizine (4.6%) as compared with dextromethorphan (10.4%). These results confirm the antitussive effectiveness of levodropropizine and point out a more favourable benefit/risk profile when compared to dextromethorphan.

[Effectiveness of and tolerance to ceftibuten in the treatment of chronic bacterial bronchitis exacerbations in an elderly population]. / Efficacia e tollerabilitá del ceftibuten nel trattamento delle esacerbazioni batteriche della bronchite cronica in una popolazione anziana.

117 patients suffering for bacterial exacerbation of chronic bronchitis were treated with ceftibuten, a new orally administered cephalosporin, at the dosage of 400 mg once a day for 7.9 days (range 5-14). The results, referring to 105 evaluable patients, underlyne ceftibutent's efficacy (good clinical results in 96.1% of 102 treated patients) and safety; before and after treatment values of spirometric tests were notable in terms of improvement of lung functions.

Evaluation of the efficacy of pidotimod in the exacerbations in patients affected with chronic bronchitis.

The efficacy and safety of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new oral synthetic immunostimulating agent, were investigated in a multicentre study, performed in 10 university and hospital centres of pneumophthisiology and respiratory physiopathology, according to a double-blind vs. placebo experimental design. Primary objective of the investigation was to verify the efficacy of pidotimod against infectious exacerbations in patients affected with chronic bronchitis. 181 inpatients or outpatients (117 male, 64 female; mean age: 62.5 years), affected with chronic bronchitis, were enrolled in the study. Pidotimod 800 mg/die or placebo sachets were administered by oral route for 60 consecutive days, followed by a 60-day follow-up period. Clinical observations were performed at baseline (D 0), after 30 (D 30) and 60 (D 60) days of treatment, as well as at the end of the follow-up (D 120). Time and frequency of infectious relapses were considered as the target variable for the evaluation of the efficacy of the drug. Clinical picture, expectoration characteristics, spirometric parameters and laboratory tests were monitored to evaluate patients' conditions. The results indicate that pidotimod is significantly more effective than placebo against infectious relapses in patients suffering from chronic bronchitis. During the first month, 9% of patients treated with pidotimod were affected with an infectious relapse vs. 39.5% of patients treated with placebo (chi 2, p < 0.001). In the second month, infectious episodes were reported by 1.2% of patients treated with the drug vs. 46.1% of patients treated with placebo (chi 2, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Phenotypic features and secretory pattern of alveolar macrophages in atopic asthmatic patients.

The aim of this study was to evaluate by cytofluorimetry, the phenotype and the activation of alveolar macrophages (CD14; CD33; CD44; CD54; CD23; HLA-DR) and, by radioimmunoassay, the "in vivo and in vitro" macrophage secretory pattern (IL-1 alpha; IL-1 beta; IL6; IL8; PGE2; PGD-1 alpha; TXB2; LTB4) in atopic patients with mild asthma in intercritical phase and with bronchial hyperreactivity (PD20 FEV1 = 377 +/- 262.8 micrograms). In asthmatic patients we have demonstrated that the number of cells recovered in BALF expressing the phenotypic features (CD14; CD33; HLA-DR; CD23; CD44; CD54) was larger than in control subjects. By analysing the culture medium of unstimulated and LPS-stimulated alveolar macrophages from asthmatic and normals we have demonstrated a greater production of IL-1 beta (p = 0.005) and IL-8 (p = 0.005) in the first group than in one second, as confirmed by a Wilcoxon test. Concerning the secretory pattern in BALF of asthmatic patients we obtained similar results, showing a significant IL-1 beta (p = 0.005) and IL-8 (p = 0.002) increase suggesting a persistent cellular activation. On the contrary we could not show any significant increase of IL-1 alpha (p = 0.31) and IL-6 (p = 0.22). The cellular activation was confirmed by increased levels of different chemical mediators such as TXB2 (p = 0.005); LTB4 (p = 0.004); PGE2 (p = 0.007); PGF-1 alpha (p = 0.008) which were recovered from BALF of asthmatic patients compared to normal subjects. In conclusion alveolar macrophages play an important role in the pathogenesis of asthma because of the presence of cytokines and mediators in BALF and in the supernatant of alveolar macrophage cultures.

Levodropropizine in the premedication to fibrebronchoscopy.

The aim of the study was to evaluate the efficacy of cough-preventing treatment with levodropropizine, a drug inhibiting peripheral cough reflexes, in patients undergoing bronchial endoscopy. Sixteen patients, aged 37-73 years, suffering from chronic obstructive lung disease in the hypersecretory phase, were included in the study. The experiment was designed as double blind with double observer, controlled versus placebo. As comparative efficacy parameters were considered the number of anaesthetic boluses (lidocaine at 2%) administered during and immediately after the manoeuvre. The number of coughs during and 10 min after bronchoscopy was registered on a magnetic tape and read by a blinded observer thereafter. Levodropropizine was given as oral drops (20 each time, equal to 60 mg active drug) 12 h and 1 h before bronchoscopy. Data analysis was performed by descriptive statistical tests and by the non-parametric Wilcoxon test for paired samples. Levodropropizine treatment significantly reduced the number of anaesthetic enemas (p less than 0.01), and presented an excellent tolerability and safety profile.

Pefloxacin in lower respiratory tract infections.

To determine the efficacy and safety of pefloxacin in the treatment of lower respiratory tract infections, a multicentre trial involving four departments of respiratory diseases was performed. One hundred and eight patients were admitted to the study: most of them were affected with exacerbations of chronic bronchitis or with pneumonia complicating lung cancer. Isolation and identification of responsible microorganisms from bronchial secretions was possible in 78 patients. Seven patients were withdrawn, one for worsening of the underlying disease and six for early side-effects. Thus, of 108 patients recruited, 101 completed the course of therapy (pefloxacin 400 mg bd for 5-14 days) and could be submitted to final evaluation. Of these 43 (42.6%) were cured and 48 (47.5%) showed improvement. Eradication of responsible microorganisms was achieved in 70 (90.9%) of 77 patients microbiologically evaluated. Side-effects of moderate severity were observed in 12 patients (gastrointestinal disturbances in 11 and dyspnoea in one); these did not necessitate discontinuation of therapy.

[Cefotetan in the therapy of respiratory infections. Multicenter research]. / Il cefotetan nella terapia delle infezioni respiratorie. Ricerca multicentrica.

In a controlled multicenter trial 291 patients have been treated with cefotetan. They suffered from acute or chronic exacerbated bronchopulmonary disorders. In 110 patients it was possible to identify the etiological agent: enterobacteria (62), non-fermentative gram-negative bacilli (10), Haemophilus influenzae (8), Branhamella catarrhalis (1), Streptococcus pneumoniae (19), Staphylococcus aureus (12), Streptococcus pyogenes (4). In the exacerbations of chronic bronchitis (203), cefotetan was generally administered at the dose of 1 g/12 h i.m., whereas it was administered at the dose of 2 g/12 h i.v. in acute infection. The mean duration of therapy was 8.8 days. Positive clinical results were obtained in 251 patients (86.2%) with eradication of the pathogen initially isolated in 90.5% of cases. Cefotetan showed good local and general tolerance. The results obtained confirm those of studies concerning limited numbers of patients and show the efficacy of cefotetan both in acute and chronic pathologies, also in patients with serious involvement of their general conditions (concomitant pathologies, high mean age).