Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19.

PURPOSE: Hypovitaminosis D is a highly spread condition correlated with increased risk of respiratory tract infections. Nowadays, the world is in the grip of the Coronavirus disease 19 (COVID 19) pandemic. In these patients, cytokine storm is associated with disease severity. In consideration of the role of vitamin D in the immune system, aim of this study was to analyse vitamin D levels in patients with acute respiratory failure due to COVID-19 and to assess any correlations with disease severity and prognosis. METHODS: In this retrospective, observational study, we analysed demographic, clinical and laboratory data of 42 patients with acute respiratory failure due to COVID-19, treated in Respiratory Intermediate Care Unit (RICU) of the Policlinic of Bari from March, 11 to April 30, 2020. RESULTS: Eighty one percent of patients had hypovitaminosis D. Based on vitamin D levels, the population was stratified into four groups: no hypovitaminosis D, insufficiency, moderate deficiency, and severe deficiency. No differences regarding demographic and clinical characteristics were found. A survival analysis highlighted that, after 10 days of hospitalization, severe vitamin D deficiency patients had a 50% mortality probability, while those with vitamin D ≥ 10 ng/mL had a 5% mortality risk (p = 0.019). CONCLUSIONS: High prevalence of hypovitaminosis D was found in COVID-19 patients with acute respiratory failure, treated in a RICU. Patients with severe vitamin D deficiency had a significantly higher mortality risk. Severe vitamin D deficiency may be a marker of poor prognosis in these patients, suggesting that adjunctive treatment might improve disease outcomes.

Sentinel lymph node biopsy in head and neck melanoma*.

AIM: The purpose of this study is to evaluate prognosis and surgical management of head and neck melanoma (HNM) and the accuracy of sentinel lymph node biopsy (SLNB). PATIENTS AND METHODS: All patients with a primary cutaneous melanoma treated starting from 01/07/1994 to 31/12/2012 in the department of Plastic and Reconstructive Surgery of Bari are included in a electronic clinical medical registry. Within the 90th day from excision of the primary lesion all patients with adverse prognostic features underwent SLNB. All patients with positive findings underwent lymphadenectomy. RESULTS: out of 680 patients affected by melanoma, 84 (12.35%) had HNM. In the HNM cohort lymphoscintigraphy was performed in 57 patients, 15 of which (26.3%) were positive. The percentage of unfound sentinel lymph node was similar both to the HNM group (5,26%) and to patients with melanoma of different sites (OMS 4,92%). There was a recurrence of disease after negative SLNB (false negatives) only in 4 cases. Recurrence-free period and survival rate at 5 years were worse in HNM cohort. CONCLUSION: SLNB of HNM has been for a long time contested due to its complex lymphatic anatomy, but recent studies agreed with this technique. Our experience showed that identification of sentinel lymph node in HNM cohort was possible in 98.25% of cases. Frequency of interval nodes is significantly higher in HNM group. The prognosis of HNM cohort is significantly shorter than OMS one. Finally, this procedure requires a multidisciplinary team in referral centers.

Heart failure with preserved ejection fraction or non-cardiac dyspnea in paroxysmal atrial fibrillation: The role of left atrial strain.

BACKGROUND: Diagnosis of heart failure with preserved ejection fraction (HFpEF) in patients with dyspnea and paroxysmal atrial fibrillation (AF) is challenging. Speckle tracking-derived left atrial strain (LAS) provides an accurate estimate of left ventricular (LV) filling pressures and left atrial (LA) phasic function. However, data on clinical utility of LAS in patients with dyspnea and AF are scarce. OBJECTIVE: To assess relationship between the LAS and the probability of HFpEF in patients with dyspnea and paroxysmal AF. METHODS: The study included 205 consecutive patients (62 ± 10 years, 58% males) with dyspnea (NYHA≥II), paroxysmal AF and preserved LV ejection fraction (≥50%), who underwent speckle tracking echocardiography during sinus rhythm. Probability of HFpEF was estimated using H2FPEF and HFA-PEFF scores, which combine clinical characteristics, echocardiographic parameters and natriuretic peptides. RESULTS: Patients with high probability of HFpEF were significantly older, had higher body mass index, NT-proBNP, E/e', pulmonary artery pressure and larger LA volume index than patients in low-to-intermediate probability groups (all p < 0.05). All components of LAS and LA strain rate showed proportional impairment with increasing probability of HFpEF (all p < 0.05). Out of the speckle tracking-derived parameters, reservoir LAS showed the largest area under the curve (AUC = 0.78, p < 0.001) and the strongest independent predictive value (OR: 1.22, 95% CI 1.08-1.38) to identify patients with high probability of HFpEF. CONCLUSIONS: Reservoir LAS shows a high diagnostic performance to distinguish HFpEF from non-cardiac causes of dyspnea in symptomatic patients with paroxysmal AF.

Microvesicles of the neurohypophysis are biochemically related to small synaptic vesicles of presynaptic nerve terminals.

Nerve endings of the posterior pituitary are densely populated by dense-core neurosecretory granules which are the storage sites for peptide neurohormones. In addition, they contain numerous clear microvesicles which are the same size as small synaptic vesicles of typical presynaptic nerve terminals. Several of the major proteins of small synaptic vesicles of presynaptic nerve terminals are present at high concentration in the posterior pituitary. We have now investigated the subcellular localization of such proteins. By immunogold electron microscopy carried out on bovine neurohypophysis we have found that three of these proteins, synapsin I, Protein III, and synaptophysin (protein p38) were concentrated on microvesicles but were not detectable in the membranes of neurosecretory granules. In addition, we have studied the distribution of the same proteins and of the synaptic vesicle protein p65 in subcellular fractions of bovine posterior pituitaries obtained by sucrose density centrifugation. We have found that the intrinsic membrane proteins synaptophysin and p65 had an identical distribution and were restricted to low density fractions of the gradient which contained numerous clear microvesicles with a size range the same as that of small synaptic vesicles. The peripheral membrane proteins synapsin I and Protein III exhibited a broader distribution extending into the denser part of the gradient. However, the amount of these proteins clearly declined in the fractions preceding the peak of neurosecretory granules. Our results suggest that microvesicles of the neurohypophysis are biochemically related to small synaptic vesicles of all other nerve terminals and argue against the hypothesis that such vesicles represent an endocytic byproduct of exocytosis of neurosecretory granules.

Protein p38: an integral membrane protein specific for small vesicles of neurons and neuroendocrine cells.

An intrinsic membrane protein of brain synaptic vesicles with Mr 38,000 (p38, synaptophysin) has recently been partially characterized (Jahn, R., W. Schiebler, C. Ouimet, and P. Greengard, 1985, Proc. Natl. Acad. Sci. USA, 83:4137-4141; Wiedenmann, B., and W. W. Franke, 1985, Cell, 41:1017-1028). We have now studied the presence of p38 in a variety of tissues by light and electron microscopy immunocytochemistry and by immunochemistry. Our results indicate that, within the nervous system, p38, like the neuron-specific phosphoprotein synapsin I, is present in virtually all nerve terminals and is selectively associated with small synaptic vesicles (SSVs). No p38 was detectable on large dense-core vesicles (LDCVs). p38 and synapsin I were found to be present in similar concentrations throughout the brain. Outside the nervous system, p38 was found in a variety of neuroendocrine cells, but not in any other cell type. In neuroendocrine cells p38 was localized on a pleiomorphic population of small, smooth-surfaced vesicles, which were interspersed among secretory granules and concentrated in the Golgi area, but not on the secretory granules themselves. Immunoblot analysis of endocrine tissues and cell lines revealed a band with a mobility slightly different from that of neuronal p38. This difference was attributable to a difference in glycosylation. The finding that p38, like synapsin I, is a component of SSVs of virtually all neurons, but not of LDCVs, supports the idea that SSVs and LDCVs are organelles of two distinct pathways for regulated neuronal secretion. In addition, our results indicate the presence in a variety of neuroendocrine cells of an endomembrane system, which is related to SSVs of neurons but is distinct from secretory granules.

Increased IL-6 and IL-4 in exhaled breath condensate of patients with nasal polyposis.

BACKGROUND AND AIM: Nasal polyposis (NP) occurs in about 1-4% of the worldwide population. Increased plasma concentrations of different pro-inflammatory cytokines have been observed in NP, and might be related to the pathogenesis of this syndrome. The present study was designed to investigate IL-6 and IL-4 concentrations in nasal and oral exhaled breath condensate of patients with early and advanced NP, and following polypectomy. METHODS: Ten individuals with polyposis in early status, twenty-three patients affected by advanced status of NP and ten healthy controls were enrolled into the study. Exhaled breath condensate was collected by all individuals, according to a previous standardised method. An immunoassay kit was used to measure IL-6 and IL-4 levels. RESULTS: Concentrations of oral and nasal exhaled IL-6 and IL-4 were significantly higher in patients with early nasal polyposis and advanced nasal polyposis, compared to healthy controls. A statistically significant decrease of nasally but not of orally exhaled IL-6 (p < 0.001) and IL-4 (p < 0.05) was observed after polypectomy. CONCLUSIONS: We consider oral and nasal exhaled condensate of IL-6 and IL-4 as valid inflammatory and oxidative stress marker in patients with nasal polyposis.

Long-term evaluation of mental fatigue by Maastricht Questionnaire in patients with OSAS treated with CPAP.

BACKGROUND: Patients with obstructive sleep apnoea syndrome (OSAS) suffer from disrupted sleep. Impaired nightly sleep leads to increase physical and mental fatigue. The effect of long term continuous positive airway pressure (CPAP) on mental fatigue in OSAS patients, assessed by Maastricht Questionnaire (MQ), has not been investigated yet. METHODS: In order to evaluate the role of CPAP in improving mental fatigue of patients with OSAS, we studied 35 patients (26 males, age < 65 years at the time of the diagnosis) affected by OSAS, established by polysomnography (PSG). Patients were divided into two groups; 19 subjects (15 males), who refused CPAP therapy, and 16 patients (11 males) well matched for sex, age, body mass index (BMI), neck circumference, duration of follow up, and severity of disease, who had been treated with CPAP for at least two years. RESULTS: All patients had severe OSAS with Respiratory Disturbance Index (RDI), of 48 +/- 20.9 (range 22-90) and 61.48 +/- 18.6 (range 34-101) respectively, for group one (untreated patients) and group two (CPAP treatment). In addition, all patients had severe impairment of mental fatigue and of daytime sleepiness, demonstrated by high values of MQ score (32.17 +/- 15.33 and 37.36 +/- 12.4, respectively) and Epworth Sleepiness Scale (ESS) (14.21 +/- 4.77 and 15.06 +/- 6.07 respectively). There was no statistical significant difference in the group one at baseline and after follow-up, in terms of BMI, MQ score, ESS, and RDI. In the CPAP group (group two), the patients reported a significant improvement of the quality of their mental health (MQ 37.36 +/- 12.4 vs. 16.41 +/- 9.02; p < 0.0001) and sleepiness (ESS 15.06 +/- 6.07 vs. 4.13 +/- 3.93; p < 0.0001) with a stable BMI. There was significant correlation between the severity of sleep apnoea, expressed as RDI, and MQ at admission compared to at the end of follow-up (r = 0.4, p < 0.05). CONCLUSIONS: This study demonstrates an evident deterioration of mental fatigue in patients with OSAS, directly correlated to the severity of nocturnal disorder breathing; however supports the hypothesis that long-term CPAP therapy significantly improves sleepiness and mental fatigue.

Use of exhaled breath condensate in the study of airway inflammation after hypertonic saline solution challenge.

STUDY OBJECTIVES: Hypertonic saline solution inhalation is suspected to produce airway inflammation. DESIGN: The aim of this study was to verify this hypothesis by measuring inflammatory markers in exhaled breath condensate (EBC) collected before and after sputum induction with hypertonic and isotonic saline solution. PATIENTS AND METHODS: We enrolled 10 patients with asthma, 10 patients with COPD, and 7 healthy subjects with no history of lung disease. Levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha were measured in EBC by a specific enzyme immunoassay kit. Exhaled pH was measured after deaeration/decarbonation by bubbling with argon (350 mL/min) for 10 min by means of a pH meter. MEASUREMENTS AND RESULTS: Exhaled IL-6 and TNF-alpha concentrations were greater and pH was decreased compared to baseline after hypertonic saline solution inhalation in each group of subjects studied. No changes were observed following isotonic saline solution inhalation. Concentrations of IL-6, TNF-alpha, and pH in EBC correlated. CONCLUSIONS: These findings suggest that hypertonic saline solution inhalation could cause a low-grade inflammation in airways, and levels of inflammatory markers such as IL-6, TNF-alpha, and pH in EBC may be a useful noninvasive way to assess and monitor airway inflammation.

Gender difference in sleep profile of severely obese patients with obstructive sleep apnea (OSA).

OBJECTIVES: Few papers addressed the gender difference in the polisomnographic features of obstructive sleep apnea (OSA). In this paper we investigated the sleep architecture and the nocturnal respiratory pattern in a group of severely obese women with OSA compared with a group of men with OSA matched by age and weight. DESIGN: A cross-sectional study. SETTING: Primary-care setting. SUBJECTS, MAIN OUTCOME MEASURES: Anthropometric parameters, respiratory function data and a full night polisomnography were evaluated in a group of 45 obese subjects, 20 females and 25 males, with a previous diagnosis of OSA. RESULTS: The group of the severely obese women with OSA presented greater disturbances of the sleep architecture than the group of the men does (wake time after sleep onset 92.6+/-52.4 vs 58.2+/-45.2 min, P<0.05; total wake time 104.8+/-51.4 vs 67.8+/-47.4, P<0.05; number of awakenings 15.5+/-3.6 vs 10.2+/-6.215, P<0.001; OSA that occurred almost exclusively during REM sleep (REM OSA) 35% vs 4%, P<0.05) and a reduced sleep efficiency (69.6+/-15.9 vs 80.3+/-14.0%, P<0.05). CONCLUSIONS: Severely obese women with OSA, even with milder OSA, present greater disturbances of the sleep architecture with a more severe sleep disruption and more frequently REM OSA in comparison with men matched by age and weight.

Presence of synapsin I in afferent and efferent nerve endings of vestibular sensory epithelia.

The presence and localization of synapsin I were investigated in the cat vestibular epithelium, using a rabbit anti-synapsin I antibody. The staining was performed by immunofluorescence or by a peroxidase-anti-peroxidase technique. A strong immunoreactivity was observed with both methods. It appeared as spherical patches distributed in the lower part of the epithelium. This distribution pattern is very similar to that of the efferent synaptic endings which are filled with microvesicles. Elongated immunoreactive segments were also observed around some hair cells. They suggest the presence of synapsin I in the afferent sensory endings contacting the hair cells. This immunoreactivity occurs in early postnatal and adult stages.

New perspectives for transcatheter aortic valve implantation: more than a "simple" alternative to surgery.

To date, the gold standard of aortic stenosis treatment is surgical valve replacement. However, in inoperable or high risk patients a valid alternative is transcatheter aortic valve implantation (TAVI). Several trials showed feasibility, efficacy and safety of TAVI, with a tailored strategy for these patients on the basis of their clinical and anatomical conditions. The selection of valve type (CoreValve® or Edwards Sapien®) and transcatheter approach (transfemoral, transapical, subclavian or direct aortic approach) is an important step in the management of aortic stenosis. However, mortality is high and it is mainly related to non-cardiac reasons, given the high clinical risk profile of these patients. Moreover, the less invasive approach, the faster recovery, the reduced morbidity and the improved psychological tolerance, typical of TAVI, suggest that this technique could be used in a broader spectrum of cases, becoming a valid therapeutic alternative even in patients with severe aortic stenosis with a low surgical risk or asymptomatics. The identification of aortic stenosis patients by the medical community and their assessment over time, before they become candidates only for "extreme" strategies, remains the main challenge.

Airway inflammation in subjects with gastro-oesophageal reflux and gastro-oesophageal reflux-related asthma.

STUDY OBJECTIVES: Asthma and gastro-oesophageal reflux (GER) are both characterized by airway inflammation. DESIGN: The purposes of this work were (i) to study airway inflammation in patients troubled by gastro-oesophageal reflux (GER) and GER associated with asthma, (ii) to ascertain whether GER can aggravate asthma by exacerbating the pre-existing airway inflammation and oxidative stress and (iii) to establish the validity of analysing breath condensate and induced sputum when studying the airways of subjects affected by GER. PATIENT S AND METHODS: We enrolled 14 patients affected by mild asthma associated with GER (40 +/-12 years), nine with mild but persistent asthma (39 +/- 13 years), eight with GER (35 +/- 11 years) and 17 healthy subjects (37 +/- 9 years). Sputum cell counts and concentrations of interleukin-4 (IL-4), IL-6 and 8-isoprostane were measured in breath condensate and supernatant. MEASUREMENTS AND RESULTS: GER-related asthma is characterized by an eosinophilic inflammation, as determined by elevated concentrations of IL-4 in breath condensate and sputum supernatant, and by sputum cell analysis. GER alone presents a neutrophilic pattern of inflammation when determined by elevated concentrations of IL-6 in sputum cell analysis. A concomitant increase has been found in 8-isoprostane in GER associated (or not associated) with asthma. CONCLUSIONS: We conclude that GER is characterized by a neutrophilic airway inflammation and by increased oxidative stress. GER does not however aggravate pre-existing airway inflammation in asthma patients. Determinations of inflammatory and oxidant markers in the breath condensate of subjects with GER reflect these measured in the induced sputum.

Influence of subclinical hypothyroidism and T4 treatment on the prevalence and severity of obstructive sleep apnoea syndrome (OSAS).

BACKGROUND: Obstructive sleep apnoea (OSA) and subclinical hypothyroidism are relatively frequent disorders that may be causally linked. However, discordant results exist on the prevalence and severity of OSA in subclinical hypothyroidism. The aim of this study was to compare the prevalence and severity of sleep-disordered breathing in individuals with or without subclinical hypothyroidism, and to investigate the possible effect of levothyroxine treatment on these patients. PATIENTS AND METHODS: One hundred and eight subjects were consecutively enrolled and divided in 3 groups, according to the TSH levels and levothyroxine therapy. The first group (Group A) was represented by 63 subjects with normal TSH and thyroid function. The other two groups included patients affected by subclinical hypothyroidism; one group (Group B) treated with levothyroxine, while the other group (Group C) was never treated with levothyroxine. Anthropometric, respiratory and polysomnographic data were evaluated in all individuals. RESULTS: The percentage of OSA, neck circumference, and body mass index (BMI) were not statistically different among the 3 groups. Respiratory disturbance index (RDI) as well as the percentage of the total number of events (apnoea-hypopnoea) by total sleep time (TST) with <90% oxyhemoglobin saturation (TSTSaO2 <90%) were not different among the groups. When we observed OSA patients, the only significant difference between groups B and C was represented by the Epworth Sleepiness Scale (ESS) (p=0.005). CONCLUSION: This study shows that subclinical hypothyroidism and treatment with levothyroxine do not influence the prevalence and severity of OSA, while sleep propensity is increased by untreated subclinical hypothyroidism.

Early and late failure of noninvasive ventilation in chronic obstructive pulmonary disease with acute exacerbation.

BACKGROUND: Despite recent encouraging results, the use of noninvasive ventilation (NIV) in the management of acute exacerbations in chronic obstructive pulmonary disease (COPD), complicated by acute respiratory failure (ARF), is not always successful. Failure of NIV may require an immediate intubation after a few hours (usually 1-3) of ventilation ('early failure') or may result in clinical deterioration (one or more days later) after an initial improvement of blood gas tension and general conditions ('late failure'). MATERIALS AND METHODS: We enrolled 122 patients affected by COPD complicated by ARF, and treated with NIV. The schedule of NIV provided sessions of 2-6 h twice daily. RESULTS: Ninety-nine (81%) patients showed a progressive improvement of the clinical parameters and were discharged. Among the remaining 23 patients, 13 had an early failure and 10 had a late failure. In the 'success' group and 'late failure' groups we found after an increase of pH 2 h of NIV (from 7.31 +/- 0.05 to 7.38 +/- 0.04 P < 0.001 and from 7.29 +/- 0.03 to 7.36 +/- 0.02 P < 0.001, respectively) and a decrease of PaCO2 (from 80.93 +/- 9.79 to 66.48 +/- 5.95 P < 0.001 and from 85.96 +/- 10.77 to 76.41 +/- 11.02 P < 0.001, respectively). After 2 h of NIV in the 'late failure' group there were no significant changes in terms of pH (from 7.20 +/- 0.10 to 7.28 +/- 0.06) nor PaCO2 (from 92.86 +/- 35.49 to 93.68 +/- 23.68). The 'early failure' group had different characteristics and, owing to more severe conditions, the value of pH, of Glasgow Coma Score, and Apache II Score were the best predictors of the failure; while, among the complications on admission, metabolic alterations were the only independently significant predictor. CONCLUSIONS: Our study confirms that NIV may be useful to avoid intubation in approximately 80% of patients with COPD complicated by moderate-severe hypercapnic respiratory failure.

High prevalence of previously unknown subclinical hypothyroidism in obese patients referred to a sleep clinic for sleep disordered breathing.

BACKGROUND AND AIM: To evaluate the prevalence of previously unknown hypothyroidism in adult male and female patients with a wide range of body mass index (BMI) values, referred to a Sleep Clinic because of sleep disordered breathing (SDB). METHODS AND RESULTS: Serum concentrations of thyroid stimulating hormone (TSH) and free thyroxin (fT4), as well as forced vital capacity (FVC), PaO2, PaCO2, the Epworth sleepiness scale (ESS), respiratory disturbance index (RDI), loud snoring, and the percentage of total sleep time (TST) with <90% oxyhemoglobin saturation (TST(saO2<90%)) were measured in 78 overweight and obese adult subjects with no previous diagnosis of hypothyroidism (age: 18-72 years). The prevalence of previously undiagnosed subclinical hypothyroidism in the population as a whole was 11.5%. BMI, TSH and ESS were significantly higher in the hypothyroid than the euthyroid subjects, but there was no significant between-group difference in RDI, TST(saO2<90%) or the other investigated variables, including the prevalence of obstructive sleep apnea (OSA). Among the hypothyroid individuals, BMI, neck circumference, ESS, RDI and TST(Sao2<90%) were significantly higher in those with than in those without OSA. Furthermore, there was a clear trend towards a lower FVC% and higher snoring score in the OSA patients. CONCLUSIONS: Our results demonstrate a higher prevalence of hypothyroidism than that commonly reported in overweight and obese individuals referred to a Sleep Clinic for polysomnography because of SDB, thus suggesting that thyroid function should be evaluated in all obese patients suffering from SDB despite economic concerns.