Huntingtin gene intermediate alleles influence the progression from subjective cognitive decline to mild cognitive impairment: A 14-year follow-up study.

BACKGROUND AND PURPOSE: Huntingtin (HTT) is a gene containing a key region of CAG repeats. HTT alleles containing from 27 to 35 CAG repeats are termed intermediate alleles (IAs). We aimed to assess the effect of IAs on progression of cognitive impairment in patients with subjective cognitive decline (SCD). METHODS: We included 106 patients with SCD. All the patients underwent neuropsychological assessments and blood sample collection at baseline. Patients were followed up for a median (interquartile range) time of 13.75 (8.17) years. We genotyped APOE and HTT at the end of the follow-up. RESULTS: Eleven out of 106 patients (10.38%, 95% confidence interval [CI] 4.57-16.18) were carriers of IAs (IA+ ). During the follow-up, 44 patients (41.51%, 95% CI 32.13-50.89) progressed to mild cognitive impairment (MCI; p-SCD group), while 62 patients (58.49%, 95% CI 49.11-67.87) did not (np-SCD group). Rate of progression to MCI was associated with IAs, age at baseline, and APOE ɛ4. We dichotomized age at baseline (<60 years = younger patients [YP], >60 years = older patients [OP]) and then classified patients into four groups: YP/IA- , YP/IA+ , OP/IA-  and OP/IA+ . The OP/IA+  group had a higher proportion of patients with progression from SCD to MCI (85.71%, 95% CI 59.79-100) as compared to the YP/IA-  group (28.57%, 95% CI 13.60-43.54, χ2  = 15.25; p < 0.001) and the OP/IA-  group (45.00%, 95% CI 32.41-57.59, χ2  = 7.903; p = 0.005). We classified patients according to APOE and IA as: ɛ4- /IA- , ɛ4- /IA+ , ɛ4+ /IA- , ɛ4+ /IA+ . The proportion of patients with progression in the ɛ4+ /IA+  group (100%) was higher as compared to the ɛ4- /IA-  group (33.33%, 95% CI 21.96-44.71, χ2  = 14.43; p < 0.001) and ɛ4+ /IA-  (55.56%, 95% CI 36.81-74.30, χ2  = 4.60; p = 0.032). CONCLUSIONS: Intermediate alleles interact with age and APOE ɛ4, increasing the risk of progression to MCI in SCD patients.

WITHDRAWN: Action plans and coping strategies in elderly COPD patients influence the result of pulmonary rehabilitation: an observational study.

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Right ventricular systolic dysfunction is related to exercise intolerance in patients with chronic obstructive pulmonary disease.

PURPOSE: To evaluate the impact of right ventricular dysfunction on exercise tolerance and potential changes resulting from exercise training in patients with chronic obstructive pulmonary disease (COPD) undergoing pulmonary rehabilitation. METHODS: Subjects were 44 patients with a history of symptomatic (Global Initiative for Chronic Obstructive Lung Disease classes 2-4) COPD attending a 4-week aerobic exercise training program. Right ventricle dysfunction was evaluated by echocardiography at admission using tricuspid annular plane systolic excursion (TAPSE). Exercise tolerance was evaluated at admission and discharge using the 6-minute walk test (6MWT). Change in distance walked (Δ6MWT) was defined as the difference between 6MWT distance at discharge minus distance at admission. Patients were divided into 2 groups according to the presence of right ventricle dysfunction (TAPSE ≤16 mm). RESULTS: Median age and left ventricular ejection fraction was 70.2 ± 5.2 years and 54.4 ± 9.1%, respectively. Of the 44 patients, 14 (31.8%) had TAPSE ≤16 mm. Baseline 6MWT distance was less in the group with TAPSE ≤16 mm compared with TAPSE >16 mm (110.2 ± 34 vs 185.7 ± 41, respectively; P = .02). After the training program, 6MWT distance increased in both groups, but there was less increase in the group with TAPSE ≤16 mm compared with TAPSE >16 mm (+24.3% vs +32.8%, respectively; P < .001). Tricuspid annular plane systolic excursion was significantly correlated to distance walked at the baseline 6MWT (r = 0.44; P = .002) and to Δ6MWT (r = .36; P = .006). CONCLUSIONS: Tricuspid annular plane systolic excursion ≤16 mm was an indicator of decreased 6MWT distance at baseline and 6MWT distance change in COPD patients undergoing pulmonary rehabilitation. This relationship seems to be independent of pulmonary function.

Long-term home noninvasive mechanical ventilation increases systemic inflammatory response in chronic obstructive pulmonary disease: a prospective observational study.

BACKGROUND: Long-term home noninvasive mechanical ventilation (NIV) is beneficial in COPD but its impact on inflammation is unknown. We assessed the hypothesis that NIV modulates systemic and pulmonary inflammatory biomarkers in stable COPD. METHODS: Among 610 patients referred for NIV, we shortlisted those undergoing NIV versus oxygen therapy alone, excluding subjects with comorbidities or non-COPD conditions. Sputum and blood samples were collected after 3 months of clinical stability and analyzed for levels of human neutrophil peptides (HNP), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha). Patients underwent a two-year follow-up. Unadjusted, propensity-matched, and pH-stratified analyses were performed. RESULTS: Ninety-three patients were included (48 NIV, 45 oxygen), with analogous baseline features. Sputum analysis showed similar HNP, IL-6, IL-10, and TNF-alpha levels (P > 0.5). Conversely, NIV group exhibited higher HNP and IL-6 systemic levels (P < 0.001) and lower IL-10 concentrations (P < 0.001). Subjects undergoing NIV had a significant reduction of rehospitalizations during follow-up compared to oxygen group (P = 0.005). These findings were confirmed after propensity matching and pH stratification. CONCLUSIONS: These findings challenge prior paradigms based on the assumption that pulmonary inflammation is per se detrimental. NIV beneficial impact on lung mechanics may overcome the potential unfavorable effects of an increased inflammatory state.

Demographic characteristics, nicotine dependence, and motivation to quit as possible determinants of smoking behaviors and acceptability of shocking warnings in Italy.

INTRODUCTION: This paper presents the final results of a cross-sectional study started in 2010. It compares the perceived efficacy of different types of tobacco health warning (texts versus shocking pictures) to quit or reduce tobacco use. METHODS: The study conducted between 2010 and 2012 in Italy enrolled adults smokers. Administering a questionnaire demographic data, smokers behaviors were collected. Showing text and graphic warnings (the corpse of a smoker, diseased lungs, etc.) the most perceived efficacy to reduce tobacco consumption or to encourage was quit. RESULTS: 666 subjects were interviewed; 6% of responders referred that they stopped smoking at least one month due to the textual warnings. The 81% of the smokers perceived that the warnings with shocking pictures are more effective in reducing/quitting tobacco consumption than text-only warnings. The younger group (<45 years), who are more motivated to quit (Mondor's score ≥ 12), and females showed a higher effectiveness of shocking warnings to reduce tobacco consumption of, 76%, 78%, and 43%, respectively with P < 0.05. CONCLUSIONS: This study suggests that pictorial warnings on cigarette packages are more likely to be noticed and rated as effective by Italian smokers. Female and younger smokers appear to be more involved by shock images. The jarring warnings also appear to be supporting those who want to quit smoking. This type of supportive information in Italy may become increasingly important for helping smokers to change their behavior.

Use of discriminant analysis in assessing pulmonary function worsening in patients with sarcoidosis by a panel of inflammatory biomarkers.

OBJECTIVES AND DESIGN: To date, no sufficiently sensitive and specific single marker has been found to predict the clinical course of sarcoidosis. We designed a cohort study to investigate whether a panel of biomarkers measured in bronchoalveolar lavage (BAL) and peripheral blood could help predict pulmonary function worsening during the clinical course of sarcoidosis. METHODS: We analyzed 30 individuals with histologically proven sarcoidosis. At baseline, participants underwent pulmonary function tests (PFTs), fiberoptic bronchoscopy and radiological investigations. BAL and blood cellular profiles were obtained from all individuals and six pro-inflammatory molecules were quantified in BAL and serum. PFTs were performed at follow-up visits over a 2-year period. Using discriminant function analysis, a canonical variable was generated to optimize the accuracy of selected variables in predicting pulmonary function worsening and was validated on a subset of nine consecutive individuals with sarcoidosis. RESULTS: A combination of 6 markers from BAL was able to predict pulmonary function worsening in 96 % of patients [95 % confidence interval (CI) 84.4-99.81]. We validated the generated formula on a group of nine patients with sarcoidosis, obtaining 77.8 % correct classification (95 % CI 45.3-93.7). CONCLUSIONS: Our results show that a combinational approach could contribute to identifying individuals likely to experience pulmonary function worsening, thus helping to decide the correct therapeutic strategies.

Mixed acid-base disorders, hydroelectrolyte imbalance and lactate production in hypercapnic respiratory failure: the role of noninvasive ventilation.

BACKGROUND: Hypercapnic Chronic Obstructive Pulmonary Disease (COPD) exacerbation in patients with comorbidities and multidrug therapy is complicated by mixed acid-base, hydro-electrolyte and lactate disorders. Aim of this study was to determine the relationships of these disorders with the requirement for and duration of noninvasive ventilation (NIV) when treating hypercapnic respiratory failure. METHODS: Sixty-seven consecutive patients who were hospitalized for hypercapnic COPD exacerbation had their clinical condition, respiratory function, blood chemistry, arterial blood gases, blood lactate and volemic state assessed. Heart and respiratory rates, pH, PaO(2) and PaCO(2) and blood lactate were checked at the 1st, 2nd, 6th and 24th hours after starting NIV. RESULTS: Nine patients were transferred to the intensive care unit. NIV was performed in 11/17 (64.7%) mixed respiratory acidosis-metabolic alkalosis, 10/36 (27.8%) respiratory acidosis and 3/5 (60%) mixed respiratory-metabolic acidosis patients (p = 0.026), with durations of 45.1 ± 9.8, 36.2 ± 8.9 and 53.3 ± 4.1 hours, respectively (p = 0.016). The duration of ventilation was associated with higher blood lactate (p<0.001), lower pH (p = 0.016), lower serum sodium (p = 0.014) and lower chloride (p = 0.038). Hyponatremia without hypervolemic hypochloremia occurred in 11 respiratory acidosis patients. Hypovolemic hyponatremia with hypochloremia and hypokalemia occurred in 10 mixed respiratory acidosis-metabolic alkalosis patients, and euvolemic hypochloremia occurred in the other 7 patients with this mixed acid-base disorder. CONCLUSIONS: Mixed acid-base and lactate disorders during hypercapnic COPD exacerbations predict the need for and longer duration of NIV. The combination of mixed acid-base disorders and hydro-electrolyte disturbances should be further investigated.

Analysis of sputum markers in the evaluation of lung inflammation and functional impairment in symptomatic smokers and COPD patients.

The pivotal role of neutrophils and macrophages in smoking-related lung inflammation and COPD development is well-established. We aimed to assess whether sputum concentrations of Human Neutrophil Peptides (HNP), Neutrophil Elastase (NE), Interleukin-8 (IL-8), and Metalloproteinase-9 (MMP-9), major products of neutrophils and macrophages, could be used to trace airway inflammation and progression towards pulmonary functional impairment characteristic of COPD. Forty-two symptomatic smokers and 42 COPD patients underwent pulmonary function tests; sputum samples were collected at enrolment, and 6 months after smoking cessation. HNP, NE, IL-8, MMP-9 levels were increased in individuals with COPD (p < 0.0001). HNP and NE concentrations were higher in patients with severe airways obstruction, as compared to patients with mild-to-moderate COPD (p =0.002). A negative correlation was observed between FEV_{1} and HNP, NE and IL-8 levels (p < 0.01), between FEV_{1}/FVC and HNP, NE and IL-8 levels (p< 0.01), and between NE enrolment levels and FEV_{1} decline after 2 years (p =0.04). ROC analysis, to discriminate symptomatic smokers and COPD patients, showed the following AUCs: for HNP 0.92; for NE 0.81; for IL-8 0.89; for MMP-9 0.81; for HNP, IL-8 and MMP-9 considered together 0.981. The data suggest that the measurement of sputum markers may have an important role in clinical practice for monitoring COPD.

Comorbidity, hospitalization, and mortality in COPD: results from a longitudinal study.

We evaluated comorbidity, hospitalization, and mortality in chronic obstructive pulmonary disease (COPD), with special attention to risk factors for frequent hospitalizations (more than three during the follow-up period), and prognostic factors for death. Two hundred eighty-eight consecutive COPD patients admitted to respiratory medicine wards in four hospitals for acute exacerbation were enrolled from 1999 to 2000 in a prospective longitudinal study, and followed up until December 2007. The Charlson index without age was used to quantify comorbidity. Clinical and biochemical parameters and pulmonary function data were evaluated as potential predictive factors of mortality and hospitalization. FEV(1), RV, PaO(2), and PaCO(2) were used to develop an index of respiratory functional impairment (REFI index). Hypertension was the most common comorbidity (64.2%), followed by chronic renal failure (26.3%), diabetes mellitus (25.3%), and cardiac diseases (22.1%). Main causes of hospitalization were exacerbation of COPD (41.2%) and cardiovascular disease (34.4%). Most of the 56 deaths (19.4%) were due to cardiovascular disease (67.8%). Mortality risk depended on age, current smoking, FEV(1), PaO(2), the REFI index, the presence of cor pulmonale, ischemic heart disease, and lung cancer. Number and length of hospital admissions depended on the degree of dyspnea and REFI index. The correct management of respiratory disease and the implementation of aggressive strategies to prevent or treat comorbidities are necessary for better care of COPD patients.

Mechanical ventilation in patients with end-stage idiopathic pulmonary fibrosis.

BACKGROUND: Acute respiratory failure (ARF) occurring during idiopathic pulmonary fibrosis (IPF) is associated with a poor prognosis. In this subset of individuals, mechanical ventilation (MV) may be required. OBJECTIVES: We analysed the characteristics of a group of IPF patients undergoing MV for ARF in order to give some indications on the supposed prognosis. METHODS: Hospital records of 34 consecutive patients with IPF, who underwent MV for ARF, were retrospectively examined. Demographic data, time from diagnosis, gas exchange, Acute Physiology and Chronic Health Evaluation (APACHE) II score, ARF causes and MV failure were recorded. RESULTS: Fifteen subjects (group A) underwent invasive MV and 19 patients (group B) non-invasive ventilation (NIV). The 2 groups were different for disease severity (APACHE II score 24.2 +/- 6 vs. 19.5 +/- 5.9; p = 0.01). Both ventilatory strategies temporarily increased PaO2/FiO2 as compared with spontaneous breathing (group A: 148.5 +/- 52 vs. 99 +/- 39, p = 0.0004; group B: 134 +/- 36 vs. 89 +/- 26, p = 0.0004). NIV reduced the respiratory rate (26 +/- 7 vs. 36 +/- 9 with spontaneous breathing; p = 0.002). Duration of MV correlated with the time of evolution of IPF (r = 0.45; p = 0.018). The in-hospital mortality rate was 85% (100% for invasive MV, 74% for NIV). Four of the 5 survivors died within 6 months from hospital discharge (range 2-6 months). CONCLUSIONS: MV does not appear to have a significant impact on the survival of patients with end-stage IPF. NIV may be useful for compassionate use, providing relief from dyspnoea and avoiding aggressive approaches.

Effect of insulin on airway responsiveness in patients with type 2 diabetes mellitus: a cohort study.

BACKGROUND: The correlation between low insulin levels and a decreased sensitivity of the muscarinic receptor has been shown on induced-diabetes animal models. We designed a cohort study with the aim of evaluating the effects of insulin therapy on airway responsiveness (AR) in human patients with type 2 diabetes mellitus. METHODS: We enrolled 92 patients with type 2 diabetes who had switched from oral anti-diabetic therapy to treatment by insulin subcutaneous injection. Patients were administered the methacholine challenge test (MCT) at time 0 (pre-insulin therapy) and at intervals of 15, 30, 90, 180, and 360 days after insulin treatment. The decline of forced expiratory volume in 1 second (FEV(1))% from baseline (Delta FEV(1)) in response to inhaled methacholine (MCH) was determined to assess airway hyper-responsiveness (AHR). RESULTS: A total of 81 patients (18 women and 63 men) completed the study. Their mean age was 58 +/- 7 years and the mean duration of disease was 13.5 +/- 7.7 years. The mean decrease of FEV(1) at pre-insulin assessment was 2.96 +/- 2.6%. Compared with the pre-insulin value, a significant increase of Delta FEV(1) was observed at 15, 30, and 90 days after treatment (6.25%, CI 95% 5.4 to 7.2, p = 0.0005; 7.64%, CI 95% 6.6 to 8.1, p < 0.001; 6.45%, CI 95% 5.5 to 7.3, p = 0.0004, respectively), while after 180 and 360 days AR was similar to pre-insulin values (Delta FEV(1), 3.62%, CI 95% 2.7 to 3.5 and 3.11%, CI 95% 7.9 to 9.3, respectively). CONCLUSIONS: The finding of an increased AR in patients with type 2 diabetes during the first 3 months of insulin therapy may underline the importance of monitoring pulmonary function and respiratory symptoms in patients switching from oral anti-diabetic drugs to insulin therapy, especially in the subset of individuals with respiratory disorders.

Effect of postural variations on carbon monoxide diffusing capacity in healthy subjects and patients with chronic obstructive pulmonary disease.

BACKGROUND: The scientific literature does not supply enough information about the effects of postural changes on diffusing lung capacity for carbon monoxide (DL(CO)) in patients with chronic obstructive pulmonary disease (COPD), in particular regarding the prone position. OBJECTIVES: We evaluated posture-related changes in DL(CO) in healthy subjects and in COPD patients in order to especially assess how prone posture affects gas exchange. METHODS: In this cross-sectional study, DL(CO) was measured in 10 healthy subjects and 30 COPD patients in standing, seated, supine and prone positions. RESULTS: In healthy individuals, DL(CO) tended to improve from the upright to the supine position (21.42 +/- 2.90 and 26.07 +/- 5.11 ml/min/mm Hg, respectively); in the same group, changing the position from upright to prone also caused significant improvements in DL(CO) (absolute value, 21.42 +/- 2.90 vs. 24.80 +/- 4.39 ml/min/mm Hg, p < 0.05, or percent of predicted, 78.58 +/- 11.12 vs. 91.44 +/- 13.23, p < 0.05) and in DL(CO) proportional to alveolar volume (DL(CO)/VA; 4.52 +/- 0.57 vs. 5.66 +/- 1.48 ml/min/mm Hg/l, p < 0.05). No significant differences in DL(CO) have been observed in COPD patients from the standing to the prone position. Multivariate linear regression models showed that the posture-related changes in DL(CO), DL(CO) expressed as percent of predicted and in DL(CO)/VA are directly correlated with the transition from upright/sitting to supine/prone. CONCLUSIONS: In healthy subjects, the effect of postural changes on DL(CO) could be explained by a more homogeneous perfusion, whereas the lack of variations in COPD patients could be attributed to the increased rigidity of lung capillaries, which could represent an early sensitive marker of damage of the alveolar capillary interface in these patients.

The combination of a smoking cessation programme with rehabilitation increases stop-smoking rate.

OBJECTIVE AND STUDY DESIGN: A parallel group study to investigate the effectiveness of a smoking cessation programme performed during routine rehabilitation practice for outpatients. PATIENTS AND METHODS: The study participants comprised an intervention group of 102 consecutive smokers who underwent a smoking cessation programme in a rehabilitation centre and a control group of 101 consecutive smokers who were referred to a smoking cessation centre in a pulmonary hospital. All participants underwent physical examination,pulmonary function tests and received identical behavioural and/or pharmacological treatment. In addition, the intervention group underwent rehabilitation practice 3 times a week for 3 months. RESULTS: The continuous abstinence rate at 12 months, which was validated by an expired air carbon monoxide concentration of 10 parts per million or less and a household interview, was 68% in the intervention group and 32% in the control group. Multivariable analysis showed that rehabilitation was significantly associated with smoking cessation after adjusting for years of smoking, number of cigarettes smoked,gender and treatment (odds ratio = 4.34, p < 0.001). CONCLUSION: This study suggests that smoking cessation programmes during routine rehabilitation may be highly effective in helping smoking withdrawal and should be a strongly recommended component of rehabilitation practice.

Rational timing of combination therapy with tiotropium and formoterol in moderate and severe COPD.

AIM: To determine which timing of therapy with formoterol (FOR) and/or tiotropium (TIO) shows the greater and more continuous functional improvement during 24 h in patients with moderate to severe COPD. METHODS: In this randomised, blind, crossover study 80 patients with stable COPD (40 moderate and 40 severe) received 5 different bronchodilator 30-day treatments in a random order. Treatments (Tr) were: Tr1: TIO 18 microg once-daily (8 am); Tr2: TIO 18 microg (8 am) + FOR 12 microg (8 pm); Tr3: FOR 12 microg twice-daily (8 am and 8 pm); Tr4: TIO 18 microg (8 am) + FOR 12 microg twice-daily (8 am and 8 pm); Tr5: FOR 12 microg twice-daily (8 am and 8 pm) + TIO 18 microg (8 pm). Spirometries were performed during 24 h (13 steps) on Day1 and Day30. End-points were: gain of FEV(1) (DeltaFEV(1)) from baseline of the Day1 and Day30, AUC (Area Under Curve), Dyspnoea Index, and as-needed use of salbutamol. RESULTS: Sixty-eight patients completed all treatments. The greater and continuous daily functional improvement was showed during Tr4 and Tr5 (Day1 +135.8 mL and +119.1 mL; Day30 +160.2 mL, and +160.5 mL, respectively). Daily means of DeltaFEV(1) were significantly different between single-drug treatments and combination therapy. Dyspnoea was greater in single-drug treatments. Less use of rescue salbutamol was reported in Tr4 (0.80 puffs/die) and Tr5 (0.71 puffs/die). CONCLUSIONS: In patients with moderate to severe COPD, combination therapy with tiotropium administered in the morning (Tr4) was the most effective; in patients with prevailing night-symptoms, treatment with tiotropium in the evening (Tr5) reduced symptoms and use of salbutamol. Tr5 showed less variability of FEV(1) during the 24 h (CV=0.256). These results are relevant for opening new ways in clinical practice.

Maximal respiratory static pressures in patients with different stages of COPD severity.

BACKGROUND: In this study, we analyzed maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) values in a stable COPD population compared with normal subjects. We evaluated the possible correlation between functional maximal respiratory static pressures and functional and anthropometric parameters at different stages of COPD. Furthermore, we considered the possible correlation between airway obstruction and MIP and MEP values. SUBJECT AND METHODS: 110 patients with stable COPD and 21 age-matched healthy subjects were enrolled in this study. Patients were subdivided according to GOLD guidelines: 31 mild, 39 moderate and 28 severe. RESULTS: Both MIP and MEP were lower in patients with severe airway impairment than in normal subjects. Moreover, we found a correlation between respiratory muscle function and some functional and anthropometric parameters: FEV1 (forced expiratory volume in one second), FVC (forced vital capacity), PEF (peak expiratory flow), TLC (total lung capacity) and height. MIP and MEP values were lower in patients with severe impairment than in patients with a slight reduction of FEV1. CONCLUSION: The measurement of MIP and MEP indicates the state of respiratory muscles, thus providing clinicians with a further and helpful tool in monitoring the evolution of COPD.