Marfan syndrome and aortic involvement: a narrative review.

Marfan syndrome (MFS) is a systemic connective tissue disease that commonly and most severely affects the ocular, skeletal, and cardiovascular systems. The aim of the manuscript is to review the aortic involvement and complications in MFS, including aortal dissection, thoracic aortic aneurysm, abdominal aortic aneurysm, and acute aortic syndrome. Dissecting thoracic aortic aneurysm and progressing aortic root enlargement are the major causes of MFS morbidity and mortality. Guidelines on aortic disease endorsed by the American College of Cardiology, and the American Heart Association recommend the measurement of the external and internal aortic diameters perpendicular to the axis of blood flow when Computed Tomography, or Magnetic Resonance Imaging, or Cardiac Echography are performed. The pathophysiology, diagnosis, prevention, and medical and surgical treatments of MFS associated with aortic complications are reported in this narrative review. Development and strengthening of centers specialized in cardiovascular diseases and MFS, together with an improvement in the knowledge of its pathogenesis through genetics and proteomics investigations, can ameliorate the prognosis of this disease.

New York Heart Association class and pulmonary artery pressure as prognostic factors of interstitial lung disease survival.

OBJECTIVE: The aim of this study was to evaluate New York Heart Association (NYHA) class and systolic pulmonary artery pressure (sPAP) as survival predictors in major interstitial lung diseases (ILD) including idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP) and hypersensitivity pneumonitis (HP) and in other ILD like granulomatosis with polyangiitis (GPA). PATIENTS AND METHODS: We analyzed survival, NYHA class, sPAP, and Octreoscan uptake index (UI) in 104 ILD patients (59 IPF, 19 NSIP, 10 HP and 16 GPA; median age 60.5 years) all referred to a single centre. RESULTS: Median survival was 68 months, with 1- and 2-year survival of 91% and 78%, respectively. Survival was lower among IPF and NSIP vs. HP and GPA patients (p=0.01). NYHA class 3-4 was more frequent among IPF (76.3%) vs. NSIP patients (31.6%; p<0.001). HP and GPA had NYHA class 1-2. NYHA class was negatively associated with survival (class 1=90.3 months vs. class 3=18.3 months and class 4=5.1 months; p=0.001). sPAP was >55 mmHg in 76.3% of patients with IPF and 35-55 mmHg in 63.2% of patients with NSIP. Patients with HP and GPA had sPAP < 55 mmHg. Among patients with IPF, NYHA and sPAP were negatively associated with survival (p<0.01) both showed a parallel trend. High-resolution computed tomography and survival were worse among IPF and NSIP vs. HP and GPA patients (p<0.001). Octreoscan UI was <10, 10-12, and >12 in IPF, NSIP, HP and GPA, respectively. Octreoscan UI was negatively associated with survival (p=0.002). CONCLUSIONS: NYHA class and sPAP are comparable ILD survival predictors. NYHA class is correlated with worse prognosis for IPF and NSIP vs. HP and GPA patients.

Stem cells therapy in acute myocardial infarction: a new era?

Stem cells transplantation after acute myocardial infarction (AMI) has been claimed to restore cardiac function. However, this therapy is still restricted to experimental studies and clinical trials. Early un-blinded studies suggested a benefit from stem cell therapy following AMI. More recent blinded randomized trials have produced mixed results and, notably, the last largest pan-European clinical trial showed the inconclusive results. Furthermore, mechanisms of potential benefit remain uncertain. This review analytically evaluates 34 blinded and un-blinded clinical trials comprising 3142 patients and is aimed to: (1) identify the pros and cons of stem cell therapy up to a 6-month follow-up after AMI comparing benefit or no effectiveness reported in clinical trials; (2) provide useful information for planning future clinical programs of cardiac stem cell therapy.

New York Heart Association class associated with imaging is a prognostic mortality risk predictor in interstitial lung diseases.

OBJECTIVE: Mortality risk factors as forced vital capacity, diffuse lung capacity for carbon monoxide, and 6-minutes' walk test were studied in clinical trials monitoring patients affected by interstitial lung diseases (ILD). However, these parameters showed scarce accuracy. Our aim was to identify New York Heart Association (NHYA) class, in association with high resolution computed tomography (HRCT) and somatostatin receptor scintigraphy (Octreoscan), as a prognostic mortality risk factor in ILD patients. PATIENTS AND METHODS: Study population comprised 128 ILD patients (78 Males and 50 Females). Histological diagnosis was usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP) and granulomatous lung disease in 59, 19 and 50 patients, respectively. Patients were monitored by NYHA class, HRCT and Octreoscan at baseline and every 3 years up to a 10-year follow up. Overall survival was calculated from the date of diagnosis until death or last follow-up update. Statistical analysis was performed using Kaplan-Meier, log-rank test (LRT), multivariate analysis with Cox proportional hazard regression model, and log-likelihood ratio test. RESULTS: Overall median survival was 89.3 months (7.4 years) with the poorer survival rate observed in UIP patients. NYHA class came out as a reliable prognostic mortality risk factor in each group of patients and prognosis was progressively worse with NYHA class increase (LRT p<0.001). A strong correlation was found between NYHA class and age, CT-score, and Octreoscan in UIP patients (p<0.001). CONCLUSIONS: The determination of NYHA class can therefore be recommended as an additional prognostic mortality risk factor in ILD patients.

SPG5 and multiple sclerosis: clinical and genetic overlap?

BACKGROUND: Autosomal recessive (AR) spastic paraplegia type 5 (SPG5) is due to mutations in the CYP7B1 gene, encoding for the cytochrome P450-7B1, responsible for oxysterols 7α-hydroxylation. Oxysterol/cholestenoic acids pool plays a role in motor neuron survival and immune response. SPG5 is characterized by white matter abnormalities at brain resonance imaging (MRI). In view of clinical presentation and MRI findings, multiple sclerosis (MS) is a possible differential diagnosis of SPG5. This study aimed to evaluate the frequency of CYP7B1 mutations in patients with MS. METHODS: One hundred and seventeen MS patients with clinical spastic paraplegia or possible AR transmission were selected for the mutational screening. RESULTS: Forty-three patients had primary progressive, 26 relapsing remitting, 26 secondary progressive, and 22 relapsing progressive MS clinical course. No CYP7B1 homozygous mutations were identified. Two novel variants and one pathogenic mutation were found at heterozygous state. CONCLUSIONS: The two novel variants cosegregated with pyramidal signs and autoimmune diseases suggesting that they might be susceptibility factors. Reduced cytochrome P450-7B1 enzymatic activity could alter the balance among neurotoxic and neuroprotective oxysterols promoting motor neuron degeneration and/or immune response.

Powerhouse failure and oxidative damage in autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease due to mutations in SACS, which encodes sacsin, a protein localized on the mitochondrial surface and possibly involved in mitochondrial dynamics. In view of the possible mitochondrial involvement of sacsin, we investigated mitochondrial activity at functional and molecular level in skin fibroblasts obtained from ARSACS patients. We observed remarkable bioenergetic damage in ARSACS cells, as indicated by reduced basal, adenosine triphosphate (ATP)-linked and maximal mitochondrial respiration rate, and by reduced respiratory chain activities and mitochondrial ATP synthesis. These phenomena were associated with increased reactive oxygen species production and oxidative nuclear DNA damage. Our results suggest that loss of sacsin is associated with oxidative stress and mitochondrial dysfunction, and thus highlight a novel mechanism in the pathogenesis of ARSACS. The involvement of mitochondria and oxidative stress in disease pathogenesis has been described in a number of other neurodegenerative diseases. Therefore, on the basis of our findings, which suggest a potential therapeutic role for antioxidant agents, ARSACS seems to fall within a larger group of disorders.

Cardiovascular risk in patients without known cardiovascular disease.

Understanding the risks of atherosclerotic cardiovascular disease (CVD) allows for better patient education and management. Multiple risk models have been validated in large patient populations and provide insights into the risks associated with CVD. When assessing such risks, we suggest using a model that predicts myocardial infarction, cardiovascular death, and/or cerebrovascular events. In this review, we analyze several risk models and stratify the risks associated with CVD. We suggest that appropriate profiling of patients at-risk of CVD will lead to better physician recognition and treatment of modifiable risk factors, appropriate application of ATP III treatment for hyperlipidemia, and achieving optimal blood pressure control.

Cosmic-ray positron energy spectrum measured by PAMELA.

Precision measurements of the positron component in the cosmic radiation provide important information about the propagation of cosmic rays and the nature of particle sources in our Galaxy. The satellite-borne experiment PAMELA has been used to make a new measurement of the cosmic-ray positron flux and fraction that extends previously published measurements up to 300 GeV in kinetic energy. The combined measurements of the cosmic-ray positron energy spectrum and fraction provide a unique tool to constrain interpretation models. During the recent solar minimum activity period from July 2006 to December 2009, approximately 24,500 positrons were observed. The results cannot be easily reconciled with purely secondary production, and additional sources of either astrophysical or exotic origin may be required.

Cosmic-ray electron flux measured by the PAMELA experiment between 1 and 625 GeV.

Precision measurements of the electron component in the cosmic radiation provide important information about the origin and propagation of cosmic rays in the Galaxy. Here we present new results regarding negatively charged electrons between 1 and 625 GeV performed by the satellite-borne experiment PAMELA. This is the first time that cosmic-ray e⁻ have been identified above 50 GeV. The electron spectrum can be described with a single power-law energy dependence with spectral index -3.18 ± 0.05 above the energy region influenced by the solar wind (> 30 GeV). No significant spectral features are observed and the data can be interpreted in terms of conventional diffusive propagation models. However, the data are also consistent with models including new cosmic-ray sources that could explain the rise in the positron fraction.

PAMELA measurements of cosmic-ray proton and helium spectra.

Protons and helium nuclei are the most abundant components of the cosmic radiation. Precise measurements of their fluxes are needed to understand the acceleration and subsequent propagation of cosmic rays in our Galaxy. We report precision measurements of the proton and helium spectra in the rigidity range 1 gigavolt to 1.2 teravolts performed by the satellite-borne experiment PAMELA (payload for antimatter matter exploration and light-nuclei astrophysics). We find that the spectral shapes of these two species are different and cannot be described well by a single power law. These data challenge the current paradigm of cosmic-ray acceleration in supernova remnants followed by diffusive propagation in the Galaxy. More complex processes of acceleration and propagation of cosmic rays are required to explain the spectral structures observed in our data.

PAMELA results on the cosmic-ray antiproton flux from 60 MeV to 180 GeV in kinetic energy.

The satellite-borne experiment PAMELA has been used to make a new measurement of the cosmic-ray antiproton flux and the antiproton-to-proton flux ratio which extends previously published measurements down to 60 MeV and up to 180 GeV in kinetic energy. During 850 days of data acquisition approximately 1500 antiprotons were observed. The measurements are consistent with purely secondary production of antiprotons in the Galaxy. More precise secondary production models are required for a complete interpretation of the results.

Predictors of survival in idiopathic interstitial pneumonia.

AIM: To evaluate the ability of newly identified clinical factors to predict prognosis and survival in idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP). METHODS: Seventy-eight patients referred to the University of Genoa and the Regional Hospital of Aosta between January 1995 and December 2006 were evaluated prospectively. Fifty-nine patients were diagnosed with IPF and 19 with NSIP on the basis of surgical lung biopsy specimens. Gender, age at diagnosis, smoking, New York Heart Association class (NYHA), systolic pulmonary artery pressure (sPAP), Octreoscan uptake index (UI), and therapy were the chosen variables. Primary end-point was survival. RESULTS: With the exception of gender and smoking history, all baseline patient characteristics correlated significantly with the diagnosis (IPF vs. NSIP). Median survival for the entire study group was 52.7 months. Univariate analysis showed poorer survival for the IPF group versus the NSIP group, and survival was significantly lower for older patients (p < 0.001). Multivariate analysis confirmed the negative prognostic effect of age (p < 0.001) on survival with a risk of death for older patients ( > OR =66 years old) being more than 4 times higher than that for younger patients (<58 yr.). NYHA class and pulmonary artery pressure were also significant predictors of survival, and all patients with a sPAP < OR = 35-mm Hg were alive at the end of the follow-up period. There was a good correlation between Octreoscan uptake index and the diagnosis. CONCLUSION: Diagnosis (IPF vs. NSIP), NYHA class, sPAP, and especially age appear to represent important prognostic indicators in the two most prevalent forms of idiopathic pulmonary fibrosis (IPF and NSIP). Lower Octreoscan uptake values were found in all patients with IPF, suggesting that this test may have a role as a new predictor of survival for differentiating IPF from NSIP.

Predictability of sustained virological response to pegylated interferon alpha-2b Plus ribavirin therapy by week-8 viral response in HIV-positive patients with chronic hepatitis C virus infection.

Chronic hepatitis C is frequent and aggressive in HIV-positive patients. Identification of early predictors of response to anti-HCV therapy is needed for a lower rate of response and higher discontinuations, compared to HCV mono-infected subjects. The aim of our study was to evaluate the predictive value of virological response (VR) at week 4-8-12 of Pegylated interferon alpha-2b (PEG-IFN) plus ribavirin (RBV) on sustained virological response (SVR) in HIV-HCV co-infected patients. 100 patients were treated with PEG-IFN (1.5 mcg/Kg/w) plus RBV (> or =10.6 mg/kg/d) and randomized for 24-48 or 48-72 weeks, respectively for genotype 2-3 and 1-4, in case of response (HCV-RNA PCR negativity) at the end of standard therapy (24 weeks for genotype 2-3, 48 weeks for genotype 1-4). Transcription-Mediated Amplification (TMA) assay for HCV-RNA was also applied. 27 patients reached end-of-treatment response (9 genotype 1-4, 18 genotype 2-3), 21 achieved SVR (8 genotype 1-4, 13 genotype 2-3). 35 patients dropped, 15 due to side-effects. SVR was statistically related to lower baseline HCV-RNA and to VR at week 4-8-12, with PPV 64%, 53% and 58%, and NPV 81%, 96% and 88%, respectively. In 27 patients, TMA was performed and confirmed standard PCR, except in two cases of relapse, who were PCR negative but TMA positive at week-12. In conclusion, VR at week 8 showed the highest NPV on SVR (96%). The study of viral kinetics requires further investigations in HIV-positive patients to guarantee a cost-effective therapy and to guide individually the duration of treatment. In this setting, TMA might be useful.

Predictors of mortality of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), a disease with histological features corresponding to usual interstitial pneumonia (UIP), is a disorder of unknown cause. Not only it is the most common subtype of idiopathic interstitial pneumonias but it is also associated with the highest mortality rate. Despite a good number of studies investigating the mortality of patients with UIP the prognostic factors that have been studied have several limitations. To date it is unclear when in the course of the disease and with what modality these patients should be treated. According to the literature we subcategorized predictors of mortality into (a) baseline predictors; (b) dynamic predictors. IPF perspectives in therapy have been also analyzed. Moreover, the principal aims of this review were: (1) to analyze and to clarify the clinical utility of different prognostic factors for IPF; (2) to enable clinicians to better evaluate the eligibility criteria for lung transplantation in the clinical practice.

Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM).

BACKGROUND: The aim of this study was to evaluate the activity and toxicity of pemetrexed and carboplatin combination as first-line chemotherapy in malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with measurable advanced MPM and a zero to two Eastern Cooperative Oncology Group (ECOG) performance status (PS) were enrolled. The schedule was pemetrexed 500 mg/m(2) in combination with carboplatin area under the curve 5, every 21 days. In all, 76 patients were treated. Median age was 65 years; median ECOG PS was zero. RESULTS: Grade 3 hematological toxicity according to World Health Organization criteria was seen in 36 (47.3%) patients; grade 4 hematological toxicity in 5 (6.5%) patients. There were 16 (21%) partial responses and 3 (4%) complete responses, for an overall response rate of 19 (25%) [95% confidence interval (CI) 15.3-34.7]. In all, 29 (39%) (95% CI 28-48) patients reported stable disease. The median survival was estimated at 14 months. CONCLUSION: This combination of carboplatin and pemetrexed is moderately active and the toxicity is acceptable.