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M Filippi,
P Preziosa,
E Pagani, M Copetti,
S Mesaros,
B Colombo,
Ma Horsfield,
A Falini,
G Comi,
H Lassmann,
Ma Rocca
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ABSTRACT: BACKGROUND: Pathologic and magnetic resonance imaging (MRI) studies have shown that cortical lesions (CLs) are a frequent finding in multiple sclerosis (MS). OBJECTIVE: To quantify microstructural damage in CLs and normal appearing (NA) cortex in relapse-onset MS patients at different stages of the disease. METHODS: Brain double inversion recovery (DIR), diffusion tensor (DT) MRI and 3D T(1)-weighted scans were acquired from 35 relapsing-remitting (RR) patients, 23 secondary progressive (SP) patients, 12 benign (B) MS patients and 41 healthy controls (HC). Diffusivity values in CLs, cortex, white matter (WM) lesions and normal-appearing white matter (NAWM) were assessed. RESULTS: Compared to HC, MS patients had a significantly lower fractional anisotropy (FA) and higher mean diffusivity (MD) in the cortex and NAWM. CLs had higher FA vs HC cortex and vs patients' cortex. Compared to RRMS patients, SPMS patients had higher WM lesion volume, higher MD in the cortex, and more severe damage to the NAWM and WM lesions. Compared to SPMS patients, BMS patients had lower MD and FA of CLs. Damage in other compartments was similar between SPMS and BMS patients. Damage in CLs had a high power to discriminate BMS from SPMS (area under the curve: 79-91%), with high specificity (85%), sensitivity (100%) and accuracy (90%). CONCLUSIONS: Microstructural imaging features of CLs differ from those of WM lesions and are likely to reflect neuronal damage and microglial activation. The nature and extent of CL damage can be used to help distinguish the different MS clinical phenotypes.
Multiple Sclerosis 08/2012; · 4.26 Impact Factor
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Grazia D'Onofrio,
Daniele Sancarlo,
Francesco Panza, Massimiliano Copetti,
Leandro Cascavilla,
Francesco Paris,
Davide Seripa,
Maria G Matera,
Vincenzo Solfrizzi,
Fabio Pellegrini,
Alberto Pilotto
[show abstract]
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ABSTRACT: Neuropsychiatric symptoms (NPS) are increasingly recognized as common in patients with dementia, both of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD). In this study, 302 demented patients, 166 with AD and 136 with VaD, were evaluated for NPS according to the Neuropsychiatric Inventory (NPI) score at the Alzheimer's Evaluation Unit of Casa Sollievo della Sofferenza Hospital-IRCCS, San Giovanni Rotondo, Italy. A comprehensive geriatric assessment was also performed in all demented patients. The means of NPI scores did not differ in two groups. The overall prevalence of NPS was similar in both groups of patients (69.7% vs. 69.4%). Patients with AD had higher frequency in agitation/aggression and irritability/lability than VaD patients. Logistic analysis demonstrated a significant association between severity of the cognitive impairment and depression and eating disorders in both AD and VaD patients. The association with agitation/aggression, irritability/lability, and aberrant motor activity was found in AD only, and with apathy in VaD patients only. In both AD and VaD patients, there was a significant association between the impairment in activities of daily living (ADL) and the majority of NPI domains. A significant association was also found between the impairment of the instrumental activities of daily living (IADL) and agitation/aggression, anxiety, aberrant motor activity in AD and depression, apathy, irritability/lability, sleep disturbance and eating disorders in both AD and VaD patients. In particular, a causal mediation analysis was performed to better understand whether the relationship of NPS to functional impairment was direct or mediated by severity of cognitive dysfunction, i.e., Clinical dementia rating scale (CDR) score. Only agitation/aggression was mediated by the CDR score in affecting ADL status in VaD patients (OR: 1.12, 95% CI: 1.01-1.27). The NPI-Distress scores showed a significantly higher levels of distress in caregivers of AD than VaD. There were significant differences between AD and VaD patients with NPS, and these symptoms varied according to dementia subtype and severity and induced marked disability in ADL and IADL, increasing, prevalently, the distress of the caregivers of AD patients.
Current Alzheimer research 06/2012; 9(6):759-71. · 4.97 Impact Factor
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ABSTRACT: BackgroundThe mortality prediction represents a key factor in the managing of elderly hospitalized patients. Since in older subjects
mortality results from a combination of biological, functional, nutritional, psychological and environmental factors, a Multidimensional
Prognostic Index (MPI) that predict short- and long-term mortality based on a standardized comprehensive geriatric assessment
(CGA) has recently been developed and validated.
ObjectiveThis study compares the accuracy in predicting the mortality of the MPI with a modified version of the MPI (m-MPI) that included
the Mini Nutritional Assessment-Short Form (MNA-SF) instead of the standard MNA.
DesignThis prospective study with a one-year follow-up included 4088 hospitalized patients aged 65 years and older. A standardized
CGA that included information on functional (Activities of Daily Living, ADL and Instrumental-ADL), cognitive (Short Portable
Mental Status Questionnaire), risk of pressure sore (Exton-Smith Scale), comorbidities (CIRS Index), medications, living status
and nutritional status (MNA and MNA-SF) was used to calculate the MPI using a previously validated algorithm.
ResultsHigher MPI values were significantly associated with higher mortality rates with a close agreement between the estimated and
the observed mortality both after 1-month (MPI1=2.8% versus m-MPI1=2.8%,p=0.946; MPI2=8.9% versus m-MPI2=9%,p=0.904; MPI3=21.9%
versus m-MPI3=21.9,p=0.978) and 1-year of follow-up (MPI1=10.8% versus m-MPI1=10.5%,p=0.686; MPI2=27.3% versus m-MPI2=28%,
p=0.495; MPI3=52.8% versus m-MPI3=52.7%,p=0.945). The estimated areas under the receiver operating characteristics (ROC) curves
suggested a clinically negligible difference between the two indices.
ConclusionThe m-MPI is as sensitive as the MPI in stratifying hospitalized elderly patients into groups at varying risk of short- and
long-term mortality, but with fewer items.
Key wordsMultidimensional Prognostic Index (MPI)–Mini Nutritional Assessment Short Form (MNASF)–mortality–prognosis–Comprehensive Geriatric Assessment (CGA)–survival
The Journal of Nutrition Health and Aging 04/2012; 15(3):169-173. · 2.69 Impact Factor
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M Maranghi,
S Prudente,
L D'Erasmo,
E Morini,
E Ciociola,
P Coletta,
A Verrienti,
S Arciello, M Copetti,
F Pellegrini,
S A Santini,
S Morano,
S Filetti,
V Trischitta
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ABSTRACT: BACKGROUND AND AIMS: Several studies have reported that the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) K121Q polymorphism (rs1044498) interacts with increased adiposity in affecting glucose homeostasis and insulin sensitivity. Conversely, one would expect that the amelioration of glucose homeostasis observed after weight loss is modulated by the ENPP1 K121Q polymorphism. The aim of our study was to test such hypothesis, in non-diabetic overweight-obese individuals. METHODS AND RESULTS: Two hundred eleven non-diabetic overweight-obese individuals were studied. Body mass index (BMI), fasting glucose, homeostasis model assessment of insulin resistance (HOMA-IR index) and lipid levels were obtained before and after 6-week lifestyle intervention (LI; diet and exercise) and their changes calculated as baseline minus 6-week values. LI decreased BMI, glucose, HOMA-IR and triglyceride levels (p < 0.001 for all). No difference across genotype groups (160 KK and 51 KQ or QQ - named as XQ - individuals) was observed in these changes. In a multivariate model, BMI changes predicted fasting glucose changes (β = 0.139 mmol/L (2.50 mg/dl) for 1 unit BMI change, p = 0.005). This correlation was not significant among KK individuals (β = 0.082; p = 0.15), while much steeper and highly significant among XQ individuals (β = 0.336; p = 0.00008) (p-value for Q121-by-weight loss interaction = 0.047). CONCLUSION: Individuals carrying the ENPP1 Q121 variant are highly responsive to the effect of weight loss on fasting glucose. This reinforces the previously suggested hypothesis that the Q121 variant interacts with adiposity in modulating glucose homeostasis.
Nutrition, metabolism, and cardiovascular diseases: NMCD 03/2012; · 3.52 Impact Factor
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ABSTRACT: BACKGROUND/OBJECTIVE We aimed to investigate whether cervical cord damage and dysfunction is associated with the presence and severity of fatigue in multiple sclerosis (MS) using a multiparametric magnetic resonance (MR) approach.
Cervical cord functional magnetic resonance imaging (fMRI) during a tactile stimulation of the right hand, and structural brain and cord MRI were acquired from 20 controls, 15 MS patients without fatigue (NF) and 20 MS patients with fatigue (F). Between-group differences in the extent of focal lesions and diffusivity abnormalities in the brain and cord, cord-normalized cross-sectional area (CSAn) and fMRI activity were assessed.
All structural MRI measures differed significantly among groups, except for cord lesion number and CSAn. Compared with controls, NF-MS patients experienced higher cord recruitment (p=0.04). Compared with F-MS, NF-MS patients had a lower brain normal-appearing white matter average fractional anisotropy (p=0.001) and increased cord recruitment (p=0.02). In patients with MS, the extent of cord recruitment was correlated with the severity of fatigue (r=-0.34, p=0.04). Compared with the other two groups, F-MS patients had a more diffuse recruitment of cord quadrants on the axial and longitudinal planes.
Abnormalities of function, but not of structure, of the cervical cord are likely to contribute to the pathogenesis of fatigue in MS.
Multiple Sclerosis 03/2012; 18(11):1552-9. · 4.26 Impact Factor
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S Mesaros,
M A Rocca,
K Kacar,
J Kostic, M Copetti,
T Stosic-Opincal,
P Preziosa,
S Sala,
G Riccitelli,
M A Horsfield,
J Drulovic,
G Comi,
M Filippi
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ABSTRACT: To assess the correlation between cognitive impairment and overall vs regional CNS damage, quantified using conventional and diffusion tensor (DT) MRI tractography in multiple sclerosis (MS).
Brain dual-echo, T1-weighted, and DT MRI data were acquired from 82 patients with MS. DT tractography was used to produce maps of white matter (WM) tracts involved in cognition. The sensory thalamocortical projections and optic radiations were studied as "control" WM tracts. The contribution of global brain damage (T2 lesion volume, normalized brain volume, gray matter [GM] volume, WM volume, DT MRI measures of normal-appearing WM and GM damage) and damage to selected WM tracts to overall cognitive impairment and to impairment at individual neuropsychological tests was assessed using a random forest (RF) analysis.
Thirty-three patients had cognitive impairment. The majority of MRI measures differed significantly between cognitively impaired and cognitively preserved (CP) patients. Significant correlations were found between performance in the majority of neuropsychological tests and global or regional brain damage (r ranging from -0.60 to 0.57). The RF analysis showed a high performance in classifying cognitively impaired vs CP patients, with a classification (C)-index = 76.8, as well as in classifying patients' impairment in individual neuropsychological tests (C-index between 75.6% and 86.6%). Measures of lesional damage in cognitive-related tracts, rather than measures of normal-appearing WM damage in the same tracts or global brain/WM/GM damage, resulted in the highest classification accuracy.
Lesions in strategic brain WM tracts contribute to cognitive impairment in MS through a multisystem disconnection syndrome.
Neurology 02/2012; 78(13):969-75. · 8.31 Impact Factor
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ABSTRACT: Aim We investigated inpatients with and without type 2 diabetes mellitus, aged over 60 years, to compare their vitamin D status and calcium homeostatic parameters Materials and Methods We studied 140 patients consecutively admitted to our Internal Medicine Unit during the year 2010 (61 from November to April, 79 from May to October). The sample encompassed 70 patients with and 70 without diabetes. At admission we measured serum calcium (Ca), phosphate (P), sodium (Na), potassium (K), creatinine (Cr), alkaline phosphatase total activity (AP), albumin adjusted serum calcium (Caalb adj), 25 hydroxy-vitamin D (25OHD), parathyroid hormone (PTH), and 24-h urinary sodium/creatinine (uNa/Cr), potassium/creatinine (uK/Cr), calcium/creatinine (uCa/Cr), phosphate/creatinine (uP/Cr) ratios and calcium excretion (Ca ex). Results 25OHD levels of patients with and without diabetes did not significantly differ. In patients without diabetes recruited from November to April, 25OHD levels were significantly lower than those from May to October, whilst patients with diabetes did not show a significant seasonal variation. PTH had opposite non-significant seasonal variations, and negatively correlated with 25OHD in both groups of patients. This correlation was lost after adjusting for age and BMI in patients with diabetes. These inpatients had higher serum P and lower uP/Cr, according to lower PTH. Their serum glucose negatively correlated with uCa/Cr and Ca ex, contrary to inpatients with other diseases. Instead, uCa/Cr and Ca ex correlated with uNa/Cr only in patients without diabetes. Conclusions Inpatients with diabetes did differ from those with other disorders for vitamin D status and calcium-phosphate homeostatic mechanism.
Journal of endocrinological investigation 01/2012; · 1.57 Impact Factor
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K Kacar,
M A Rocca, M Copetti,
S Sala,
S Mesaros,
T Stosic Opincal,
D Caputo,
M Absinta,
J Drulovic,
V S Kostic,
G Comi,
M Filippi
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ABSTRACT: In MS, the relation between clinical and MR imaging measures is still suboptimal. We assessed the correlation of disability and specific impairment of the clinical functional system with overall and regional CNS damage in a large cohort of patients with MS with different clinical phenotypes by using a random forest approach.
Brain conventional MR imaging and DTI were performed in 172 patients with MS and 46 controls. Cervical cord MR imaging was performed in a subgroup of subjects. To evaluate whether MR imaging measures were able to correctly classify impairment in specific clinical domains, we performed a random forest analysis.
Between-group differences were found for most of the MR imaging variables, which correlated significantly with clinical measures (r ranging from -0.57 to 0.55). The random forest analysis showed a high performance in identifying impaired versus unimpaired patients, with a global error between 7% (pyramidal functional system) and 31% (Ambulation Index) in the different outcomes considered. When considering the performance in the unimpaired and impaired groups, the random forest analysis showed a high performance in identifying patients with impaired sensory, cerebellar, and brain stem functions (error below 10%), while it performed poorly in defining impairment of visual and mental systems (error of 91% and 70%, respectively). In analyses with a good level of classification, for most functional systems, damage of the WM fiber bundles subserving their function, measured by using DTI tractography, had the highest classification power.
Random forest analysis, especially if applied to DTI tractography data, is a valuable approach, which might contribute to overcoming the MS clinical-MR imaging paradox.
American Journal of Neuroradiology 11/2011; 32(11):2098-102. · 2.93 Impact Factor
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F Agosta,
E Scola,
E Canu,
A Marcone,
G Magnani,
L Sarro, M Copetti,
F Caso,
C Cerami,
G Comi,
S F Cappa,
A Falini,
M Filippi
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ABSTRACT: White matter (WM) tract damage was assessed in patients with the behavioral variant frontotemporal dementia (bvFTD) and the 3 primary progressive aphasia (PPA) variants and compared with the corresponding brain atrophy patterns. Thirteen bvFTD and 20 PPA patients were studied. Tract-based spatial statistics and voxel-based morphometry were used. Patients with bvFTD showed widespread diffusion tensor magnetic resonance imaging (DT MRI) abnormalities affecting most of the WM bilaterally. In PPA patients, WM damage was more focal and varied across the 3 syndromes: left frontotemporoparietal in nonfluent, left frontotemporal in semantic, and left frontoparietal in logopenic patients. In each syndrome, DT MRI changes extended beyond the topography of gray matter loss. Left uncinate damage was the best predictor of frontotemporal lobar degeneration diagnosis versus controls. DT MRI measures of the anterior corpus callosum and left superior longitudinal fasciculus differentiated bvFTD from nonfluent cases. The best predictors of semantic PPA compared with both bvFTD and nonfluent cases were diffusivity abnormalities of the left uncinate and inferior longitudinal fasciculus. This study provides insights into the similarities and differences of WM damage in bvFTD and PPA variants. DT MRI metrics hold promise to serve as early markers of WM integrity loss that only at a later stage may be detectable by volumetric measures.
Cerebral Cortex 10/2011; · 6.54 Impact Factor
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Nutrition, metabolism, and cardiovascular diseases: NMCD 09/2011; 22(2):e5-6. · 3.52 Impact Factor
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M A Rocca,
M A Horsfield,
S Sala, M Copetti,
P Valsasina,
S Mesaros,
V Martinelli,
D Caputo,
T Stosic-Opincal,
J Drulovic,
G Comi,
M Filippi
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[hide abstract]
ABSTRACT: In this multicenter study, a new semiautomatic method for segmenting the cervical cord from C2 to C5 was used to investigate the correlation between cord atrophy and clinical disability in a large sample of patients with multiple sclerosis (MS).
T2 and 3-dimensional T1-weighted cervical cord scans and dual-echo brain scans were acquired from 143 healthy controls, 22 patients with clinically isolated syndromes (CIS), 101 patients with relapsing-remitting MS (RRMS), 79 patients with secondary progressive MS (SPMS), 58 patients with benign MS (BMS), and 75 patients with primary progressive MS (PPMS) in 3 European centers. Normalized cervical cord cross-sectional area (CSAn) was measured by an active surface cord model. Between-group comparisons were performed using linear mixed-effect models. A nonparametric kernel estimator was used to obtain smoothed plots of CSA along the cervical cord.
Cord CSAn was significantly lower in PPMS vs healthy controls, BMS vs RRMS, SPMS vs BMS, and RRMS. From C2 to C5, a net separation and definition of the plots of patients with BMS, PPMS, and SPMS was seen with respect to those of the other study groups. CSAn was correlated with Expanded Disability Status Scale (r = -0.49, p < 0.0001), with a differential effect among disease clinical phenotypes: no association in either CIS or in BMS; association in RRMS (r = -0.30, p = 0.001), SPMS (r = -0.34, p = 0.001), and PPMS (r = -0.27, p = 0.01).
Cervical cord atrophy provides a relevant and useful marker for the characterization of clinical heterogeneity of patients with MS. The stability of this measure among different centers supports its use as potential outcome measure to monitor disease progression in multicenter trials.
Neurology 06/2011; 76(24):2096-102. · 8.31 Impact Factor
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ABSTRACT: Double inversion recovery (DIR) sequences have improved the detection of cortical lesions (CLs) in adult patients with multiple sclerosis (MS). We evaluated the presence and frequency of CLs in pediatric patients with relapsing-remitting MS (RRMS) in comparison to adult patients with MS with the same clinical phenotype.
Using a 3.0-T scanner, brain DIR, dual-echo, and 3-dimensional T1-weighted scans were acquired from 24 pediatric patients with RRMS, 15 adult patients with RRMS, and 10 pediatric healthy controls. CLs and white matter (WM) lesions were identified, and their volumes measured. Brain gray matter and WM volumes were also calculated. Between-group comparisons were performed using χ(2), Mann-Whitney, and analysis of variance tests. Poisson regressions for count data were used to model the number of lesions of the 2 groups of patients.
Compared to adults, pediatric patients had shorter disease duration and lower disability. WM lesion number and volume did not differ between pediatric and adult patients with MS. CLs were detected in 2 (8%) pediatric and 10 (66%) adult patients. Median CL volume was lower in pediatric than adult patients with RRMS (p = 0.0003). Regression analysis showed that pediatric patients had a lower number of CLs than adults (p = 0.0003), after adjusting for age, gender, Expanded Disability Status Scale score, and disease duration.
CLs are rare in pediatric patients with MS. Since pediatric patients with MS have a clinical onset closer to the biological onset of the disease than adult patients with MS, our findings indicate that CL formation is likely not to be an initial event in this disease.
Neurology 03/2011; 76(10):910-3. · 8.31 Impact Factor
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ABSTRACT: We investigated whether the functional connections to the primary sensorimotor cortex (SMC) at rest are abnormal in 26 patients with amyotrophic lateral sclerosis (ALS) and whether such changes are related to the corticospinal tract (CST) damage, measured using diffusion tensor magnetic resonance imaging (DT MRI). ALS patients versus controls showed a significantly increased functional connectivity between the left SMC and the right cingulate cortex, parahippocampal gyrus, and cerebellum-crus II. No right SMC connectivity changes were found. The pattern of increased functional connectivity to the left SMC was more widespread when considering only patients with no CST DT MRI abnormalities than the whole group of patients. In this patient group, functional connectivity was also increased between the right SMC and the right parahippocampal gyrus. On the contrary, in ALS patients with CST damage (as assessed using DT MRI) versus controls, functional connectivity was increased between the left SMC and the right cingulate cortex only, while it was decreased between the right SMC and the right cerebellum-lobule VI. In ALS patients, disease severity correlated with reduced SMC functional connectivity. Functional brain changes do occur in ALS with mild disability. These changes might have a role in compensating for (limited) structural damage and might exhaust with increasing burden of disease pathology.
Cerebral Cortex 03/2011; 21(10):2291-8. · 6.54 Impact Factor
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ABSTRACT: Interest has been increasing in the use of transthoracic ultrasound for the study of the pleuropulmonary disease. US imaging depends mainly on the physical interactions between ultrasound waves and the tissues being examined. In the thoracic region, the prescence of the chest wall and the air-containing pulmonary tissues cause various artifacts that strongly influence the resulting images. At the interface between tissues and air, the ultrasound beam is totally reflected and produces simple reverberation, comet-tail artifacts, and ring-down artifacts.We report the findings of transthoracic ultrasound in normal healthy subjects and in those who had undergone pneumonectomy.This experience shows that, in terms of the ultrasound artifacts mentioned above, the postpneumonectomy cavity is not significantly different from the healthy lung.
Journal of Ultrasound 03/2011; 14(1):22-7.
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ABSTRACT: Insulin resistance is associated with reduced serum adiponectin and increased albuminuria levels. Thus, one would anticipate an inverse relationship between circulating adiponectin and albuminuria. However, several studies have described a 'paradoxical' elevation of serum adiponectin in patients with elevated albuminuria. These findings may have been confounded by the presence of diseases and related treatments known to affect circulating adiponectin and albuminuria. We therefore studied the relationship between circulating adiponectin and albuminuria in the absence of such confounders.
To this purpose, the relationship between adiponectin isoforms and albumin:creatinine ratio (ACR) was investigated in a family-based sample of 634 non-diabetic untreated white individuals with normal kidney function. We also investigated whether the two variables share a common genetic background and addressed the specific role of the gene encoding adiponectin on that background by genotyping several ADIPOQ single nucleotide polymorphisms (SNPs).
ACR was directly associated with high molecular weight (HMW) adiponectin isoform (p = 0.024). The two variables shared some genetic correlation (ρ(g) = 0.38, p = 0.04). ADIPOQ promoter SNP rs17300539 was associated with HMW adiponectin (p = 4.8 × 10(-5)) and ACR (p =0.0027). The genetic correlation between HMW adiponectin and ACR was no longer significant when SNP rs17300539 was added to the model, thus reinforcing the role of this SNP in determining both traits.
Our study shows a positive, independent correlation between HWM adiponectin and ACR. ADIPOQ variability is associated with HMW adiponectin and ACR, and explains some of the common genetic background shared by these traits, thus suggesting that ADIPOQ and HMW adiponectin modulate albuminuria levels.
Diabetologia 01/2011; 54(4):812-8. · 6.81 Impact Factor
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L. A. Muscarella,
R. Barbano,
V. D'Angelo, M. Copetti,
M. Coco,
T. Balsamo,
A. la Torre,
A. Notarangelo,
M. Troiano,
S. Parisi,
N. Icolaro,
D. Catapano,
V. M. Valori,
F. Pellegrini,
G. Merla,
M. Carella,
V. M. Fazio,
P. Parrella
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ABSTRACT: In light with the view that KEAP1 loss of function may impact tumour behavior and modify response to chemotherapeutical agents, we sought to determine whether KEAP1 gene is epigenetically regulated in malignant gliomas. We developed a Quantitative Methylation Specific PCR (QMSP) assay to analyze 86 malignant gliomas and 20 normal brain tissues. The discriminatory power of the assay was assessed by Receiving Operating Characteristics (ROC) curve analysis. The AUC value of the curve was 0.823 (95%CI: 0.764-0.883) with an optimal cut off value of 0.133 yielding a 74% sensitivity (95%CI: 63%-82%) and an 85% specificity (95%CI: 64%-95%). Bisulfite sequencing analysis confirmed QMSP results and demonstrated a direct correlation between percentage of methylated CpGs and methylation levels (Spearman's Rho 0.929, P=0.003). Remarkably, a strong inverse correlation was observed between methylation levels and KEAP1 mRNA transcript in tumour tissue (Spearman's Rho -0.656 P=0.0001) and in a cell line before and after treatment with 5-azacytidine (P=0.003). RECPAM multivariate statistical analysis studying the interaction between MGMT and KEAP1 methylation in subjects treated with radiotherapy and temozolomide (n=70), identified three prognostic classes of glioma patients at different risk to progress. While simultaneous methylation of MGMT and KEAP1 promoters was associated with the lowest risk to progress, patients showing only MGMT methylation were the subgroup at the higher risk (HR 5.54, 95% CI 1.35-22.74). Our results further suggest that KEAP1 expression is epigenetically regulated. In addition we demonstrated that KEAP1 is frequently methylated in malignant gliomas and a predictor of patient's outcome.
Epigenetics. 01/2011; 6(3):317-25.
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L. A. Muscarella,
V. D'Alessandro,
A. la Torre, M. Copetti,
A. De Cata,
P. Parrella,
M. Sperandeo,
F. Pellegrini,
V. Frusciante,
E. Maiello,
G. Merla,
V. M. Fazio,
G. Vendemiale
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Somatostatin (SS) acts as a universal endocrine off-switch, and also inhibits the growth of neuroendocrine tumours through its specific receptors (SSTRs). Somatostatin receptors are G-protein-coupled receptors, which are encoded by five separate genes (SSTR1-5). Short peptide analogues demonstrate specific binding only for the subgroup consisting of SSTR2a, SSTR3 and SSTR5. Moreover, previous studies reported that expression of mRNA for SSTR2a correlated with therapeutic outcome in patients with carcinoid tumours treated with somatostatin analogs. PURPOSE: To develop and apply a Real Time Quantitative PCR technique (RT-qPCR) to compare and contrast the mRNA levels of SSTR2a, SSTR3 and SSTR5 in Neuroendocrine Lung Cancer affected patients. METHODS: Peripheral blood samples from 21 neuroendocrine lung cancer affected patients (14 SCLC, 6 LC and 1 LCNEC) subjected to scintigraphy with (111)In-DTPA-D-Phe(1)-octreotide (OctreoScan) and 24 healthy blood donors were investigated by RT-qPCR. mRNA levels for SSTR2a, SSTR3 and SSTR5 were measured in peripheral blood samples with a relative quantification method using plasmid dilutions as calibration curves and GAPDH as reference gene. RESULTS: A statistically significant increase in target genes/GAPDH copy number ratio was found for SSTR2a (median 38; IQR 22-141) and SSTR5 (median 51; IQR 19-499) in neuroendocrine lung cancer affected patients as compared with samples from healthy blood donors (P </= 0.0003 and P </= 0.0005). Since low levels of expression were detected in the control group for all three genes, optimal cut-off values were assessed using ROC curve analyses and were equal to 9.05 for SSTR2a and 16.97 for SSTR5. These cut off values resulted in a sensitivity of 86% (95%IC 65-95) for both markers and a specificity of 83% (95%IC 64-93%) and 79% (95%IC 60-91%) for SSTR2a and SSTR5 respectively. Comparison between OctreoScan results and RT-qPCR analysis demonstrated agreement in 76% of the cases. CONCLUSIONS: Our results suggest that SSTR2a and SSTR5 mRNAs are detectable in peripheral blood of neuroendocrine lung cancer affected patients using real-time quantitative PCR, with a good agreement with OctreoScan. The high sensitivity of this non-invasive molecular technique suggests that this method could represent a useful tool in the clinical management of neuroendocrine lung cancers.
Cell Oncol (Dordr). 01/2011;
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L. A. Muscarella,
P. Parrella,
V. D'Alessandro,
A. la Torre,
R. Barbano,
A. Fontana,
A. Tancredi,
V. Guarnieri,
T. Balsamo,
M. Coco, M. Copetti,
F. Pellegrini,
P. De Bonis,
M. Bisceglia,
G. Scaramuzzi,
E. Maiello,
V. M. Valori,
G. Merla,
G. Vendemiale,
V. M. Fazio
[show abstract]
[hide abstract]
ABSTRACT: The KEAP1/Nrf2 pathway is a master regulator of several redox-sensitive genes implicated in resistance of tumor cells against chemotherapeutic drugs. Recent data suggest that epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression. We performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 47 non-small cell lung cancer tissues and normal specimens. Promoter methylation analysis was performed using a quantitative methylation specific PCR assay in real time. Methylation at the KEAP1 promoter region was detected in 22 out of the 47 NSCLCs (47%) and in none of the normal tissues analyzed. Somatic mutations were detected in 7 out of the 47 tumors (15%) and loss of heterozygosity (LOH) in 10 out of the 47 (21%) of the cases. Overall, we found at least one molecular alteration in 57% of the cases. Approximately one third of the tumors had two alterations and this feature was associated with higher risk of disease progression in univariate COX regression analysis (HR = 3.62; 95% CI 1.24-10.65, p = 0.02). This result was confirmed by Kaplan-Meier analysis, which demonstrated an association between worst outcome and KEAP1 double alterations (p = 0.01, Log rank test). Our results further suggest that deregulation of the NRF2/KEAP1 system could play a pivotal role in the cancerogenesis of NSCLC. In addition identifying patients with KEAP1 genetic and epigenetic abnormalities may contribute to disease progression prediction and response to therapy in lung cancer patients.
Epigenetics. 01/2011; 6(6):710-9.
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[show abstract]
[hide abstract]
ABSTRACT: The mortality prediction represents a key factor in the managing of elderly hospitalized patients. Since in older subjects mortality results from a combination of biological, functional, nutritional, psychological and environmental factors, a Multidimensional Prognostic Index (MPI) that predict short- and long-term mortality based on a standardized comprehensive geriatric assessment (CGA) has recently been developed and validated.
This study compares the accuracy in predicting the mortality of the MPI with a modified version of the MPI (m-MPI) that included the Mini Nutritional Assessment-Short Form (MNA-SF) instead of the standard MNA.
This prospective study with a one-year follow-up included 4088 hospitalized patients aged 65 years and older. A standardized CGA that included information on functional (Activities of Daily Living, ADL and Instrumental-ADL), cognitive (Short Portable Mental Status Questionnaire), risk of pressure sore (Exton-Smith Scale), comorbidities (CIRS Index), medications, living status and nutritional status (MNA and MNA-SF) was used to calculate the MPI using a previously validated algorithm.
Higher MPI values were significantly associated with higher mortality rates with a close agreement between the estimated and the observed mortality both after 1-month (MPI1=2.8% versus m-MPI1=2.8%,p=0.946; MPI2=8.9% versus m-MPI2=9%,p=0.904; MPI3=21.9% versus m-MPI3=21.9,p=0.978) and 1-year of follow-up (MPI1=10.8% versus m-MPI1=10.5%,p=0.686; MPI2=27.3% versus m-MPI2=28%, p=0.495; MPI3=52.8% versus m-MPI3=52.7%,p=0.945). The estimated areas under the receiver operating characteristics (ROC) curves suggested a clinically negligible difference between the two indices.
The m-MPI is as sensitive as the MPI in stratifying hospitalized elderly patients into groups at varying risk of short- and long-term mortality, but with fewer items.
The Journal of Nutrition Health and Aging 01/2011; 15(3):169-73. · 2.69 Impact Factor
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S Prudente,
R Baratta,
F Andreozzi,
E Morini,
M G Farina,
A Nigro, M Copetti,
F Pellegrini,
E Succurro,
L Di Pietrantonio,
C Brufani,
F Barbetti,
B Dallapiccola,
G Sesti,
V Trischitta,
L Frittitta
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ABSTRACT: The results of studies on the genetics of complex traits need to be replicated and to reach robust statistical significance before they can be considered as established. We here tried to replicate the previously reported association between the TRIB3 Q84R polymorphism (rs2295490) and glucose homeostasis.
Three samples of Europeans with fasting glucose <7.0 mmol/l were studied. In sample 1 (n=791), the association between TRIB3 Q84R and impaired glucose regulation (IGR; defined as impaired fasting glucose and/or impaired glucose tolerance and/or type 2 diabetes by OGTT) and insulin sensitivity (ISI), and its interplay with early-phase insulin secretion (i.e. disposition index [DI]) were analysed. Sample 2 (n=374) and sample 3 (n=394) were used to replicate the association with IGR and insulin sensitivity (by glucose clamp), respectively. Genotyping was performed by TaqMan allele discrimination.
R84 carriers were at higher risk of IGR: OR for the additive model 1.54, p=0.004, and 1.63, p=0.027, in samples 1 and 2, respectively. In sample 1, both ISI (p=0.005) and DI (p=0.043) were progressively lower from QQ to QR and RR individuals. A 'triangulation approach' indicated that the association with IGR was mostly mediated by DI rather than by ISI changes (i.e. being the expected ORs 1.51 and 1.25, respectively). In sample 3, glucose disposal was 38.8+/-17.7, 33.8+/-14.4, and 31.6+/-13.3 micromol min(-1)kg(-1), p=0.022, in QQ, QR and RR individuals, respectively.
Our data confirm that the TRIB3 R84 variant affects glucose homeostasis and suggest this effect is due to an alteration of the interplay between insulin sensitivity and secretion.
Diabetologia 07/2010; 53(7):1354-61. · 6.81 Impact Factor
