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Sara Volpe, Cosimo Tortorella, Vincenzo Solfrizzi, Giuseppina Piazzolla Interdisciplinary Department of Medicine, University of Bari “Aldo Moro” Medical School, Bari, 70124, ItalyCorrespondence: Giuseppina PiazzollaInterdisciplinary Department of Medicine, University of Bari “Aldo Moro” Medical School, Policlinico, Piazza G. Cesare 11, Bari, 70124, ItalyFax +39 080 5478126Email giuseppina.piazzolla@uniba.itIntroduction: New antidiabetic drugs have simplified treatment regimens in patients with type-2 diabetes (T2D). More importantly, they have proven to reduce cardiovascular risk by lowering insulin-resistance, blood pressure and body weight, in addition to avoiding inappropriate insulin therapy, responsible for hypoglycemic episodes and weight gain. In this context, accurate assessment of the metabolic status of T2D patients becomes essential. The C-peptide assay is a simple but often overlooked test that can provide a fundamental contribution to the correct disease classification and optimal therapeutic management of diabetic patients.Clinical Case: We report the case of a 72-year-old patient, treated with insulin for 26 years after a diagnosis of type-1 diabetes (T1D), resulting in inadequate glycemia control and a severe evolution of cardiovascular complications. After an accurate evaluation of the clinical history, phenotype and laboratory data, including the determination of C-peptide serum levels, a diagnosis was made of T2D not T1D. Considering the patient’s very high cardiovascular risk and dysmetabolic profile, insulin therapy was discontinued and more appropriate therapy with dulaglutide and metformin was instituted. These overall therapeutic modifications yielded remarkable clinical advantages in terms of the glycometabolic profile, weight reduction, abdominal circumference and body mass index decrease, as well as a better quality of life, with complete resolution of the dangerous hypoglycemic episodes.Conclusion: In the era of new cardioprotective antidiabetic drugs, we believe the importance of the C-peptide assay should be re-evaluated in order to avoid misdiagnosis and to improve the therapeutic approach to T2D.Keywords: diabetes, metabolic syndrome, hypoglycemia, obesity, dulaglutide, quality of life

Serena Ruggieri,1 Carla Tortorella,2 Claudio Gasperini31Department of Neurology and Psychiatry, Sapienza University of Rome “Sapienza”, Rome, Italy; 2Department of Basic Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy; 3Department of Neurosciences, S Camillo Forlanini Hospital, Rome, ItalyAbstract: The last two decades have seen the introduction of several therapies for multiple sclerosis (MS). These therapies are intended to work at different levels of the disease, typically targeting direct symptom management, brief corticosteroid administration for acute exacerbations, and the regular use of disease-modifying drugs. Nevertheless, in clinical practice, disease-modifying drugs or immunosuppressive treatments are frequently associated with suboptimal response in terms of efficacy and several side effects leading to poor patient adherence, so the proportion of relapsing–remitting MS patients not adequately responding to disease-modifying therapy have been reported to range from 7% to 49%. Natalizumab and fingolimod are the newest US Food and Drug Administration-approved agents that have been added to the MS treatment armamentarium, but their use is limited by a less known safety profile and recognized specific risk. Thus, there is an important need for new therapeutic strategies, especially those that may offer greater patient satisfaction and safer risk profile in order to optimize therapeutic outcomes. A number of potential therapies for MS are now in late-stage development. Effective, safe, and well-tolerated therapies may improve compliance and empower patients with a level of independence not presently possible. To meet these characteristics, most of these therapies are oral compounds. Herein, we review the pharmacology and efficacy of dimethyl fumarate (BG-12) to date and its role in the evolving marketplace.Keywords: disease-modifying drugs, nuclear factor erythroid-derived 2 (E2)-related factor, Nrf2, oxidative stress, neuroprotection, oral treatment

In the last years, change in multiple sclerosis (MS) therapeutic scenario has highlighted the need for an improved doctor-patient communication in advance of treatment initiation in order to allow patient's empowerment in the decision-making process. Aims: The aims of our project were to review the strategies used by Italian MS specialists to inform patients about treatment options and to design a multicentre shared document that homogenizes the information about disease-modifying treatment (DMTs) and the procedure of taking informed consent in clinical practice. Results: The new resource, obtained by consensus among 31 neurologists from 27 MS Centres in Italy with the supervision of a medico-legal advisor, received the aegis of Italian Neurological Society (SIN) and constitutes a step toward a standardized decision process around DMTs in MS. [ABSTRACT FROM AUTHOR]

The article presents a study which aims to investigate the relationship between functional magnetic resonance imaging (fMRI) correlates of attention performance and cerebrospinal fluid (CSF) neurofilament light chain (NFL) levels in patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). It notes the assessment of CSF NFL by ELISA technique. It reveals a relationship between CSF NFL levels and load-dependent failure of putaminal recruitment pattern in CIS.

The article presents a study which assess the functional resonance imaging (fMRI) patter of brain activation in clinically isolated syndrome (CIS) patients. It states that twenty-seven untreated CIS patients and 32 age- and sex-matched healthy controls (Hcs) have pass through fMRI while executing the Variable Attentional Control (VAC) task. Results show that CIS patients had decreased accuracy and greater reaction time at the VAC task unlike with Hcs.

PM10 samples were collected in Civitavecchia (Rome, Italy) during a monitoring campaign performed between August and September 2008; elemental, ionic and organic characterisation of the samples was carried out. Three receptor models (Chemical Mass Balance, Absolute Principal Component Scores and Positive Matrix Factorisation) were applied to identify PM10 sources and their contributions. The results obtained by the models were compared in order to perform a robust characterisation of the sources. Seven emission sources were considered relevant for the area under investigation and their profiles were used to run CMB. Source percentage contributions to the total particulate matter samples were evaluated: the greater contribution was obtained for Traffic (39%), the lower for Marine Aerosol (3%). Five factors were selected to perform the multivariate receptor models (APCS and PMF) after the application of explorative Principal Component Analysis to the dataset. Furthermore, attention was focused on the characterisation of source profiles and contributions obtained by PMF because it best reconstructed the PM mass of the samples. The percentage contributions of the five sources to the total PM samples were estimated: the greater contribution was obtained for resuspended matter (22%), the lower for combustions (17%). The results of the source apportionment studies can be used by air quality managers to develop appropriate control strategy. However, the differences in sources profiles and weights obtained by the models were related to their specific approaches: further investigations are suggested in order to develop sources profiles more reliable for the area under investigation. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Recent findings support greater efficacy of early vs. delayed interferon beta (IFNbeta) treatment in patients with a first clinical event suggestive of multiple sclerosis (MS). We aimed to evaluate the effectiveness of early IFNbeta treatment in definite relapsing-remitting MS (RRMS) and to assess the optimal time to initiate IFNbeta treatment with regard to the greatest benefits on disability progression. METHODS: A cohort of 2,570 IFNbeta-treated RRMS patients was prospectively followed for up to 7 years in 15 Italian MS Centers. A Cox proportional hazards regression model adjusted for propensity score (PS) quintiles was used to assess differences between groups of patients with early vs. delayed IFNbeta treatment on risk of reaching a 1-point progression in the Expanded Disability Status Scale (EDSS) score, and the EDSS 4.0 and 6.0 milestones. A set of PS-adjusted Cox hazards regression models were calculated according to different times of treatment initiation (within 1 year up to within 5 years from disease onset). A sensitivity analysis was performed to assess the robustness of findings. RESULTS: The lowest hazard ratios (HRs) for the three PS quintiles-adjusted models were obtained by a cutoff of treatment initiation within 1 year from disease onset. Early treatment significantly reduced the risk of reaching a 1-point progression in EDSS score (HR = 0.63; 95% CI = 0.48-0.85; p < 0.002), and the EDSS 4.0 milestone (HR = 0.56; 95% CI = 0.36-0.90; p = 0.015). Sensitivity analysis showed the bound of significance for unmeasured confounders. INTERPRETATION: Greater benefits on disability progression may be obtained by an early IFNbeta treatment in RRMS. Ann Neurol 2009;66:513-520. [ABSTRACT FROM AUTHOR]

Fas-stimulated neutrophils from elderly individuals show impaired granulocyte macrophage-colony-stimulating factor (GM-CSF)-induced apoptosis cell rescue. Herein, this defect was found to be associated with a significant reduction in GM-CSF-mediated Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Using Akt and ERK1/2 inhibitors, we demonstrated that both kinases were critical for GM-CSF antiapoptotic effects. Whereas Akt inhibition also affected GM-CSF-dependent ERK1/2 phosphorylation, ERK1/2 inhibition did not affect GM-CSF-induced Akt phosphorylation, suggesting that phosphoinositide 3-kinase (PI3-K)/Akt and ERK1/2 are activated in series and that PI3-K is located upstream of ERK1/2 along the GM-CSF-dependent signaling pathway. No age-associated changes in GM-CSF receptor expression were observed. Interestingly, both suppressors of cytokine signaling (SOCS)1 and SOCS3 proteins were significantly higher in unstimulated neutrophils from elderly individuals and, unlike in young individuals, did not further increase following GM-CSF cell triggering. These results indicate that defective PI3-K/Akt/ERK1/2 activation, likely dependent on elevated SOCS1 and SOCS3 levels, may affect the GM-CSF capacity to delay neutrophil apoptosis in elderly persons. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase-9 (MMP-9) is involved in blood–brain barrier (BBB) disruption in active multiple sclerosis (MS), while MMP-2 seems to be associated with the chronic progressive phase of the disease. Recombinant interferon beta-1a (rIFNβ-1a) is effective in restoring the BBB. We studied the relationships between serum MMP-9, MMP-2, TIMP-1 and TIMP-2 and different magnetic resonance imaging (MRI) measures of disease activity in MS patients during treatment with rIFNβ-1a. Twenty-one relapsing–remitting (RR) MS patients underwent longitudinally simultaneous blood withdrawals and MRI (before and after standard dose (SD) and triple dose (TD) of gadolinium (Gd)) examinations before and during 48 weeks of rIFNβ-1a (Rebif® 22 mcg three times a week) treatment. Serum MMP-9, MMP-2, TIMP-1 and TIMP-2 were measured, MMP-9 to TIMP-1 and MMP-2 to TIMP-2 ratios were calculated and the numbers of Gd-SD, Gd-TD, new-Gd-SD, new-Gd-TD and new-T2 lesions counted. Serum MMP-9/TIMP-1 ratio (P <0.0001), as well as the numbers of 'active' lesions ( P ranging from 0.0004 to 0.005) decreased during treatment. Moreover, serum MMP-9/TIMP-1 ratio proved to be a good positive predictor (estimate =0.85; P <0.05) of the numbers of MRI Gd-TD active lesions. These data confirm that serum MMP-9/TIMP-1 ratio may be viewed as a reliable marker and may be predictive of MRI activity in RR MS. [ABSTRACT FROM AUTHOR]

Several magnetic resonance (MR) techniques have proved to be sensitive enough to detect the subtle pathological changes that post-mortem studies showed to occur in the normal-appearing white matter (NAWM) from patients with multiple sclerosis (MS). Although these abnormalities can be detected in other neurological conditions, they seem to be more frequent and diffuse in MS. However, the contribution of NAWM changes to the diagnosis is still unclear. Their nature is also unknown and perhaps differs in different phases and clinical manifestations of the disease. Nevertheless, the extent and severity of NAWM damage seems to be relevant in causing disability and influencing the clinical evolution in MS patients. This review will summarize the present knowledge about MR-detected NAWM changes in MS and their relevance to the diagnosis and the understanding of disease evolution. [ABSTRACT FROM AUTHOR]

Context: Studies have shown that an inflammatory response may be elicited by mechanical ventilation used for recruitment or derecruitment of collapsed lung units or to overdistend alveolar regions, and that a lung-protective strategy may reduce this response.Objective: To test the hypothesis that mechanical ventilation induces a pulmonary and systemic cytokine response that can be minimized by limiting recruitment or derecruitment and overdistention.Design and Setting: Randomized controlled trial in the intensive care units of 2 European hospitals from November 1995 to February 1998, with a 28-day follow-up.Patients: Forty-four patients (mean [SD] age, 50 [18] years) with acute respiratory distress syndrome were enrolled, 7 of whom were withdrawn due to adverse events.Interventions: After admission, volume-pressure curves were measured and bronchoalveolar lavage and blood samples were obtained. Patients were randomized to either the control group (n = 19): tidal volume to obtain normal values of arterial carbon dioxide tension (35-40 mm Hg) and positive end-expiratory pressure (PEEP) producing the greatest improvement in arterial oxygen saturation without worsening hemodynamics; or the lung-protective strategy group (n = 18): tidal volume and PEEP based on the volume-pressure curve. Measurements were repeated 24 to 30 and 36 to 40 hours after randomization.Main Outcome Measures: Pulmonary and systemic concentrations of inflammatory mediators approximately 36 hours after randomization.Results: Physiological characteristics and cytokine concentrations were similar in both groups at randomization. There were significant differences (mean [SD]) between the control and lung-protective strategy groups in tidal volume (11.1 [1.3] vs 7.6 [1.1] mL/kg), end-inspiratory plateau pressures (31.0 [4.5] vs 24.6 [2.4] cm H2O), and PEEP (6.5 [1.7] vs 14.8 [2.7] cm H2O) (P<.001). Patients in the control group had an increase in bronchoalveolar lavage concentrations of interleukin (IL) 1beta, IL-6, and IL-1 receptor agonist and in both bronchoalveolar lavage and plasma concentrations of tumor necrosis factor (TNF) alpha, IL-6, and TNF-alpha, receptors over 36 hours (P<.05 for all). Patients in the lung-protective strategy group had a reduction in bronchoalveolar lavage concentrations of polymorphonuclear cells, TNF-alpha, IL-1beta, soluble TNF-alpha receptor 55, and IL-8, and in plasma and bronchoalveolar lavage concentrations of IL-6, soluble TNF-alpha receptor 75, and IL-1 receptor antagonist (P<.05). The concentration of the inflammatory mediators 36 hours after randomization was significantly lower in the lung-protective strategy group than in the control group (P<.05).Conclusions: Mechanical ventilation can induce a cytokine response that may be attenuated by a strategy to minimize overdistention and recruitment/derecruitment of the lung. Whether these physiological improvements are associated with improvements in clinical end points should be determined in future studies. [ABSTRACT FROM AUTHOR]

Proton magnetic resonance spectroscopy ([sup 1] H-MRS) is considered a suitable investigation technique for obtaining in vivo information on pathological changes in multiple sclerosis (MS) brain. The main betabolites identified are choline-containing compounds, creatine, N-acetylaspartate (NAA), lactate, mobile lipids, myo-inositol, glutamate and glutamine. Proton spectra may be acquired from localized volumes of interest on single MS lesions or from the entire brain by [sup 1] H-MRS imaging.An increase of choline and lipids (markers of demyelination) and the presence of lactate (marker of acute inflammatory reaction) have been demonstrated in active Gd-enhancing MS plaques. A reduction of NAA (marker of neuronal or axonal damage) has been found in inactive MS lesions. The recent evidence of an early NAA decrease in active plaques and in normal appearing white matter suggests that axonal damage is an early event in the evolution of demyelinating lesions. The correlation between NAA decrease and clinical disability conforms that axonal damage has important functional consequences, and indicates that the prevention of irreversible axonal loss might be a major target for the design and the timing of therapeutical strategies. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the role of proton MR spectroscopy (1H-MRS) in detecting metabolic changes in diffuse or focal lesions in the brain of patients infected with HIV.Methods: Sixty HIV seropositive patients (25 with HIV related encephalopathies, 20 with toxoplasmosis, eight with progressive multifocal leukoencephalopathies (PMLs), and seven with lymphomas) and 22 HIV seronegative neurological controls were examined with a combined MRI and 1H-MRS technique using a Siemens 1.5 Tesla Magnetom. Spectra (Spin Echo sequence, TE 135 ms) were acquired by single voxel, localised on focal lesions in toxoplasmosis, PML, lymphomas, and HIV encephalopathies and on the centrum semiovale of neurological controls. Choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), lactate, and lipids were evaluated in each spectrum and NAA/Cr, NAA/Cho, and Cho/Cr ratios were calculated.Results: A significant decrease in NAA/Cr and NAA/Cho ratios were found in all HIV diagnostic groups in comparison with neurological controls (p<0.003), suggesting neuronal or axonal damage independent of brain lesion aetiology. However, the NAA/Cr ratio was significantly lower in PML and lymphomas than in HIV encephalopathies (p<0.02) and toxoplasmosis (p<0.05). HIV encephalopathies, lymphomas, and toxoplasmosis showed a significant increase in the Cho/Cr ratio in comparison with neurological controls (p<0.03) without between group differences. The presence of a lipid signal was more frequent in lymphomas (71%) than in other HIV groups (Fisher's test, p=0.00003). The presence of mobile lipid resonance together with a high Cho/Cr ratio in lymphomas may be related to an increased membrane synthesis and turnover in tumour cells. A lactate signal (marker of inflammatory reaction), was found in all but one patient with PML lesions (75%), but had a lower incidence in the other HIV diagnostic groups (Fisher's test, p=0.00024).Conclusion: 1H-MRS shows a high sensitivity in detecting brain involvement in HIV related diseases, but a poor specificity in differential diagnosis of HIV brain lesions. Nevertheless, the homogeneous metabolic pattern that characterises PML suggests the usefulness of 1H-MRS as an adjunct to MRI in differentiating CNS white matter lesions, such as HIV encephalopathies, from PML. [ABSTRACT FROM AUTHOR]

PM10 samples were collected simultaneously at three representative areas (urban, industrial, and rural areas). Their morphology and elemental composition were determined by scanning electron microscopy coupled with energy-dispersive analysis (SEM-EDS). Twenty-four chemical parameters (C, O, Na, Mg, Al, Si, P, Cd, Cl, K, Ca, S, Sn, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, W, and Pb) were determined and three morphological parameters (area, roundness, and fractal dimension) were measured by Image Pro Analyzer 6.3. The particles were classified into ten groups based on morphology and elemental composition: Ca-rich and metal particles, soot aggregates, cenosphere, alumosilicates, sea salt, calcium sulfate, spherical particles of iron, biological carbonaceous particles, and various. Particles of natural origin were predominantly found in the coarse size fraction and particles of anthropogenic origin in the fine size fraction. The greatest contribution to particulate matter belonged to aluminum-silicates and calcium-rich particles. The cenosphere were recognized only in the coastal urban site, while all the other particles were present in each site. The coastal industrial site was characterized by the prevalence of alumosilicates and Ca-rich particles, due to construction activity in this site during the sampling period (movement of vehicles, transport of terrigenous materials, and use of construction products). The coastal urban site was characterized by a higher amount of soot and by the presence of cenosphere, due to the presence of vehicular traffic. [ABSTRACT FROM AUTHOR]