MR Imaging Signs of Gadolinium Retention Are Not Associated with Long-Term Motor and Cognitive Outcomes in Multiple Sclerosis.

BACKGROUND AND PURPOSE: The long-term impact of gadolinium retention in the dentate nuclei of patients undergoing administration of seriate gadolinium-based contrast agents is still widely unexplored. The aim of this study was to evaluate the impact of gadolinium retention on motor and cognitive disability in patients with MS during long-term follow-up. MATERIALS AND METHODS: In this retrospective study, clinical data were obtained from patients with MS followed in a single center from 2013 to 2022 at different time points. These included the Expanded Disability Status Scale score to evaluate motor impairment and the Brief International Cognitive Assessment for MS battery to investigate cognitive performances and their respective changes with time. The association with qualitative and quantitative MR imaging signs of gadolinium retention (namely, the presence of dentate nuclei T1-weighted hyperintensity and changes in longitudinal relaxation R1 maps, respectively) was probed using different General Linear Models and regression analyses. RESULTS: No significant differences in motor or cognitive symptoms emerged between patients showing dentate nuclei hyperintensity and those without visible changes on T1WIs (P = .14 and 0.92, respectively). When we tested possible relationships between quantitative dentate nuclei R1 values and both motor and cognitive symptoms, separately, the regression models including demographic, clinical, and MR imaging features explained 40.5% and 16.5% of the variance, respectively, without any significant effect of dentate nuclei R1 values (P = .21 and 0.30, respectively). CONCLUSIONS: Our findings suggest that gadolinium retention in the brains of patients with MS is not associated with long-term motor or cognitive outcomes.

The Italian Society of Rheumatology clinical practice guidelines for the management of large vessel vasculitis.

OBJECTIVE: Since of the last publication of last recommendations on primary large-vessel vasculitis (LVV) endorsed by the Italian Society of Rheumatology (SIR) in 2012, new evidence emerged regarding the diagnosis and the treatment with conventional and biologic immunosuppressive drugs. The associated potential change of clinical care supported the need to update the original recommendations. METHODS: Using the grading of recommendations assessment, development and evaluation (GRADE)-ADOLOPMENT framework, a systematic literature review was performed to update the evidence supporting the European Alliance of Associations for Rheumatology (EULAR) guidelines on LVV as reference. A multidisciplinary panel of 12 expert clinicians, a trained nurse, and a patients' representative discussed the recommendation in cooperation with an Evidence Review Team. Sixty-one stakeholders were consulted to externally review and rate the recommendations. RESULTS: Twelve recommendations were formulated. A suspected diagnosis of LVV should be confirmed by imaging or histology. In active GCA or TAK, the prompt commencement of high dose of oral glucocorticoids (40-60 mg prednisone-equivalent per day) is strongly recommended to induce clinical remission. In selected patients with GCA (e.g., refractory or relapsing disease or patients at risk of glucocorticoid related adverse effects) the use of an adjunctive therapy (tocilizumab or methotrexate) is recommended. In all patients diagnosed with TAK, adjunctive therapies, such as conventional synthetic or biological immunosuppressants, should be given in combination with glucocorticoids. CONCLUSIONS: The new set of SIR recommendations was formulated in order to provide a guidance on both diagnosis and treatment of patients suspected of or with a definite diagnosis of LVV.

Unraveling Deep Gray Matter Atrophy and Iron and Myelin Changes in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Modifications of magnetic susceptibility have been consistently demonstrated in the subcortical gray matter of MS patients, but some uncertainties remain concerning the underlying neurobiological processes and their clinical relevance. We applied quantitative susceptibility mapping and longitudinal relaxation rate relaxometry to clarify the relative contribution of atrophy and iron and myelin changes to deep gray matter damage and disability in MS. MATERIALS AND METHODS: Quantitative susceptibility mapping and longitudinal relaxation rate maps were computed for 91 patients and 55 healthy controls from MR images acquired at 3T. Applying an external model, we estimated iron and myelin concentration maps for all subjects. Subsequently, changes of deep gray matter iron and myelin concentration (atrophy-dependent) and content (atrophy-independent) were investigated globally (bulk analysis) and regionally (voxel-based and atlas-based thalamic subnuclei analyses). The clinical impact of the observed MRI modifications was evaluated via regression models. RESULTS: We identified reduced thalamic (P < .001) and increased pallidal (P < .001) mean iron concentrations in patients with MS versus controls. Global myelin and iron content in the basal ganglia did not differ between the two groups, while actual iron depletion was present in the thalamus (P < .001). Regionally, patients showed increased iron concentration in the basal ganglia (P ≤ .001) and reduced iron and myelin content in thalamic posterior-medial regions (P ≤ .004), particularly in the pulvinar (P ≤ .001). Disability was predicted by thalamic volume (B = -0.341, P = .02), iron concentration (B = -0.379, P = .005) and content (B = -0.406, P = .009), as well as pulvinar iron (B = -0.415, P = .003) and myelin (B = -0.415, P = .02) content, independent of atrophy. CONCLUSIONS: Quantitative MRI suggests an atrophy-related iron increase within the basal ganglia of patients with MS, along with an atrophy-independent reduction of thalamic iron and myelin correlating with disability. Absolute depletions of thalamic iron and myelin may represent sensitive markers of subcortical GM damage, which add to the clinical impact of thalamic atrophy in MS.

Treatment of Giant Cell Arteritis and Takayasu Arteritis-Current and Future.

PURPOSE OF REVIEW: Guidelines for the management of large vessel vasculitides have been recently updated by several scientific societies. We have evaluated the current recommendations for treatment of giant cell arteritis (GCA) and Takayasu arteritis (TA) and addressed potential future therapeutic strategies. RECENT FINDINGS: While glucocorticoids (GCs) remain the gold standard for induction of remission, many patients relapse and acquire high cumulative GC exposure. Thus, GC-sparing therapies such as methotrexate are recommended for selected patients with GCA and all patients with TA. Recent high-quality evidence shows that tocilizumab is an effective GC-sparing agent in GCA. Non-biologic and biologic immunomodulators also appear to have GC-sparing properties in TA. Tocilizumab is now considered to be part of the standard treatment for GCA, particularly with relapsing disease, but questions on its use such as length of treatment and monitoring of disease activity remain open. High-quality evidence to guide treatment of TA is still lacking.

A novel framework for spatial normalization of dose distributions in voxel-based analyses of brain irradiation outcomes.

PURPOSE: To devise a novel Spatial Normalization framework for Voxel-based analysis (VBA) in brain radiotherapy. VBAs rely on accurate spatial normalization of different patients' planning CTs on a common coordinate system (CCS). The cerebral anatomy, well characterized by MRI, shows instead poor contrast in CT, resulting in potential inaccuracies in VBAs based on CT alone. METHODS: We analyzed 50 meningioma patients treated with proton-therapy, undergoing planning CT and T1-weighted (T1w) MRI. The spatial normalization pipeline based on MR and CT images consisted in: intra-patient registration of CT to T1w, inter-patient registration of T1w to MNI space chosen as CCS, doses propagation to MNI. The registration quality was compared with that obtained by Statistical Parametric Mapping software (SPM), used as benchmark. To evaluate the accuracy of dose normalization, the dose organ overlap (DOO) score was computed on gray matter, white matter and cerebrospinal fluid before and after normalization. In addition, the trends in the DOOs distribution were investigated by means of cluster analysis. RESULTS: The registration quality was higher for the proposed method compared to SPM (p < 0.001). The DOO scores showed a significant improvement after normalization (p < 0.001). The cluster analysis highlighted 2 clusters, with one of them including the majority of data and exhibiting acceptable DOOs. CONCLUSIONS: Our study presents a robust tool for spatial normalization, specifically tailored for brain dose VBAs. Furthermore, the cluster analysis provides a formal criterion for patient exclusion in case of non-acceptable normalization results. The implemented framework lays the groundwork for future reliable VBAs in brain irradiation studies.

Voxel-based analysis in radiation oncology: A methodological cookbook.

Recently, 2D or 3D methods for dose distribution analysis have been proposed as evolutions of the Dose Volume Histogram (DVH) approaches. Those methods, collectively referred to as pixel- or voxel-based (VB) methods, evaluate local dose response patterns and go beyond the organ-based philosophy of Normal Tissue Complication Probability (NTCP) modelling. VB methods have been introduced in the context of radiation oncology in the very last years following the virtuous example of neuroimaging experience. In radiation oncology setting, dose mapping is a suitable scheme to compare spatial patterns of local dose distributions between patients who develop toxicity and who do not. In this critical review, we present the methods that include spatial dose distribution information for evaluating different toxicity endpoints after radiation therapy. The review addresses two main topics. First, the critical aspects in dose map building, namely the spatial normalization of the dose distributions from different patients. Then, the issues related to the actual dose map comparison, i.e. the viable options for a robust VB statistical analysis and the potential pitfalls related to the adopted solutions. To elucidate the different theoretical and technical issues, the covered topics are illustrated in relation to practical applications found in the existing literature. We conclude the overview on the VB philosophy in radiation oncology by introducing new phenomenological approaches to NTCP modelling that accounts for inhomogeneous organ radiosensitivity.

Non-Gaussian models of diffusion weighted imaging for detection and characterization of prostate cancer: a systematic review and meta-analysis.

The importance of Diffusion Weighted Imaging (DWI) in prostate cancer (PCa) diagnosis have been widely handled in literature. In the last decade, due to the mono-exponential model limitations, several studies investigated non-Gaussian DWI models and their utility in PCa diagnosis. Since their results were often inconsistent and conflicting, we performed a systematic review of studies from 2012 examining the most commonly used Non-Gaussian DWI models for PCa detection and characterization. A meta-analysis was conducted to assess the ability of each Non-Gaussian model to detect PCa lesions and distinguish between low and intermediate/high grade lesions. Weighted mean differences and 95% confidence intervals were calculated and the heterogeneity was estimated using the I2 statistic. 29 studies were selected for the systematic review, whose results showed inconsistence and an unclear idea about the actual usefulness and the added value of the Non-Gaussian model parameters. 12 studies were considered in the meta-analyses, which showed statistical significance for several non-Gaussian parameters for PCa detection, and to a lesser extent for PCa characterization. Our findings showed that Non-Gaussian model parameters may potentially play a role in the detection and characterization of PCa but further studies are required to identify a standardized DWI acquisition protocol for PCa diagnosis.

The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

OBJECTIVE: To evaluate the basal/total ratio of daily insulin dose (b/T) in outpatients with diabetes type 1 (DM1) and type 2 (DM2) on basal-bolus regimen, by investigating whether there is a relationship with HbA1c and episodes of hypoglycemia. METHODS: Multicentric, observational, cross-sectional study in Italy. Adult DM1 (n = 476) and DM2 (n = 541) outpatients, with eGFR >30 mL/min/1.73 m2, on a basal-bolus regimen for at least six months, were recruited from 31 Italian Diabetes services between March and September 2016. Clinicaltrials.govID: NCT03489031. RESULTS: Total daily insulin dose was significantly higher in DM2 patients (52.3 ± 22.5 vs. 46 ± 20.9 U/day), but this difference disappeared when insulin doses were normalized for body weight. The b/T ratio was lower than 0.50 in both groups: 0.46 ± 0.14 in DM1 and 0.43 ± 0.15 in DM2 patients (p = 0.0011). The b/T was significantly higher in the patients taking metformin in both groups, and significantly different according to the type of basal insulin (Degludec, 0.48 in DM1 and 0.44 in DM2; Glargine, 0.44 in DM1 and 0.43 in DM2; Detemir, 0.45 in DM1 and 0.39 in DM2). The b/T ratio was not correlated in either group to HbA1c or incidence of hypoglycemia (<40 mg/dL, or requiring caregiver intervention, in the last three months). In the multivariate analysis, metformin use and age were independent predictors of the b/T ratio in both DM1 and DM2 patients, while the type of basal insulin was an independent predictor only in DM1. CONCLUSION: The b/T ratio was independent of glycemic control and incidence of hypoglycemia.

Correction to: The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

[This corrects the article DOI: 10.1007/s40200-018-0358-2.].

Chronic pain: the burden of disease and treatment innovations.

Musculoskeletal conditions are the most frequent cause of chronic pain and affect around 1 in 5 adults in Europe. When chronic pain occurs, it becomes disease itself, with substantial clinical, social and economic impact. Efficacy and tolerability problems are encountered with all therapeutic strategies available to treat musculoskeletal pain. This often limits effective analgesia and patients' long term compliance, with the result that chronic pain is persistently underestimated and undertreated. Tapentadol is a novel, centrally acting analgesic that has been recently commercialized for the treatment of chronic pain. This new molecule, by combining two distinct mechanisms of action, µ-opioid receptor agonism (MOR) and noradrenaline reuptake inhibition (NRI), introduces a new pharmacological class called MOR-NRI. Several studies demonstrated promising results in the management of both nociceptive and neuropathic pain and good tolerability profile, particularly concerning side effects, compared to traditional opioids. This novel analgesic represents a possible therapeutic option also in the rheumatologic field, particularly in the treatment of osteoarthritis and low back pain.

Life-threatening onset of systemic vasculitis requiring intensive care unit admission: a case series.

OBJECTIVES: Onset of ANCA-associated vasculitis (AAV) can be abrupt with life-threatening manifestations requiring Intensive Care Unit (ICU) admission. A high level of suspicion leading to prompt diagnosis is essential. Our objective was to investigate the epidemiologic characteristics and the type of life-threatening manifestations. METHODS: Medical records of AAV patients were analysed, selecting those with an ICU onset to identify predictive signs or symptoms and past medical history warnings useful for diagnosis. RESULTS: Out of 90 patients with AAV, 10 (11.1%) showed an ICU onset. The most frequent AAV diagnosed in the ICU was eosinophilic granulomatosis with polyangiitis (EGPA) (60%), followed by granulomatosis with polyangiitis (GPA) (20%) and microscopic polyangiitis (MPA) (20%). Cardio-pulmonary involvement was the main cause for ICU admission (70%) and significantly distinguished the ICU onset group from other AAV. The most frequent anamnestic warnings were history of asthma (50%), nasal polyps (30%), eosinophilia (30%). Symptoms shortly preceding ICU admission were arthralgia, fever (30%) and purpuric lesions (20%). ANCA were positive in 60% of patients. Mean Birmingham Vasculitis Activity Score (BVAS) at diagnosis was 16±8.43 and 0.88±1.45 at the end of follow up. All patients survived with a 10% rate of chronic kidney disease and a mean Vasculitis Damage Index (VDI) of 2±1.15. CONCLUSIONS: Keeping a high level of suspicion for AAV is mandatory, particularly when treating life-threatening onset manifestations in the ICU. A history of asthma, nasal polyps, eosinophilia and arthralgia should always be investigated. ANCA are negative in about half of cases, therefore clinical expertise and strict collaboration with the rheumatologist are still pivotal.

X-ray crystallographic and kinetic investigations of 6-sulfamoyl-saccharin as a carbonic anhydrase inhibitor.

6-Sulfamoyl-saccharin was investigated as an inhibitor of 11 α-carbonic anhydrase (CA, EC 4.2.1.1) isoforms of human (h) origin, hCA I-XIV, and X-ray crystallographic data were obtained for its adduct with hCA II, the physiologically dominant isoform. This compound possesses two potential zinc-binding groups, the primary sulfamoyl one and the secondary, acylatedsulfonamide. Saccharin itself binds to the Zn(II) ion from the CA active site coordinating with this last group, in deprotonated (SO2N(-)CO) form. Here we explain why 6-sulfamoyl-saccharin, unlike saccharin, binds to the metal ion from the hCA II active site by its primary sulfonamide moiety and not the secondary one as saccharin itself. Our study is useful for shedding new light to the structure-based drug design of isoform-selective CA inhibitors of the sulfonamide type.

A multiparametric and multiscale approach to automated segmentation of brain veins.

Cerebral vein analysis provides a fundamental tool to study brain diseases such as neurodegenerative disorders or traumatic brain injuries. In order to assess the vascular anatomy, manual segmentation approaches can be used but are observer-dependent and time-consuming. In the present work, a fully automated cerebral vein segmentation method is proposed, based on a multiscale and multiparametric approach. The combined investigation of the R2(*)- and a Vesselness probability-map was used to obtain a fast and highly reliable classification of venous voxels. A semiquantitative analysis showed that our approach outperformed the previous state-of-the-art algorithm both in sensitivity and specificity. Inclusion of this tool within a parametric brain framework may therefore pave the way for a quantitative study of the intracranial venous system.

Perivascular fibrosis and IgG4-related disease: a case report.

Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized fibroinflammatory condition which can potentially involve any organ. Some characteristic histopathologic features with lymphoplasmacytic infiltrate, an increased number of IgG4+ cells, storiform fibrosis and obliterative phlebitis are the mainstay for diagnosis. Serum IgG4 levels often increase. We report the case of a patient with perivascular fibrotic lesions involving the aortic arch and the splenic hilum, with a surgical biopsy-proven diagnosis of IgG4-related disease. The patient is now undergoing a low-dose corticosteroid maintenance therapy without evidence of new localizations of the disease. This case highlights the need for increasing awareness and recognition of this new, emerging clinical condition.

Structural, dynamic and photophysical properties of a fluorescent dye incorporated in an amorphous hydrophobic polymer bundle.

The properties of a low molecular weight organic dye, namely 4-naphthyloxy-1-methoxy-2,2,6,6-tetramethylpiperidine, covalently bound to an apolar polyolefin were investigated by means of a multi-level approach, combining classical molecular dynamics simulations, based on purposely parameterized force fields, and quantum mechanical calculations based on density functional theory (DFT) and its time-dependent extension (TD-DFT). The structure and dynamics of the dye in its embedding medium were analyzed and discussed taking the entangling effect of the surrounding polymer into account, and also by comparing the results to those obtained for a different environment, i.e. toluene solution. Finally, the influence was investigated of long lived cages found in the polymeric embedding on photophysical properties, in terms of the slow and fast dye's internal dynamics, by comparing computed IR and UV spectra with their experimental counterparts.

Carbonic anhydrase IX as a target for designing novel anticancer drugs.

Carbonic anhydrase IX (CA IX) is a tumor associated protein, since it is highly expressed in a multitude of carcinomas, while it is present in a limited number of normal tissues. It is a multi-domain protein consisting of an N-terminal proteoglycan-like (PG) domain, a catalytic domain, a trans-membrane portion (TM) and an intracytoplasmatic (IC) segment. These domains have peculiar biochemical and physiological features. Among these, only the PG domain is unique among the CA family. This review focuses on the most recent molecular and catalytic features uncovered of this enzyme, the role of its different domains in tumor physiology, and its three dimensional structure which has recently been solved. In addition, we present recent advances in the development of antibodies and small inhibiting molecules able to target CA IX for diagnostic and therapeutic applications.