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Background and purpose: Dimethyl fumarate (DMF) causes a mean lymphocyte count drop of approximately 30% in relapsing–remitting multiple sclerosis (RRMS) patients. The relationship between this reduction and DMF effectiveness is controversial. The objective was to investigate if the decrease in absolute lymphocyte count (ALC) from baseline during DMF treatment is associated with clinical and magnetic resonance imaging (MRI) disease activity. A secondary aim was to evaluate ALC variations over time in a real‐life cohort of DMF‐treated patients. Methods: Demographic, laboratory, clinical and MRI data were collected in this observational multicentre study, conducted on RRMS patients treated with DMF for at least 6 months. Multivariate Cox models were performed to evaluate the impact of 6‐month ALC drop on time to no evidence of disease activity (NEDA‐3) status loss. NEDA‐3 is defined as absence of clinical relapses, MRI disease activity and confirmed disability progression. Results: In all, 476 patients (312 females, age at DMF start 38.4 ± 9.97 years) were analysed up to 5‐year follow‐up. A greater lymphocyte decrease was associated with a lower risk of NEDA‐3 status loss (hazard ratio 0.87, P = 0.01). A worse outcome in patients with lower ALC drop (<11.5%), compared with higher tertiles (11.5%–40.5% and >40.5%), was observed (P = 0.008). The nadir of ALC drop (−33.6%) and 35% of grade III lymphopaenia cases occurred after 12 months of treatment. Conclusion: A higher lymphocyte count drop at 6 months is related to better outcomes in DMF‐treated patients. A careful ALC monitoring should be pursued up to 24 months of treatment. [ABSTRACT FROM AUTHOR]

Background: The novel proteasome inhibitor carfilzomib alone or in combination with other agents is already one of the standard therapies for relapsed and/or refractory multiple myeloma (MM) patients and produces impressive response rates in newly diagnosed MM as well. However, carfilzomib-related cardiovascular adverse events (CVAEs) - including hypertension (all grades: 12.2%; grade ≥3: 4.3%), heart failure (all grades: 4.1%; grade ≥3: 2.5%) and ischemic heart disease (all grades: 1.8%; grade ≥3: 0.8%) - may lead to treatment suspensions. At present, there are neither prospective studies nor expert consensus on the prevention, monitoring and treatment of CVAEs in myeloma patients treated with carfilzomib.Methods: An expert panel of the European Myeloma Network in collaboration with the Italian Society of Arterial Hypertension and with the endorsement of the European Hematology Association aimed to provide recommendations to support health professionals in selecting the best management strategies for patients, considering the impact on outcome and the risk-benefit ratio of diagnostic and therapeutic tools, thereby achieving myeloma response with novel combination approaches whilst preventing CVAEs.Results: Patients scheduled to receive carfilzomib need a careful cardiovascular evaluation before treatment and an accurate follow-up during treatment.Conclusions: A detailed clinical assessment before starting carfilzomib treatment is essential to identify patients at risk for CVAEs, and accurate monitoring of blood pressure and of early signs and symptoms suggestive of cardiac dysfunction remains pivotal to safely administer carfilzomib without treatment interruptions or dose reductions. [ABSTRACT FROM AUTHOR]

Distance-based and generalization-based methods are two families of artificial intelligence techniques that have been successfully used over a wide range of real-world problems. In the first case, general algorithms can be applied to any data representation by just changing the distance. The metric space sets the search and learning space, which is generally instance-oriented. In the second case, models can be obtained for a given pattern language, which can be comprehensible. The generality-ordered space sets the search and learning space, which is generally model-oriented. However, the concepts of distance and generalization clash in many different ways, especially when knowledge representation is complex (e.g., structured data). This work establishes a framework where these two fields can be integrated in a consistent way. We introduce the concept of distance-based generalization, which connects all the generalized examples in such a way that all of them are reachable inside the generalization by using straight paths in the metric space. This makes the metric space and the generality-ordered space coherent (or even dual). Additionally, we also introduce a definition of minimal distance-based generalization that can be seen as the first formulation of the Minimum Description Length (MDL)/Minimum Message Length (MML) principle in terms of a distance function. We instantiate and develop the framework for the most common data representations and distances, where we show that consistent instances can be found for numerical data, nominal data, sets, lists, tuples, graphs, first-order atoms, and clauses. As a result, general learning methods that integrate the best from distance-based and generalization-based methods can be defined and adapted to any specific problem by appropriately choosing the distance, the pattern language and the generalization operator. [ABSTRACT FROM AUTHOR]

On 6 April 2009, an earthquake struck L' Aquila. The San Salvatore Hospital was evacuated, and a field hospital was built. The study aimed to assess the epidemiologic impact of the earthquake through the analysis of patient population admitted to the field hospital during a 2-month period following the disaster. We retrospectively evaluated causes of hospitalisation and demographic data of patients admitted to (i) the Division of Internal Medicine and (ii) the Division of Emergency Medicine of the field hospital from 6 April, 2009 to 29 May, 2009. All data were compared with the admissions made at the same divisions of the San Salvatore Hospital during the same period of previous year. (i) Patient group ( n = 102) and comparison group ( n = 108). Mean patient age was higher, patients living in L' Aquila were more numerous, while mean length of stay was lower after than before the earthquake. Infectious diseases increased, while 'other' diseases decreased after the disaster both in admission and in discharge diagnoses. Gastroenterological diseases decreased with the earthquake but only in admission diagnoses. (ii) Patient group ( n = 5255) and comparison group ( n = 6564). Triage codes changed with the earthquake. Cardiovascular, psychiatric, gynaecological, infectious and chronic diseases increased, while pneumologic, gastroenterological, traumatic and 'other' diseases decreased after the quake. The number of hospitalised patients decreased with the tremor, while those discharged transferred to other hospitals and those who rejected hospitalisation increased. A natural disaster completely changes causes of hospitalisation in the Divisions of Internal and Emergency Medicine. These findings can be useful for the design of specific intervention programmes and for softening the detrimental effects of quakes. [ABSTRACT FROM AUTHOR]

Background: The Raynaud phenomenon (RP) is an exaggerated and reversible vasospasm of small arteries triggered by cold or emotional stress. Primary RP (PRP) term is used when the underlying condition is unknown. An altered regulation in vascular tone and/or release of soluble mediators from activated platelets plays a role in PRP through an increased oxidative stress. We assessed platelet activation and oxidative stress in patients with PRP by measuring platelet PAC-1, an index of glycoprotein (Gp) IIb/IIIa receptor activation, thromboxane A2 (TXA2), an index of platelet activation and 8-epi-prostaglandin F2α (8-epi-PGF2α), a marker of endogenous in vivo peroxidation. Methods: Eighteen asymptomatic patients with PRP (age 41.37 ± 16.94 years; 17 women, 1 man) and 18 healthy subjects (age of 35.11 ± 13.16 years; 16 women, 2 men) were studied. PAC-1 was analysed by flow cytometry while circulating TXB2, a stable metabolite of TXA2 and 8-epi-PGF2α levels were assessed by ELISA kit. Results: Our results show a significant platelet activation in PRP patients as indicated by increased PAC-1 expression (65.29 ± 15.24%; P < 0.001), TXB2 (1477.83 ± 454.04 pg/mL; P= 0.003) and 8-epi-PGF2α circulating levels (42.50 ± 14.14 ng/mL; P < 0.001). An inverse correlation between the degree of PAC-1 expression and TXB2 levels ( r=−0.527; P= 0.02) was also found in PRP patients, suggesting that downregulation of GpIIb/IIIa receptor expression may occur during thrombocytopoiesis, as a consequence of the chronic exposure to increased TXB2 concentration. Conclusions: Our study for the first time shows a marked activation of GpIIb/IIIa receptor in asymptomatic patients with PRP and supports antiplatelet therapy in PRP patients. [ABSTRACT FROM AUTHOR]

Objective To conduct a long-term, prospective, randomized controlled trial evaluating rituximab (RTX) therapy for severe mixed cryoglobulinemia or cryoglobulinemic vasculitis (CV). Methods Fifty-nine patients with CV and related skin ulcers, active glomerulonephritis, or refractory peripheral neuropathy were enrolled. In CV patients who also had hepatitis C virus (HCV) infection, treatment of the HCV infection with antiviral agents had previously failed or was not indicated. Patients were randomized to the non-RTX group (to receive conventional treatment, consisting of 1 of the following 3: glucocorticoids; azathioprine or cyclophosphamide; or plasmapheresis) or the RTX group (to receive 2 infusions of 1 gm each, with a lowering of the glucocorticoid dosage when possible, and with a second course of RTX at relapse). Patients in the non-RTX group who did not respond to treatment could be switched to the RTX group. Study duration was 24 months. Results Survival of treatment at 12 months (i.e., the proportion of patients who continued taking their initial therapy), the primary end point, was statistically higher in the RTX group (64.3% versus 3.5% [ P < 0.0001]), as well as at 3 months (92.9% versus 13.8% [ P < 0.0001]), 6 months (71.4% versus 3.5% [ P < 0.0001]), and 24 months (60.7% versus 3.5% [ P < 0.0001]). The Birmingham Vasculitis Activity Score decreased only after treatment with RTX (from a mean ± SD of 11.9 ± 5.4 at baseline to 7.1 ± 5.7 at month 2; P < 0.001) up to month 24 (4.4 ± 4.6; P < 0.0001). RTX appeared to be superior therapy for all 3 target organ manifestations, and it was as effective as conventional therapy. The median duration of response to RTX was 18 months. Overall, RTX treatment was well tolerated. Conclusion RTX monotherapy represents a very good option for severe CV and can be maintained over the long term in most patients. [ABSTRACT FROM AUTHOR]

Objective: Brief screening tools for dementia for use by non-specialists in primary care have yet to be validated in non-western settings where cultural factors and limited education may complicate the task. We aimed to derive a brief version of cognitive and informant scales from the Community Screening Instrument for Dementia (CSI-D) and to carry out initial assessments of their likely validity.Methods: We applied Mokken analysis to CSI-D cognitive and informant scale data from 15 022 participants in representative population-based surveys in Latin America, India and China, to identify a subset of items from each that conformed optimally to item response theory scaling principles. The validity coefficients of the resulting brief scales (area under ROC curve, optimal cutpoint, sensitivity, specificity and Youden's index) were estimated from data collected in a previous cross-cultural validation of the full CSI-D.Results: Seven cognitive items (Loevinger H coefficient 0.64) and six informant items (Loevinger H coefficient 0.69) were selected with excellent hierarchical scaling properties. For the brief cognitive scale, AUROC varied between 0.88 and 0.97, for the brief informant scale between 0.92 and 1.00, and for the combined algorithm between 0.94 and 1.00. Optimal cutpoints did not vary between regions. Youden's index for the combined algorithm varied between 0.78 and 1.00 by region.Conclusion: A brief version of the full CSI-D appears to share the favourable culture- and education-fair screening properties of the full assessment, despite considerable abbreviation. The feasibility and validity of the brief version still needs to be established in routine primary care. [ABSTRACT FROM AUTHOR]

OBJECTIVE: No single previous study has evaluated serum levels of the proinflammatory cytokines interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNFalpha) in patients with hepatitis C virus-associated mixed cryoglobulinemia (HCV-MC). This study was undertaken to evaluate serum levels of these cytokines in patients with HCV-MC. METHODS: Serum IL-1beta, IL-6, and TNFalpha were assayed in 43 patients with HCV-MC, in 43 sex- and age-matched patients with chronic HCV without cryoglobulinemia, and in 43 sex- and age-matched controls. RESULTS: HCV-MC patients showed significantly higher mean IL-1beta, IL-6, and TNFalpha levels than did the controls (P < 0.01) or the HCV patients (P

OBJECTIVE: To determine the clinical and immunologic features of systemic sclerosis (SSc) in a large group of children and describe the clinical evolution of the disease and compare it with the adult form. METHODS: Data on 153 patients with juvenile SSc collected from 55 pediatric rheumatology centers in Europe, Asia, and South and North America were analyzed. Demographic, clinical, and immunologic characteristics of children with juvenile SSc at the onset, at diagnosis, and during the disease course were evaluated. RESULTS: Raynaud's phenomenon was the most frequent symptom, followed by skin induration in approximately 75% of patients. Musculoskeletal symptoms were present in one-third of patients, and the most frequently involved internal organs were respiratory and gastrointestinal, while involvement of renal, cerebral, and cardiovascular systems was extremely rare. Antinuclear antibodies were present in the sera of 81% of patients. Anti-topoisomerase I (Scl-70) and anticentromere antibodies were found to be positive in 34% and 7.1% of patients, respectively. Involvement of the respiratory, gastrointestinal, and cardiovascular systems was more frequent and occurred earlier in patients who died than in those who survived. Compared with the adult form, juvenile SSc appears to be less severe, with the involvement of fewer internal organs, particularly at the time of diagnosis, and has a less characterized immunologic profile. CONCLUSION: This study provides information on the largest collection of patients with juvenile SSc ever reported. Juvenile SSc appears to be less severe than in adults because children have less internal organ involvement, a less specific autoantibody profile, and a better long-term outcome. [ABSTRACT FROM AUTHOR]

Interleukin-1β (IL-1β) is involved in hypothalamic regulation of corticotrophin-releasing hormone secretion, autonomic activation and consequent downstream modulation of the neuroimmune response. Previously, we have shown that IL-1β depolarises parvocellular neurones in the paraventricular nucleus (PVN) of the hypothalamus, and these effects are dependent on attenuation of γ-amino butyric acid (GABA)-ergic input. In the present study, using whole-cell patch clamp recordings of rat neurones in a slice preparation of the PVN, we show that the effects of IL-1β are abolished in the presence of a cyclooxygenase (COX)-2 inhibitor, NS-398, indicating a dependence on prostaglandin (PG) synthesis and activation. In response to 1 µ M PGE2, 64% of parvocellular neurones tested exhibited a clear depolarisation, which was abolished in the presence of tetrodotoxin (TTX). Furthermore, neurones responsive to both IL-1β and PGE2 exhibited a decrease in the frequency of inhibitory post-synaptic potentials, suggesting that effects of these modulators are mediated via a decrease in GABA-ergic input to these neurones. A proportion (44% and 40%, respectively) of putative GABA-ergic neurones in the halo region surrounding the PVN demonstrated hyperpolarising responses to 1 n M IL-1β and 1 µ M PGE2, and these effects were maintained in TTX. Furthermore, direct hyperpolarising effects of IL-1β were blocked in the presence of NS-398. Together, these data suggest that PGE2, synthesised in response to IL-1β-activation of COX-2 expressing cells, directly hyperpolarises putative GABA-ergic neurones in the halo zone surrounding and projecting to the PVN, resulting in a decrease in GABA-ergic input to parvocellular neurones and consequent depolarisation. These data further elucidate the cellular mechanisms by which IL-1β exerts its neuroimmune-related actions in the PVN. [ABSTRACT FROM AUTHOR]

The effects of nitrogen (N) fertilization of a rye pasture (Secale cereale L.) on the chemical composition of forage and its utilization in vivo and in situ were investigated in winter (W) and early spring (S). Half of the paddock to be assayed was spread with 93 kg urea-N ha-1 (treatment F), and the other half was not fertilized (treatment NF). Each experiment lasted for 17 days; apparent dry matter digestibility in vivo, voluntary dry matter intake (DMI) and digestible DMI were measured on nine rams per treatment. Two rumen cannulated animals per treatment were under the same feeding regime, and used to collect samples of rumen contents. The concentrations of ammonia (NH3) and short-chain fatty acids and pH were measured in these samples. The offered forage was also incubated in the rumen of three Holstein-Friesian steers to estimate its degradation parameters in situ. Fertilization with N increased total N and decreased dry matter (DM) and non-structural carbohydrate concentrations in both periods. DMI was reduced by fertilization. The rumen concentrations of NH3 were higher in F than in NF in both periods. In both periods, the effective DM degradability of forage was higher in F than in NF. N fertilization affects chemical composition, voluntary intake and rumen digestion of forage from rye pasture. [ABSTRACT FROM AUTHOR]

Interleukin-1β (IL-1β) is involved in hypothalamic regulation of corticotropin releasing hormone (CRH) secretion and consequent downstream modulation of the neuroimmune response. In this study, whole-cell patch clamp recordings of rat parvocellular neurones in a slice preparation of the paraventricular nucleus (PVN) of the hypothalamus were performed to examine the cellular effects of IL-1β. In response to 1 nM IL-1β, 65% of parvocellular neurones tested exhibited a clear depolarization, which was abolished in the presence of tetrodotoxin (TTX). This depolarization was partially dependent on nitric oxide formation, as demonstrated by attenuation of the response in the presence of N-ω-nitro-L-arginine methylester, a nitric oxide synthase inhibitor. The effects of IL-1β on responsive parvocellular neurones were associated with a decrease in the frequency of inhibitory post synaptic potentials (IPSPs). Bicuculline administration blocked the effects of IL-1β, suggesting that this cytokine modulates GABA-ergic output, resulting in a decrease in inhibitory input (IPSPs) and consequent depolarization. These data support the conclusion that IL-1β influences the excitability of parvocellular neurones in the PVN, as a secondary consequence of nitric oxide generation and modulation of GABAergic inhibitory input to these cells. They elucidate cellular correlates underlying the well-established neuroimmune roles of IL-1β in the paraventricular nucleus of the hypothalamus. [ABSTRACT FROM AUTHOR]

Many patients chronically infected by hepatitis C virus (HCV) experience symptoms like fatigue, dyspnea and reduced physical activity. However, in many patients, these symptoms are not proportional to the liver involvement and could resemble symptoms of chronic heart failure. To our knowledge, no study evaluated serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) in a large series of patients with HCV chronic infection (HCV+). Serum NT-proBNP was assayed in 50 patients HCV+ and in 50 sex- and age-matched controls. HCV+ patients showed significantly higher mean NT-proBNP level than controls (P = 0.001). By defining high NT-proBNP level as a value higher than 125 pg/mL (the single cut-off point for patient under 75 years of age), 34% HCV+ and 6% controls had high NT-proBNP (Fisher exact test; P < 0.001). With a cut-off point of 300 pg/mL (used to rule out chronic heart failure in patients under 75 years of age) 10% HCV+ and 0 controls had high NT-proBNP (Fisher exact test; P = 0.056). With a cut-off point of 900 pg/mL (used for ruling in chronic heart failure in patients with age 50-75) 8% HCV+ patients and 0 controls had high NT-proBNP (Fisher exact test; P = 0.12). The study demonstrates high levels of circulating NT-proBNP in HCV+ patients compared to healthy controls. The increase of NT-proBNP may indicate the presence of a sub-clinical cardiac dysfunction. Further prospective studies quantifying these symptoms in correlation with echocardiography are needed to confirm this association. [ABSTRACT FROM AUTHOR]

The article discusses data obtained through 24-hours ambulatory blood pressure monitoring (ABPM) in two hypertensive patients during the 2009 earthquake of L'Aquila. It offers a graphical representation of 24-hour ABPM in the two patients such as patient A, and Patient B, that was recorded during the earthquake and after two years. It concludes as cardiovascular care must be raised both in the short and long term after an earthquake.

A letter to the editor is presented in response to the article "CSF Levels of betaamyloid 1-42, tau and phosphorylated tau protein in CADASIL," by P. Formichi and colleagues, in a 2008 issue.

An abstract of the study "Right Ventricular Overload and Cardiovascular Neuroendocrine Derangement in Systemic Sclerosis," by M. Emdin and colleagues is presented.

Serum cryoglobulins are found in a wide spectrum of disorders but are often transient and without clinical implications. Monoclonal cryoglobulins are usually associated with haematological disorders, whereas mixed cryoglobulins are found in many infectious and systemic disorders. So called essential mixed cryoglobulinaemia shows a striking association with hepatitis C virus (HCV) infection (> 90%). It is a systemic vasculitis (leucocytoclastic vasculitis) with cutaneous and multiple visceral organ involvement. Chronic HCV infection can lead to a constellation of autoimmune and neoplastic disorders. In this review, the aetiology, diagnosis, disease heterogeneity, and treatment of cryoglobulinaemia are discussed. [ABSTRACT FROM AUTHOR]

Background: Despite longstanding epidemiologic data on the association between increased serum triglycerides and cardiovascular events, the exact level at which risk begins to rise is unclear. The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension has conceived a protocol aimed at searching for the prognostic cutoff value of triglycerides in predicting cardiovascular events in a large regional-based Italian cohort., Methods and Results: Among 14 189 subjects aged 18 to 95 years followed-up for 11.2 (5.3-13.2) years, the prognostic cutoff value of triglycerides, able to discriminate combined cardiovascular events, was identified by means of receiver operating characteristic curve. The conventional (150 mg/dL) and the prognostic cutoff values of triglycerides were used as independent predictors in separate multivariable Cox regression models adjusted for age, sex, body mass index, total and high-density lipoprotein cholesterol, serum uric acid, arterial hypertension, diabetes, chronic renal disease, smoking habit, and use of antihypertensive and lipid-lowering drugs. During 139 375 person-years of follow-up, 1601 participants experienced cardiovascular events. Receiver operating characteristic curve showed that 89 mg/dL (95% CI, 75.8-103.3, sensitivity 76.6, specificity 34.1, P <0.0001) was the prognostic cutoff value for cardiovascular events. Both cutoff values of triglycerides, the conventional and the newly identified, were accepted as multivariate predictors in separate Cox analyses, the hazard ratios being 1.211 (95% CI, 1.063-1.378, P =0.004) and 1.150 (95% CI, 1.021-1.295, P =0.02), respectively., Conclusions: Lower (89 mg/dL) than conventional (150 mg/dL) prognostic cutoff value of triglycerides for cardiovascular events does exist and is associated with increased cardiovascular risk in an Italian cohort.

Aim: Periodontal diseases are associated with cardiovascular risk factors/diseases, and whether home oral hygiene practices are inversely related to the same conditions could carry relevant practical implications. We investigated the association of home oral hygiene habits with hypertension., Materials and Methods: During World Hypertension Day 2020, a nationwide cross-sectional survey was conducted on volunteers ≥18 years at 733 Italian pharmacies. Participants underwent standardized blood pressure (BP) measurement and answered a questionnaire on cardiovascular risk factors, oral health status, and home oral hygiene habits (toothbrushing daily frequency and manual/electric toothbrush). The association between home oral care habits and BP was assessed using multivariate logistic regression. Interactions between exposures and outcome were formally tested., Results: Among the 4506 participants (44.8% males, 66.1 ± 37.8 years), 47.6% reported brushing ≥3 times/day and 23.4% declared using the electric toothbrush. Brushing ≥3 versus &lt;3 times/day and use of electric versus manual toothbrush were associated with 19% (odds ratio [OR]: 0.81, 95% confidence interval [CI] 0.70-0.94) and 28% (OR: 0.72, 95% CI 0.61-0.85) lower odds of hypertension, respectively. No significant additive interaction was observed in the association of exposures with the outcome., Conclusions: Regular daily brushing and electric toothbrushing are associated with a better BP profile in a real-world context. Future interdisciplinary research is warranted to test these findings., (© 2022 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Aim: Periodontitis is a relapsing-remitting disease. Compared with bleeding on probing (BoP), expression of disease activity, periodontal inflamed surface area (PISA), incorporates chronic disease parameters. We tested the association of PISA and BoP with blood pressure (BP) in NHANES III., Materials and Methods: A total of 8,614 subjects (≥30 years) with complete periodontal and BP examinations were enrolled. PISA was derived from periodontal probing depth and BoP. The association of PISA and BoP with high/uncontrolled BP was examined by multiple-adjusted models. Inflammatory markers were tested as possible mediators. A machine learning (ML) approach was used to define the relative importance of PISA and BoP and estimate the power of BP status prediction., Results: Compared to no inflammation, severe PISA and BoP were associated with 43% (p < .001) and 32% (p = .006) higher odds of high/uncontrolled BP (≥130/80 mmHg), and with higher systolic BP by ≈4 (p < .001) and 5 (p < .001) mmHg, respectively. Inflammatory markers appeared to mediate this association with various extents, without threshold effect. BoP predicted high/uncontrolled BP more efficiently than PISA using ML., Conclusion: PISA and BoP describe the association of periodontal inflammation and hypertension with subtle differences. The contribution of local inflammation to the global inflammatory burden might explain the observed findings., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Diabetic macular edema (DME) is a leading cause of vision loss and blindness. The aim of this study was to evaluate the economic benefits of introducing additional alternative technologies (Dexamethasone intravitreal implant - DEX - and Aflibercept injections), compared with the historical scenario of Ranibizumab intravitreal injections., Methods: A 3-year budget impact model was developed, taking into consideration the perspective of the Lombardy Region Healthcare Service (LRHS). Total administration costs (real-life data retrieved from clinical practice at three Departments of Ophthalmology) as well as costs related to the management of potential adverse events (information collected from the literature) were analysed., Results: Over a 36-month horizon, the results showed that a higher consumption of DEX could lead to significant economic savings for the Regional Healthcare Service, ranging from a minimum of -4.35% (if DEX were used only in the second-line of treatment) to a maximum of -12.97% (if DEX were used in both the first-line and second-line), including the potential impact of adverse events. Therapy costs with Aflibercept and Ranibizumab were similar., Conclusions: This study demonstrates that concentrating all eligible patients within the Ranibizumab regimen is unlikely to represent a cost-effective strategy. Indeed, significant economic advantages would be achieved by introducing the other licensed alternatives, Dexamethasone implant and Aflibercept, thus optimising DME Italian healthcare expenditure. The results demonstrate DEX as an advantageous technological alternative for the target population affected by DME, both as a first- and second-line treatment option, reducing the economic burden of the pathology for the Regional/National Health Service., (© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav-1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav-1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav-1-null mice and humans with a prevalent variant in the CAV1 gene., Methods and Results: In mouse studies, cav-1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high- to low-density lipoprotein (all P<0.001 versus wild type). Moreover, cav-1 knockout mice displayed hypertriglyceridemia and higher mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia (P<0.01), total cholesterol (P<0.05), resistin (P<0.05), and described enzymes, with no effect on insulin or triglycerides. In the human study, we analyzed the CAV1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40-3.64]) and low high-density lipoprotein (odds ratio 1.54 [95% CI 1.01-3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high-density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav-1 expression in adipose tissues by the rs926198 minor allele., Conclusions: Our findings in mice and humans suggested that decreased cav-1 expression may activate the effect of aldosterone/MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MR-independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype-mediated cav-1 deficiency., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are an emerging class of low-density lipoprotein cholesterol (LDL-C)-lowering agents. In spite of their known effects on lipids, the impact of these drugs on systemic inflammation is less known. We aimed to investigate the effect of PCSK9 inhibitors on high-sensitivity C-reactive protein (hs-CRP) levels through a meta-analysis of randomized controlled trials (RCTs)., Methods: A systematic literature search of Medline, SCOPUS and Google Scholar was conducted up to December 2015 to identify RCTs assessing changes in hs-CRP concentrations during treatment with PCSK9 inhibitors. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics., Results: Sixteen treatment arms, with a total of 2546 participants, were included. Random-effects meta-analysis did not show any significant effect of PCSK9 inhibitors on hs-CRP levels (WMD: 0.002 mg l(-1) , CI: -0.017, 0.021; P = 0.807; I(2) = 37.26%). This effect size was robust, not sensitive to any single study, and not affected by the type of PCSK9 inhibitor (evolocumab: WMD: 0.002 mg l(-1) , CI: -0.02, 0.02; P = 0.855; alirocumab WMD: 0.15 mg l(-1) , CI: -0.11, 0.40; P = 0.259; I(2) = 0%), or dosing frequency (biweekly: WMD: 0.13 mg l(-1) , CI: -0.20, 0.46; P = 0.433; I(2) = 55.19%; monthly: WMD: 0.003 mg l(-1) , CI: -0.01, 0.01; P = 0.59; I(2) = 0%). Random-effects meta-regression did not suggest any association of changes in hs-CRP levels with changes in plasma LDL-C concentrations (P = 0.697) or cumulative dosage of the drug (P = 0.980)., Conclusions: This meta-analysis of RCTs did not suggest an effect of PCSK9 inhibitors on hs-CRP concentrations., (© 2016 The British Pharmacological Society.)

Objective: To assess fetal and maternal outcomes in women with systemic sclerosis (SSc)., Methods: Prospectively collected data on 99 women with SSc from 25 Italian centers were analyzed retrospectively. Women with SSc were observed during 109 pregnancies (from 2000 to 2011), and outcomes were compared to those in the general obstetric population (total of 3,939 deliveries). The maternal age at conception was a mean ± SD 31.8 ± 5.3 years, and the median disease duration at conception was 60 months (range 2-193 months)., Results: SSc patients, compared to the general obstetric population, had a significantly increased frequency of preterm deliveries (25% versus 12%) and severe preterm deliveries (<34 weeks of gestation) (10% versus 5%), intrauterine growth restriction (6% versus 1%), and babies with very-low birth weight (5% versus 1%). Results of multivariable analysis showed that corticosteroid use was associated with preterm deliveries (odds ratio [OR] 3.63, 95% confidence interval [95% CI] 1.12-11.78), whereas the use of folic acid (OR 0.30, 95% CI 0.10-0.91) and presence of anti-Scl-70 antibodies (OR 0.26, 95% CI 0.08-0.85) were protective. The disease remained stable in most SSc patients, but there were 4 cases of progression of disease within 1 year from delivery, all in anti-Scl-70 antibody-positive women, 3 of whom had a disease duration of <3 years., Conclusion: Women with SSc can have successful pregnancies, but they have a higher-than-normal risk of preterm delivery, intrauterine growth restriction, and babies with very-low birth weight. Progression of the disease during or after pregnancy is rare, but possible. High-risk multidisciplinary management should be standard for these patients, and pregnancy should be avoided in women with severe organ damage and postponed in women with SSc of recent onset, particularly if the patient is positive for anti-Scl-70 antibodies., (Copyright © 2012 by the American College of Rheumatology.)

Hepatitis C virus (HCV), which is both a hepatotropic and a lymphotropic virus, has been proposed as a possible causative agent of mixed cryoglobulinaemia. This 'benign' lymphoproliferative disorder can switch over to a malignant B-cell non-Hodgkin's lymphoma (NHL). Therefore HCV infection has been investigated in a series of 50 unselected Italian patients with B-cell NHL. Antibodies against HCV were found in 30% of NHL and HCV viraemia in 32% of cases. HCV-related markers were detected in 34% (17/50) of our NHL patients; this prevalence is particularly significant when compared with HCV seropositivity in Hodgkin's lymphoma (3%) and healthy controls (1.3%).

According to DSM-III-R a positive diagnosis of alcohol dependence requires the presence of at least three of nine symptoms of a core dependence syndrome. In this study the presence of the nine symptoms according to degree of the severity of dependence is examined in 99 patients (mild, n = 23; moderate, n = 26; and severe, n = 50). It is shown that although the cut-off point for a positive diagnosis of dependence is the presence of "any three" out of nine DSM-III-R criteria, specific symptoms ("excessive drinking", "desire or efforts to control drinking", and "drinking despite major problems") have a high probability of occurrence across the dependence severity range (mild, moderate or severe). Conversely, other symptoms appear prominently only in the more severe cases ("much time devoted to alcohol", "important activities given up", and "drinking to relieve withdrawal"). The results suggest that in the DSM-III-R criteria for alcohol dependence some symptoms are more frequently associated with the diagnosis, while other symptoms are associated with severity of the alcohol dependence disorder.

The prevalence of antibodies to hepatitis C virus (HCVAb) was investigated in 52 unselected patients with mixed cryoglobulinemia and in 84 patients with other systemic immunologic diseases. HCVAb were detected by an enzyme-linked immunosorbent assay, and their specificity was evaluated by a recombinant-based immunoblot assay. The presence of HBV-related markers was investigated in the same samples. HCVAb were found in 54% of mixed cryoglobulinemia patients, and the finding was confirmed by recombinant-based immunoblot assay in all cases. HCVAb and/or HBV markers were present in 70% of the patients. HCVAb seropositivity was significantly more frequent in mixed cryoglobulinemia patients with biopsy-proven liver involvement (P less than 0.01) and with increased serum transaminase levels (P less than 0.01). HCVAb were virtually absent in control patients with other immunologic diseases. These results support the notion that viral agents, i.e., HCV and possibly HBV, have a role in the pathogenesis of mixed cryoglobulinemia patients.

Albumin and IgG were determined in serum and cerebrospinal fluid (CSF) of patients with early-onset Alzheimer's disease (AD, n. 13), senile dementia of Alzheimer type (SDAT, n. 33), vascular dementia divided into multi-infarct (MID, n. 9) and probable vascular (PVD, n. 11) dementia. Albumin and IgG ratio and IgG index were calculated. CSF albumin and albumin ratio were significantly higher in MID patients indicating an increased BBB permeability. IgG ratio and IgG index did not show any significant difference among groups. These results do not provide evidence for BBB damage in AD/SDAT, while in MID the increase of CSF albumin and albumin ratio is suggestive of BBB dysfunction.

Fifty-three patients (34 who had diffuse scleroderma, and 19 who had CREST syndrome [calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias]) were studied by noninvasive procedures, including resting electrocardiogram (ECG), continuous 24-hour Holter ECG monitoring, M-mode echocardiography, and 2-dimensional echocardiography. Only 22 patients (42%) had abnormalities such as conduction defects, supraventricular or ventricular arrhythmias, or ST-T changes detected on resting ECG. In contrast, using Holter monitoring, the number of conduction abnormalities seen increased from 10 to 16 patients and transient ST-T changes increased from 2 to 18 patients. Forty-eight patients had ventricular arrhythmias, with multiform ventricular premature beats in 21 (40%), pairs of runs of ventricular tachycardia in 15 patients (28%), and 1 or more runs of ventricular tachycardia in 7 (13%). Echocardiography detected asymmetric septal hypertrophy in 10 patients, impaired ventricular function in 9 patients, congestive cardiomyopathy in 2, mitral prolapse in 4, and pericardial effusion in 3 patients. Multiform and/or repetitive ventricular premature beats occurred more frequently in patients with echocardiographic abnormalities, but were also present in patients who had normal findings on echocardiographic examination. Cardiac involvement was not correlated with clinical variants of scleroderma (CREST syndrome or diffuse scleroderma), nor with other signs and symptoms of the disease. Thus, cardiac involvement is found much more frequently than would be expected from clinical symptoms or from results of resting ECG alone; therefore, Holter monitoring and echocardiography should be included in the routine workup of patients who have scleroderma.

Purified IgM rheumatoid factors (RF; 3 monoclonal and 2 polyclonal) were shown to inhibit, in a dose-dependent manner, 2 complement-mediated functions, i.e., the immune complex solubilization capacity and the inhibition of immune precipitation. Inhibition of immune complex solubilization capacity occurred only if RF was added at the same time as, but not after, addition of the complement source. Experimental evidence suggests that the effects of RFs were not related to their anticomplementary activity, but rather required the attachment of RF to the Fc region of the IgG molecule. Although no clinical data are available so far, it might be plausible that these newly described properties of RF have biologic relevance.