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The discipline of fracture mechanics was born almost a century ago through the pioneering work of A.A. Griffith, and saw particularly rapid growth in the second half of 20th century when it became an indispensable tool in the development of advanced transportation, civil construction, and energy systems. Forty years ago, Materials & Design published a series of papers devoted to the state-of-the-art in the field of Fracture Mechanics. The present review reflects the lasting legacy and surviving importance of this theme: it is associated with the Virtual Special Issue on nanoscale materials testing and characterisation, and focuses on the modern experimental approaches to fine scale fracture toughness evaluation, with particular emphasis on micro-cantilever bending and micro-pillar splitting. The fundamental aspects of these approaches are overviewed, and their application to a range of systems is described. Implications for further development of these methods are discussed. Keywords: Fracture toughness, Micro-scale, Focused ion beam milling, Material characterisation, Micro-mechanics

Interstitial lung disease (ILD) is a relevant cause of morbidity and mortality in patients with autoimmune rheumatic diseases (ARDs). In the last years, an acute exacerbation (AE) - defined as an acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality - has been reported to occur in virtually all ILD types, including ARD-ILD. The aim of this review is to describe the available and investigational treatments in patients affected by AE-ARD-ILD in light of the very low quality of evidence available. Currently, management consists of efforts to identify reversible triggers of respiratory decline, such as drugs effective in ARDs and infections, including opportunistic infections, together with supportive treatments. AE-ILD, AE-ARD-ILD and acute respiratory distress syndrome share histopathologically similar findings of diffuse alveolar damage in most cases. Identification of triggers and risk factors might contribute to early diagnosis and treatment of AE-ILD, before the alveolar damage becomes irreversible. In patients with acute respiratory distress syndrome, the role of steroids and immunosuppressants remains controversial. Also, many uncertainties characterize the management of AE-ARD-ILD because of the lack of evidence and of an unquestionable effective therapy. At this time, no effective evidence-based therapeutic strategies for AE-ARD-ILD are available. In clinical practice, AE-ARD-ILD is often empirically treated with high-dose systemic steroids and antibiotics, with or without immunosuppressive drugs. Randomized controlled trials are needed to better understand the efficacy of current and future drugs for the treatment of this clinical relevant condition., Competing Interests: Declaration of competing interest The Authors have no Conflict of Interest related to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Early diagnosis of interstitial lung diseases secondary to connective tissue diseases is critical for the treatment and survival of patients. The symptoms, like dry cough and dyspnea, appear late in the clinical history and are not specific, moreover, the current approach to confirm the diagnosis of interstitial lung disease is based on high resolution computer tomography. However, computer tomography involves x-ray exposure for patients and high costs for the Health System, therefore preventing its use for a massive screening campaign in elder people. In this work we investigate the use of deep learning techniques for the classification of pulmonary sounds acquired from patients affected by connective tissue diseases. The novelty of the work consists of a suitably developed pre-processing pipeline for de-noising and data augmentation. The proposed approach is combined with a clinical study where the ground truth is represented by high resolution computer tomography. Various convolutional neural networks have provided an overall accuracy as high as 91% in the classification of lung sounds and have led to an overwhelming diagnostic accuracy in the range 91%-93%. Modern high performance hardware for edge computing can easily support our algorithms. This solution paves the way for a vast screening campaign of interstitial lung diseases in elder people on the basis of a non-invasive and cheap thoracic auscultation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: MS has received payments or honoraria for lectures or presentations from BMS, Pfizer, and Boehringer-Ingelheim; and fees for participation on advisory boards from BMS, Lilly, Amgen, Janssen, Boehringer-Ingelheim, and Celltrion. CS declares participation on an advisory board for Lilly. AM has received payments or honoraria for lectures or presentations from BMS, Lilly, and Boehringer-Ingelheim; and fees for participation on advisory boards from BMS, Lilly, and Boehringer-Ingelheim.

Competing Interests: MS reports payments or honoraria for lectures and presentations from Bristol Myers Squibb, Pfizer, and Boehringer-Ingelheim and fees for participation on Advisory Board from Bristol Myers Squibb, Lilly, Amgen, Janssen, Boehringer-Ingelheim, and Celltrion. AM reports payments or honoraria for lectures and presentations from Bristol Myers Squibb, Lilly, and Boehringer-Ingelheim and reports fees for participation on Advisory Board from Bristol Myers Squibb, Lilly, and Boehringer-Ingelheim.

The coronavirus disease 2019 (COVID-19) has severely stressed the sanitary systems of all countries in the world. One of the main issues that physicians are called to tackle is represented by the monitoring of pauci-symptomatic COVID-19 patients at home and, generally speaking, everyone the access to the hospital might or should be severely reduced. Indeed, the early detection of interstitial pneumonia is particularly relevant for the survival of these patients. Recent studies on rheumatoid arthritis and interstitial lung diseases have shown that pathological pulmonary sounds can be automatically detected by suitably developed algorithms. The scope of this preliminary work consists of proving that the pathological lung sounds evidenced in patients affected by COVID-19 pneumonia can be automatically detected as well by the same class of algorithms. In particular the software VECTOR, suitably devised for interstitial lung diseases, has been employed to process the lung sounds of 28 patient recorded in the emergency room at the university hospital of Modena (Italy) during December 2020. The performance of VECTOR has been compared with diagnostic techniques based on imaging, namely lung ultrasound, chest X-ray and high resolution computed tomography, which have been assumed as ground truth. The results have evidenced a surprising overall diagnostic accuracy of 75% even if the staff of the emergency room has not been suitably trained for lung auscultation and the parameters of the software have not been optimized to detect interstitial pneumonia. These results pave the way to a new approach for monitoring the pulmonary implication in pauci-symptomatic COVID-19 patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Objective: Recently the term "interstitial pneumonia with autoimmune features" (IPAF) has been proposed to identify patients with interstitial lung disease and autoimmune characteristics, not fulfilling the criteria for specific connective tissue diseases (CTD). Only few data are available about the clinical and serological features of IPAF patients, their survival and the possible evolution in a CTD. The aims of the study were to investigate the demographic and clinico-serologic features of patients with IPAF, their relationship to survival, and the possible evolution in a definite CTD., Patients and Methods: Fifty-two patients were consecutively enrolled and prospectively followed for 45 ± 31.6 months. Data about disease onset, serological, clinical and therapeutic features, pulmonary function tests and high-resolution computed tomography were periodically repeated. The survival of patients with IPAF was compared with that of 104 patients with idiopathic pulmonary fibrosis (IPF)., Results: The clinical domain for IPAF was satisfied in 44 patients, serological domain in 49 and the morphological domain in 29 patients. During the follow-up, a definite CTD was diagnosed in 7 patients, in particular Sjogren's syndrome in 4 patients, rheumatoid arthritis in 2, and polymyositis in the last. The estimated 5-year survival of IPAF patients 69.5 ± 7.8%, significantly higher than survival observed in IPF patients, and the baseline value of FVC and DLCO were the only factors associated to death., Conclusions: IPAF seems to a distinct entity, with a low tendency to evolve in a definite CTD. Nevertheless, further studies are needed to better define the clinical evolution and the outcome of IPAF., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Some of the manifestations of mixed cryoglobulinemia syndrome (MCS) can be severe or life-threatening, and should be rapidly contained but, as the therapeutic approaches to such conditions are largely based on anecdotal data, a consensus conference was organised by the Italian Group for the Study of Cryoglobulinemia (GISC) with the aim of providing a set of recommendations based on an in-depth survey of the available data and expert opinion., Methods: The consensus panel, which included specialists working in different medical fields involved in the management of MCS patients, was first asked to divide the manifestations of MCS into severe or life-threatening conditions on the basis of their own experience, after which a complete literature review was carried out in accordance with the Cochrane guidelines for systematic reviews., Results: Therapeutic plasma exchange (TPE) was considered the elective first-line treatment in the case of life-threatening manifestations of MCS (LT-MCS) and patients with severe clinical symptoms (S-MCS) who fail to respond to (or who are ineligible for) other treatments. The data supporting the combined use of cyclophosphamide and TPE were considered limited and inconclusive. High-dose pulsed glucocorticoid (GCS) therapy can be considered the first-line treatment of severe MCS, generally in association with TPE. Rituximab (RTX)-based treatments should be considered in patients with skin ulcers, peripheral neuropathy or glomerulonephritis, and in patients with persistent LT-MCS after TPE. In patients with hepatitis C virus-related MCS with S-MCS, viral eradication should be attempted as soon as a patient's condition allows the use of direct-acting antivirals., (Copyright © 2019. Published by Elsevier B.V.)

Objective: The project aimed to collect expert consensus statements for the profiling of patients with axial spondyloarthritis (axSpA) candidate to biologic agents (bDMARDs) treatment, in order to better define the drivers for the best treatment choice., Methods: The 6 more interesting topics about axSpA patient profiling were identified by the project steering committee and a panel of axSpA Italian experts. A systematic literature review (SLR) was performed for each of the selected topics according to the PICO format. Two rounds of a modified Delphi process were conducted. In the 1st round, the steering committee evaluated the results of the SLR in order to formulate statements for each topic. In the 2nd round, the experts panel discussed, rephrased when needed, and voted the level of agreement (on a 5-point Likert-type scale) for each statement. Consensus was defined as ≥66% agreement., Results: The topics selected for the analysis were the differential efficacy of available bDMARDs on enthesitis/dactylitis, uveitis, radiographic progression and cardiovascular involvement, and the clinical response in non radiographic-axSpA and in patients receiving a second-line bDMARD. The Delphi rounds formulated 19 statements, all reaching the defined level of consensus in a second round including 25 rheumatologists highly skilled in the management of axSpA., Conclusion: Identified consensus statements can help clinicians to apply to routine-care settings the results from clinical studies and international recommendations, providing a guide for individualization of treatment strategy in axSpA patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The diagnosis of interstitial lung diseases in patients affected by rheumatoid arthritis is fundamental to improving their survival rate. In particular, the average survival time of patients affected by rheumatoid arthritis with pulmonary implications is approximately 3 years. The gold standard for confirming the diagnosis of this disease is computer tomography. However, it is very difficult to raise diagnosis suspicion because the symptoms of the disease are extremely common in elderly people. The detection of the so-called velcro crackle in lung sounds can effectively raise the suspicion of an interstitial disease and speed up diagnosis. However, this task largely relies on the experience of physicians and has not yet been standardized in clinical practice. The diagnosis of interstitial lung diseases based on thorax auscultation still represents an underexplored field in the study of rheumatoid arthritis. In this study, we investigate the problem of the automatic detection of velcro crackle in lung sounds. In practice, the patient is auscultated using a digital stethoscope and the lung sounds are saved to a file. The acquired digital data are then analysed using a suitably developed algorithm. In particular, the proposed solution relies on the empirical observation that the audio bandwidth associated with velcro crackle is larger than that associated with healthy breath sounds. Experimental results from a database of 70 patients affected by rheumatoid arthritis demonstrate that the developed tool can outperform specialized physicians in terms of diagnosing pulmonary disorders. The overall accuracy of the proposed solution is 90.0%, with negative and positive predictive values of 95.0% and 83.3%, respectively, whereas the reliability of physician diagnosis is in the range of 60-70%. The devised algorithm represents an enabling technology for a novel approach to the diagnosis of interstitial lung diseases in patients affected by rheumatoid arthritis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is associated with significant morbidity and mortality. Similarities have been observed between patients with idiopathic pulmonary fibrosis (IPF) and the UIP (usual interstitial pneumonia) form of RA-ILD. The GAP (gender, age, physiology) model has been shown to predict mortality in patients with IPF, but its ability to predict mortality in RA-ILD is not known., Methods: We identified 309 patients with RA-ILD at 4 academic centers with ongoing longitudinal cohorts of patients with ILD. The primary endpoint was mortality. To handle missing data (n = 219 subjects with complete dataset), multiple imputation by iterative chained equations was used. Using the GAP model as a baseline, we assessed improvements in mortality risk prediction achieved by incorporating additional variables. Model discrimination was assessed using the c-index, and calibration was checked by comparing observed and expected incidence of death., Results: Patients had a mean age of 65 years and were predominantly female (54%). The mean forced vital capacity (FVC) % predicted was 73 and the mean diffusing capacity for carbon monoxide (DL CO ) % predicted was 55. Twenty-four percent of the 236 patients with a high-resolution computed tomography scan available for review had a definite UIP pattern. The original GAP model, including gender, age, FVC%, and DL CO %, had a c-index of 0.746 in our cohort. Calibration of this model was satisfactory at 1, 2 and 3 years. Model discrimination was not meaningfully improved by adding other clinical variables., Conclusion: The GAP model that was derived for IPF performs similarly as a mortality risk prediction tool in RA-ILD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Hepatitis C virus (HCV) infection is responsible for both hepatic and extra-hepatic disorders (HCV-EHDs); these latter are correlated on one hand clearly with HCV lymphotropism causing immune-system dysregulation as well as with viral oncogenic potential, and on the other hand probably with chronic inflammatory status causing cardio-metabolic complications as well as neurocognitive disturbances. The spectrum of HCV-EHDs ranges from mild or moderate manifestations, such as arthralgia, sicca syndrome, peripheral neuropathy, to severe, life-threatening complications, mainly vasculitis and neoplastic conditions. Given the clinical heterogeneity of HCV-EHDs, HCV-infected individuals are inevitably referred to different specialists according to the presenting/prevalent symptom(s); therefore, the availability of comprehensive diagnostic guidelines is necessary for a patient's whole assessment that is decisive for early diagnosis and correct therapeutic approach of various hepatic and HCV-EHDs, regardless of the specific competencies of different physicians or referral centers. In this respect, a multidisciplinary network of experts, the International Study Group of Extrahepatic Manifestations Related to Hepatitis C Virus Infection (ISG-EHCV), was organized with the intention to formulate diagnostic guidelines for the work-up of possible HCV-EHDs. There was a broad consensus among ISG-EHCV members on the proposed guidelines, which essentially are based on two main levels of patient's assessment. At the referral stage, it is proposed that all patients with HCV infection should be invariably examined by means of first-line diagnostic procedures including virological and hepatic parameter evaluation, as well as the detection of clinical findings that may suggest one or more HCV-EHDs. This preliminary assessment should reveal specific HCV-EHDs, which will be deeper analyzed by means of second-line, targeted investigations. The proposed multidisciplinary expert statement represents the first attempt to draw comprehensive diagnostic guidelines for HCV-infected individuals encompassing the entire spectrum of HCV-related disorders, namely typical hepatic manifestations along with less common, often unpredictable HCV-EHDs. The HCV-EHDs may compromise to a substantial degree the overall disease outcome in a significant number of HCV-infected individuals that renders their timely identification and treatment an imperative. In conclusion, the application of standardized but thorough diagnostic guidelines of HCV-EHDs is advisable at the referral stage as well as during the follow-up period of HCV infected patients. It is envisioned that the proposed strategy will result in improvement of clinical outcomes in such patients., (Copyright © 2016. Published by Elsevier B.V.)

Background: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the lungs, varying from idiopathic interstitial pneumonias to secondary variants, including the ILDs associated to connective tissue diseases (CTDs). In addition, a number of patients are recognized as unclassifiable ILD (U-ILD), because of the inability to reach a definite diagnosis; some of them show autoimmune manifestations not fulfilling the classification criteria of a given CTD. The term interstitial pneumonia with autoimmune features (IPAF) has been recently proposed for this particular ILD subset., Methods: Here, we report our experience resulting from the integrated - pneumology/rheumatology - approach to patients with suspected ILDs or CTDs referred to our university-based Center for the Rare Pulmonary Diseases and Rheumatology Unit, from January 2009 to June 2015, with particular attention to the above-mentioned U-ILD, IPAF, and undifferentiated connective tissue disease (UCTD). The comparative analysis of these clinical variants was carried out; moreover, the observed findings were compared with the results of the updated review of the literature., Results: After the first clinical assessment, the U-ILD were identified in 50 patients; afterwards, on the basis of clinico-serological and radiological findings U-ILD group was subdivided into 2 subgroups, namely U-ILD without any clinical extra-thoracic manifestations and/or immunological alterations (15 pts) and IPAF according to the above-mentioned classification criteria (35 pts). Patients with either IPAF or U-ILD were compared with a series of 52 stable UCTD (disease duration ≥3 years), followed at our Rheumatology Unit. Some important differences were evidenced among the 3 series of U-ILD, IPAF, and UCTD: firstly, female gender was more frequent in patients with UCTD (86%) or IPAF (69%) compared with U-ILD (60%) or idiopathic pulmonary fibrosis (24%; p=0.001). In addition, UCTD patients were younger and showed longer disease duration. More interestingly, both UCTD and IPAF series show a comparable prevalence of various clinical manifestations, with the exception of the interstitial lung involvement detectable in a very small percentage of UCTD patients. Concordantly, the review of the literature evidenced two main subsets of U-ILD, one is characterized by isolated unclassifiable interstitial pneumonia and another one composed by subjects with clinically prevalent lung involvement in the setting of not definite CTD, the recently proposed IPAF., Conclusion: We hypothesize that IPAF and UCTD might represent two clinical variants of the same systemic autoimmune disorders. The marked difference regarding the prevalence of ILD, which is the clinical hallmark of IPAF but very rare in UCTD, may at least in part reflect a selection bias of patients generally referred to different specialist centers, i.e. pneumology or rheumatology, according to the presence/absence of clinically dominant ILD, respectively. Well-integrated, interdisciplinary teams are recommended for the assessment and management of these patients in the clinical practice. Finally, the cooperation between multidisciplinary groups with different experiences may be advisable for a validation study of the proposed nomenclature and classification criteria of these indefinable ILD/CTD variants., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Capillaroscopy is a noninvasive imaging technique for the in vivo study of microcirculation. The role of a qualitative evaluation of capillaroscopy in the assessment of Raynaud's phenomenon secondary to scleroderma spectrum disorder, particularly systemic sclerosis (SSc), is well defined. The usefulness of capillaroscopy in the follow-up of SSc patients and the possible prognostic role for the appearance of typical SSc vascular and visceral involvement, namely, digital ulcers, pulmonary arterial hypertension, and mortality, is suggested by many authors but still under debate. In this regard, and for a reliable and repeatable longitudinal evaluation of SSc microangiopathy, a quantitative analysis should be required. In this review, we describe the current classifications proposed to define the SSc microvascular involvement and the scoring methods suggested for a semiquantitative and quantitative analysis of microangiopathy and its correlation with clinical manifestations of disease.

The clinical spectrum and prognosis of systemic sclerosis (SSc) seem to vary among patients' populations recruited during different time periods. In order to verify this possible evolution we investigated the clinico-serological and survival rate in a large Italian SSc series (821 patients; 746 females, 75 males; mean age 53.7±13.9SD years) recruited between 2000 and 2011. The observed findings were compared with previous studies of the world literature.Compared to older Italian SSc series, the present patients' population showed a significantly increased prevalence of limited cutaneous SSc (from 72 to 87.5%; p ≤.0001) and serum anti-centromere antibodies (from 39 to 47,4%; p ≤.001), with a significant reduction of lung (from 81 to 63.7%; p ≤.0001), heart (from 35 to 20.5%; p ≤.0001), and renal involvement (from 10 to 3.8%; p ≤.0001), and skin ulcers (from 54 to 16.5%; p ≤.0001). Cumulative 10th-year survival showed a clear-cut increase (80.7%) compared to our previous series (69.2%). These findings were mirrored by the results of survival studies published during the last five decades, grouped according to the time periods of patients'' recruitment at the referral centers. A clear progression of 10th-year survival rates was detectable, from the 54% median survival of the oldest studies (1935-1974) to 74% and 83.5% of the more recent SSc series, 1976-1999 and after 1999, respectively. In conclusion, the favorable evolution of SSc pathomorphosis and prognosis during the last decades might be related to more diffuse physician/patient awareness of this harmful disease and availability of diagnostic tools, the consequent wider recruitment of patients in the early stages of the disease, as well as to the improved therapeutic strategies., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: To better define the convulsive status epilepticus (CSE) as a possible manifestation at the onset of Panayiotopoulos syndrome (PS) and to assess its prognostic value in these children., Methods: Children with CSE and diagnostic criteria of PS were identified, followed clinically and compared with a group of patients with PS without CSE from 1993 to 2012., Results: We identified 37 patients with CSE at the onset of PS. During the same period we identified 72 children with autonomic symptoms of PS without CSE. The first episode of CSE occurred at a mean age of 6.5 years. Generalized clonic seizures were the most common ictal event and one-third of the patients required admission to Intensive Care Units. Interictal EEGs showed occipital spike activity in 31 (83.7%) subjects. Only 14 (37.8%) patients were treated with valproic acid and for two of them (5.40%) it was necessary to administer other drugs. There were no intractable cases. The overall prognosis was excellent. After the first event, 15 subjects (40.54%) experienced at least another typical PS seizure, but all patients were seizure free at the last follow-up., Conclusion: CSE is not uncommon in PS and it may occur at the onset of benign childhood epilepsy, without leading to a poor prognosis., (Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: Intravesical instillation of BCG (ivBCG) is an effective and safe immunotherapy of bladder carcinoma but it may have, as side effect, a reactive arthritis (ReA). The authors describe 5 cases observed during their own clinical experience along with the updated review of the literature on this topic., Methods: Seventy-three papers were present in the world literature, each reporting almost 1 case for a total of 112 patients. However, the review focused on 61 papers, selected on the basis of reporting suitable for a correct clinical evaluation; thus, a total of 89 patients, including the cases observed in our clinic, were carefully analyzed., Results: Among the 89 patients identified 73 were males and 16 females. Europe is the geographical area with the higher number of reports, namely 80.6% of the papers including 74.2% of the patients. The Mediterranean area accounts for 62.9% of the papers and 59.6% of the cases. The symptoms of ReA appeared after a mean number of instillations of 5.8. Polyarthritis was present in 55.1%, oligoarthritis in 37.0% and monoarthritis in 7.9%. Polyarthritis was symmetric in 51.0% and asymmetric in 49.0% of the cases; oligoarthritis was symmetric in 33.3% and asymmetric in 66.7% of the cases. Overall, an asymmetric distribution of arthritis was present in 59.6%. Knee and ankle were the joints most frequently involved. The antigen HLA B27 was positive in 42.6%. The synovial fluid analysis was defined as flogistic-aseptic in 71.9% of the patients. Arthritis was recovered within 6months in 93.2% of the cases and in 70.5% of the patients within the first two months. NSAIDs and corticosteroids, alone or in conjunction with other drugs, are used in 65.1% and in 40.4% of the cases, respectively. The clinical features of ivBCG ReA are compared with ReA from other triggering agents, from which it differs for some clinical aspects and overlaps for others., Conclusions: Compared with a previous report, this review allows to modify some figures of this topic as a reduced prevalence of polyarthritis (from 70% to 55.1%) and of spinal and sacroiliac involvement; polyarthritis remains the more frequent clinical pattern of ivBCG ReA that, however, is characterized by rather asymmetrical distribution and involvement of the large joints of lower limbs. A definite linkage to HLA B27 is present, although without prognostic value. Moreover, arthritis is aseptic, has a latency time from antigen exposure, and is associated with extra-articular features as commonly observed in ReA from other triggering agents. Arthritis is usually benign and rarely develops into a chronic form. NSAIDs and/or corticosteroids are largely effective. Noteworthy, the overall clinical picture of arthritis triggered by ivBCG emerging from this updated review is comparable to that of ReA from other bacterial agents., (© 2013 Elsevier B.V. All rights reserved.)

The association between systemic sclerosis (SSc) and cancer was widely described, particularly with breast and lung carcinoma; while, data regarding possible associations between cancer and SSc features are still scarce. We retrospectively evaluated the prevalence of lung cancer in our SSc patient cohort (318 SSc patients, 31 M and 287 F, age 51.5±14.5SD years, disease duration 10.3±6.5SD years) and clinico-serological factors potentially associated to the development of this malignancy. A review of the world literature about this topic was also done. We found that lung cancer complicated 16/318 (5%) SSc patients; namely 11/287 females (4%) and 5/31 males (16.1%). Median age of SSc patients with lung cancer was 54 (range 38-72) years for female patients, and 63 (range 40-73) for males; 13/16 patients died because of the neoplasia. Considering the incidence of lung carcinoma in sex/age-matched general population of the same geographical area, the percentages of lung cancer in our SSc series are about 2.5 and >5 times higher for male and female patients, respectively. The presence of lung cancer significantly correlated with male sex (p=0.011), presence of anti-Scl70 antibodies (p=0.0007), cyclophosphamide therapy (p=0.0001), forced vital capacity (FVC) <75% (p=0.0001), and lung fibrosis (p=0.0127); moreover patients with cancer have a significantly lower age at the diagnosis of SSc (p=0.009) and longer disease duration (p=0.0175). The logistic regression analysis confirmed a significant association with the anti-Scl70 antibodies (OR 6.4, 95%IC 1.7-24.1; p=0.006) and the reduction of FVC (OR 6.7, 95%IC 2.2-20.7; p=0.001) only. Overall, the prevalence of lung cancer in the subset of SSc patients with anti-Scl70 antibodies was 12/105 (11.4%), 9/40 (22.5%) in patients with FVC% reduction, and 7/22 (31.8%) in patients with both. In literature, the median prevalence of lung cancer in SSc series was 2.4% (range 0-4.2%); even if sporadic, associations with lung involvement or antiScl70 autoantibodies were raised, according to our findings. Our study confirmed the higher frequency of lung cancer among SSc patients compared to general population, particularly within patients' subset with serum anti-Scl70 antibodies and lung involvement., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To evaluate the risk of serious infections (SIs) in RA patients receiving anti-TNF therapy on the basis of the data included in the GISEA register., Methods: The study involved 2769 adult patients with long-standing RA (mean age 53.2±13.4 years; mean disease duration 9.0±8.3 years) enrolled in the GISEA register, who had been treated for at least 6 months with TNF inhibitors or had discontinued therapy due to SI: 837 (30%) treated with infliximab (IFN), 802 (29%) with adalimumab (ADA), and 1130 (41%) with etanercept (ETN)., Results: 176 patients had experienced at least one of the 226 Sis during the 9 years of treatment with an anti-TNF agent, an overall incidence of 31.8/1000 patient-years (95% CI 25.2-38.3): 23.7/1000 patient-years (95% CI 13.1-34.2) on ADA; 12.8/1000 patient-years (95% CI 6.3-19.4) on ETN and 65.1/1000 patient-years (95% CI 48.4-81.8) on IFN. The risk was higher in the first than in the second year of treatment, but this difference was not statistically significant (p=0.08) (38.9% of the SIs were recorded in the first 12 months of treatment). The risk of SI was significantly different among the three treatment groups (p<0.0001). Multivariate models confirmed that the use of steroids (p<0.046), concomitant DMARD treatment during anti-TNF therapy (p=0.004), advanced age at the start of anti-TNF treatment (p<0.0001), and the use of IFN or ADA rather than ETN (respectively p<0.0001 and p=0.023) were strong and statistically significant predictors of infection., Conclusions: Anti-TNF therapy is associated with a small but significant risk of SI that is associated with the concomitant use of steroids, advanced age at the start of anti-TNF treatment, and the type of anti-TNF agent., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: Mixed cryoglobulinemia syndrome (MCs) is a systemic vasculitis characterized by multiple organ involvement due to the vascular deposition of immune-complexes, mainly the cryoglobulins. B-lymphocyte expansion represents the underlying pathological alteration frequently triggered by hepatitis C virus (HCV) infection. The treatment of MCs syndrome is generally based on antiviral drugs and/or immunosuppressors, among which rituximab, an anti-CD20 monoclonal antibody, has been usefully employed for both cutaneous and visceral MCs organ involvement. This multicenter study retrospectively evaluated the effects of rituximab in a large series of patients with active MCs. The observed results were compared to those emerging from the updated review of the literature on this topic., Methods: The study included 87 patients (male/female 19/68, mean age 62.3±11.4SD years, mean disease duration 9±6.2SD years, HCV infection in 92% of cases) with active cryoglobulinemic vasculitis evaluated before rituximab monotherapy and after 6-month follow-up by means of main clinico-serological parameters. A PubMed search up to May 31, 2011, was done to find published clinical studies, including case reports of MCs treated with rituximab., Results: A significant clinical improvement was observed in a relevant percentage of cases, regardless the presence/absence of associated HCV infection; namely, complete/partial remission of pre-treatment active manifestations was observed in 74% of skin purpuric lesions, up to 87% of non-healing vasculitic leg ulcers, and 44% of the peripheral neuropathy, mainly paresthesias (patient's visual analogical scale from 62±25 to 37±27; p≤.0001). Moreover, cryoglobulinemic nephropathy, observed in 38 patients, significantly improved in 95% of cases (serum creatinine from 1.8±1.1SD to 1.4±0.8SD mg/dl, p≤.0001; 24-hour proteinuria from 2.2±2.1SD to 0.9±1.7SD g/24h, p≤.0001), with complete remission in the 50%. Among 6 patients with complicating non-Hodgkin's B-cell lymphoma a complete or partial remission was observed in 5/6. A complete remission of abdominal vasculitis was also observed in one patient. These beneficial effects were mirrored by the improvement of cryoglobulinemic serological hallmarks, namely cryocrit and low complement C4, in half cases. The safety of rituximab was confirmed by the small number of side effects recorded during the 6-month follow-up. On the whole, the results of the present study are in keeping with those reported in 39 papers present in world literature, including a total of 279 MCs patients., Conclusions: Rituximab may be regarded as useful and safe pathogenetic treatment of cryoglobulinemic vasculitis. The actual role of this drug should be definitely confirmed by randomized controlled trials, as well as its position in the therapeutical strategy, mainly with respect to antiviral treatment in HCV-associated MCs., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Chronic intestinal pseudo-obstruction is a life-threatening condition of unknown pathogenic mechanisms. Chronic intestinal pseudo-obstruction can be a feature of mitochondrial disorders, such as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare autosomal-recessive syndrome, resulting from mutations in the thymidine phosphorylase gene. MNGIE patients show elevated circulating levels of thymidine and deoxyuridine, and accumulate somatic mitochondrial DNA (mtDNA) defects. The present study aimed to clarify the molecular basis of chronic intestinal pseudo-obstruction in MNGIE. Using laser capture microdissection, we correlated the histopathological features with mtDNA defects in different tissues from the gastrointestinal wall of five MNGIE and ten control patients. We found mtDNA depletion, mitochondrial proliferation, and smooth cell atrophy in the external layer of the muscularis propria, in the stomach and in the small intestine of MNGIE patients. In controls, the lowest amounts of mtDNA were present at the same sites, as compared with other layers of the gastrointestinal wall. We also observed mitochondrial proliferation and mtDNA depletion in small vessel endothelial and smooth muscle cells. Thus, visceral mitochondrial myopathy likely causes gastrointestinal dysmotility in MNGIE patients. The low baseline abundance of mtDNA molecules may predispose smooth muscle cells of the muscularis propria external layer to the toxic effects of thymidine and deoxyuridine, and exposure to high circulating levels of nucleosides may account for the mtDNA depletion observed in the small vessel wall.

Mixed cryoglobulinemia (MC) is a systemic small-vessel vasculitis; B-cell expansion is the biological substrate of the disease. It can be regarded as benign lymphoproliferative condition that may evolve to frank lymphoma. HCV infection is the main causative factor of MC, as well as of other overlapping disorders, through multifactorial and multistep pathogenetic process. HCV-related B-cell proliferation represents an important model of virus-driven autoimmune/neoplastic disorder. The term HCV syndrome is referred to a wide spectrum of both hepatic and extrahepatic disorders. The present review analyzes the complex virological, clinico-pathological, and therapeutic implications of B-cell proliferation, with or without HCV infection, in MC patients.

Hepatitis C virus (HCV) chronic infection may be associated with a great number of both hepatic and extrahepatic manifestations. HCV lymphotropism is responsible for poly-oligoclonal B-lymphocyte expansion, which is the common underlying alteration in a significant percentage of HCV-infected individuals. The consequent production of different autoantibodies and immune-complexes, including cryoglobulins, may lead to organ- and non-organ-specific immunological alterations. Mixed cryoglobulinemia, a small-vessel systemic vasculitis, is characterized by the coexistence of autoimmune and lymphoproliferative alterations; therefore, it represents the prototype of HCV-associated disorders. Moreover, HCV shows an oncogenic potential; several studies support its pathogenetic link with some malignancies, mainly hepatocellular carcinoma and B-cell lymphomas. On the whole, HCV-related disorders present a heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. While the majority of HCV-infected individuals is asymptomatic or may develop only liver manifestations, a significant percentage of them may develop a variable combination of autoimmune lymphoproliferative disorders. The resulting multiform clinico-pathological condition can be termed HCV syndrome. The natural history of HCV syndrome is the expression of multifactorial and multistep pathogenetic process, which usually proceeds from mild, often isolated manifestations to systemic immune-mediated disorders, and less frequently to overt malignancies.

Study Objective: To determine maternal and neonatal effects of three different induction drugs (thiopental sodium, propofol, and midazolam) for cesarean section., Design: Randomized, double-blind study., Setting: Inpatient obstetric department at a general hospital., Patients: 90 healthy patients undergoing elective cesarean section with general anesthesia., Interventions: 3 groups of 30 patients each receiving thiopental 5 mg/kg, propofol 2.4 mg/kg, or midazolam 0.3 mg/kg for induction of anesthesia., Measurements and Main Results: Time to induce anesthesia, hemodynamic changes, depth of anesthesia, recovery after anesthesia, placental transfer, and neonatal outcome (Apgar and neurobehavioral examinations) were studied. In the thiopental and midazolam groups, systolic blood pressure and heart rate rose following endotracheal intubation and skin incision (p < 0.001 and p < 0.0025, respectively), while in the propofol group, there was significant hypotension after induction (p < 0.005). Electroencephalographic patterns showed a light depth of anesthesia with propofol and midazolam between anesthesia induction and delivery, confirmed by the presence of clinical signs of light anesthesia in 50% of propofol patients and 43% of midazolam patients. Time to induce anesthesia was longer with midazolam (p < 0.0001). Neonates in the midazolam and propofol groups had lower Apgar and neurobehavioral scores than those in the thiopental group. Umbilical artery to umbilical vein ratios were above 1 in the propofol and midazolam groups., Conclusion: Thiopental still remains the first-choice induction drug for cesarean section. The slow induction time with midazolam may put the mother at risk for pulmonary inhalation. A plane of anesthesia that may risk awareness and potential neonatal depression is the main drawback of the two newer induction drugs.

In 56 women undergoing elective caesarean section, general anaesthesia was induced with either propofol 1% or thiopentone 2.5% followed by 50% nitrous oxide in oxygen and isoflurane 0.75% until delivery. In the thiopentone group the arterial pressure rose following tracheal intubation and skin incision, while in the propofol group there was a significant tendency to hypotension immediately following induction of anaesthesia. There were differences in electroencephalogram (EEG) between the groups, while laryngoscopy, intubation and surgical stimulation had no effect on EEG pattern. Recovery after anaesthesia did not differ between groups. None of the patients had recall of the intraoperative period, but 53% of patients induced with propofol showed signs of light anaesthesia between induction and delivery. Neonates in the propofol group had lower Apgar scores 1 min after birth than those in the thiopentone group, but these differences were no longer significant at 5 min. No differences were noted in neurobehavioural status at 1, 4 and 24 h.

Study Objective: To determine the clinical effects of the alkalinization of 2% mepivacaine with epinephrine used for epidural block during cesarean section., Design: Randomized, double-blind, placebo-controlled (standard commercial preparation of 2% mepivacaine with epinephrine) study., Setting: Inpatient obstetric department at a general hospital., Patients: Seventy patients scheduled for elective cesarean section under epidural anesthesia., Interventions: Two groups of 35 patients each receiving either the standard commercial preparation of mepivacaine or the pH-adjusted solution (prepared with the addition of 0.1 meq/ml of sodium bicarbonate to the standard commercial solution)., Measurements and Main Results: Measurements of sensory (pinprick) and motor (Bromage's criteria) block were taken at 1- to 2-minute intervals beginning after the completion of the epidural injection. Increasing the pH of the mepivacaine resulted in a significant shortening of the time of analgesia onset (9.3 minutes compared with 16.01 minutes, p less than 0.01) and of peak effect (11.1 minutes compared with 21.2 minutes, p less than 0.01). The alkalinization did not affect duration of the block, intensity of motor block, or mean dose of local anesthetic used., Conclusion: The alkalinization allowed the surgery to proceed more rapidly, significantly decreasing the time interval between epidural block and delivery of the infant.

Three cases are described in which Wharton's jelly was completely absent around the umbilical cord arteries but was present around the umbilical vein. All three instances of this anomaly were associated with perinatal death.