The positive side of the coin: Sars-Cov-2 pandemic has taught us how much Telemedicine is useful as standard of care procedure in real life.

Patients and health workers were at high risk of infection during the Sars-Cov-2 pandemic lockdown. For this reason, other medical and clinical approaches such as Telemedicine were necessary. Despite Telemedicine was born before COVID-19, the pandemic was the opportunity to accelerate a process already underway for at least a decade and to blow all the barriers away. Our aim is to describe the experience of Telemedicine during and immediately after the first lockdown to assure the follow-up in a 'virtual' outpatient clinic dedicated to Rheumatic and Musculoskeletal Diseases (RMDs) and to give an overview of Telemedicine in the rheumatology field. We retrospectively evaluated the patient flow to our rheumatology division from March to September 2020 and, in accordance with local restrictions, three periods were selected. In the 1st period, 96.96% of the outpatient clinic cases were shifted to Telemedicine; these decreased to 52.45% in the 2nd period, while the 3rd period was characterized by the return of the patients at the clinic (97.6%). Diagnostic procedures were postponed during the 1st period, reduced drastically during the 2nd and performed regularly during the third period. Intravenous infusions were maintained as much as possible during the three periods, to assure therapeutic continuity. Shifting stable patients to Telemedicine has the potential to allow continuity of care, while reducing the risk of contagion during a pandemic. In the next future, the integration of Telemedicine as standard of care for specific clinical applications might assure assistance for RMDs patients also in non-pandemic conditions.

Autoimmune Diseases in Patients with Cushing's Syndrome after Resolution of Hypercortisolism: Case Reports and Literature Review.

INTRODUCTION: Cushing's syndrome (CS) is a clinical condition characterized by excessive cortisol production, associated with metabolic complications, such as diabetes mellitus, dyslipidemia, metabolic syndrome, hypertension, and cardiovascular diseases. Nowadays, the occurrence of autoimmune diseases in CS have not been completely evaluated in the previous studies. OBJECTIVE: The aim of this study was to evaluate the occurrence of autoimmune diseases in CS patients after successfully treated. MATERIALS AND METHODS: From January 2001 to December 2017, in our Secondary Hypertension Unit, we evaluated 147 CS patients (91 with ACTH-independent disease, 54 with ACTH-dependent disease, and 2 patients with ectopic ACTH production. RESULTS: 109 CS patients (74.1%) were surgically treated (67 ACTH-independent CS patients (61.5%) undergone adrenalectomy and 42 ACTH-dependent CS (38.5%) undergone transsphenoidal surgery) and evaluated after 6, 12, and 24 months after clinical and biochemical remission of disease. In 9 (8.3%) of overall treated CS patients (8.3%), during follow-up, we observed the onset of some manifestations of autoimmune diseases. In particular, one patient had a systemic lupus erythematosus, one patient had rheumatoid arthritis, 4 patients reported autoimmune thyroiditis (Basedow-Graves' disease and Hashimoto's thyroiditis), one patient had clinical features of psoriasis, one patient showed myasthenia gravis, and one patient had giant cell arteritis. CONCLUSIONS: Our results demonstrate that patients successfully treated for CS could develop autoimmune diseases. Therefore, after treatment, CS patients need to be strictly monitored in order to evaluate the possible onset of autoimmune diseases.

Illustrating Pathologies in the First Years of the Miscellanea Curiosa, 1670-1687.

The Miscellanea Curiosa, sive Ephemeridum Medico-Physicarum Germanicarum, the learned periodical published in different German cities under the aegis of the Academia Leopoldina Naturae Curiosorum, contained many cases of an anatomical nature. The Miscellanea Curiosa in its first years actively participated in the development of anatomia practica, the anatomical practice of observing the signs of diseases in cadavers and connecting them to what had been observed at the bedside. The illustrations that accompanied the post-mortem reports published in the Miscellanea Curiosa allow one to assess the evolution of the pathological illustration itself. This article is thus intended to serve as a contribution to the rediscovery of the origins of this visual genre. A learned journal like the Miscellanea Curiosa, which appeared regularly, provided an ideal venue for the process of accumulating, cross-referencing and--in the final analysis--selecting, serializing and systematizing the knowledge that would form the foundations of modern pathology, by providing a wealth of evidence and images observed at the dissection table.

Transitional connective tissue diseases: description of four cases.

UNLABELLED: The term overlap syndromes (OS) is used to define a group of disorders characterized by the presence, in the same patient, of clinical features typical for more than one definite connective tissue disease (CTD). OBJECTIVE: To show that patients may not only have an overlap of two or more CTDs but may also change their disease phenotype from that of a definite CTD to another. PATIENTS AND METHODS: Retrospective analysis of medical records of four patients with a disease duration of about thirty years and a transition from a well definite CTD into another. RESULTS: The first patient was diagnosed, at the beginning of the 1980s, as affected by diffuse cutaneous systemic sclerosis (dcSSc) and developed systemic lupus erythematosus (SLE) twenty-five years later. The second and the third patients were diagnosed with SLE at the beginning of their disease: the second patient developed, in the course of her disease, an overlap syndrome (OS) SSc/rheumatoid arthritis (RA) and the third SSc and finally microscopic polyangiitis (MPA). The fourth patient was diagnosed as primary Sjogren's syndrome (SS) then as rheumatoid arthritis (RA) and finally developed SLE. CONCLUSIONS: Patients may not only show an overlap of two or more CTDs but also a transition from a well definite CTD into another. We propose the term "transitional connective tissue diseases" (TCTDs) to define their disease. A higher number of patients may allow us to better identify this new subgroup of CTDs and probably, also, predictors of evolution.

High power laser therapy treatment compared to simple segmental physical rehabilitation in whiplash injuries (1° and 2° grade of the Quebec Task Force classification) involving muscles and ligaments.

INTRODUCTION: whiplash is a frequent post traumatic pathology caused by muscle, tendon and capsular elements over stretching. The authors conducted a short term prospective randomised study to test the effectiveness of a multi wave High Power Laser Therapy (HPLT) versus conventional simple segmental physical rehabilitation (PT) included in Italian tariff nomenclature performance physiotherapy Study Design: prospective randomised study (Level II). MATERIAL AND METHODS: the authors identified 135 homogeneous patients with whiplash grade 1 - 2 of the Quebec Task Force classification (QTFC). INAIL, the Italian National Workers Insurance, based in Milan, was reliable source for identifying patients. All patients with whiplash injuries grade 1 or 2 QTFC, were eligible for the study, starting from April 28 2010 to September 30 2010. Patients referred to a Coordinator (C.M.) who applied the inclusion and exclusion criteria. Patients who agreed to participate were randomly assigned to one of the two treatment groups. Dates for initial treatment session were arranged, including cervical spine X-ray, and assessment. Each patient gave informed consent for participation and agreed to adopt only the study treatment for 6 weeks. Group A (84 patients) was treated with High Power Laser Therapy (HPLT), Group B (51 patients) received conventional simple segmental physical rehabilitation (PT). During the treatment period, no other electro-medical therapy, analgesics or anti-inflammatory drugs were allowed. All patients were assessed at baseline (T0) and at the end of the treatment period (T1) using a Visual Analogical Scale (VAS), (T2) the date of return to work was registered afterwards. RESULTS: there was a reduction in VAS pain scores at T1. Group A (VAS = 20) Group B (VAS = 34,8) (p =0.0048). Laser treatment allowed quick recovery and return to work (T2). Group A after 48 days against 66 days of Group B (p=0.0005). CONCLUSIONS: results suggest that High Power Laser Therapy - is an effective treatment in patients with whiplash injury, compared to conventional simple segmental physical rehabilitation.

Differential expression of junctional adhesion molecules in different stages of systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by early perivascular inflammation, microvascular endothelial cell (MVEC) activation/damage, and defective angiogenesis. Junctional adhesion molecules (JAMs) regulate leukocyte recruitment to sites of inflammation and ischemia-reperfusion injury, vascular permeability, and angiogenesis. This study was undertaken to investigate the possible role of JAMs in SSc pathogenesis. METHODS: JAM-A and JAM-C expression levels in skin biopsy samples from 25 SSc patients and 15 healthy subjects were investigated by immunohistochemistry and Western blotting. Subcellular localization of JAMs in cultured healthy dermal MVECs and SSc MVECs was assessed by confocal microscopy. Serum levels of soluble JAM-A (sJAM-A) and sJAM-C in 64 SSc patients and 32 healthy subjects were examined by enzyme-linked immunosorbent assay. RESULTS: In control skin, constitutive JAM-A expression was observed in MVECs and fibroblasts. In early-stage SSc skin, JAM-A expression was strongly increased in MVECs, fibroblasts, and perivascular inflammatory cells. In late-stage SSc, JAM-A expression was decreased compared with controls. JAM-C was weakly expressed in control and late-stage SSc skin, while it was strongly expressed in MVECs, fibroblasts, and inflammatory cells in early-stage SSc. Surface expression of JAM-A was higher in early-stage SSc MVECs and increased in healthy MVECs stimulated with early-stage SSc sera. JAM-C was cytoplasmic in resting healthy MVECs, while it was recruited to the cell surface upon challenge with early-stage SSc sera. Early-stage SSc MVECs exhibited constitutive surface JAM-C expression. In SSc, increased levels of sJAM-A and sJAM-C correlated with early disease and measures of vascular damage. CONCLUSION: Our findings indicate that JAMs may participate in MVEC activation, inflammatory processes, and impaired angiogenesis in different stages of SSc.

Lung ultrasound for the screening of interstitial lung disease in very early systemic sclerosis.

BACKGROUND: A high percentage of patients with systemic sclerosis (SSc) develop interstitial lung disease (ILD) during the course of the disease. Promising data have recently shown that lung ultrasound (LUS) is able to detect ILD by the evaluation of B-lines (previously called ultrasound lung comets), the sonographic marker of pulmonary interstitial syndrome. OBJECTIVE: To evaluate whether LUS is reliable in the screening of ILD in patients with SSc. METHODS: Fifty-eight consecutive patients with SSc (54 women, mean age 51±14 years) who underwent a high resolution CT (HRCT) scan of the chest were also evaluated by LUS for detection of B-lines. Of these, 32 patients (29 women, mean age 51±15 years) fulfilled the criteria for a diagnosis of very early SSc. RESULTS: At HRCT, ILD was detected in 88% of the SSc population and in 41% of the very early SSc population. A significant difference in the number of B-lines was found in patients with and without ILD on HRCT (57±53 vs 9±9; p<0.0001), with a concordance rate of 83%. All discordant cases were false positive at LUS, providing a sensitivity and negative predictive value of 100% in both SSc and very early SSc. CONCLUSIONS: ILD may be detected in patients with very early SSc. The presence of B-lines at LUS examination correlates with ILD at HRCT. LUS is very sensitive for detecting ILD even in patients with a diagnosis of very early SSc. The use of LUS as a screening tool for ILD may be feasible to guide further investigation with HRCT.

Increased serum levels and tissue expression of matrix metalloproteinase-12 in patients with systemic sclerosis: correlation with severity of skin and pulmonary fibrosis and vascular damage.

OBJECTIVE: To determine serum concentrations and tissue expression of matrix metalloproteinase-12 (MMP-12) and their correlation with clinical features in patients with systemic sclerosis (SSc). METHODS: Serum MMP-12 levels from 72 patients with SSc and 42 healthy volunteers were examined by ELISA. Immunohistochemical expression of MMP-12 was analysed in skin biopsies from 20 patients with SSc and 13 healthy subjects and lung biopsies from three patients with SSc-related interstitial lung disease (ILD) and five controls. RESULTS: Circulating levels of MMP-12 were significantly increased in patients with SSc compared with healthy controls. Serum MMP-12 levels were significantly higher in both patients with limited cutaneous SSc and those with diffuse cutaneous SSc than in healthy controls, and correlated positively with the extent of skin involvement. MMP-12 levels were raised in SSc patients with ILD compared with patients without ILD, and correlated with severity of lung restriction. Increased serum levels of MMP-12 were also associated with the presence of digital ulcers and severity of nailfold capillary abnormalities. In contrast to almost undetectable MMP-12 expression in healthy skin, MMP-12 was strongly expressed in keratinocytes, dermal endothelial cells, fibroblasts/myofibroblasts and inflammatory cells in the skin of patients with SSc. Affected lung tissue from patients with SSc-related ILD showed strong MMP-12 expression in capillary vessels, inflammatory cells, alveolar macrophages and fibroblasts in the thickened alveolar septa, while faint expression was observed in normal lung tissue. CONCLUSIONS: MMP-12 levels are increased in patients with SSc and are associated with severity of skin and pulmonary fibrosis and peripheral vascular damage.

Evidence for reduced angiogenesis in bone marrow in SSc: immunohistochemistry and multiparametric computerized imaging analysis.

OBJECTIVE: Dysfunctional angiogenesis is a pathogenetic marker of SSc. Circulating levels of endothelial progenitor cells are reduced, and mesenchymal stromal cells show a reduced differentiation into endothelial cells and capacity to form capillaries. This suggests that pathophysiologically relevant changes may already exist in SSc bone marrow (BM) stromal cells that may affect downstream angiogenesis. The aim of this study is to evaluate, in SSc BM, angiogenesis, cellular immune system and fibrosis. METHODS: Eight SSc patients affected by a severe dcSSc and screened for autologous haematopoietic stem cells transplantation (HSCT) underwent a BM biopsy. BM biopsies were compared with six healthy controls. To evaluate angiogenesis and cellular immunity, the following antibodies were used: vascular endothelial growth factor (VEGF), kinase insert domain-containing receptor/fetal liver kinase-1 (KDR/flk-1), MMP-9 and CD34. To evaluate fibrosis, silver impregnation for reticulum was used. The number of vessels, the mean area of vascularization, the perimeter and microvessel density (MVD) were measured with a multiparametric computerized imaging analysis. RESULTS: A significant reduction in BM vascularity was found, while VEGF expression was much higher in SSc BM samples. Two patients had a Grade 2, whereas another two had a Grade 1 fibrosis. CONCLUSION: In SSc, BM is characterized by a reduction of microvascular density and number of vessels and a significant increase of VEGF. This indicates that BM may be involved in the process of loss of angiogenesis, despite the presence of high local and systemic levels of VEGF.

Bone marrow-derived mesenchymal stem cells from early diffuse systemic sclerosis exhibit a paracrine machinery and stimulate angiogenesis in vitro.

OBJECTIVE: To characterise bone marrow-derived mesenchymal stem cells (MSCs) from patients with systemic sclerosis (SSc) for the expression of factors implicated in MSC recruitment at sites of injury, angiogenesis and fibrosis. The study also analysed whether the production/release of bioactive mediators by MSCs were affected by stimulation with cytokines found upregulated in SSc serum and tissues, and whether MSCs could modulate dermal microvascular endothelial cell (MVEC) angiogenesis. METHODS: MSCs obtained from five patients with early severe diffuse SSc (SSc-MSCs) and five healthy donors (H-MSCs) were stimulated with vascular endothelial growth factor (VEGF), transforming growth factor ß (TGFß) or stromal cell-derived factor-1 (SDF-1). Transcript and protein levels of SDF-1 and its receptor CXCR4, VEGF, TGFß(1) and receptors TßRI and TßRII were evaluated by quantitative real-time PCR, western blotting and confocal microscopy. VEGF, SDF-1 and TGFß(1) secretion in culture supernatant was measured by ELISA. MVEC capillary morphogenesis was performed on Matrigel with the addition of MSC-conditioned medium. RESULTS: In SSc-MSCs the basal expression of proangiogenic SDF-1/CXCR4 and VEGF was significantly increased compared with H-MSCs. SSc-MSCs constitutively released higher levels of SDF-1 and VEGF. SDF-1/CXCR4 were upregulated after VEGF stimulation and CXCR4 redistributed from the cytoplasm to the cell surface. VEGF was increased by SDF-1 challenge. VEGF, TGFß and SDF-1 stimulation upregulated TGFß(1), TßRI and TßRII in SSc-MSCs. TßRII redistributed from the cytoplasm to focal adhesion contacts. SSc-MSC-conditioned medium showed a greater proangiogenic effect on MVECs than H-MSCs. Experiments with blocking antibodies showed that MSC-derived cytokines were responsible for this potent proangiogenic effect. CONCLUSION: SSc-MSCs constitutively overexpress and release bioactive mediators/proangiogenic factors and potentiate dermal MVEC angiogenesis.

Implantable cardioverter defibrillator prevents sudden cardiac death in systemic sclerosis.

OBJECTIVE: Cardiac involvement means a poor prognosis in systemic sclerosis (SSc). Conduction defects and arrhythmias are frequent in patients with SSc, and may result in sudden cardiac death. We tested whether electrophysiologic studies and implantation of cardioverter defibrillators are recommended when ventricular arrhythmias are present. METHOD: A cardioverter defibrillator was implanted in 10 patients with SSc who had heart involvement. RESULT: After 36 months, analysis of the device showed several episodes of ventricular tachycardia in 3 patients, which were promptly reverted by electrical shock delivery. CONCLUSION: In patients with SSc who are affected by ventricular arrhythmias, the implantation of a cardioverter defibrillator may prevent sudden cardiac death.

Overexpression of VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, leads to insufficient angiogenesis in patients with systemic sclerosis.

RATIONALE: Systemic sclerosis (SSc) is characterized by widespread microangiopathy, fibrosis, and autoimmunity. Despite the lack of angiogenesis, the expression of vascular endothelial growth factor A (VEGF) was shown to be upregulated in SSc skin and circulation; however, previous studies did not distinguish between proangiogenic VEGF(165) and antiangiogenic VEGF(165)b isoforms, which are generated by alternative splicing in the terminal exon of VEGF pre-RNA. OBJECTIVE: We investigated whether VEGF isoform expression could be altered in skin and circulation of patients with SSc. METHODS AND RESULTS: Here, we show that the endogenous antiangiogenic VEGF(165)b splice variant is selectively overexpressed at both the mRNA and protein levels in SSc skin. Elevated VEGF(165)b expression correlated with increased expression of profibrotic transforming growth factor-ß1 and serine/arginine protein 55 splicing factor in keratinocytes, fibroblasts, endothelial cells, and perivascular inflammatory cells. Circulating levels of VEGF(165)b were significantly higher in patients with SSc than in control subjects. Microvascular endothelial cells (MVECs) isolated from SSc skin expressed and released higher levels of VEGF(165)b than healthy MVECs. Transforming growth factor-ß1 upregulated the expression of VEGF(165)b and serine/arginine protein 55 in both SSc and healthy MVECs. In SSc MVECs, VEGF receptor-2 was overexpressed, but its phosphorylation was impaired. Recombinant VEGF(165)b and SSc-MVEC-conditioned medium inhibited VEGF(165)-mediated VEGF receptor-2 phosphorylation and capillary morphogenesis in healthy MVECs. The addition of anti-VEGF(165)b blocking antibodies abrogated the antiangiogenic effect of SSc-MVEC-conditioned medium. Capillary morphogenesis was severely impaired in SSc MVECs and could be ameliorated by treatment with recombinant VEGF(165) and anti-VEGF(165)b blocking antibodies. CONCLUSIONS: In SSc, a switch from proangiogenic to antiangiogenic VEGF isoforms may have a crucial role in the insufficient angiogenic response to chronic ischemia.

An optimal decision making model for supporting week hospital management.

Week Hospital is an innovative inpatient health care organization and management, by which hospital stay services are planned in advance and delivered on week-time basis to elective patients. In this context, a strategic decision is the optimal clinical management of patients, and, in particular, devising efficient and effective admission and scheduling procedures, by tackling different requirements such as beds' availability, diagnostic resources, and treatment capabilities. The main aim is to maximize the patient flow, by ensuring the delivery of all clinical services during the week. In this paper, the optimal management of Week Hospital patients is considered. We have developed and validated an innovative integer programming model, based on clinical resources allocation and beds utilization. In particular, the model aims at scheduling Week Hospital patients' admission/discharge, possibly reducing the length of stay on the basis of an available timetable of clinical services. The performance of the model has been evaluated, in terms of efficiency and robustness, by considering real data coming from a Week Hospital Rheumatology Division. The experimental results have been satisfactory and demonstrate the effectiveness of the proposed approach.

[Neo-'hippocratism' in Bernardino Ramazzini]. / L'ippocratismo di Bernardino Ramazzini. per la costruzione di una medicina sociale.

Neo-hippocratism is a rational and mechanic method to explain pathological phenomena and discover the causes of diseases. Bernardino Ramazzini uses Hippocratic empirical observation to investigate the relations between the alterations of the air - due to mephitic vapours, of organic and inorganic origin - and the development of pathological processes. His notion of corruption of the atmosphere as the origin of epidemics and specific diseases, and that of prevention as the main strategy of modern medicine, is developed in medical literature and in the public medicine projects of the end of the Seventeenth century.

Digital ulcers in scleroderma: staging, characteristics and sub-setting through observation of 1614 digital lesions.

OBJECTIVE: To evaluate in SSc, the frequency of digital lesions and the morphology, characteristics, natural course and time to healing of 1614 digital ulcers (DUs). METHODS: One hundred SSc patients were followed up for 4 years. In the first step, the digital lesions were observed and classified at the time of presentation [digital pitting scar (DPS); DU; calcinosis; gangrene]. In the second step, DUs were divided into subsets according to their origin and main features. In the third step, the time to healing was recorded for each DU and the influence of DU main characteristics on time to healing was also evaluated. RESULTS: In the first step, 1614 digital lesions were observed: DPS, 712 (44.1%) lesions; DU, 785 (48.6%); calcinosis, 110 (6.8%); and gangrene, 7 (0.8%). In the second step, DUs were subsetted as follows: DU developed on DPS (8.8%), pure DU; DU developed on calcinosis (60%); DU derived from gangrene. In the third step, the mean time to healing was 25.6 (15.6) days in DPS, 76.2 (64) days in pure DU, 93.6 (59.2) days in calcinosis ulcers and 281.1 (263.3) in gangrene. CONCLUSIONS: In SSc, digital lesions are represented by DPS, DU, calcinosis and gangrene, and provide an evidence-based DU subsetting according to their origin and main characteristics. Subsetting may be helpful for a precise DU evaluation and staging, and in randomized controlled trials for a precise identification of those DUs that are to be included in therapeutic studies.