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Background: Immune checkpoint inhibitor hypophysitis (IIHs) is an emerging problem in cancer patients treated with immune checkpoint inhibitors (ICIs). We aimed to describe the clinical and molecular features of a multicenter series of IIHs. Methods: Demographic and clinical features were retrospectively collected for all cases. Anti-pituitary and anti-hypothalamus autoantibodies were also measured. Results: Nine patients were included. Six patients were treated with nivolumab and three with ipilimumab. Secondary hypoadrenalism was diagnosed in all patients. Pituitary MRI showed pituitary enlargement in two cases and no abnormalities in the other seven. Anti-pituitary antibodies were positive in 57.1% of cases and anti-hypothalamus antibodies in 85.7% of cases. Multidisciplinary treatments were established by a neuroendocrinologist and oncologists: all patients were treated with hydrocortisone replacement; ICI was withdrawn in two cases. At follow-up, hypoadrenalism persisted in all cases. Pituitary enlargement on MRI spontaneously recovered in the two affected patients. We found that the typical features of hypophysitis involved more frequently females and patients treated with ipilimumab. Conclusions: Although this study did not clarify if autoimmune secondary hypoadrenalism and ICI hypophysitis on brain imaging are two sides of the same disease, our preliminary data underline the need for molecular studies of IIHs and of autoimmune ICIs-related hypopituitarism.

Este artículo describe el proceso de diseño y las características de un cuestionario y una pauta de observación intradomiciliaria desarrollados para evaluar tanto transversal como longitudinalmente la relación vivienda-barrio-salud en el marco de transformaciones urbanas llevadas a cabo en poblaciones de elevada vulnerabilidad socio-territorial. Los instrumentos se desarrollaron para el estudio longitudinal multimétodos RUCAS (Regeneración Urbana, Calidad de Vida y Salud), un experimento natural cuyo objetivo principal es evaluar el impacto en salud y calidad de vida de un programa de Regeneración de Conjuntos Habitacionales en dos conjuntos de vivienda social en Chile. El diseño de los instrumentos siguió cuatro etapas principales: (1) revisión narrativa de la literatura para definir las dimensiones del estudio, y de instrumentos existentes para identificar ítems apropiados para su medición; (2) validación de contenido con expertos; (3) pre-test; y (4) estudio piloto. El cuestionario resultante, compuesto de 262 ítems, tiene en cuenta las distintas etapas del ciclo vital y cuestiones de género. La pauta de observación intradomiciliaria (77 ítems) es aplicada por el/la encuestadora. Los instrumentos abordan (i) características de la situación residencial actual que sabidamente afectan la salud y serán intervenidas por el programa; (ii) dimensiones de la salud potencialmente afectadas por la situación residencial y/o por la intervención dentro de los plazos del estudio (4 años); (iii) otras condiciones de salud y relacionadas con la salud que sean relevantes, aun cuando no se verán modificadas dentro de los plazos del estudio, y (iv) dimensiones socioeconómicas, ocupacionales y demográficas relevantes. Los instrumentos han mostrado ser una herramienta capaz de abordar la multidimensionalidad de los procesos de transformación urbana en contextos de pobreza urbana en vivienda formal. This article describes the design and characteristics of a questionnaire and an intradomiciliary observation tool developed to assess the housing-neighborhood-health relationship both cross-sectionally and longitudinally in the context of urban transformations carried out in populations of high socio-territorial vulnerability. The instruments were developed for the multi-method longitudinal study RUCAS (Urban Regeneration, Quality of Life and Health), a natural experiment aiming to assess the quality of life and health impact of a comprehensive Urban Regeneration Program in two social housing complexes in Chile. The design of the instruments followed four main stages: (1) narrative review of the literature to define the dimensions of the study, and of existing measurement instruments to identify appropriate items for measuring them; (2) content validation with experts; (3) pre-test; and (4) pilot study. The resulting questionnaire, composed of 262 items, considers the different stages of the life course and gender issues. The intradomiciliary observation tool (77 items) is applied by the interviewer. The instruments assess (i) characteristics of the current residential situation that are known to affect health and will be intervened by the program; (ii) dimensions of health potentially affected by the residential situation and/or by the intervention within the time frame of the study (4 years); (iii) other health and health-related conditions that are relevant, even if changes will not be modified within the time frame of the study; and (iv) relevant socioeconomic, occupational and demographic dimensions. The instruments have shown to be capable of addressing the multidimensionality of urban transformation processes in contexts of urban poverty in formal housing. Este artigo descreve o processo de desenho e as características de um questionário e uma diretriz de observação intradomiciliar desenvolvida para avaliar, tanto transversal quanto longitudinalmente, a relação moradia-vizinhança-saúde no âmbito das transformações urbanas realizadas em populações de alta vulnerabilidade sócio-territorial. Os instrumentos foram desenvolvidos para o estudo longitudinal multimétodo RUCAS (Regeneração Urbana, Qualidade de Vida e Saúde), uma experiência natural destinada a avaliar a relação moradia-vizinhança-saúde e o impacto na saúde de um programa de regeneração habitacional em dois conjuntos habitacionais sociais no Chile. A concepção dos instrumentos seguiu quatro etapas principais: (1) revisão narrativa da literatura para definir as dimensões do estudo, e dos instrumentos existentes para identificar itens apropriados para a medição; (2) validação do conteúdo com especialistas; (3) pré-teste; e (4) estudo piloto. O questionário resultante, composto de 262 itens, leva em conta diferentes estágios do ciclo de vida e questões de gênero. A diretriz de observação intradomiciliar (77 itens) é aplicada pelo entrevistador. Os instrumentos abordam (i) características da situação atual da moradia que são conhecidas por afetar a saúde e serão intervencionadas pelo programa; (ii) dimensões da saúde potencialmente afetadas pela moradia e/ou pela intervenção dentro do prazo do estudo (4 anos); (iii) outras condições de saúde e relacionadas à saúde que são relevantes, mesmo que não sejam modificadas dentro do prazo do estudo; e (iv) dimensões sócioeconômicas, ocupacionais e demográficas relevantes. Os instrumentos projetados demonstraram ser uma ferramenta capaz de abordar a multidimensionalidade dos processos de transformação urbana em contextos de pobreza urbana na habitação formal.

Cardiovascular complications after lower extremity revascularization (LER) are common in diabetic patients with peripheral arterial disease (PAD) and chronic limb threatening ischemia (CLTI). The Klotho-FGF23 axis is associated with endothelial injury and cardiovascular risk. We aimed to analyze the relationship between Klotho-FGF23 serum levels and the incidence of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after LER in diabetic patients with PAD and CLTI. Baseline levels of Klotho, and FGF23, and their association with subsequent incidence of MACE and MALE were analyzed in a prospective, non-randomized study in a population of diabetic patients with PAD and CLTI requiring LER. A total of 220 patients were followed for 12 months after LER. Sixty-three MACE and 122 MALE were recorded during follow-up period. Baseline lower Klotho serum levels (295.3 ± 151.3 pg/mL vs 446.4 ± 171.7 pg/mL, p vs 53.2 ± 15.4 pg/mL, p vs 495.4 ± 183.9 pg/mL, p

Background: Cardiovascular complications after lower extremity revascularization (LER) are common in diabetic patients with peripheral arterial disease (PAD) and chronic limb threatening ischemia (CLTI). The Klotho-FGF23-CPP axis is associated with endothelial injury and cardiovascular risk.The aim of this study was to analyze the relationship between Klotho-FGF23-CPP serum levels and the incidence of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after LER in diabetic patients with PAD and CLTI.Methods: Baseline levels of Klotho, FGF23, and CPP, and their association with subsequent incidence of MACE and MALE were analyzed in a prospective, non-randomized study in a population of diabetic patients with PAD and CLTI requiring LER.Results: A total of 220 patients were followed for 12 months after LER. Sixty-three MACE and 122 MALE were recorded during follow-up period. Baseline lower Klotho serum levels (295.3 ± 151.3 pg/mL vs 446.4 ± 171.7 pg/mL, pvs 53.2 ± 15.4 pg/mL, p vs 269.3 ± 184.3 pg/mL, p vs 495.4 ± 183.9 pg/mL, pConclusions: Klotho-FGF23-CPP axis imbalance is a potential biomarker for increased cardiovascular risk after LER in diabetic patients with PAD and CLTI.

Background Carotid atherosclerosis represents one of the complications of diabetes mellitus. In particular, plaque instability contributes to disease progression and stroke incidence. High mobility group box-1 (HMGB1) is a nuclear protein involved in promotion and progression of atherosclerosis and cardiovascular diseases. The aim of this study was to analyze the relationship between HMGB1 serum levels, main inflammatory cytokines, the presence of internal carotid stenosis and unstable plaque in a diabetic population. Research design and methods We studied 873 diabetic patients, including 347 patients with internal carotid artery stenosis (ICAS) who underwent carotid endarterectomy and 526 diabetic patients without internal carotid artery stenosis (WICAS). At baseline, HMGB1 and the main inflammatory cytokines serum levels were evaluated. For ICAS patients, the histological features of carotid plaque were also collected to differentiate them in patients with stable or unstable atherosclerotic lesions. Results We found that HMGB1 serum levels, osteoprotegerin, high-sensitivity C-reactive protein, tumor necrosis factor-alpha and interleukin-6, were significantly higher in diabetic ICAS patients compared to diabetic WICAS patients. Among ICAS patients, individuals with unstable plaque had higher levels of these cytokines, compared to patients with stable plaque. A multivariable stepwise logistic regression analysis showed that HMGB1 and osteoprotegerin remained independently associated with unstable plaque in ICAS patients. Conclusions The present study demonstrated that HMGB1 is an independent risk factor for carotid plaque vulnerability in an Italian population with diabetes mellitus, representing a promising biomarker of carotid plaque instability and a possible molecular target to treat unstable carotid plaques and to prevent stroke.

Hand, foot, and mouth disease (HFMD) is a childhood febrile disease. Oral lesions and papulovesicular lesions on the hands and feet are the clinical signs of the disease. In our case, a 17-year-old boy presented to the emergency department, where he was diagnosed with HFMD. After 6 days, he felt intense pain in his right testicle, and therefore an ultrasound (US) examination was performed. US detected a hypoechoic mass-like area in the right testis. Viral etiology was suspected, and no therapy was prescribed. After a little more than 3 months, US examination showed a reduced lesion size. Viral epididymo-orchitis should be suspected in young men with a recent history of HFMD and testicular pain.

In December 2019 in Wuhan (China), a bat-origin coronavirus (2019-nCoV), also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified, and the World Health Organization named the related disease COVID-19. Its most severe manifestations are pneumonia, systemic and pulmonary thromboembolism, acute respiratory distress syndrome (ARDS), and respiratory failure. A swab test is considered the gold standard for the diagnosis of COVID-19 despite the high number of false negatives. Radiologists play a crucial role in the rapid identification and early diagnosis of pulmonary involvement. Lung ultrasound (LUS) and computed tomography (CT) have a high sensitivity in detecting pulmonary interstitial involvement. LUS is a low-cost and radiation-free method, which allows a bedside approach and needs disinfection of only a small contact area, so it could be particularly useful during triage and in intensive care units (ICUs). High-resolution computed tomography (HRCT) is particularly useful in evaluating disease progression or resolution, being able to identify even the smallest changes.

OBJECTIVE Peripheral artery disease (PAD) is one of the most relevant complications of diabetes. Although several pharmacological and revascularization approaches are available for treating patients with diabetes and PAD, an endovascular approach is often associated with postprocedural complications that can increase the risk for acute limb ischemia or amputation. However, no definitive molecular associations have been described that could explain the difference in outcomes after endovascular treatment in patients with diabetes, PAD, and chronic limb-threatening ischemia (CLTI). RESEARCH DESIGN AND METHODS We evaluated the relationship between the levels of the main cytokines associated with diabetic atherosclerosis and the outcomes after endovascular procedures in patients with diabetes, PAD, and CLTI. RESULTS A total of 299 patients with below-the-knee occlusive disease who were undergoing an angioplasty procedure were enrolled. The levels of key cytokines—osteoprotegerin (OPG), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP)—were measured, and major adverse limb events (MALE) and major adverse cardiovascular events (MACE) were assessed 1, 3, 6, and 12 months after the procedure. There was a linear trend from the lowest to the highest quartile for each cytokine at baseline and incident MALE. A linear association was also observed between increasing levels of each cytokine and incident MACE. Receiver operating characteristics models were constructed using clinical and laboratory risk factors, and the inclusion of cytokines significantly improved the prediction of incident events. CONCLUSIONS We demonstrated that elevated OPG, TNF-α, IL-6, and CRP levels at baseline correlate with worse vascular outcomes in patients with diabetes, PAD, and CLTI undergoing an endovascular procedure.

Background Type-2 diabetes mellitus is one of the major risk factors of atherosclerosis, particularly in peripheral artery disease (PAD). Several studies have documented a correlation between omentin-1 serum levels, atherosclerosis, and cardiovascular diseases. However, a clear link between circulating omentin-1 and PAD in diabetic patients has yet to be established. The aim of this study was to investigate the potential role of omentin-1 in PAD in type-2 diabetic patients. Methods In this cross-sectional study, we analyzed omentin-1 serum levels by ELISA in 600 type-2 diabetic patients with (n = 300) and without (n = 300) PAD at Fontaine’s stage II, III, or IV. Results We found that omentin-1 serum levels were significantly lower in diabetic patients with PAD than in diabetic controls (29.46 vs 49.24 ng/mL, P

Background/aim The aim of the study was to compare the diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI), multiparametric ultrasound (mpUS) and US/MRI fusion imaging techniques in the detection of prostate cancer. Patients and methods A total of 82 patients with persistently high prostate specific antigen (PSA) levels after medical therapy were prospectively evaluated. All patients underwent digital rectal examination, mpMRI, mpUS and prostate biopsy. Results Histological outcome was positive for prostate cancer (PCa) in 46/82 patients (56.1%). MpMRI detected 54/82 lesions; histological analysis confirmed PCa in 44 lesions (sensitivity 91.3% and specificity 66.7%). Ratio estimation with semiquantitative elastography, between lesions and the peripheral portion showed a higher sensitivity and specificity compared to strain ration (SR) evaluation between lesions and adenomas (sensitivity 84.8% vs. 78.3%; specificity 66.6% vs. 61.1%). Quantitative analysis of contrast-enhanced ultrasound (CEUS) showed 40.0% sensitivity and 97.2% specificity. A total of 54 lesions detected by mpMRI and MRI/TRUS fusion targeted biopsy had a high number of positive samples (81.5%). Conclusion mpMRI is more accurate than mpUS which still remains a valuable technique used after MRI for prostate fusion-guided biopsy.

Vesicoureteral reflux (VUR) is a common urological complication in renal transplant patients.of this study is to evaluate the performance of contrast-enhanced voiding urosonography (CEvUS) in the diagnosis and classification of reflux into the renal allograft, to evaluate and classify VUR into the allograft using voiding cystourethrography (VCUG) and CEvUS, to compare the two methods, and to propose a new classification of reflux into the allograft based on CEvUS and VCUG assessment, in line with the international reflux grading system. From January 2017 to July 2019, 84 kidney transplant patients were enrolled. All patients underwent VCUG and CEvUS. In 76 cases there was agreement between VCUG and CEvUS (90 %) (Kappa = 0.7). The sensitivity of CEvUS using VCUG as the gold standard was 90 %, and the specificity was 92 %. Of the 7 cases diagnosed by VCUG and not by CEvUS, 6 were grade 1 and 1 was grade 2. Transplant patients with reflux symptoms should undergo CEvUS. If the outcome is negative, VCUG should be performed. The classification that we propose is better suited to describe VUR in transplant patients, because it is simpler and takes into account whether reflux occurs not only during urination but also when the bladder is relaxed.Vesikoureteraler Reflux (VUR) ist eine häufige urologische Komplikation bei Patienten mit Nierentransplantation. ZIEL: dieser Studie ist es, die Leistung der kontrastmittelverstärkten Miktionsurosonografie (CEmUS) bei der Diagnose und Klassifizierung des Reflux in das Nieren-Allotransplantat zu bewerten, den VUR in das Allotransplantat mittels Miktionszystourethrografie (MCU) und CEmUS zu bewerten und zu klassifizieren, die beiden Methoden zu vergleichen und eine neue Klassifikation des Reflux in das Allotransplantat basierend auf der CEmUS- und MCU-Beurteilung in Übereinstimmung mit dem internationalen Reflux-Klassifikationssystem vorzuschlagen. Von Januar 2017 bis Juli 2019 wurden 84 nierentransplantierte Patienten eingeschlossen. Bei allen Patienten wurden MCU und CEmUS durchgeführt. In 76 Fällen bestand Übereinstimmung zwischen MCU und CEmUS (90 %) (Kappa = 0,7). Die Sensitivität von CEmUS bei Verwendung der MCU als Goldstandard betrug 90 %, die Spezifität betrug 92 %. Von den 7 Fällen, die mittels MCU, aber nicht durch CEmUS diagnostiziert wurden, hatten 6 Patienten Grad 1 und 1 Patient hatte Grad 2. Transplantationspatienten mit Refluxsymptomen sollten sich einer CEmUS unterziehen. Wenn das Ergebnis negativ ist, sollte eine MCU durchgeführt werden. Die von uns vorgeschlagene Klassifikation ist besser geeignet, um den VUR bei Transplantationspatienten zu beschreiben, da sie einfacher ist und berücksichtigt, ob der Reflux nicht nur bei der Blasenentleerung, sondern auch bei entspannter Blase auftritt.

Background The treatment of acromegaly resistant to first-generation somatostatin receptor ligands (SRLs) is often difficult. Pegvisomant and Pasireotide LAR are mostly used in these subset of patients, as second line therapies. Choice of the type of second line therapies is difficult, since predictors of response are still unclear, impairing personalized therapy. We aimed to investigate predictors of response to Pegvisomant and Pasireotide LAR. Methods Seventy-four acromegaly patients entered this observational, cross-sectional and retrospective study if (i) resistant to high dose first-generation SRLs and (ii) treated with Pegvisomant and Pasireotide LAR for at least 12 consecutive months. Patients treated with radiotherapy in the previous 10 years were excluded. Results Fourty-one patients were treated with Pegvisomant and 33 with Pasireotide LAR. At the end of the study, acromegaly was controlled in 35 patients treated with Pegvisomant (85.4%) and in 23 treated with Pasireotide LAR (69.7%). In this cohort, a poor Pegvisomant response and a shorter progression free time were observed in cases with tumor extension to the third ventricle (P = 0.004, HR: 1.6, 95%CI: 1.2–4.6), with a Ki67-Li >4% (P = 0.004, HR: 3.49, 95%CI: 1.4–4.0) and with pre-treatment IGF-I >3.3×ULN (P=0.03, HR: 1.3, 95%CI: 1.1–6.0). A poor Pasireotide LAR response and a shorter progression free time were observed in cases with tumor extension to the third ventricle (P=0.025, HR: 1.6 95%CI: 1.4–3.4), pre-treatment IGF-I >2.3×ULN (P=0.049, HR: 2.4, 95%CI: 1.4–8.0), absent/low SST5 membranous expression (P=0.023 HR: 4.56 95%CI: 1.3–6.4) and in patients carried the d3-delated GHR isoform (P=0.005, HR: 11.37, 95%CI: 1.3–20.0). Conclusion Molecular and clinical biomarkers can be useful in predicting the responsiveness to Pegvisomant and Pasireotide LAR.

Introduction Primary autoimmune hypophysitis (PAHs) is a rare inflammatory disease of the pituitary gland. Although largely investigated, the pathogenesis of PAH is not completely clarified. We aimed to investigate the immune response in PAHs. Material and methods Serum anti-pituitary and anti-hypothalamus antibodies (respectively APAs and AHAs) were investigated though an indirect immunofluorescence on monkey hypophysis and hypothalamus slides, serum cytokines though an array membrane and cell-mediated immunity though the white blood cells count. Results Nineteen PAH cases entered the study. APA or AHA were identified in all cases. APA were detected in 13 patients (68.4%) and AHA in 13 patients (68.4%). Ten patients (52.6%) were simultaneously positive for both APA and AHA. The prevalence of APAs and AHAs was higher as compared to those observed in 50 health controls (respectively 14% p p = 0.004) and in 100 not-secreting pituitary adenoma (NFPAs) (respectively 22% p = 0.002 and 8% p p p = 0.002). No differences were identified between PAHs and controls at qualitative and quantitative analysis of serum cytokines and white blood cells count. Conclusions This study suggest that APA and AHA may be detected in an high percentage of PAH cases and that their simultaneous identification may be useful for the differential diagnosis between PAH and NFPAs, in an appropriate clinical context.

Background Peripheral artery disease (PAD) represents one of the most relevant vascular complications of type 2 diabetes mellitus (T2DM). Moreover, T2DM patients suffering from PAD have an increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Sortilin, a protein involved in apolipoproteins trafficking, is associated with lower limb PAD in T2DM patients. Objective To evaluate the relationship between baseline serum levels of sortilin, MACE and MALE occurrence after revascularization of T2DM patients with PAD and chronic limb-threatening ischemia (CLTI). Research design and methods We performed a prospective non-randomized study including 230 statin-free T2DM patients with PAD and CLTI. Sortilin levels were measured before the endovascular intervention and incident outcomes were assessed during a 12 month follow-up. Results Sortilin levels were significantly increased in individuals with more aggressive PAD (2.25 ± 0.51 ng/mL vs 1.44 ± 0.47 ng/mL, p p Conclusions This study demonstrates that sortilin correlates with incidence of MACE and MALE after endovascular revascularization in a diabetic population with PAD and CLTI.

Background Cardiovascular complications represent the major cause of morbidity and mortality of type 2 diabetes mellitus (T2DM) patients. In particular, peripheral artery disease (PAD) represents a frequent T2DM vascular complication and a risk factor for the development of major adverse cardiovascular events (MACE). Among adipokines, omentin-1 serum levels are reduced in T2DM patients with PAD and are inversely related to disease severity. Objective To study the relationship between omentin-1 levels, at baseline, with outcomes after endovascular procedures in T2DM patients with PAD and chronic limb-threatening ischemia (CLTI). Research design and methods We enrolled for our prospective non-randomized study, 207 T2DM patients with PAD and CLTI, requiring revascularization. Omentin-1 serum levels were collected before revascularization and patients incidence outcomes were evaluated at 1, 3, 6 and 12 months. Results Omentin-1 was reduced in patients with more severe disease (27.24 ± 4.83 vs 30.82 ± 5.48 ng/mL, p vs 31.33 ± 5.29 ng/mL, p vs 31.34 ± 5.54 ng/mL, p Conclusions We demonstrated that reduced omentin-1 levels, at baseline, are related with worse vascular outcomes in T2DM patients with PAD and CLTI undergoing an endovascular procedure.

PURPOSE Primary hypophysitis is a rare disease, with an autoimmune aetiology. As few papers have investigated genetic of hypophysitis, our aim was to evaluate HLA status in a single-centre series of patients. PATIENTS AND METHOD A retrospective, longitudinal and cross-sectional study was conducted. In consecutive Caucasian patients, clinically or histologically diagnosed for primary autoimmune hypophysitis (PAH), the HLA genotype having been determined. This cohort was compared with a control group. Anti-pituitary and anti-hypothalamus auto-antibodies evaluation was included. RESULTS 16 patients were enrolled. Fourteen patients were female (87.5%). According to HLA-DR status, we found the following: 9 of 16 patients (56.3%) haplotypes that were associated with coeliac disease (CD). Among these, 5 carried the DR7-DQ2 heterozygote haplotype (55.5%) while the remaining ones only the following haplotypes: DR3-DQ2 homozygote (25%), DR4-DQ2 heterozygote (25%), DR4-DQ8 heterozygote (50%) and DR4-DQ8 homozygote (25%), respectively. A total of 12 CD-associated haplotypes were identified. In PAH, we found a significantly higher frequency of patients carrying CD-associated HLA haplotypes as compared to the control group (respectively, 75% vs 48% P = .03; OR: 3.25 95%IC:1.1-10.3), particularly, for DQ2 and DQ8 haplotypes. DQ2 haplotype was detected in 50% of PAH and 38.4% of the control group (P = .3), while DQ8 haplotype in 25% of PAH and 7.2% of the control group (P = .01 OR:4.3 95%IC:1.3-14.7). CONCLUSION Our data suggest that PAH and CD share some HLA haplotypes, reinforcing the knowledge of their association. HLA haplotypes, particularly DQ8, may play a role in PAH management and diagnosis, also suggesting the predisposition to other autoimmune diseases.

Peripheral arterial disease (PAD), is a major health problem. Many studies have been focused on the possibilities of treatment offered by vascular regeneration. Human adipose-derived stem cells (HASCs), multipotent CD34+ stem cells found in the stromal-vascular fraction of adipose tissues, which are capable to differentiate into multiple mesenchymal cell types. The High mobility group box 1 protein (HMGB1) is a nuclear protein involved in angiogenesis. The aim of the study was to define the role of HMGB1 in cell therapy with HASCs, in an animal model of PAD. We induced unilateral ischemia in mice and we treated them with HASCs, with the specific HMGB1-inihibitor BoxA, with HMGB1 protein, and with the specific VEGF inhibitor sFlt1, alternately or concurrently. We measured the blood flow recovery in all mice. Immunohistochemical and ELISA analyses was performed to evaluate the number of vessels and the VEGF tissue content. None auto-amputation occurred and there have been no rejection reactions to the administration of HASCs. Animals co-treated with HASCs and HMGB1 protein had an improved blood flow recovery, compared to HASCs-treated mice. The post-ischemic angiogenesis was reduced when the HMGB1 pathway was blocked or when the VEGF activity was inhibited, in mice co-treated with HASCs and HMGB1. In conclusion, the HASCs treatment can be used in a mouse model of PAD to induce post-ischemic angiogenesis, modulating angiogenesis by HMGB1. This effect is mediated by VEGF activity. Although further data are needed, these findings shed light on possible new cell treatments for patients with PAD.

Background Peripheral arterial disease (PAD) is an important determinant of the excessive morbidity and mortality in atherosclerotic patients, especially in patients with critical limb ischemia (CLI). Several studies recently conducted have demonstrated that the RANK/RANKL/OPG system plays an important role in the metabolism of the bone and in vascular pathology, including atherogenesis and arterial calcification and is involved in plaque instability and rupture by inducing plaque calcification. Aim and methods The aim of the present study to evaluate whether the rs3134069, the rs2073617, and the rs2073618 polymorphisms of the OPG gene, the rs9533156 and the rs2277438 gene variants of the RANKL gene and the rs1805034 gene polymorphism of the RANK gene are associated with presence and severity of PAD in general Italian population. Our study included 1221 patients (523 with PAD and 698 controls without PAD). Results We found that the rs3134069, the rs2073617, and the rs2073618 polymorphisms of the OPG gene, the rs9533156 gene variants of the RANKL gene and the rs1805034 gene polymorphism of the RANK gene were significantly and independently associated with PAD. We also found that these five polymorphisms act synergistically in patients with PAD and are associated with different levels of risk for PAD and CLI, depending on the number of high-risk genotypes carried concomitantly by a given individual. Discussion Genetic variations of rs3134069, rs2073617, and rs2073618 on the OPG gene, rs9533156 on the RANKL gene and rs1805034 on the RANK gene are associated with the risk to develop PAD and these five gene polymorphisms act synergistically in patients with PAD and are associated with different risk for PAD.

The aim of the study was to compare the diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI), multiparametric ultrasound (mpUS) and US/MRI fusion imaging techniques in the detection of prostate cancer.A total of 82 patients with persistently high prostate specific antigen (PSA) levels after medical therapy were prospectively evaluated. All patients underwent digital rectal examination, mpMRI, mpUS and prostate biopsy.Histological outcome was positive for prostate cancer (PCa) in 46/82 patients (56.1%). MpMRI detected 54/82 lesions; histological analysis confirmed PCa in 44 lesions (sensitivity 91.3% and specificity 66.7%). Ratio estimation with semiquantitative elastography, between lesions and the peripheral portion showed a higher sensitivity and specificity compared to strain ration (SR) evaluation between lesions and adenomas (sensitivity 84.8% vs. 78.3%; specificity 66.6% vs. 61.1%). Quantitative analysis of contrast-enhanced ultrasound (CEUS) showed 40.0% sensitivity and 97.2% specificity. A total of 54 lesions detected by mpMRI and MRI/TRUS fusion targeted biopsy had a high number of positive samples (81.5%).mpMRI is more accurate than mpUS which still remains a valuable technique used after MRI for prostate fusion-guided biopsy.

After the age of 30 years, GFR progressively declines at an average rate of 8 mL/min/1.73 m/decade. A problem of advanced age is that the evaluation of renal function on the basis of indicators valid in young adults, such as creatininemia, is unreliable. In fact, many patients with chronic renal failure may have serum creatinine levels within the normal range even if they have a significant reduction in renal function. Ultrasound has become a routine method of investigation in renal disease: kidney size and parenchymal echogenicity are considered markers of renal function, so US is useful in assessing the presence and degree of renal failure. CEUS is useful in the evaluation of kidney disease in the elderly: the increased hemodynamic resistance of renal microvessels reduces perfusion in the renal cortex, so fewer microbubbles enter the renal cortex. EcoColor and EcoDoppler are also useful in the evaluation of senile alterations: here, the distribution of color-signals, as compared to that in the young adult population, appears more attenuated, limited to intersegmental and interlobar districts. Among the ecoDoppler parameters, the resistance index can be considered a marker of renal damage progression, with attention needing to paid to possible concomitant confounding factors. Ultrasonography, color-Doppler and CEUS are a non-invasive and convenient modality for managing kidney disease; their integration with anamnestic, objective and laboratory data permits fast and reliable clinical, diagnostic, and therapeutic classification. It also allows early therapeutic intervention and, ultimately, improvements in patient management.

Background Sortilin is a 95-kDa protein which has recently been linked to circulating cholesterol concentration and lifetime risk of developing significant atherosclerotic disease. Sortilin is found inside different cell types and circulating in blood. Higher circulating sortilin concentration has been found in patients with coronary atherosclerosis compared to control subjects. Sortilin concentration is influenced by statin therapy. Methods We enrolled statin-naïve subjects with type 2 diabetes mellitus and we performed a cross-sectional study to evaluate the association between sortilin levels and the presence of clinically significant lower limb peripheral artery disease (PAD) in a population of statin-free diabetic subjects. Results Out of the 154 patients enrolled in our study, 80 patients were free from PAD, while 74 had clinically significant PAD. Sortilin concentration was significantly higher in the latter group compared to the former (1.61 ± 0.54 ng/mL versus 0.67 ± 0.30 ng/mL, P

SummaryIntroduction Growth hormone deficiency is considered the most important factor determining skeletal fragility in hypopituitary patients. Osteoblasts and chondrocytes express growth hormone (GH) receptor. Two GH receptor isoforms (GHRi) have been identified: they differ for the presence/absence of a protein fragment encoded by exon 3 of GHR gene. Consequently, three genotypes were identified: carriers of both the full-length proteins (flfl-GHR), carriers of one full-length protein and one deleted protein (fld3-GHR) and carriers of both deleted proteins (d3d3-GHR). This polymorphism confers a higher sensitivity to endogenous GH and to recombinant human GH (rhGH); its effect on bone metabolism and skeletal fragility is unknown. The aim of this article was to investigate the role of GHRi in predicting skeletal fragility in adult-onset GHD (AO-GHD) patients. Subjects and methods A cross-sectional study was conducted to investigate the association between the d3-GHR isoform and the prevalence of morphometric vertebral fractures (VFs) in AO-GHD. Ninety-three AO-GHD were enrolled. Forty-nine patients carried flfl-GHRi (52·7%), and 44 patients (47·3%) carried at least one allele of the d3-GHR isoform. Thirty-two VFs were documented. Fifty-seven patients underwent rhGH replacement therapy. Results Median age was significantly higher in fractured patients as compared to nonfractured ones; d3-carrier patients showed a lower VF risk as compared to flfl-GHRi (OR: 0·37, 95% IC: 0·24–0·55, P < 0·0001). This finding was also confirmed in AO-GHD undergoing rhGH replacement therapy. Conclusion This study suggests that d3-GHR may protect AO-GHD particularly when treated with rhGH from the risk of VFs.

Background Human cord blood (CB) endothelial colony forming cells (ECFCs) are endowed with high vascular regenerative ability in immunodeficient mice, but their immunogenicity and susceptibility to rejection in immunocompetent models has yet to be explored. Methods We injected CB ECFCs in non-immuno-suppressed C57BL/6 J mice after having induced the hindlimb ischemia and we investigated their contribution to the recovery from the ischemic injury. Human ECFCs (hECFCs) were administered by intramuscular injection and hindlimb blood perfusion was measured by laser Doppler analysis at 7-day intervals for 28 days after treatment. Mice were sacrificed after 7 and 28 days and immunohistochemistry for specific human (CD31) and mouse (von Willebrand factor) endothelial antigens was carried out. Before euthanasia, blood samples to assess cytokines and angiogenic growth factor levels were collected. Results Mice injected with hECFCs showed a prompter and greater recovery of blood flow than controls. Several endothelial cells of human origin were detected at day7 after injection and their number declined progressively. Likewise, a progressive increase of mouse-derived vascular structures were observed, paralleled by the amplified endogenous production of various soluble mediators of angiogenesis, including Vascular Endothelial Growth Factor and Fibroblast Growth Factor. Conclusions Overall, our findings are consistent with the hypothesis that human ECFCs might expand the endogenous vascular repair potential of recipients and support their possible HLA-independent unconventional use.

Background High mobility group box-1 (HMGB-1) is a nuclear protein also acting as inflammatory mediator, whilst osteoprotegerin (OPG), member of tumor necrosis factor receptor superfamily, is indicated as marker of vascular calcification. Peripheral artery disease (PAD) and type 2 diabetes (T2D) are clinical conditions characterized by elevated serum inflammatory markers and vascular calcification enhancement. The aim of this study was to investigate the potential role of HMGB-1, OPG and several inflammatory mediators such as C-reactive protein (HsCRP), tumor necrosis factor-alpha and interleukin-6 (IL-6) on the presence and severity of peripheral artery disease in patients with T2D. Methods In this retrospective observational study, we have analyzed HMGB-1, OPG and inflammatory cytokines serum levels in 1393 type 2 diabetic patients with PAD and without PAD (WPAD). Results HMGB-1 (7.89 ± 15.23 ng/mL), OPG (6.54 ± 7.76 pmol/L), HsCRP (15.6 ± 14.4 mg/L) and IL-6 (56.1 ± 28.6 pg/mL) serum levels were significantly higher in patients with PAD than in those WPAD (3.02 ± 8.12 ng/mL, P ˂ 0.001; 2.98 ± 2.01 pmol/L, P

Background Rheumatoid arthritis (RA) is associated with vascular disease (1). Recent findings demonstrated that the risk of peripheral arterial occlusive disease is increased in patients with RA compared to the general population (2). However, the pathogenesis is not fully understood. High-mobility group box-1 (HMGB1) is a nuclear protein involved in inflammatory responses (3) and RA-like synovitis (4). Objectives Aim of the present study was to analyze the relationship between HMGB1 and peripheral arterial disease in collagen antibody-induced arthritis (CAIA). Methods BALB/c mice were injected with monoclonal anti-collagen antibody cocktail followed by lipopolysaccharide to induce arthritis. After the induction of arthritis, we studied ischemia-induced neovascularization in the ischemic hind limb of arthritic and control mice. Results We found that the perfusion recovery was significantly attenuated arthritic mice, compared to control mice. The immunohistochemical analysis for the CD31 demonstrated a reduced number of vessel in mice with experimental arthritis. The selective blockade of HMGB1 in arthritic mice resulted in restored blood flow recovery and capillary density in the ischemic muscle. Cytokine enzyme-linked immunosorbent assay (ELISA) analyses performed on peripheral blood demonstrated a significant reduction of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α in mice where HMGB1 was blocked. Interestingly, the selective blockade of HMGB1 resulted in an increase of the peripheral IL-17A concentration. Conclusions HMGB1 pathway is involved in an experimental vasculopathy induced in a RA-like model. The proangiogenic cytokine IL-17A is increased when HMGB1 is inhibited. Although further data are needed, these findings provide new evidence regarding the pathogenesis of vascular complications observed in patients with RA. References Roman MJ, Salmon JE. Cardiovascular manifestations of rheumatologic diseases. Circulation. 2007 Nov 13;116(20):2346–55. Chuang YW, Yu MC, Lin CL, Yu TM, Shu KH, Huang ST, Kao CH. Risk of peripheral arterial occlusive disease in patients with rheumatoid arthritis. A nationwide population-based cohort study. Thromb Haemost. 2016 Jan;115(2):439–45. Biscetti F, Ghirlanda G, Flex A. Therapeutic potential of high mobility group box-1 in ischemic injury and tissue regeneration. Curr Vasc Pharmacol. 2011 Nov;9(6):677–81. Biscetti F, Flex A, Pecorini G, Angelini F, Arena V, Stigliano E, Gremese E, Tolusso B, Ferraccioli G. The role of high-mobility group box protein 1 in collagen antibody-induced arthritis is dependent on vascular endothelial growth factor. Clin Exp Immunol. 2016 Apr;184(1):62–72. Disclosure of Interest None declared

Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family and plays a role in atherosclerosis. OPG has been hypothesized to modulate vascular functions; however, its role in mediating atherosclerosis is controversial. Epidemiological data in patients with cardiovascular disease (CVD) indicate that OPG serum levels are associated with several inflammatory markers, myocardial infarction events, and calcium scores, suggesting that OPG may be causative for CVD. The present study aimed to evaluate whether the OPG gene (TNFRSF11B) polymorphisms are involved in the development of peripheral arterial occlusive disease (PAOD) and critical limb ischemia (CLI) in patients with type 2 diabetes. This genetic association study included 402 diabetic patients (139 males and 263 females) with peripheral arterial occlusive disease and 567 diabetic subjects without peripheral arterial occlusive disease (208 males and 359 females). The T245G, T950C, and G1181C polymorphisms of the OPG gene were analyzed by polymerase chain reaction and restriction fragment length polymorphism. We found that the T245G, T950C, and G1181C gene polymorphisms of the OPG gene were significantly (27.9 vs. 12.2 %, P