Publications by authors named "Raffaele Landolfi"

116 Publications

Scurvy: A Disease not to be Forgotten.

Nutr Clin Pract 2020 Dec 23. Epub 2020 Dec 23.

Department of Internal Medicine, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico - Università Cattolica del Sacro Cuore, Roma, Italy.

An 18-year-old man presented to our hospital with muscular pain, diffuse petechiae, spontaneous thigh ecchymosis, edema and pain of the right knee, bilateral pretibial subcutaneous nodules, and gingival hypertrophy and hemorrhage. His history was positive for a mixed anxiety-depressive disorder and a restrictive diet caused by self-diagnosed food allergies. Skin lesions appeared like hyperkeratotic papules with coiled hairs and perifollicular hemorrhages. A diagnosis of scurvy was made upon demonstration of low serum levels of ascorbic acid. An allergy evaluation found cross-reactivity between pollens and food, related to the presence of panallergens. Moreover, we found that our patient was also affected by celiac disease. In conclusion, scurvy should be considered in the differential diagnosis of patients with petechiae and ecchymosis, especially when food restriction, malabsorption, or psychiatric disorders are present.
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http://dx.doi.org/10.1002/ncp.10616DOI Listing
December 2020

Nonalcoholic fatty liver disease (NAFLD) severity is associated to a nonhemostatic contribution and proinflammatory phenotype of platelets.

Transl Res 2021 May 7;231:24-38. Epub 2020 Nov 7.

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, Roma, Italy; UOSD Malattie Emorragiche e Trombotiche, Dipartimento di Diagnostica per immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy. Electronic address:

Nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease and ranges from simple steatosis to nonalcoholic steatohepatitis. Recently, a platelet role in NAFLD pathogenesis and progression has been reported in mouse models and in patients. We investigated whether platelets are involved in liver and systemic inflammation processes in NAFLD. In this exploratory study we recruited 24 consecutive patients with biopsy-proven diagnosis of NAFLD and 17 healthy volunteers. We measured plasma levels of inflammatory markers by ELISA. We investigated hemostatic and inflammatory transcripts in circulating platelets and leukocytes from NAFLD patients. We analyzed platelet and neutrophil extracellular traps (NET) accumulations in liver sinusoids using CD42 and H3 citrullinated histones immunohistochemical staining on liver biopsies. NAFLD patients had increased inflammation markers and lipolysaccharides plasma levels. We found significant increase of inflammatory transcripts in circulating platelets and not in leukocytes of NAFLD subjects compared with healthy controls. We demonstrated increased intrahepatic platelet accumulation that correlated with NAFLD activity score (NAS) score and intrahepatic neutrophil extracellular traps (NET) formation in liver biopsies of NAFLD patients. NET formation was higher in livers with higher NAS and inflammation scores. The presence of low-grade systemic inflammation and proinflammatory changes of circulating platelets indicate that platelets participate on systemic inflammatory changes associated with NAFLD. Liver platelet accumulation and liver NET formation, together with low-grade endotoxemia, suggest that platelets may act to protect the liver from invading microorganisms by favoring local NET formation.
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http://dx.doi.org/10.1016/j.trsl.2020.11.003DOI Listing
May 2021

Cardiovascular Disease and SARS-CoV-2: the Role of Host Immune Response Versus Direct Viral Injury.

Int J Mol Sci 2020 Oct 30;21(21). Epub 2020 Oct 30.

Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy.

The 2019 novel coronavirus [2019-nCoV], which started to spread from December 2019 onwards, caused a global pandemic. Besides being responsible for the severe acute respiratory syndrome 2 [SARS-CoV-2], the virus can affect other organs causing various symptoms. A close relationship between SARS-CoV-2 and the cardiovascular system has been shown, demonstrating an epidemiological linkage between SARS-CoV-2 and cardiac injury. There are emerging data regarding possible direct myocardial damage by 2019-nCoV. In this review, the most important available evidences will be discussed to clarify the precise mechanisms of cardiovascular injury in SARS-CoV-2 patients, even if further researches are needed.
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http://dx.doi.org/10.3390/ijms21218141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663579PMC
October 2020

"Early transfusion of convalescent plasma in older patients with COVID-19 to prevent disease progression: A structured summary of a study protocol for a randomised controlled trial".

Trials 2020 Oct 22;21(1):875. Epub 2020 Oct 22.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Objectives: The primary objective is to demonstrate that COVID-19 convalescent plasma (CCP) prevents progression to severe pneumonia in elderly COVID-19 pneumonia patients with chronic comorbidities. Secondary objectives are to demonstrate that CCP decreases the viral load in nasopharyngeal swabs and increases the anti-SARS-CoV-2 antibody titre in recipients.

Trial Design: This is a randomized, open-label, parallel group, phase II/III study with a superiority framework. The trial starts with a screening phase II designed with two-tailed alpha=0.2. In case of positive results, the trial will proceed in a formally comparative phase III (alpha=0.05).

Participants: Adult patients with confirmed or suspected COVID-19 who are at risk according to CDC definition are eligible. Inclusion criteria are all the following: age ≥ 65; pneumonia at CT scan; PaO2/FiO2 ≥300 mmHg; presence of one or more comorbidities; signed informed consent. Exclusion criteria are one of the following: age < 65; PaO2/FiO2 < 300 mmHg; pending cardiopulmonary arrest; refusal to blood product transfusions; severe IgA deficiency; any life-threatening comorbidity or any other medical condition which, in the opinion of the investigator, makes the patient unsuitable for inclusion. The trial is being conducted at three reference COVID-19 centres in the middle of Italy.

Intervention And Comparator: Intervention: COVID-19 Convalescent Plasma (CCP) in addition to standard therapy. Patients receive three doses (200 ml/day on 3 consecutive days) of ABO matched CCP. Comparator: Standard therapy MAIN OUTCOMES: A. Primary outcome for Phase II: Proportion of patients without progression in severity of pulmonary disease, defined as worsening of 2 points in the ordinal scale of WHO by day 14. B. Primary outcome for Phase III: Proportion of patients without progression in severity of pulmonary disease, defined as worsening of 2 points in the ordinal scale of WHO by day 14. Secondary outcomes for Phase III: Decreased viral load on nasopharyngeal swab at days 6, 9 and 14; Decreased viremia at days 6 and 9; Increased antibody titer against SARS-CoV2 at days 30 and 60; Proportion of patients with negative of SARS-CoV2 nasopharyngeal swab at day 30; Length of hospital stay; Mortality rate at day 28; Total plasma related adverse event (day 60); Total non-plasma related adverse events (day 60); Severe adverse events (SAE) (day 60).

Randomisation: Treatment allocation is randomized with a ratio 1:1 in both phase II and phase III. Randomization sequences will be generated at Fondazione Policlinico Gemelli IRCCS through the RedCap web application. Randomized stratification is performed according to age (under/over 80 years), and sex.

Blinding (masking): None, this is an open-label trial.

Numbers To Be Randomised (sample Size): Phase II: 114 patients (57 per arm). Phase III: 182 patients (91 per arm) TRIAL STATUS: The trial recruitment started on May 27, 2020. The anticipated date of recruitment completion is April 30, 2021. The protocol version is 2 (May 10, 2020).

Trial Registration: The trial has been registered on ClinicalTrials.gov (May 5, 2020). The Identifier number is NCT04374526 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-020-04821-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578576PMC
October 2020

Sarilumab use in severe SARS-CoV-2 pneumonia.

EClinicalMedicine 2020 Oct 2;27:100553. Epub 2020 Oct 2.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Dipartimento di Scienze Mediche e Chirurgiche, Rome, Italy.

Background: Interleukin-6 signal blockade showed preliminary beneficial effects in treating inflammatory response against SARS-CoV-2 leading to severe respiratory distress. Herein we describe the outcomes of off-label intravenous use of Sarilumab in severe SARS-CoV-2-related pneumonia.

Methods: 53 patients with SARS-CoV-2 severe pneumonia received intravenous Sarilumab; pulmonary function improvement or Intensive Care Unit (ICU) admission rate in medical wards, live discharge rate in ICU treated patients and safety profile were recorded. Sarilumab 400 mg was administered intravenously on day 1, with eventual additional infusion based on clinical judgement, and patients were followed for at least 14 days, unless previously discharged or dead.

Findings: Of the 53 SARS-CoV-2 patients receiving Sarilumab, 39(73·6%) were treated in medical wards [66·7% with a single infusion; median PaO/FiO:146(IQR:120-212)] while 14(26·4%) in ICU [92·6% with a second infusion; median PaO/FiO: 112(IQR:100-141.5)].Within the medical wards, 7(17·9%) required ICU admission, 4 of whom were re-admitted to the ward within 5-8 days. At 19 days median follow-up, 89·7% of medical inpatients significantly improved (46·1% after 24 h, 61·5% after 3 days), 70·6% were discharged from the hospital and 85·7% no longer needed oxygen therapy. Within patients receiving Sarilumab in ICU, 64·2% were discharged from ICU to the ward and 35·8% were still alive at the last follow-up. Overall mortality rate was 5·7%.

Interpretation: IL-6R inhibition appears to be a potential treatment strategy for severe SARS-CoV-2 pneumonia and intravenous Sarilumab seems a promising treatment approach showing, in the short term, an important clinical outcome and good safety.
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http://dx.doi.org/10.1016/j.eclinm.2020.100553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531933PMC
October 2020

Association between omentin-1 and major cardiovascular events after lower extremity endovascular revascularization in diabetic patients: a prospective cohort study.

Cardiovasc Diabetol 2020 10 7;19(1):170. Epub 2020 Oct 7.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

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 < 0.001). Overall, 84 MACE and 96 major adverse limb events (MALE) occurred during the 12-month follow-up. We observed that omentin-1 levels were lower in patients with MACE (26.02 ± 4.05 vs 31.33 ± 5.29 ng/mL, p < 0.001) and MALE (26.67 ± 4.21 vs 31.34 ± 5.54 ng/mL, p < 0.001). The association between omentin-1, MACE and MALE remained significant after adjusting for major risk factors in a multivariate analysis. Receiver operating characteristics (ROC) curve using omentin-1 levels predicted incidence events (area under the curve = 0.80).

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.
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http://dx.doi.org/10.1186/s12933-020-01151-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542958PMC
October 2020

Sortilin levels correlate with major cardiovascular events of diabetic patients with peripheral artery disease following revascularization: a prospective study.

Cardiovasc Diabetol 2020 09 25;19(1):147. Epub 2020 Sep 25.

Department of Internal Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, Roma, 00168, Italia.

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 < 0.001). During follow-up, 83 MACE and 116 MALE occurred. In patients, who then developed MACE and MALE, sortilin was higher. In particular, 2.46 ± 0.53 ng/mL vs 1.55 ± 0.42 ng/mL, p < 0.001 for MACE and 2.10 ± 0.54 ng/mL vs 1.65 ± 0.65 ng/mL, p < 0.001 for MALE. After adjusting for traditional atherosclerosis risk factors, the association between sortilin and vascular outcomes remained significant in a multivariate analysis. In our receiver operating characteristics (ROC) curve analysis using sortilin levels the prediction of MACE incidence improved (area under the curve [AUC] = 0.94) and MALE (AUC = 0.72).

Conclusions: This study demonstrates that sortilin correlates with incidence of MACE and MALE after endovascular revascularization in a diabetic population with PAD and CLTI.
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http://dx.doi.org/10.1186/s12933-020-01123-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519536PMC
September 2020

Anabolic Hormones Deficiencies in Heart Failure With Preserved Ejection Fraction: Prevalence and Impact on Antioxidants Levels and Myocardial Dysfunction.

Front Endocrinol (Lausanne) 2020 12;11:281. Epub 2020 May 12.

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.

In heart failure with reduced ejection fraction, catabolic mechanisms have a strong negative impact on mortality and morbidity. The relationship between anabolic hormonal deficiency and heart failure with preserved ejection fraction (HFpEF) has still been poorly investigated. On the other hand, oxidative stress is recognized as a player in the pathogenesis of HFpEF. Therefore, we performed a cohort study in HFpEF aimed to (1) define the multi-hormonal deficiency prevalence in HFpEF patients; (2) investigate the relationships between hormonal deficiencies and echocardiographic indexes; (3) explore the modulatory activity of anabolic hormones on antioxidant systems. 84 patients with diagnosis of HFpEF were enrolled in the study. Plasma levels of N-terminal pro-brain natriuretic peptide, fasting glucose, insulin, lipid pattern, insulin-like growth factor-1, dehydroepiandrosterone-sulfate (DHEA-S), total testosterone (T, only in male subjects) were evaluated. Hormonal deficiencies were defined according to T.O.S.C.A. multi-centric study, as previously published. An echocardiographic evaluation was performed. Plasma total antioxidant capacity (TAC) was measured using the system metmyoglobin -HO and the chromogen ABTS, whose radical form is spectroscopically revealed; latency time (LAG) in the appearance of ABTS• is proportional to antioxidants in sample. Multiple deficiencies were discovered. DHEA-S deficiency in 87% of patients, IGF-1 in 67% of patients, T in 42%. Patients with DHEA-S deficiency showed lower levels of TAC expressed by LAG (mean ± SEM 91.25 ± 9.34 vs. 75.22 ± 4.38 s; < 0.05). No differences between TAC in patients with or without IGF-1 deficiency were found. A trend toward high level of TAC in patients without hormonal deficiencies compared with patients with one or multiple deficiencies was found. Regarding echocardiographic parameters, Left Atrial and Left Atrial Volume Index were significantly higher in patients with low IGF-1 values (mean ± SD 90.84 ± 3.86 vs. 72.83 ± 3.78 mL; 51.03 ± 2.33 vs. 40.56 ± 2.46 mL/m, respectively; < 0.05). Our study showed high prevalence of anabolic deficiencies in HFpEF. DHEA-S seems to influence antioxidant levels; IGF-1 deficiency was associated with alteration in parameters of myocardial structure and dysfunction. These data suggest a role of anabolic hormones in the complex pathophysiological mechanisms of HFpEF and could represent the basis for longitudinal studies and investigations on possible benefits of replacement therapy.
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http://dx.doi.org/10.3389/fendo.2020.00281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235369PMC
May 2020

Biomarkers of vascular disease in diabetes: the adipose-immune system cross talk.

Intern Emerg Med 2020 04 9;15(3):381-393. Epub 2020 Jan 9.

U.O.C. Clinica Medica e Malattie Vascolari, Catholic University School of Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Francesco Vito, 1, 00168, Rome, Italy.

Experimental and clinical studies aimed at investigating the mechanism(s) underlying vascular complications of diabetes indicate that a great number of molecules are involved in the pathogenesis of these complications. Most of these molecules are inflammatory mediators or markers generated by immune or adipose tissue. Some of them, i.e. resistin and sortilin, have been shown to be involved in the cross talk between adipocytes and inflammatory cells. This interaction is an attractive area of research, particularly in type 2 diabetes and obesity. Other proteins, such as adiponectin and visfatin, appear to be more promising as possible vascular markers. In addition, some molecules involved in calcium/phosphorus metabolism, such as klotho and FGF23, have an involvement in the pathogenesis of diabetic vasculopathy, which appears to be dependent on the degree of vascular impairment. Inflammatory markers are a promising tool for treatment decisions while measuring plasma levels of adipokines, sortilin, Klotho and FGF23 in adequately sized longitudinal studies is expected to allow a more precise characterization of diabetic vascular disease and the optimal use of personalized treatment strategies.
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http://dx.doi.org/10.1007/s11739-019-02270-6DOI Listing
April 2020

High Mobility Group Box-1 and Diabetes Mellitus Complications: State of the Art and Future Perspectives.

Int J Mol Sci 2019 Dec 11;20(24). Epub 2019 Dec 11.

U.O.C. Clinica Medica e Malattie Vascolari, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy.

Diabetes mellitus (DM) is an endemic disease, with growing health and social costs. The complications of diabetes can affect potentially all parts of the human body, from the heart to the kidneys, peripheral and central nervous system, and the vascular bed. Although many mechanisms have been studied, not all players responsible for these complications have been defined yet. High Mobility Group Box-1 (HMGB1) is a non-histone nuclear protein that has been implicated in many pathological processes, from sepsis to ischemia. The purpose of this review is to take stock of all the most recent data available on the role of HMGB1 in the complications of DM.
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http://dx.doi.org/10.3390/ijms20246258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940913PMC
December 2019

Internists feel the rhythm.

Intern Emerg Med 2020 03 9;15(2):183-185. Epub 2019 Oct 9.

Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, Roma, 00168, Italia.

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http://dx.doi.org/10.1007/s11739-019-02202-4DOI Listing
March 2020

Inflammatory Cytokines Associated With Failure of Lower-Extremity Endovascular Revascularization (LER): A Prospective Study of a Population With Diabetes.

Diabetes Care 2019 10 1;42(10):1939-1945. Epub 2019 Aug 1.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

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.
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http://dx.doi.org/10.2337/dc19-0408DOI Listing
October 2019

The Role of the Microbiota in the Diabetic Peripheral Artery Disease.

Mediators Inflamm 2019 8;2019:4128682. Epub 2019 May 8.

Fondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. Clinica Medica e Malattie Vascolari, Rome, Italy.

Vascular complications of diabetes mellitus represent a major public health problem. Although many steps forward have been made to define the causes and to find the best possible therapies, the problem remains crucial. In recent years, more and more evidences have defined a link between microbiota and the initiation, promotion, and evolution of atherosclerotic disease, even in the diabetic scenario. There is an urgency to develop the knowledge of modern medicine about the link between gut microbiota and its host's metabolic pathways, and it would be useful to understand and justify the interindividual diversity of clinical disease presentation of diabetic vascular complication even if an optimization of pharmacological treatment has been made or in the case of young patients where hypertension, dyslipidemia, and diabetes are not able to justify a very quick progress of atherosclerotic process. The aim of the present review is to gather all the best available evidence in this regard and to define a new role of the microbiota in this field, from biomarker to possible therapeutic target.
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http://dx.doi.org/10.1155/2019/4128682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530226PMC
January 2020

Association between plasma omentin-1 levels in type 2 diabetic patients and peripheral artery disease.

Cardiovasc Diabetol 2019 06 5;18(1):74. Epub 2019 Jun 5.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo F. Vito 1, 00168, Roma, Italy.

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 < 0.001) and that the levels gradually decreased in proportion to disease severity (P < 0.05). The association between omentin-1 levels and PAD remained significant after adjusting for major risk factors in a multivariate analysis.

Conclusions: Our results suggest that omentin-1 is reduced in type 2 diabetic patients with PAD and that omentin-1 levels are related to disease severity.
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http://dx.doi.org/10.1186/s12933-019-0880-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549359PMC
June 2019

The Role of the Stem Cells Therapy in the Peripheral Artery Disease.

Int J Mol Sci 2019 May 7;20(9). Epub 2019 May 7.

Fondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. Clinica Medica e Malattie Vascolari, 00168 Roma, Italy.

Vascular complications of diabetes mellitus are an important issue for all clinicians involved in the management of this complex pathology. Although many therapeutic advances have been reached, peripheral arterial disease is still an unsolved problem that each year compromises the quality of life and life span of affected patients. Oftentimes, patients, after ineffective attempts of revascularization, undergo greater amputations. At the moment, there is no effective and definitive treatment available. In this scenario, the therapeutic use of stem cells could be an interesting option. The aim of the present review is to gather all the best available evidence in this regard and to define a new role of the stem cells therapy in this field, from biomarker to possible therapeutic target.
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http://dx.doi.org/10.3390/ijms20092233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539394PMC
May 2019

Sortilin levels are associated with peripheral arterial disease in type 2 diabetic subjects.

Cardiovasc Diabetol 2019 01 11;18(1). Epub 2019 Jan 11.

U.O.C. Clinica Medica e Malattie Vascolari, Department of Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo F. Vito 1, 00168, Rome, Italy.

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 < 0.01) and there was a trend toward increased sortilin levels as disease severity increased. The association of sortilin levels with PAD remained after adjusting for major risk factors in a multivariate analysis.

Conclusions: We showed that sortilin is significantly and independently associated with the presence of lower limb PAD in a statin-free diabetic population and it may be a promising marker for clinically significant atherosclerosis of the lower limbs. Further studies are needed to confirm this finding and to evaluate its clinical usefulness.
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http://dx.doi.org/10.1186/s12933-019-0805-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329108PMC
January 2019

Fever of unknown origin and splenomegaly: A case report of blood culture negative endocarditis.

Medicine (Baltimore) 2017 Dec;96(50):e9197

Institute of Internal Medicine Laboratory of Vascular Biology and Genetics, Catholic University of the Sacred Heart, Fondazione University Hospital A. Gemelli, Rome, Italy.

Rationale: Fever of unknown origin (FUO) can be determined by different conditions among which infectious diseases represent the main cause.

Patient Concerns: A young woman, with a history of aortic stenosis, was admitted to our unit for a month of intermittent fever associated with a new diastolic heart murmur and splenomegaly. Laboratory tests were negative for infectious screening. The total body computed tomography (CT) scan excluded abscesses, occulted neoplasia, or lymphadenopathy.

Diagnoses: The transthoracic and transesophageal echocardiogram showed an aortic valve vegetation. Three sets of blood cultures were negative for all microorganisms tested. According to these findings, Bartonella endocarditis was suspected and the serology tests performed were positive. Finally, real-time polymerase chain reaction (RT-PCR) detected Bartonella henselae DNA on tissue valve.

Interventions: The patient underwent heart valve surgery and a treatment of Ampicillin, Gentamicin, and oral Doxycycline was prescribed for 16 days and, successively, with Doxycycline and Ceftriaxone for 6 weeks.

Outcomes: After surgery and antibiotic therapy, patient continued to do well.

Lessons: Bartonella species are frequently the cause of negative blood culture endocarditis. Molecular biology techniques are the only useful tool for diagnosis. Valvular replacement is often necessary and antibiotic regimen with Gentamicin and either Ceftriaxone or Doxycycline is suggested as treatment.Echocardiogram and blood cultures must be performed in all cases of FUO. When blood cultures are negative and echocardiographic tools are indicative, early use of Bartonella serology is recommended.
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http://dx.doi.org/10.1097/MD.0000000000009197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815747PMC
December 2017

Fecal calprotectin in management of Clostridium difficile infection: a longitudinal study.

Scand J Gastroenterol 2018 05 24;53(5):567-572. Epub 2017 Oct 24.

a Institute of Internal Medicine , Catholic University , Rome , Italy.

Background: Clostridium difficile infection (CDI) is characterized by a relevant intestinal neutrophil infiltrate. So far, role of fecal calprotectin in CDI, has been investigated only in few studies, mainly focused on diagnosis of the disease.

Aim: By a longitudinal design, we assess fecal calprotectin concentrations (FCCs) in subjects with CDI, evaluating the correlation between fecal marker and response to therapy.

Methods: Clinical (diarrhea scoring) and laboratory (FCCs and leucocytes count) evaluation was performed in 56 subjects with CDI at time of diagnosis (T) and after a week from starting of therapy (T). Clinical response to therapy at T was related with both T and T FCC values. FCCs were also related to all-cause 30-day mortality, recurrence and death, both of them within 90 days.

Results: FCCs at T were significantly increased in subjects with persistence of diarrhea in respect to the other ones (285.5 ± 270 µg/g vs 150.7 ± 147 µg/g, respectively; p < .05). Patients who did not respond to therapy showed higher, but not significative, FCCs at T than patients who responded. No correlation was found among FCCs, both at T and T, and the other outcomes.

Conclusions: Longitudinal evaluation of FCCs in patients with CDI could support physicians in clinical management of disease, for example in term of duration (10 vs 14 days) or type (first vs second line therapy). Further and larger studies could confirm the eventual role of this marker in prognostic algorithms, mainly in prediction of recurrence.
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http://dx.doi.org/10.1080/00365521.2017.1392598DOI Listing
May 2018

The angiogenic properties of human adipose-derived stem cells (HASCs) are modulated by the High mobility group box protein 1 (HMGB1).

Int J Cardiol 2017 Dec 22;249:349-356. Epub 2017 Sep 22.

Laboratory of Vascular Biology and Genetics, Department of Medicine, Fondazione Policlinico Universitario "A. Gemelli", Catholic University School of Medicine, Rome, Italy; Department of Internal Medicine, Fondazione Policlinico Universitario "A. Gemelli", Catholic University School of Medicine, Rome, Italy.

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.
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http://dx.doi.org/10.1016/j.ijcard.2017.09.165DOI Listing
December 2017

Serum high mobility group box-1 and osteoprotegerin levels are associated with peripheral arterial disease and critical limb ischemia in type 2 diabetic subjects.

Cardiovasc Diabetol 2017 08 8;16(1):99. Epub 2017 Aug 8.

Laboratory of Vascular Biology and Genetics, Catholic University School of Medicine, Rome, Italy.

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 < 0.001; 7.05 ± 4.4 mg/L, P < 0.001; 37.5 ± 20.2 pg/mL, P < 0.001 respectively). Moreover HMGB-1 (P < 0.001), OPG (P < 0.001), HsCRP (P < 0.001) and IL-6 (P < 0.001) serum levels were positively correlated with clinical severity of PAD. HMGB-1 (adjusted OR 12.32; 95% CI 3.56-23.54, P = 0.023) and OPG (adjusted OR 3.53; 95% CI 1.54-6.15, P = 0.019) resulted independent determinants of PAD in patients with T2D after adjusting for the conventional cardiovascular risk factor and established inflammatory mediators.

Conclusions: In T2D patients HMGB-1 and OPG serum levels are higher in patients affected by PAD and independently associated with its occurrence and clinical severity.
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http://dx.doi.org/10.1186/s12933-017-0581-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549317PMC
August 2017

Sepsis in Internal Medicine wards: current knowledge, uncertainties and new approaches for management optimization.

Ann Med 2017 11 27;49(7):582-592. Epub 2017 May 27.

a Department of Medical Sciences , Gemelli Hospital, Catholic University of Rome , Rome , Italy.

Sepsis represents a global health problem in terms of morbidity, mortality, social and economic costs. Although usually managed in Intensive Care Units, sepsis showed an increased prevalence among Internal Medicine wards in the last decade. This is substantially due to the ageing of population and to multi-morbidity. These characteristics represent both a risk factor for sepsis and a relative contra-indication for the admission to Intensive Care Units. Although there is a lack of literature on the management of sepsis in Internal Medicine, the outcome of these patients seems to be gradually improving. This is due to Internists' increased adherence to guidelines and "bundles". The routine use of SOFA score helps physicians in the definition of septic patients, even if the optimal score has still to come. Point-of-care ultrasonography, lactates, procalcitonin and beta-d-glucan are of help for treatment optimization. The purpose of this narrative review is to focus on the management of sepsis in Internal Medicine departments, particularly on crucial concepts regarding diagnosis, risk assessment and treatment. Key Messages Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The prevalence of sepsis is constantly increasing, affecting more hospital patients than any other disease. At least half of patients affected by sepsis are admitted to Internal Medicine wards. Adherence to guidelines, routine use of clinical and lab scores and point-of-care ultrasonography are of help for early recognition of septic patients and treatment optimization.
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http://dx.doi.org/10.1080/07853890.2017.1332776DOI Listing
November 2017

Intralobar Pulmonary Sequestration and Increased Serum CA 19-9.

Eur J Case Rep Intern Med 2017 20;4(4):000583. Epub 2017 Feb 20.

Department of Internal Medicine, Gemelli Hospital, Catholic University, Rome, Italy.

Intralobar pulmonary sequestration is an uncommon congenital lung anomaly which consists of a mass of normal lung tissue not connected to the normal tracheobronchial tree and supplied by an anomalous systemic artery. Carbohydrate antigen 19-9 (CA 19-9) is widely accepted as a tumour marker for biliary, pancreatic and gastrointestinal cancer. However, CA 19-9 may also be increased in patients with benign disease. We describe the case of a 56-year-old woman with intralobar pulmonary sequestration who underwent unnecessary and extensive diagnostic abdominal examinations because of an increase in CA 19-9 serum levels.

Learning Points: Knowledge of pulmonary sequestration causing increased serum CA 19-9 is important for the internist because it can help in the differential diagnosis even with neoplastic disease.Such awareness can also decrease the use of antibiotics.Familiarity with the condition can reduce the number of invasive examinations performed to exclude neoplasms of the gastrointestinal tract.
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http://dx.doi.org/10.12890/2017_000583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346763PMC
February 2017

[Venous thromboembolism in critically ill patients: analysis of the main age-related risk factors and definition of specific scores.]

Recenti Prog Med 2016 Sep;107(9):480-484

Medicina Interna, Università "Cattolica", Policlinico Gemelli, Roma.

Introduction: Venous thromboembolism (VTE) is the third most common cardiovascular illness after acute coronary syndrome and stroke and and the most common preventable cause of hospital-related death. Several studies have demonstrated a significant reduction of fatal pulmonary embolism attributed to the introduction of thromboprophylactic measures and changes in hospital practices. However, the influence of some demographical variables, especially age, has largely been under appreciated.

Methods: Using the date of the TEVere study, we have studied 187 patients with VTE and 350 case-control, and we proceeded to analyze the major risk factors for venous thromboembolism, separately for three age groups (≤60 years, 60-75 years, >75 years). Patients came from the departments of internal medicine and emergency medicine for 21 hospitals. In this subgroup, we have examined the main risk factors for the individual classes of age and have proposed, through a logistic regression analysis, 3 different types of scores, specific for each age class. We then compared the individual scores obtained with the Kucher's score.

Results: It was found that in the class of patients with a lower age of 60, the main risk factors found to be estrogen-progestagen treatment (p=0.004) and family history of VTE (p=0.047), while in older patients (>75 years) the main risk factors were immobilization (p=0.005) and chronic venous insufficiency (p=0.001). In common for the three classes the presence of an evolutionary malignancy and previous episodes of VTE. Through the ROC curve analysis, it was found that the results for the three proposed scores improved sensitivity compared to Kucher's score. However our results showed that the only score of the intermediate class showed a statistically significant difference for prediction of the thromboembolic risk (p=0.0264 (AUROC 0.7946; 95% CI, 0.75 to 0.80, AUROC 0.7042; 95% CI, 0.68. to 0.72).

Discussion: Our study emphasizes the importance of carrying a correct stratification, which also consider the patient's age and therefore the concomitant pathologies. In fact, although the age of the patient cannot be considered as the only criterion to start the thromboprophylaxis, as highlighted in literature, you need to consider each individual patient, with its own peculiarities.

Conclusion: This study showed the difficulty in identifying the key risk factors that are responsible for thromboembolic disease and has emerged the opportunity to be evaluated by larger studies, the use of specific scores by age groups.
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http://dx.doi.org/10.1701/2354.25228DOI Listing
September 2016

Modulation of microbiota as treatment for intestinal inflammatory disorders: An uptodate.

World J Gastroenterol 2016 Aug;22(32):7186-202

Antonella Gallo, Giovanna Passaro, Raffaele Landolfi, Massimo Montalto, Institute of Internal Medicine, Fondazione Policlinico "Agostino Gemelli", Catholic University of Sacred Heart, 00168 Rome, Italy.

Alterations of intestinal microflora may significantly contribute to the pathogenesis of different inflammatory and autoimmune disorders. There is emerging interest on the role of selective modulation of microflora in inducing benefits in inflammatory intestinal disorders, by as probiotics, prebiotics, synbiotics, antibiotics, and fecal microbiota transplantation (FMT). To summarize recent evidences on microflora modulation in main intestinal inflammatory disorders, PubMed was searched using terms microbiota, intestinal flora, probiotics, prebiotics, fecal transplantation. More than three hundred articles published up to 2015 were selected and reviewed. Randomized placebo-controlled trials and meta-analysis were firstly included, mainly for probiotics. A meta-analysis was not performed because of the heterogeneity of these studies. Most of relevant data derived from studies on probiotics, reporting some efficacy in ulcerative colitis and in pouchitis, while disappointing results are available for Crohn's disease. Probiotic supplementation may significantly reduce rates of rotavirus diarrhea. Efficacy of probiotics in NSAID enteropathy and irritable bowel syndrome is still controversial. Finally, FMT has been recently recognized as an efficacious treatment for recurrent Clostridium difficile infection. Modulation of intestinal flora represents a very interesting therapeutic target, although it still deserves some doubts and limitations. Future studies should be encouraged to provide new understanding about its therapeutical role.
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http://dx.doi.org/10.3748/wjg.v22.i32.7186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997632PMC
August 2016

Autoantibodies to post-translationally modified type I and II collagen in Charcot neuroarthropathy in subjects with type 2 diabetes mellitus.

Diabetes Metab Res Rev 2017 02 5;33(2). Epub 2016 Oct 5.

Centre for Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK.

Aims: Charcot neuroarthropathy (CN) is a disabling complication, culminating in bone destruction and involving joints and articular cartilage with high inflammatory environment. Its real pathogenesis is as yet unknown. In autoinflammatory diseases, such as rheumatoid arthritis, characterized by inflammation and joint involvement, autoantibodies against oxidative post-translationally modified (oxPTM) collagen type I (CI) and type II (CII) were detected. Therefore, the aim of our study was to assess the potential involvement of autoimmunity in charcot neuroarthropathy, investigating the presence of autoantibodies oxPTM-CI and oxPTM-CII, in participants with charcot neuroarthropathy.

Methods: In this case-control study, we enrolled 124 participants with type 2 diabetes mellitus (47 with charcot neuroarthropathy, 37 with diabetic peripheral neuropathy without charcot neuroarthropathy, and 40 with uncomplicated diabetes), and 32 healthy controls. The CI and CII were modified with ribose and other oxidant species, and the modifications were evaluated with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Binding of sera from the participants was analyzed with enzyme-linked immunosorbent assay.

Results: Age, body mass index, waist and hip circumferences, and lipid profile were similar across the 4 groups, as well as glycated hemoglobin and duration of diabetes among people with diabetes. An increased binding to both native and all oxidation-modified forms of CII was found in participants with CN and diabetic neuropathy. Conversely, for CI, an aspecific increased reactivity was noted.

Conclusions: Our results detected the presence of autoantibodies against oxidative post-translational modified collagen, particularly type 2 collagen, in participants with charcot neuroarthropathy and diabetic neuropathy, suggesting the possible involvement of autoimmunity. Further studies are required to understand the role of autoimmunity in the pathogenesis of charcot neuroarthropathy.
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http://dx.doi.org/10.1002/dmrr.2839DOI Listing
February 2017

Perception of Thromboembolism Risk: Differences between the Departments of Internal Medicine and Emergency Medicine.

Keio J Med 2016 ;65(2):39-43

Emergency Department, Fatebenefratelli Isola Tiberina Hospital, Rome, Italy.

The latest developments in emergency medicine (EM) have introduced new typologies of patients that have not been taken into account in previous studies of venous thromboembolism (VTE) risk. The aim of the current study was to evaluate by comparing the main international risk scores whether different perceptions of VTE risk exist in internal medicine (IM) departments and in EM departments. This cross-sectional observational study involved 23 IM and 10 EM departments of 21 different hospitals. The patient data were collected by physicians who were blinded to the purpose of the study. The data were analyzed using the main international risk scores. We analyzed 742 patients, 222 (30%) hospitalized in EM departments and the remaining 520 (70%) in IM departments. We found that fewer patients at risk for VTE were treated with low-molecular-weight heparin (LMWH) in EM departments than in IM departments. Moreover, there was significant statistical difference in the use of LMWH between IM and EM departments when the Padua score and immobilization criteria were used to assess the risk. The infrequent use of LMWH in EM patients may have several causes. For example, in EM departments, treatment of acute illness often takes higher priority than VTE risk evaluation. Moreover, immobilization criteria cannot be evaluated for all EM patients because of the intrinsic time requirements. For the aforementioned reasons, we believe that a different VTE risk score is required that takes into account the peculiarities of EM, and establishing such a score should be the object of future study.
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http://dx.doi.org/10.2302/kjm.2015-0004-OADOI Listing
April 2017

Controversies in venous thromboembolism: the unique case of isolated distal deep vein thrombosis.

Intern Emerg Med 2016 Sep 28;11(6):775-9. Epub 2016 Apr 28.

Division of Internal Medicine and Vascular Diseases, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Largo Agostino Gemelli 8, 00168, Rome, Italy.

Venous thromboembolism (VTE) represents the third leading cause of cardiovascular mortality, and it is the main cause of preventable mortality in hospitalized patients. Among VTE, there is the unique case of isolated distal deep vein thrombosis (IDDVT), which still lacks an agreement in terms of optimal therapeutic strategy. Although most IDDVTs are self-limiting and associated with a very low risk of embolic complications, still not all IDDVTs can be safely identified as stable. Lack of strong scientific evidence, fear of thromboembolic complications, and risk of bleeding upon initiation of anticoagulant treatment result in very heterogeneous therapeutic strategies among physicians. Here, we provide a comprehensive review of the literature, highlight the many controversial issues regarding IDDVTs, and call for a consensus of experts aimed to shed new light on the gray areas of IDDVT management and therapy.
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http://dx.doi.org/10.1007/s11739-016-1453-3DOI Listing
September 2016

Abnormal proplatelet formation and emperipolesis in cultured human megakaryocytes from gray platelet syndrome patients.

Sci Rep 2016 Mar 18;6:23213. Epub 2016 Mar 18.

Department of Internal Medicine, Policlinico Agostino Gemelli, Catholic University, Rome, Italy.

The Gray Platelet Syndrome (GPS) is a rare inherited bleeding disorder characterized by deficiency of platelet α-granules, macrothrombocytopenia and marrow fibrosis. The autosomal recessive form of GPS is linked to loss of function mutations in NBEAL2, which is predicted to regulate granule trafficking in megakaryocytes, the platelet progenitors. We report the first analysis of cultured megakaryocytes from GPS patients with NBEAL2 mutations. Megakaryocytes cultured from peripheral blood or bone marrow hematopoietic progenitor cells from four patients were used to investigate megakaryopoiesis, megakaryocyte morphology and platelet formation. In vitro differentiation of megakaryocytes was normal, whereas we observed deficiency of megakaryocyte α-granule proteins and emperipolesis. Importantly, we first demonstrated that platelet formation by GPS megakaryocytes was severely affected, a defect which might be the major cause of thrombocytopenia in patients. These results demonstrate that cultured megakaryocytes from GPS patients provide a valuable model to understand the pathogenesis of GPS in humans.
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http://dx.doi.org/10.1038/srep23213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796794PMC
March 2016