Iron and Heart Failure: Current Concepts and Emerging Pharmacological Paradigms

Background: Emerging evidence has recognized that anemia and iron deficiency are recurrent comorbidities in chronic heart failure (HF) and several trials have established that iron administration improves myocardial asset and clinical scenario in HF. Purpose: Recent acquisitions suggest that iron deficiency represents a concrete bias in the pathogenetic mechanism of chronic HF, so we have investigated the putative role of the hepcidin/ferroportin axis in the cardiovascular setting to advocate novel pharmacological and clinical approaches. Methods: Here, after an excursus on iron metabolism, we first reviewed the ongoing studies on novel iron targeted compounds. Then, we summarize large clinical interventional studies conducted on patient suffering from iron deficiency and HF which have tested the effects of drugging iron regard QoL, hospitalizations and cardiovascular death. Results: Novel compounds such as hepcidin agonist (PTG 300), synthetic human hepcidin (LJPC-401) and anti FPN (Vamifeport) are ongoing in iron overloaded patients, while the hepcidin blocker (PRS-080) is under investigation in anemic patients. Noteworthy, novel insights could arise from the results of a Phase IV interventional study regarding the modification of hepcidin pathway in a large cohort of HF patients (n = 1992) by sodium glucose cotransporter 2 inhibitors. To date, several studies highlight the beneficial effect of iron administration in cardiovascular setting and latest evidences consider hepcidin level as a novel biomarker of cardiac injury and atherosclerosis. Conclusions: We advocate that data from ongoing studies will suggest novel iron targeted therapies for diagnosis, prognosis and therapy transferable in selected heart failed patients.

Use of antibiotics in the treatment of Crohn’s disease

Many data coming from animal models and clinical observations support an involvement of intestinal microbiota in the pathogenesis of Crohn's disease(CD). It is hypothesized in fact,that the development of chronic intestinal inflammation is caused by an abnormal immune response to normal flora in genetically susceptible hosts.The involvement of bacteria in CD inflammation has provided the rationale for including antibiotics in the therapeutic armamentarium.However, randomized controlled trials have failed to demonstrate an efficacy of these drugs in patients with active uncomplicated CD,even if a subgroup of patients with colonic location seems to get benefit from antibiotics. Nitroimidazole compounds have been shown to be efficacious in decreasing CD recurrence rates in operated patients,and the use of metronidazole and ciprofloxacin is recommended in perianal disease.However,the appearance of systemic side effects limits antibiotic long-term employment necessary for treating a chronic relapsing disease.Rifaximin,characterized by an excellent safety profile,has provided promising results in inducing remission of CD.

5-ASA in ulcerative colitis:Improving treatment compliance

5-aminosalicylic acid(5-ASA)compounds are a highly effective treatment for ulcerative colitis(UC).While UC patient compliance in clinical studies is over 90%, only 40%of patients in every day life take their prescribed therapy.Adherence to medication has been emphasized recently by a Cochrane meta-analysis that has suggested that future trials of 5-ASA in UC should look at patient compliance rather than drug efficacy. Better compliance can be obtained by reducing the number of tablets and times of administration.Given that the 5-ASA formulations have different delivery systems that split the active moiety in various regions of the intestine,it is particularly important that an adequate dose of the drug arrives at the inflamed part of the colon.5-ASA Multi matrix(MMx)is a novel,high strength(1.2 g),oral formulation designed for oncedaily dosing.It releases the active moiety throughout the colon.Different studies with this compound have shown that it is as effective as 5-ASA enema in the treatment of mild-to-moderate,left-sided UC,and is comparable to a pH-dependent,delayed release 5-ASA (Asacol ),even if given once daily.Recently,the effectiveness in the acute phase of UC has been confirmed also in maintenance.In conclusion,at present,5-ASA MMx seems theoretically the best agent for maintaining patient compliance,and consequently,treatment effectiveness.

Vedolizumab for inflammatory bowel disease:from randomized controlled trials to real-life evidence

The biologic antitumor necrosis factor alpha(anti-TNFα) agents have revolutionised the treatment of inflammatorybowel disease(IBD). However,some patients experience primary nonresponse,loss of response,or intolerance. Therefore,introducing a newer class of therapy with a mechanism of action that acts on different inflammatory pathways involved in IBD pathogenesis is appealing. Vedolizumab is a fully humanised monoclonal antibody that selectively targets α4β7 integrin. Based on the results of the pivotal clinical GEMINI trials,vedolizumab was approved for the treatment of adult patients with moderately to severely active ulcerative colitis(UC) and Crohn's disease(CD) refractory or intolerant to either conventional therapy or TNFα inhibitors. This review describes the efficacy,safety,and tolerability of vedolizumab reported in both randomized,controlled,clinical trials and from real-world experience in patients with UC and CD in order to identify its place in treatment algorithms for IBD.

Comparative outcome of stapled trans-anal rectal resection and macrogol in the treatment of defecation disorders

AIM:To prospectively assess the eff icacy and safety of stapled trans-anal rectal resection(STARR) compared to standard conservative treatment,and whether preoperative symptoms and findings at defecography and anorectal manometry can predict the outcome of STARR.METHODS:Thirty patients(Female,28;age:51 ± 9 years) with rectocele or rectal intussusception,a defecation disorder,and functional constipation were submitted for STARR.Thirty comparable patients(Female,30;age 53 ± 13 years),who presented with symptoms of rectocele or rectal intussusception and were treated with macrogol,were assessed.Patients were interviewed with a standardized questionnaire at study enrollment and 38 ± 18 mo after the STARR procedure or during macrogol treatment.A responder was def ined as an absence of the Rome Ⅲ diagnostic criteria for functional constipation.Defecography and rectoanal manometry were performed before and after the STARR procedure in 16 and 12 patients,respectively.RESULTS:After STARR,53% of patients were responders;during conservative treatment,75% were responders.After STARR,30% of the patients reported the use of laxatives,17% had intermittent anal pain,13% had anal leakage,13% required digital facilitation,6% experienced defecatory urgency,6% experienced fecal incontinence,and 6% required re-intervention.During macrogol therapy,23% of the patients complained of abdominal bloating and 13% of borborygmi,and 3% required digital facilitation.No preoperative symptom,defecographic,or manometric finding predicted the outcome of STARR.Post-operative defecography showed a statistically significant reduction(P < 0.05) of the rectal diameter and rectocele.The postoperative anorectal manometry showed that anal pressure and rectal sensitivity were not significantly modified,and that rectal compliance was reduced(P = 0.01).CONCLUSION:STARR is not better and is less safe than macrogol in the treatment of defecation disorders.It could be considered as an alternative therapy in patients unresponsive to macrogol.

Rifaximin and Crohn's disease

In a recent article,Longman and Swaminath analyzed our paper on the use of rifaximin in patients with moderately active Crohn’s disease(CD).Here we report some considerations concerning their article.The exploratory post-hoc subgroup analysis showed that early-stage disease and,differently from that written by Longman and Swaminath,also colonic involvement seemed to be associated with a significant higher efficacy of rifaximin-EIR 800 mg twice daily.Early-stage disease is generally considered as the more easily treatable phase of CD,and the better response to rifaximin in Crohn’s colitis is in accordance with the high concentration of bacteria in the colon.In addition,patients with C reactive protein level>5 mg/L achieved remission more significantly than patients with normal values,thus suggesting that the symptoms were probably caused by inflammation instead of by non-inflammatory causes.We also analyze the role of rifaximin against gut bacteria and the clinical situations that could obtain the best results from antibiotics.

Non-cirrhotic portal hypertension with large regenerative nodules: A diagnostic challenge

Non-cirrhotic portal hypertension is a poorly understood condition characterized by portal hypertension in the absence of conventional hepatic cirrhosis and described in association with blood coagulation disorders, myeloproliferative and immunological diseases and with exposure to toxic drugs. Very recently, precise classification criteria have been proposed in order to define four distinct subcategories. The present case highlights how the clinical presentation, the confounding results from imaging studies, and the difficulties in the histological evaluation often render cases of non-cirrhotic portal hypertension a real diagnostic challenge. It also underscores the classification problems which can be faced once this diagnosis is performed. Indeed, the different subcategories proposed result from the prevalent subtypes in a spectrum of hepatic regenerative responses to a variety of injuries determining microcirculatory dis-turbances. More flexibility in classification should derive from this etiopathogenic background.

Diagnostic Accuracy of MRI in Primary Cervical Cancer

Introduction: Magnetic resonance imaging (MRI) studies obtained during the initial staging of patients affected by uterine cervical cancer were compared to the final histological report after surgery. Methods: Data were retrieved from published papers. Results: MRI detection of lymph node metastases shows a sensitivity of 49.3% (1209 patients) and a specificity of 87.7% (1182 patients). Parametrial involvement detection has 66.2% sensitivity (1288 patients) and 83.6% specificity (1282 patients). MRI tumor size evaluation shows significant error. Even detection of over 1 cm diameter primary tumor can fail. MRI appears promising in the detection of myometrial and endometrial involvement. Conclusions: Primary uterine cervical cancer evaluation with routine MRI has a limited accuracy especially in the detection of lymph node involvement and parametrial invasion. It is not sensitive enough to replace histology of dissected nodes and parametria. Tumor size estimation is imprecise. Detection of myometrial and endometrial invasion using MRI might be possible. Awareness of MRI limitations is crucial in primary cervical cancer staging.

Identification of the second CFTR mutation in patients with congenital bilateral absence of vas deferens undergoing ART protocols

Congenital bilateral absence of vas deferens （CBAVD） is a manifestation of the mildest form of cystic fibrosis （CF） and is characterized by obstructive azoospermia in otherwise healthy patients. Owing to the availability of assisted reproductive technology, CBAVD patients can father children. These fathers are at risk of transmitting a mutated allele of the CF transmembrane conductance regulator （CFTR） gene, responsible for CF, to their offspring. The identification of mutations in both CFTR alleles in CBAVD patients is a crucial requirement for calculating the risk of producing a child with full-blown CF if the female partner is a healthy CF carrier. However, in the majority of CBAVD patients, conventional mutation screening is not able to detect mutations in both CFTR alleles, and this difficulty hampers the execution of correct genetic counselling. To obtain information about the most represented CFTR mutations in CBAVD patients, we analysed 23 CBAVD patients, 15 of whom had a single CFTR mutation after screening for 36 mutations and the 5T allele. The search for the second CFTR mutation in these cases was performed by using a triplex approach： （i） first, a reverse dot-blot analysis was performed to detect mutations with regional impact; （ii） next, multiple ligation-dependent probe amplification assays were conducted to search for large rearrangements; and （iii） finally, denaturing high-performance liquid chromatography was used to search for point mutations in the entire coding region. Using these approaches, the second CFTR mutation was detected in six patients, which increased the final detection rate to 60.8%.

Left atrial voltage remodeling after pulmonary venous isolation with multipolar radiofrequency ablation

Purpose: Pulmonary vein isolation (PVI) is the accepted primary endpoint for catheter ablation of atrial fibrillation (AF). The aim of this study was to evaluate the level of PVI by PVAC, a multipolar circular catheter utilizing bipolar/unipolar radiofrequency (RF) energy. Methods: Twenty patients with paroxysmal AF underwent PVAC ablation. PVI was validated by voltage reduction and pacing tests. Before and after RF ablation, left atrium (LA) and PV electroanatomic mapping (EAM) were performed by EnSite NavX system. Voltage abatement was considered for potentials 24mm: 9/20 (45%) vs 11/57 (19%),

Successful radiofrequency ablation of long-standing persistent atrial fibrillation in a patient with esophageal achalasia

A 54-year-old man was referred for ablation of symptomatic drug-refractory long-lasting persistent atrial fibrillation. His past medical history was negative for cardiac disease but included a diagnosis of esophageal achalasia. The patient underwent an ablation procedure, guided by barium esophagram, including isolation of the pulmonary veins, ablation of complex fractionated left atrial electrograms recorded on the sep-tal wall and, finally, linear ablation of the cavo-tricuspid isthmus. The ablation procedure was performed with multielectrode ablation catheters using duty-cycled bipolar/unipolar radiofrequency energy. During 6 months of follow-up no recurrences of atrial fibrillation were documented. The reported case demonstrates how an ablation procedure for long-standing persistent AF may be safely performed even in a patient presenting with a achalasia, outlining the mega-esophagus position with a simple barium paste.

Modifications of Coronay Artery Calcifications (CAC) and Correlations with C Reactive Protein (CRP) Levels in Renal Recipients after the First Year of Transplantation

The purpose of the present study was to determine the association between presence and progression of Coronary Artery Calcifications (CAC) quantified with Agatston Score (AS) and inflammatory index as CRP and other parameters in unselected renal transplant recipients. Forty-five patients were underwent a baseline Multislice CT (MSCT) at the time of renal transplant and a repeat evaluation 12 - 16 months later. After second MSCT recipients were divided in three groups: Gr1 (26 patients) with absence of CAC at basal and second MSCT, Gr2 (11 patients) with reduction of CAC after one year and Gr3 (8 patients) with increased values of CAC after one year. Mean +/- Standard deviation of basal and after one year values of AS and CRP were respectively: Gr1: 2 +/-3;2 +/- 5 and 0.4 +/- 0.3;0.55 +/- 0.67;Gr2: 317 +/- 288;212 +/- 242 and 0.9 +/- 1.1;0.55 +/- 0.6;Gr3: 854 +/- 1168;1032 +/- 1153 and 0.8 +/- 0.8;1.1 +/-?0.96. We found capacity of renal transplantation to protect against development of new calcium deposits in recipients without CAC at time of transplantation. While we confirmed association in Gr2 between reduction of CAC with reduction of CRP levels and in Gr3 between increased levels of CRP with increasing of CAC. Conclusion: In this preliminary study, renal transplantation appears to slow down or increasing CAC, in strict association with modifications of CRP levels. Long term studies are needed to confirm our preliminary data and to determine the effects of CAC on cardiovascular morbidity and mortality in renal transplant recipients.

肝脏双能CT(DECT)检查:常规与虚拟平扫影像的比较

目的比较肝脏双能CT(DECT)检查病人的常规平扫(CU)与虚拟平扫(VU)的影像质量和噪声,并评估辐射剂量减低的可能。材料与方法研究包括40例连续病人。

Layered enhancement at magnetic resonance enterography in inflammatory bowel disease: A meta-analysis

BACKGROUND Documentation of disease activity in patients affected by Crohn’s disease(CD)is mandatory in order to manage patients properly.Magnetic resonance imaging(MRI)is considered the reference cross-sectional technique for the assessment of CD activity.Among MRI findings,layered pattern(LP)of contrast enhancement seems to be one of the most significant signs of severe disease activity;however,it has also been associated with chronic disease and mural fibrosis.AIM To systematically evaluate the accuracy of LP of contrast enhancement in the diagnosis of active inflammation in patients with CD.METHODS In February 2019,we searched the MEDLINE and Cochrane Central Register of Controlled Trials databases for studies evaluating the diagnostic accuracy of LP of contrast enhancement on MRI for the detection of active inflammation in patients with CD.To be included,studies had to use histopathologic analysis(endoscopy or surgery)as the reference standard.Risk of bias and applicability concerns of the included studies were evaluated by using items from the Quality Assessment for Diagnostic Accuracy Studies 2(QUADAS-2)tool.Pooled sensitivity and specificity were determined using a bivariate random-effect model.Heterogeneity was quantified by using the I2 statistic.Our meta-analysis received no funding,and the review protocol was not published or registered in advance.RESULTS Of the 1383 studies identified,five articles were finally selected for quantitative and qualitative synthesis(245 patients,238 of whom had histopathologically confirmed CD,144 with active inflammation and 94 with inactive disease).The meta-analysis showed a pooled sensitivity of 49.3%(95%CI:41%-57.8%;I2:90.7%)and specificity of 89.1%(95%CI:81.3%-94.4%;I^2:48.6%).Pooled PLR and NLR were 3.3(95%CI:1.9-5.7;I2:6.1%)and 0.6(95%CI:0.5-0.9;I2 70.5%),respectively.SDOR was 6.8(95%CI:2.6-17.6;I2:27.1%).The summary ROC curve showed an area under the curve(AUC)of 0.82(SE 0.06;Q*0.76).High risk of bias and applicability concerns were observed in the domains of patient selection for one included study.CONCLUSION LP on contrast-enhanced MRI is a specific finding to rule out active inflammation in patients with CD.Further studies using a prespecified definition of LP on contrast-enhanced MRI are needed to support our findings.

Non-Conventional MRI Techniques as an Alternative Role to the Clinical Diagnosis in Alzheimer’s Disease

Improved methods for early diagnosis and non-invasive surrogates for the diagnosis of disease severity in Alzheimer’s disease (AD) are becoming the new challenge. Dementia can now be accurately determined through clinical evaluation, cognitive screening, basic laboratory evaluation and structural imaging. Magnetic resonance (MRI) techniques are being evaluated as possible surrogate measures to monitor disease progression. The purpose of this work is to correlate the results of combined advanced MR techniques with neuropsychological performance in order to identify a sensible and sensitive imaging approach to quantify neurodegenerative disease progression. One of the most relevant evidences in our study is the degeneration of the fibers of the corpus callosum in the pathogenesis of cognitive disorders in AD patients, as demonstrated by the relationship between altered neuropsychological tests and reduced FA (Fractional Anisotrophy) values of the corpus callosum in such patients. This data is also integrated by the evidence of anatomic reduction of the total volume of the corpus callosum assessed by FreeSurfer, thus supporting the hypothesis that the “brain disconnects” play a key role in the pathogenesis of AD. Statistical evaluation of regression consisting in the identification of different numerical coefficients that are multiplied by the thickness of the right fusiform value or by the volume of left inferoparietal region and left middle-temporal region, allows us to obtain the predictive numeric value of the related neuropsychological test. Combination of non-conventional magnetic resonance imaging, including morphometry, spectroscopy, MD (mean diffusivity) and FA evaluation, could be an alternative to clinic in the evaluation of neurodegeneration in AD.

意大利Hailey-Hailey病患者ATP2C1基因突变分析

Hailey-Hailey disease (HHD) is a rare autosomal dominant disorder characterized by recurrent skin lesions predominantly involving the body folds. It is caused by heterozygous mutations in the ATP2C1 gene, encoding the human secretory pathway Ca2+ /Mn2+ - ATPase protein 1 (hSPCA1). In this report we describe the molecular studies performed in eight HHD cases from Italy that led us to identify six different mutations scattered through the ATP2C1 gene in seven of eight cases. Four of the detected mutations were novel. Our results confirm the high allelic heterogeneity of the ATP2C1 gene and support the notion that HHD is a genetically homogeneous disorder. Furthermore, we created a table summarizing all previously reported ATP2C1 mutations, adapting the nomenclature, if needed, according to the guidelines of the Human Genome Variation Society.

Left hepatectomy with concomitant cavo-atrial and biliary tumor thrombectomy for invasive hepatocellular carcinoma:a video report

Introduction Representing the prevalent primary hepatic malignancy,hepatocellular carcinoma(HCC)is concurrently the sixth most common cancer worldwide and the third dominant cause of mortality due to cancer(1,2).The preponderance of such neoplasms is secondary to cirrhosis,primarily induced by viral hepatitis,alcohol abuse or exposure to other hepatotoxins.Over the last decades,however,metabolic disorders such as obesity and insulin resistance,have established as key players in the chronic damage of liver parenchyma,eventually contributing to the development of the large spectrum of chronic hepatopathies known as non-alcoholic fatty liver disease(NAFLD)(3).