Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis

In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

History and evolution of the use of oral mucosa for urethral reconstruction

We report here the history and evolution of the use of oral mucosa in reconstructive urethral surgery since it was first used for urethroplasty in 1894.Since that time,many authors have contributed to develop,improve and popularize the use of oral mucosa as a substitute material.Paediatric urologists should be considered pioneers on the use of oral mucosa as they used it to repair primary and failed hypospadias.The use of oral mucosa to repair penile and bulbar urethral strictures was described,for the first time,in 1993.Important evolutions in the technique for harvesting oral mucosa from the cheek were reported in 1996.Today,oral mucosa is considered the gold standard material for any type of anterior urethroplasty in a one-or two-stage repair due to its biological and structural characteristics that make it a highly versatile that is adaptable to any environment required by the reconstructive urethral surgery.As the future approaches,tissue engineering techniques will provide patients with new materials originating from the oral epithelial mucosal cells,which are cultured and expanded into a scaffold.However,the path to reach this ambitious objective is still long and many difficulties must be overcome along the way.

Sequence of events leading to primary biliary cholangitis

Primary biliary cholangitis(PBC)is a chronic cholestatic liver disease that is observed more frequently in middle-aged women.This disorder is considered an autoimmune disease,since liver injury is sustained by the presence of selfdirected antimitochondrial antibodies targeting the bile duct cells.The prognosis may vary depending on an early diagnosis and response to therapy.However,nearly a third of patients can progress to liver cirrhosis,thus requiring a liver transplant.Traditional immunosuppressive therapies,commonly employed for other autoimmune diseases,have limited effects on PBC.In fact,dramatic functional changes that occur in the biliary epithelium in the course of inflammation play a major role in perpetuating the injury.In this minireview,after a background on the disease and possible predisposing factors,the sequential cooperation of cellular/molecular events leading to end-stage PBC is discussed in detail.The rise and maintenance of the autoimmune process,as well as the response of the biliary epithelia during inflammatory injury,are key factors in the progression of the disease.The so-called“ductular reaction(DR)”,intended as a reactive expansion of cells with biliary phenotype,is a process frequently observed in PBC and partially understood.However,recent findings suggest a strict relationship between this pathological picture and the progression to liver fibrosis,cell senescence,and loss of biliary ducts.All these issues(onset of chronic inflammation,changes in secretive and proliferative biliary functions,DR,and its relationship with other pathological events)are discussed in this manuscript in an attempt to provide a snapshot,for clinicians and researchers,of the most relevant and sequential contributors to the progression of this human cholestatic disease.We believe that interpreting this disorder as a multistep process may help identify possible therapeutic targets to prevent evolution to severe disease.

Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations:lessons from recent clinical trials

We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors.Specifically,we discussed randomized clinical trials in subjects with Alzheimer's disease,Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations,and glucocerebrosidase-associated Parkinson's disease.Learning potential lessons to improve future therapeutic approaches is the aim of this review.Two long-term,controlled trials on three anti-β-amyloid monoclonal antibodies(solanezumab,gantenerumab and crenezumab)in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits.A major trial on tominersen,an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease,was prematurely interrupted because the drug failed to show higher efficacy than placebo and,at highest doses,led to worsened outcomes.A 28-week trial of tofersen,an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy.A trial of venglustat,a potent and brain-penetrant glucosylceramide synthase inhibitor,in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo.We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies,antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.

Management of negative pressure wound therapy in the treatment of diabetic foot ulcers

Diabetic foot(DF) is a common complication of diabetes and the first cause of hospital admission in diabetic patients. In recent years several guidelines have been proposed to reinforce the the management of DF with a notable increase in diabetes knowledge and an overall reduction of amputations. Significant improvements have been reached in the treatment of diabetic foot ulcers(DFUs) and nowadays clinicians have several advanced medications to apply for the best local therapy. Among these, negative pressure wound therapy(NPWT) is a useful adjunct in the management of chronic and complex wounds to promote healing and wound bed preparation for surgical procedures such as skin grafts and flap surgery. NPWT has shown remarkable results although its mechanisms of action are not completely understood. In this paper, we offer a complete overview of this medication and its implication in the clinical setting. We have examined literature related to NPWT concerning human, animal and in vitro studies, and we have summarized why, when and how we can use NPWT to treat DFUs. Further we have associated our clinical experience to scientific evidence in the field of diabetic foot to identify a defined strategy that could guide clinician in the use of NPWT approaching to DFUs.

Metabolic aspects of adult patients with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome(MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance(IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD.

Levofloxacin/amoxicillin-based schemes vs quadruple therapy for Helicobacter pylori eradication in second-line

Worldwide prevalence of Helicobacter pylori(H.pylori) infection is approximately 50%,with the highest being in developing countries.We compared cure rates and tolerability(SE) of second-line anti-H.pylori levofloxacin/amoxicillin(LA)-based triple regimens vs standard quadruple therapy(QT).An English language literature search was performed up to October 2010.A meta-analysis was performed including randomized clinical trials comparing 7-or 10-d LA with 7-d QT.In total,10 articles and four abstracts were identified.Overall eradication rate in LA was 76.5%(95% CI:64.4%-97.6%).When only 7-d regimens were included,cure rate was 70.6%(95% CI:40.2%-99.1%),whereas for 10-d combinations,cure rate was significantly higher(88.7%;95% CI:56.1%-109.9%;P < 0.05).Main eradication rate for QT was 67.4%(95% CI:49.7%-67.9%).The 7-d LA and QT showed comparable efficacy [odds ratio(OR):1.09;95% CI:0.63-1.87],whereas the 10-d LA regimen was significantly more effective than QT(OR:5.05;95% CI:2.74-9.31;P < 0.001;I 2 = 75%).No differences were reported in QT eradication rates among Asian and European studies,whereas LA regimens were more effective in European populations(78.3% vs 67.7%;P = 0.05).Incidence of SE was lower in LA therapy than QT(OR:0.39;95% CI:0.18-0.85;P = 0.02).A higher rate of side effects was reported in Asian patients who received QT.Our findings support the use of 10-d LA as a simple second-line treatment for H.pylori eradication with an excellent eradication rate and tolerability.The optimal second-line alternative scheme might differ among countries depending on quinolone resistance.

De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature

BACKGROUND Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients. AIM To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients. METHODS A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy.RESULTS Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences. CONCLUSION The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of de novo malignancies and may also help in treating liver transplant patients suffering from cancer.

Moving forward in the treatment of cholangiocarcinoma

Despite being the second most frequent primary liver tumor in humans,early diagnosis and treatment of cholangiocarcinoma(CCA)are still unsatisfactory.In fact,survival after 5 years is expected in less than one fourth of patients diagnosed with this disease.Rare incidence,late appearance of symptoms and heterogeneous biology are all factors contributing to our limited knowledge of this cancer and determining its poor prognosis in the clinical setting.Several efforts have been made in the last decades in order to achieve an improved classification/understanding with regard to the diverse CCA forms.Location within the biliary tree has helped to distinguish between intrahepatic,perihilar and distal CCA types.Sequence analysis contributed to identifying several characteristic genetic aberrations in CCA that may also serve as possible targets for therapy.Novel findings are expected to significantly improve the management of this malignancy in the near future.In this changing scenario our review focuses on the current and future strategies for CCA treatment.Both systemic and surgical treatments are discussed in detail.The results of the main studies in this field are reported,together with the ongoing trials.The current findings suggest that an integrated multidisciplinary approach to this malignancy would be helpful to improve its outcome.

Ten years of hip fractures in Italy: For the first time a decreasing trend in elderly women

AIM:To evaluate the hospitalization rate of femoralneck fractures in the elderly Italian population over ten years.METHODS:We analyzed national hospitalizations records collected at central level by the Ministry of Health from 2000 to 2009.Age-and sex-specific rates of fractures occurred at femoral neck in people≥65 years old.We performed a sub-analysis over a three-year period(2007-2009),presenting data per five-year age groups,in order to evaluate the incidence of the hip fracture in the oldest population.RESULTS:We estimated a total of 839008 hospitalizations due to femoral neck fractures between 2000 and2009 in people≥65,with an overall increase of 29.8%over 10 years.The incidence per 10000 inhabitants remarkably increased in people≥75,passing from158.5 to 166.8(+5.2%)and from 72.6 to 77.5(+6.8%)over the ten-year period in women and men,respectively.The oldest age group(people>85 years old)accounted for more than 42%of total hospital admissions in 2009(n=39000),despite representing only 2.5%of the Italian population.Particularly,women aged>85accounted for 30.8%of total fractures,although they represented just 1.8%of the general population.The results of this analysis indicate that the incidence of hip fractures progressively increased from 2000 to 2009,but a reduction can be observed for the first time in women≤75(-7.9%between 2004 and 2009).CONCLUSION:Incidence of hip fractures in Italy are continuously increasing,although women aged 65-74years old started showing a decreasing trend.

Phrenic nerve displacement by intrapericardial balloon inflation during epicardial ablation of ventricular tachycardia: Four case reports

BACKGROUND Phrenic nerve(PN)injury is one of the recognized possible complications following epicardial ablation of ventricular tachycardia(VT).High-output pacing is a widely used maneuver to establish a relationship between the PN and the ablation catheter tip.An absence of PN capture is usually considered an indication that it is safe to ablate,and that successful ablation may be performed at adjacent sites.However,PN capture may impact the procedural outcome.Only a few cases have been reported in the literature that avoid PN injury by using different techniques.CASE SUMMARY Three patients with a previous history of myocarditis and one patient with ischemic cardiomyopathy underwent epicardial ablation for drug-refractory VT.Before the procedure,transthoracic echocardiogram,coronary angiogram,and cardiac magnetic resonance imaging were performed on all patients.Under general anesthesia,endo/epicardial three-dimensional anatomical and substrate maps of the left ventricle were accomplished.Before radiofrequency delivery,the course of the PN was identified by provoking diaphragmatic stimulation with high-output pacing from the distal electrode of the ablation catheter.In every case,a scar region with late potentials was mapped along the PN course.After obtaining another epicardial access,a second introducer sheath was placed,and a vascular balloon catheter was inserted into the epicardial space and inflated with saline solution to separate the PN from the epicardium.Once the absence of PN capture had been proven,radiofrequency was applied to aim for complete late potential elimination and avoid VT induction.CONCLUSION PN injury can occur as one of the complications following epicardial VT ablation procedures,and may prevent successful ablation of these arrhythmias.PN displacement by using large balloon catheters into the epicardial space seems to be feasible and reproducible,avoid procedure-related morbidity,and improve ablation success when performed in selected centers and by experienced operators.

The Benefits of Non-Surgical Periodontal Treatment in Association with Gastric Eradication

Periodontitis is a chronic degenerative disease which is inflammatory and whose bacteriological aetiology interests the hard and soft tissues supporting the dental elements. A typical characteristic of periodontitis is its correlation with other branches of medicine since periodontal disease is often associated with several other illnesses or systemic conditions which exacerbate or predispose the course of the disease. Amongst the most frequent gastroduodenal diseases are those associated with Helicobacter pylori (Hp) infections such as acute gastritis, chronic atrophic gastritis, gastric atrophy, gastritis ulcers, dysplasia, duodenal ulcer, gastric cancer, gastric MALT-lymphoma. Transmission of the microorganism occurs through iatrogenic pathways (faecal-oral, oral-oral) and through food and water ingestion. From this the possible role of the oral cavity becomes evident as a means of transmitting the microorganism and as an extra-gastric reservoir of Hp which develops inside the oral plaque, the main aetiological agent of periodontal disease. Considering that in a patient affected with periodontal disease the oral cavity presents elevated indices of bacterial plaque in association with infrabony pockets one is brought to ask if it might represent a favourable habitat for Hp colonisation. Furthermore, another query that one might pose is whether the presence of Hp in the oral cavity might be the cause of relapse in gastric infections caused by Hp. Consequently, might non-surgical periodontal treatment, in association with an eradicating gastric therapy, foster decontamination of the microorganism in the oral cavity leading to a better prevention of relapse and re-infection of the gastric cavity? Could non-surgical periodontal treatment thus mean prevention of gastric diseases brought on by Helicobacter pylori? The objective of this study is therefore to evaluate the incidence of periodontal disease and oral Hp infection in patients affected by gastric Hpinfection and to determine the possible benefits of the association of non-surgical periodontal therapy with eradicating gastric therapy compared with treatment that involves just the eradicating gastric therapy in patients who are affected by periodontal disease and Hp infection.

Anomalies Observed in VLF and LF Radio Signals on the Occasion of the Western Turkey Earthquake(M_(W)=5.7)on May 19,2011

Since 2009 a network of VLF (20 - 60 kHz) and LF (150 - 300 kHz) radio receivers is operating in Europe in order to study the disturbances produced by the earthquakes on the propagation of these signals. In 2011 the network was formed by nine receivers, of which three are located in Italy and one is in Austria, Greece, Portugal, Romania, Russia and Turkey. On May 19, 2001 an earthquake (Mw = 5.7) occurred in western Turkey, that is inside the “sensitive” area of the network. The radio data collected during April-May 2011 were studied using the Wavelet spectra, the Principal Component Analysis and the Standard Deviation trends as different methods of analysis. Evident anomalies were revealed both in the signals broadcasted by the TRT transmitter (180 kHz) located near Ankara and in a VLF signal coming from a transmitter located in Western Europe and collected by the receiver TUR of the network located in eastern Turkey. Evident precursor phases were pointed out. Some differences in the efficiency of the three analysis methods were revealed.

Chronic rejection after liver transplantation:Opening the Pandora’s box

Chronic rejection(CR)of liver allografts causes damage to intrahepatic vessels and bile ducts and may lead to graft failure after liver transplantation.Although its prevalence has declined steadily with the introduction of potent immunosuppressive therapy,CR still represents an important cause of graft injury,which might be irreversible,leading to graft loss requiring re-transplantation.To date,we still do not fully appreciate the mechanisms underlying this process.In addition to T cell-mediated CR,which was initially the only recognized type of CR,recently a new form of liver allograft CR,antibody-mediated CR,has been identified.This has indeed opened an era of thriving research and renewed interest in the field.Liver biopsy is needed for a definitive diagnosis of CR,but current research is aiming to identify new non-invasive tools for predicting patients at risk for CR after liver transplantation.Moreover,the minimization or withdrawal of immunosuppressive therapy might influence the establishment of subclinical CR-related injury,which should not be disregarded.Therapies for CR may only be effective in the“early”phases,and a tailored management of the immunosuppression regimen is essential for preventing irreversible liver damage.Herein,we provide an overview of the current knowledge and research on CR,focusing on early detection,identification of non-invasive biomarkers,immunosuppressive management,re-transplantation and future perspectives of CR.

Osteomyelitis in diabetic foot:A comprehensive overview

Foot infection is a well recognized risk factor for major amputation in diabetic patients. The osteomyelitis is one of the most common expression of diabetic foot infection, being present approximately in present in 10%-15% of moderate and in 50% of severe infectious process. An early and accurate diagnosis is required to ensure a targeted treatment and reduce the risk of major amputation. The aim of this review is to report a complete overview about the management of diabetic foot osteomyelitis. Epidemiology, clinical aspects, diagnosis and treatment are widely described according to scientific reccomendations and our experience.

Alimentary regimen in non-alcoholic fatty liver disease:Mediterranean diet

Non-alcoholic fatty liver disease(NAFLD)is the most common liver disease worldwide.The mechanisms of the underlying disease development and progression are awaiting clarification.Insulin resistance and obesity-related inflammation status,among other possible genetic,dietary,and lifestyle factors,are thought to play the key role.There is no consensus concerning the pharmacological treatment.However,the dietary nutritional management to achieve weight loss is an essential component of any treatment strategy.On the basis of its components,the literature reports on the effectiveness of the Mediterranean diet in reducing cardiovascular risk and in preventing major chronic diseases,including obesity and diabetes.New evidence supports the idea that the Mediterranean diet,associated with physical activity and cognitive behaviour therapy,may have an important role in the prevention and the treatment of NAFLD.

New obesity classification criteria as a tool for bariatricsurgery indication

Obesity plays relevant pathophysiological role in the development of health problems, arising as result of complex interaction of genetic, nutritional, and metabolic factors. Due to the role of adipose tissue in lipid and glucose metabolism, and low grade inflammation, it is necessary to classify obesity on the basis of body fat composition and distribution, rather than the simply increase of body weight, and the Body Mass Index. The new term of adiposopathy(‘‘sick fat'') clearly defines the pathogenic role of adipose tissue. Four phenotypes of obese individuals have been described:(1) normal weight obese(NWO);(2) metabolically obese normal weight;(3) metabolically healthy obese; and(4) metabolically unhealthy obese or "at risk" obese. Moreover, sarcopenic obesity has been related to all the phenotypes. The category of normal weight lean, represented by metabolically healthy normal weight has been classified to distinguish from NWO. It is crucial to recommend a bariatric surgery taking into account adiposopathy and sick fat that occurs with the expansion of fat mass, changing the inflammatory and metabolic profile of the patient. Body fat percentage and genetic polymorphism have to be evaluated to personalize the best bariatric surgery intervention.

COVID-19 in normal,diseased and transplanted liver

Starting from December 2019 the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has extended in the entire world giving origin to a pandemic.Although the respiratory system is the main apparatus involved by the infection,several other organs may suffer coronavirus disease 2019(COVID-19)-related injuries.The human tissues expressing angiotensin-converting enzyme 2(ACE2)are all possible targets of viral damage.In fact myocarditis,meningo-encephalitis,acute kidney injury and other complications have been described with regard to SARS-CoV-2 infection.The liver has a central role in the body homeostasis contributing to detoxification,catabolism and also synthesis of important factor such as plasma proteins.ACE2 is significantly expressed just by cholangiocytes within the liver,however transaminases are increased in more than one third of COVID-19 patients,at hospital admission.The reasons for liver impairment in the course of this infection are not completely clear at present and multiple factors such as:Direct viral effect,release of cytokines,ischemic damage,use of hepatotoxic drugs,sepsis,and others,may contribute to damage.While COVID-19 seems to elicit just a transient alteration of liver function tests in subjects with normal hepatic function,of concern,more severe sequelae are frequently observed in patients with a reduced hepatic reserve.In this review we report data regarding SARS-CoV-2 infection in subjects with normal or diseased liver.In addition the risks of COVID-19 in immunosuppressed patients(either transplanted or suffering for autoimmune liver diseases)are also described.