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Cadaveric bone marrow mesenchymal stem cells:first experience treating a patient with large severe burns

Burns & Trauma 2015年第2期3卷 74-82页

作者： Eduardo Mansilla Gustavo H.Marín Mirta Berges Silvia Scafatti Jaime Rivas Andrea Núñez Martin Menvielle Roberto Lamonega Cecilia Gardiner hugo drago Flavio Sturla Mercedes Portas Silvia Bossi Maria Victoria Castuma Sandra Peña Luengas Gustavo Roque Karina Martire Jose Maria Tau Gabriel Orlandi Adrian Tarditti Tissue Engineering Regenerative Medicine and Cell Therapies LaboratoryCUCAIBAProvince of Buenos Aires Ministry of HealthTransplantation ProgramLa PlataProvince of Buenos AiresArgentina Burns and Plastic Surgery Department San Martín HospitalProvince of Buenos Aires Ministry of HealthLa PlataProvince of Buenos AiresArgentina Burns Hospital Buenos Aires CityArgentina Department of Chemistry Mayaguez CampusUniversity of Puerto RicoMayaguezPuerto RicoUSA.

Background:In January 2005,Rasulov et al.originally published"First experience in the use of bone marrow mesenchymal stem cells(MSCs)for the treatment of a patient with deep skin burns".Here,we present the first ever treated patient with cadaveric bone marrow mesenchymal stem cells(CMSCs)in the history of Medicine.Methods:A young man,who severely burned 60%of his total body surface with 30%of full-thickness burns while working with a grass trimmer that exploded,was involved in the study.MSCs were obtained from the bone marrow of a cadaver donor in a routine procurement procedure of CUCAIBA,the Province of Buenos Aires,Argentina,Ministry of Health,Transplantation Agency,cultured,expanded,and applied on the burned surfaces using a fibrin spray after early escharotomy.Results:So far,our preliminary experience and our early results have been very impressive showing an outstanding safety data as well as some impressive good results in the use of CMSCs.Conclusions:Based on al this,we think that improvements in the use of stem cells for burns might be possible in the near future and a lot of time as well as many lives could be saved by many other research teams all over the world.CMSCs will probably be a real scientific opportunity in Regenerative Medicine as well as in Transplantation.

关键词： Burns Cadaveric Transplantation Skin regeneration Mesenchymal stem cells

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Pancreatic neuroendocrine tumors:Are tumors smaller than 2 cm truly indolent?

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 1756-1762页

作者： Sergio Hoyos Pablo Posada-Moreno Natalia Guzman-Arango Romario Chanci-drago Jaime Chavez Alvaro Andrés-Duarte Santiago Salazar-Ochoa Hepatobilary and Liver Transplant Unit Hospital Pablo Tobon Uribe and Gastrohepathology Group Universidad de AntioquiaMedellin 050034AntioquiaColombia Department of General Surgery Universidad Pontificia BolivarianaMedellín 050034AntioquiaColombia

BACKGROUND Pancreatic neuroendocrine tumors(PNETs)are relatively rare but rank as the second most common pancreatic neoplasm.They can be functional,causing early metabolic disturbances due to hormone secretion,or non-functional and diagnosed later based on tumor size-related symptoms.Recent diagnoses of PNETs under 2 cm in size have sparked debates about their management;some practitioners advocate for surgical removal and others suggest observation due to the tumors’lower potential for malignancy.However,it is unclear whether managing these small tumors expectantly is truly safe.AIM To evaluate poor prognostic factors in PNETs based on tumor size(>2 cm or<2 cm)in surgically treated patients.METHODS This cohort study included 64 patients with PNETs who underwent surgical resection between 2006 and 2019 at a high-complexity reference hospital in Medellín,Colombia.To assess patient survival,quarterly follow-ups were conducted during the first year after surgery,followed by semi-annual con-sultations at the hospital's hepatobiliary surgery department.Qualitative variables were described using absolute and relative frequencies,and quantitative variables were expressed using measures of central tendency and their corresponding measures of dispersion.RESULTS The presence of lymph node involvement,neural involvement,and lymphovascular invasion were all associated with an increased risk of mortality,with hazard ratios of 5.68(95%CI:1.26–25.61,P=0.024),6.44(95%CI:1.43–28.93,P=0.015),and 24.87(95%CI:2.98–207.19,P=0.003),respectively.Neural involvement and lymphovascular invasion were present in tumors smaller than 2 cm in diameter and those larger than 2 cm in diameter.The recurrence rates between the two tumor groups were furthermore similar:18.2%for tumors smaller than 2 cm and 21.4%for tumors larger than 2 cm.Patient survival was additionally comparable between the two tumor groups.CONCLUSION Tumor size does not dictate prognosis;lymph node and lymphovascular involvement affect mortality,which high-lights that histopath

关键词： Neuroendocrine tumor Pancreatic neoplasm Pancreas Pancreatic neuroendocrine neoplasm Pancreatic neuroendocrine tumors

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Viral infections in orthopedics: A systematic review and classification proposal

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World Journal of Orthopedics 2022年第11期13卷 1015-1028页

作者： Konstantinos Sidiropoulos Savvas Ilias Christofilos Konstantinos Tsikopoulos Dimitrios Kitridis Lorenzo drago Gabriele Meroni Carlo Luca Romanò Venu Kavarthapu General Hospital of Serres Serres 62100Greece Department of Genetics Evolution and EnvironmentUniversity College LondonLondon WC1E 6BTUnited Kingdom Department of Orthopaedics 404 Army General HospitalLarissa 41222Greece the First Department of Orthopaedics Aristotle University of ThessalonikiThessaloniki 54124Greece Department of Biomedical Sciences for Health and Microbiome University of MilanMilan 20133Italy Department of Biomedical Surgicaland Dental SciencesOne Health UnitUniversity of MilanMilan 20133Italy Gruppo di Studio SIOT Infezioni-Clinica San Gaudenzio-Novara-Gruppo Policlinico di Monza University of MilanMilan 20100Italy Trauma and OrthopaedicsKings College Hospital LondonDenmark HillLondon SE59RSUnited Kingdom

BACKGROUND Although the impact of microbial infections on orthopedic clinical outcomes is well recognized,the influence of viral infections on the musculoskeletal system might have been underestimated.AIM To systematically review the available evidence on risk factors and musculoskeletal manifestations following viral infections and to propose a pertinent classification scheme.METHODS We searched MEDLINE,Cochrane Central Register of Controlled Trials(CENTRAL),the Reference Citation Analysis(RCA),and Scopus for completed studies published before January 30,2021,to evaluate risk factors and bone and joint manifestations of viral infection in animal models and patient registries.Quality assessment was performed using SYRCLE's risk of bias tool for animal studies,Moga score for case series,Wylde score for registry studies,and Newcastle-Ottawa Scale for case-control studies.RESULTS Six human and four animal studies were eligible for inclusion in the qualitative synthesis.Hepatitis C virus was implicated in several peri-and post-operative complications in patients without cirrhosis after major orthopedic surgery.Herpes virus may affect the integrity of lumbar discs,whereas Ross River and Chikungunya viruses provoke viral arthritis and bone loss.CONCLUSION Evidence of moderate strength suggested that viruses can cause moderate to severe arthritis and osteitis.Risk factors such as pre-existing rheumatologic disease contributed to higher disease severity and duration of symptoms.Therefore,based on our literature search,the proposed clinical and pathogenetic classification scheme is as follows:(1)Viral infections of bone or joint;(2)Active bone and joint inflammatory diseases secondary to viral infections in other organs or tissues;and(3)Viral infection as a risk factor for post-surgical bacterial infection.

关键词： Viral infection Musculoskeletal system Bone and joint manifestations Chikungunya Zika Hepatitis C virus Herpesviridae Ross River virus Cross-reactivity Classification

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In vitro laboratory infection research in orthopaedics:Why,when,and how

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世界骨科杂志:英文版 2023年第8期14卷 598-603页

作者： Konstantinos Tsikopoulos Lorenzo drago Gabriele Meroni Dimitrios Kitridis Byron Chalidis Fotios Papageorgiou Paraskevi Papaioannidou 1^(st)Department of Pharmacology School of MedicineFaculty of Health SciencesAristotle University of ThessalonikiThessaloniki 54124Greece Department of Biomedical Sciences for Health School of MedicineUniversity of MilanMilan 20133Italy Department of Biomedical Surgical and Dental SciencesUniversity of MilanMilan 20133Italy 1^(st)Department of Orthopaedic School of MedicineFaculty of Health SciencesAristotle University of ThessalonikiThessaloniki 57010Greece Department of Orthopaedic Surgery 404 General Army HospitalLarisa 41222Greece 1^(st)Department of Pharmacology Aristotle University of ThessalonikiThessaloniki 54124Greece

The musculoskeletal system involves multiple tissues which are constantly exposed to being exposed to various biological and mechanical stimuli.As such,isolating and studying a particular system from a complex human clinical environment is not always a realistic expectation.On top of that,recruitment limitations,in addition to the nature of orthopaedic interventions and their associated cost,sometimes preclude consideration of human trials to answer a clinical question.Therefore,in this mini review,we sought to rationalize the rapid evolution of biomedical research at a basic scientific level and explain why the perception of orthopaedic conditions has fundamentally changed over the last decades.In more detail,we highlight that the number of orthopaedic in vitro publications has soared since 1990.Last but not least,we elaborated on the minimum requirements for conducting a scientifically sound infection-related laboratory experiment to offer valuable information to clinical practitioners.We also explained the rationale behind implementing molecular biology techniques,ex vivo experiments,and artificial intelligence in this type of laboratory research.

关键词： Biofilm In vitro Laboratory research Methodology

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Dose escalation of adalimumab as a strategy to overcome anti-drug antibodies:A case report of infantile-onset inflammatory bowel disease

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World Journal of Gastroenterology 2023年第38期29卷 5428-5434页

作者： Silvana Ancona Sara Signa Chiara Longo Giuliana Cangemi Roberta Carfora Enrico drago Alessandro La Rosa Marco Crocco Andrea Chiaro Paolo Gandullia Serena Arrigo Dipartimento di Neuroscienze RiabilitazioneOftalmologiaGenetica e Scienze Materno-Infantili(DINOGMI)Universitàdegli Studi di GenovaGenova 16126Italy Pediatric Gastroenterology and Endoscopy Unit IRCCS Istituto Giannina GasliniGenova 16147Italy Chromatography and Mass Spectrometry Section Central Laboratory of AnalysisIRCCS Istituto Giannina GasliniGenova 16147Italy

BACKGROUND Treatment of infantile-onset inflammatory bowel disease(IO-IBD)is often challenging due to its aggressive disease course and failure of standard therapies with a need for biologics.Secondary loss of response is frequently caused by the production of anti-drug antibodies,a well-known problem in IBD patients on biologic treatment.We present a case of IO-IBD treated with therapeutic drug monitoring(TDM)-guided high-dose anti-tumor necrosis factor therapy,in which dose escalation monitoring was used as a strategy to overcome anti-drug antibodies.CASE SUMMARY A 5-mo-old boy presented with a history of persistent hematochezia from the 10th d of life,as well as relapsing perianal abscess and growth failure.Hypoalbuminemia,anemia,and elevated inflammatory markers were also present.Endoscopic assessment revealed skip lesions with deep colic ulcerations,inflammatory anal sub-stenosis,and deep fissures with persistent abscess.A diagnosis of IO-IBD Crohn-like was made.The patient was initially treated with oral steroids and fistulotomy.After the perianal abscess healed,adalimumab(ADA)was administered with concomitant gradual tapering of steroids.Clinical and biochemical steroid-free remission was achieved with good trough levels.After 3 mo,antibodies to ADA(ATA)were found with undetectable trough levels;therefore,we optimized the therapy schedule,first administering 10 mg weekly and subsequently up to 20 mg weekly(2.8 mg/kg/dose).After 2 mo of high-dose treatment,ATA disappeared,with concomitant high trough levels and stable clinical and biochemical remission of the disease.CONCLUSION TDM-guided high-dose ADA treatment as a monotherapy overcame ATA production.This strategy could be a good alternative to combination therapy,especially in very young patients.

关键词： Infantile-onset inflammatory bowel disease Adalimumab Loss of response Dose escalation Anti-drug antibodies Case report

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Gastric per-oral endoscopic myotomy:Indications,technique,results and comparison with surgical approach

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World Journal of Gastrointestinal Surgery 2022年第1期14卷 12-23页

作者： Maria Chiara Verga Stefano Mazza Francesco Azzolini Fabrizio Cereatti Clara Benedetta Conti Andrea drago Sara Soro Biagio Elvo Roberto Grassia Gastroenterology and Digestive Endoscopy Unit ASST CremonaCremona 26100Italy Gastroenterology and Digestive Endoscopy Unit Ospedale San Raffaele IRCCSMilano 20132Italy Digestive and Interventional Endoscopy Unit ASST MonzaMonza 20800Italy

Gastroparesis is a chronic disease of the stomach that causes a delayed gastric emptying,without the presence of a stenosis.For 30 years the authors identified pylorospasm as one of the most important pathophysiological mechanisms determining gastroparesis.Studies with EndoFLIP,a device that assesses pyloric distensibility,increased the knowledge about pylorospasm.Based on this data,several pyloric-targeted therapies were developed to treat refractory gastroparesis:Surgical pyloroplasty and endoscopic approach,such as pyloric injection of botulinum and pyloric stenting.Notwithstanding,the success of most of these techniques is still not complete.In 2013,the first human gastric per-oral endoscopic myotomy(GPOEM)was performed.It was inspired by the POEM technique,with a similar dissection method,that allows pyloromyotomy.Therapeutical results of GPOEM are similar to surgical approach in term of clinical success,adverse events and post-surgical pain.In the last 8 years GPOEM has gained the attention of the scientific community,as a minimally invasive technique with high rate of clinical success,quickly prevailing as a promising therapy for gastroparesis.Not surprisingly,in referral centers,its technical success rate is 100%.One of the main goals of recent studies is to identify those patients that will respond better to the therapies targeted on pylorus and to choose the better approach for each patient.

关键词： Gastric per-oral endoscopic myotomy Pyloroplasty Gastroparesis EndoFLIP Pyloromyotomy Gastroparesis cardinal symptom index

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Endoscopic management of gastrointestinal leaks and fistulae: Whatoption do we have?

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World Journal of Gastroenterology 2020年第29期26卷 4198-4217页

作者： Fabrizio Cereatti Roberto Grassia Andrea drago Clara Benedetta Conti Gianfranco Donatelli Digestive Endoscopy and Gastroenterology Unit Cremona HospitalCremonaCremona 26100Italy Department of Interventional Endoscopy Hospital Prive PeupliersRamsay SantéParis 75013France

Gastrointestinal leaks and fistulae are serious, potentially life threateningconditions that may occur with a wide variety of clinical presentations. Leaks aremostly related to post-operative anastomotic defects and are responsible for animportant share of surgical morbidity and mortality. Chronic leaks and longstanding post-operative collections may evolve in a fistula between twoepithelialized structures. Endoscopy has earned a pivotal role in the managementof gastrointestinal defects both as first line and as rescue treatment. Endotherapyis a minimally invasive, effective approach with lower morbidity and mortalitycompared to revisional surgery. Clips and luminal stents are the pioneer ofgastrointestinal (GI) defect endotherapy, whereas innovative endoscopic closuredevices and techniques, such as endoscopic internal drainage, suturing systemand vacuum therapy, has broadened the indications of endoscopy for themanagement of GI wall defect. Although several endoscopic options are currentlyused, a standardized evidence-based algorithm for management of GI defect isnot available. Successful management of gastrointestinal leaks and fistulaerequires a tailored and multidisciplinary approach based on clinical presentation,defect features (size, location and onset time), local expertise and the availabilityof devices. In this review, we analyze different endoscopic approaches, which weselected on the basis of the available literature and our own experience. Then, weevaluate the overall efficacy and procedural-specific strengths and weaknesses ofeach approach.

关键词： Leak Fistula Endotherapy Over-the-scope clip Suturing system Endovacuum therapy Endoscopic internal drainage Self-expandable metal stent

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Tackling dipeptidyl peptidase Ⅳ in neurological disorders

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Neural Regeneration Research 2018年第1期13卷 26-34页

作者： Ghaith Al-Badri Gian Marco Leggio Giuseppe Musumeci Rubina Marzagalli Filippo drago Alessandro Castorina School of Life Sciences Faculty of Science University of Technology Sydney Sydney Australia Section of Pharmacology Department of Biomedical and Biotechnological Sciences University of Catania Catania Italy Section of Human Anatomy and Histology Department of Biomedical and Biotechnological Sciences University of Catania Catania Italy Discipline of Anatomy and Histology School of Medical Sciences The University of Sydney Sydney Australia

Dipeptidyl peptidase IV （DPP-IV） is a serine protease best known for its role in inactivating glucagon-like peptide-1 （GLP-1）, pituitary adenylate cyclase-activating polypeptide （PACAP） and glucose-dependent insulinotropic peptide （GIP）, three stimulators of pancreatic insulin secretion with beneficial effects on glucose disposal. Owing to the relationship between DPP-IV and these peptides, inhibition of DPP-IV enzyme activity is considered as an attractive treatment option for diabetic patients. Nonetheless, increasing studies support the idea that DPP-IV might also be involved in the development of neurological disorders with a neuroinflammatory component, potentially through its non-incretin activities on immune cells. In this review article, we aim at highlighting recent literature describing the therapeutic value of DPP-IV inhibitors for the treatment of such neurological conditions. Finally, we will illustrate some of the promising results obtained using berberine, a plant extract with potent inhibitory activity on DPP-IV.

关键词： neurodegeneration inflammation immune system insulin diabetes alkaloids berberine

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Effect of Lactobacillus rhamnosus HN001 and Bifidobacterium longum BB536 on the healthy gut microbiota composition at phyla and species level: A preliminary study

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World Journal of Gastroenterology 2017年第15期23卷 2696-2704页

作者： Marco Toscano Roberta De Grandi Laura Stronati Elena De Vecchi Lorenzo drago Laboratory of Clinical Microbiology Department of Biomedical Science for HealthUniversity of Milan Department of Cellular Biotechnology and Hematology Laboratory of Clinical Chemistry and Microbiology IRCCS Galeazzi Orthopaedic InstituteUniversity of Milan

AIM To evaluate the ability of Lactobacillus rhamnosus HN001 and Bifidobacterium longum BB536 to colonize the intestinal environment of healthy subjects and modify the gut microbiota composition.METHODS Twenty healthy Italian volunteers, eight males and twelve females, participated in the study. Ten subjects took a sachet containing 4 × 109 colony-forming units(CFU) of Bifidobacterium longum BB536 and 109 CFU of Lactobacillus rhamnosus HN001, 30 min before breakfast(pre-prandial administration), while ten subjects took a sachet of probiotic product 30 min after breakfast(post-prandial administration). The ability ofLactobacillus rhamnosus HN001 and Bifidobacterium longum BB536 to colonize human gut microbiota was assessed by means of quantitative real-time PCR, while changes in gut microbiota composition were detected by using Ion Torrent Personal Genome Machine.RESULTS Immediately after 1-mo of probiotic administration, B. longum BB536 and L. rhamnosus HN001 load was increased in the majority of subjects in both preprandial and post-prandial groups. This increase was found also 1 mo after the end of probiotic oral intake in both groups, if compared to samples collected before probiotic consumption. At phyla level a significant decrease in Firmicutes abundance was detected immediately after 1-mo of B. longum BB536 and L. rhamnosus HN001 oral intake. This reduction persisted up to 1 mo after the end of probiotic oral intake together with a significant decrease of Proteobacteria abundance if compared to samples collected before probiotic administration. Whereas, at species level, a higher abundance of Blautia producta, Blautia wexlerae and Haemophilus ducrey was observed, together with a reduction of Holdemania filiformis, Escherichia vulneris, Gemmiger formicilis and Streptococcus sinensis abundance. In addition, during follow-up period we observed a further reduction in Escherichia vulneris and Gemmiger formicilis, together with a decrease in Roseburia faecis and Ruminococcus gnavus abundance. Conversely, the abu

关键词： Probiotics 内脏 microbiota Bifidobacterium 乳杆菌人的健康

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SARS-CoV-2 in inflammatory bowel disease population:Antibodies,disease and correlation with therapy

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World Journal of Gastrointestinal Endoscopy 2022年第3期14卷 153-162页

作者： Clara Benedetta Conti Elsa Mainardi Sara Soro Sophie Testa Annalisa De Silvestri Andrea drago Fabrizio Cereatti Roberto Grassia Department of Gastroenterology and Digestive Endoscopy ASST CremonaCremona 26100Italy Department of Laboratory Medicine Haemostasis and Thrombosis CenterASST CremonaCremona 26100Italy Department of Clinic Epidemiology and Biometric Scientific DirectionFondazione IRCCS Policlinico San MatteoPavia 27100Italy

BACKGROUND Guidelines recommend to cease inflammatory bowel disease(IBD)biologic therapy during coronavirus disease 2019(COVID-19).AIM To investigate severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)antibody positivity in an IBD cohort,COVID-19 disease severity and to evaluate the correlation with clinical/therapeutic variables.METHODS Prospective observational cohort study.IBD patients were tested for SARS-CoV-2 IgG.Data on COVID-19 disease,demographics/therapeutics and clinical features of the IBD population were collected.IgG≥7 was set for SARS-CoV-2 antibody positivity.Throat swab was performed in cases of IgG positivity.Correlations between antibody positivity or COVID-19 symptoms and therapeutic/clinical data were assessed.RESULTS In total,103 IBD patients were enrolled.Among them,18.4%had IgG≥7.Multivariate analysis of antibody positivity correlated only with IBD treatment.For IgG≥7,the odds ratio was 1.44 and 0.16 for azathioprine and mesalazine,respectively,vs biologic drugs(P=0.0157 between them).COVID-19 related symptoms were reported in 63%of patients with IgG positivity.All but one patient with COVID-19 symptoms did not require ceasing IBD treatment or hospitalization. IBDtreatment and body mass index correlated with COVID-19 disease development with symptoms.CONCLUSIONThe IBD population does not have a higher risk of severe COVID-19. The relative risk of havingSARS-CoV-2 antibodies and symptoms was higher for patients taking azathioprine, then biologictherapy and lastly mesalazine. None of the patients under biologic therapy developed severeCOVID-19.

关键词： Inflammatory bowel disease SARS-CoV-2 COVID-19 Biologic treatment SARS-CoV-2 antibody Inflammatory bowel disease therapy

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