Articoli di riviste: "Hemolytic uremic syndrome Prevention"

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Yoshiya, Kunihiko, Kouichi Nakanishi, Seiko Itoh, Kazumoto Iijima, Norishige Yoshikawa, Hajime Nakamura, Tae Takeda e Kazuhiro Kobayashi. "Etiology and prevention of hemolytic uremic syndrome". Nihon Shoni Jinzobyo Gakkai Zasshi 7, n. 2 (1994): 161–63. http://dx.doi.org/10.3165/jjpn.7.161.

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Afshar-Kharghan, Vahid. "Atypical hemolytic uremic syndrome". Hematology 2016, n. 1 (2 dicembre 2016): 217–25. http://dx.doi.org/10.1182/asheducation-2016.1.217.

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Abstract Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) that affects multiple organs and the kidneys in particular. aHUS can be sporadic or familial and is most commonly caused by dysregulation of the alternative complement pathway. The initial attack of aHUS can occur at any age, and is associated with a high rate of progression to end stage renal disease. Many aHUS patients relapse in the native or transplanted kidneys, and require close monitoring and long-term management. Availability of anticomplement therapy has revolutionized the management of aHUS, and can change the natural course of aHUS by inducing hematologic remission, improving or stabilizing kidney functions, and preventing graft failure. As a result, it is important to succeed in the challenging task of differentiating aHUS from other TMAs and initiate adequate treatment early during the course of disease. Considering the high cost of currently available anticomplement therapy, it is important also from a financial point of view to accurately diagnose aHUS early during the course of disease and determine the necessary length of therapy. This highlights the need for development of precise complement functional and genetic studies with rapid turnaround time.

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Goldwater, Paul N. "Treatment and prevention of enterohemorrhagicEscherichia coliinfection and hemolytic uremic syndrome". Expert Review of Anti-infective Therapy 5, n. 4 (agosto 2007): 653–63. http://dx.doi.org/10.1586/14787210.5.4.653.

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Haslam, David B. "Molecular Decoys: Novel Approaches to the Prevention of Hemolytic Uremic Syndrome". Pediatric Research 48, n. 3 (settembre 2000): 267–68. http://dx.doi.org/10.1203/00006450-200009000-00001.

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Joseph, Adrien, Aurélie Cointe, Patricia Mariani Kurkdjian, Cédric Rafat e Alexandre Hertig. "Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review". Toxins 12, n. 2 (21 gennaio 2020): 67. http://dx.doi.org/10.3390/toxins12020067.

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The severity of human infection by one of the many Shiga toxin-producing Escherichia coli (STEC) is determined by a number of factors: the bacterial genome, the capacity of human societies to prevent foodborne epidemics, the medical condition of infected patients (in particular their hydration status, often compromised by severe diarrhea), and by our capacity to devise new therapeutic approaches, most specifically to combat the bacterial virulence factors, as opposed to our current strategies that essentially aim to palliate organ deficiencies. The last major outbreak in 2011 in Germany, which killed more than 50 people in Europe, was evidence that an effective treatment was still lacking. Herein, we review the current knowledge of STEC virulence, how societies organize the prevention of human disease, and how physicians treat (and, hopefully, will treat) its potentially fatal complications. In particular, we focus on STEC-induced hemolytic and uremic syndrome (HUS), where the intrusion of toxins inside endothelial cells results in massive cell death, activation of the coagulation within capillaries, and eventually organ failure.

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TARR, PHILLIP I. "Escherichia coli O157: H7: Overview of Clinical and Epidemiological Issues". Journal of Food Protection 57, n. 7 (1 luglio 1994): 632–37. http://dx.doi.org/10.4315/0362-028x-57.7.632.

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Escherichia coli O157:H7 is an important and common human pathogen which causes diarrhea, bloody diarrhea (hemorrhagic colitis) and the life threatening post-diarrheal disorder, hemolytic uremic syndrome (HUS). Escherichia coli O157:H7 produces one or two potent cytotoxins, designated Shiga-like toxins (or verocytotoxins) I and II. While additional serotypes of cytotoxin-producing E. coli may cause human disease, E. coli O157:H7 is the most important such enteric pathogen in the United States. Epidemiologic data suggest that the incidence of hemolytic uremic syndrome is probably increasing. Until data emerge from controlled studies, conservative management of infected patients remains the mainstay of therapy, rather than specific antibacterial or antitoxin therapy. The serious nature of illness caused by E. coli O157:H7 should make prevention of human infection with this pathogen a high priority for the food industry.

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Davin, Jean-Claude, Charles Majoie, Jaap Groothoff, Valentina Gracchi, Antonia Bouts, Timothy H. J. Goodship e Chantal Loirat. "Prevention of large-vessel stenoses in atypical hemolytic uremic syndrome associated with complement dysregulation". Pediatric Nephrology 26, n. 1 (24 luglio 2010): 155–57. http://dx.doi.org/10.1007/s00467-010-1608-9.

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Nuernberger, Jens, Oliver Witzke, Russell P. Rother, Thomas Philipp, Udo Vester, Hideo Baba, Lothar Bernd Zimmerhackl e Andreas Kribben. "Successful Treatment of Atypical Hemolytic Uremic Syndrome with the Complement Inhibitor Eculizumab." Blood 112, n. 11 (16 novembre 2008): 2294. http://dx.doi.org/10.1182/blood.v112.11.2294.2294.

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Abstract Background: Atypical hemolytic uremic syndrome (aHUS) is a rare microangiopathic hemolytic anemia characterized by the uncontrolled progression of the alternative complement pathway due to genetic or acquired dysregulation of steady state alternative pathway activity leading to a proinflammatory and prothrombotic condition. Atypical HUS is characterized by intravascular hemolysis, consumptive thrombocytopenia, and microvascular glomerular thrombosis with the formation of thrombi in glomerular capillaries. As the thrombotic microangiopathy is particularly severe in the renal microvasculature, the disease inevitably leads to acute kidney injury with most cases progressing to end-stage-renal-disease. Eculizumab is a complement inhibitor that has been shown to completely and consistently block the activation of the terminal complement cascade thereby preventing the generation of the proinflammatory and prothrombotic molecules C5a and C5b-9. In recent phase 3 clinical studies in patients with the rare hemolytic disease paroxysmal nocturnal hemoglobinuria, chronic eculizumab treatment was shown to be safe, and demonstrated an effective reduction in intravascular hemolysis and a 85% reduction in thrombotic events. Aim: The safety and efficacy of eculizumab in the management of aHUS. We sought to investigate the potential benefit of the complement inhibitor eculizumab in aHUS, a disease characterized by uncontrolled progression of the alternative complement pathway. Methods: Two aHUS patients that were unresponsive to plasmapheresis were dosed with 600 mg of eculizumab to inhibit the terminal complement cascade. The patients were monitored closely for adverse events and platelet counts, creatinine and haptoglobin were assessed. PK/PD analyses were performed on one of the two patients. Results: We report aHUS in two patients successfully treated with the complement inhibitor eculizumab. The first was a 37-year old female with recurrence of aHUS after renal transplantation. At the age of 25 years, the patient developed aHUS with end-stage-renal- disease and stayed on dialysis until she received a first cadaveric kidney transplant 5 years later. This first transplant was lost 5 weeks after transplantation due to chronic aHUS. A second attempt of kidney transplantation was undertaken using a calcineurin-inhibitor free immunosuppressive protocol and despite immediate plasmapheresis (4 times), aHUS worsened (platelet count dropping, haptoglobin decreasing, creatinine increasing) indicating a high probability of repeated renal transplant loss. The patient was characterized as having a missense mutation in the gene encoding the complement regulatory protein factor H. The current literature indicates that patients with such mutations have a high incidence of graft rejection (7 of 8 grafts rejected). Eculizumab was therefore administered and resulted in immediate and complete inhibition of terminal complement activation for at least 5 days. During the week following treatment, platelet count increased, hemolysis normalized (as assessed by haptoglobin levels), and transplant function recovered (as assessed by creatinine levels) indicating successful reversal of aHUS (see Figure A). The second patient was an 18-year old female with first the initial manifestation of aHUS. After a total of 18 plasmaphereses, the young patient was referred to our hospital with aHUS. When symptoms persisted despite another three plasmaphereses in our University hospital, we decided to administer eculizumab. Over the following week, platelet count normalized, hemolysis was reversed, and renal function partially recovered (see Figure B). Summary: This is the first report evaluating the use of a complement inhibitor as a potential therapy for the treatment of aHUS. These data suggest that eculizumab therapy results in a reduction in thrombotic microangiopathy and hemolysis as evidenced by a reversal of thrombocytopenia, the normalization of hemolytic parameters, and the recovery of kidney transplant function. These data suggest the eculizumab modifies the course of aHUS and warrant further clinical investigation to confirm whether complement inhibition with eculizumab is an effective treatment of this devastating and life-threatening disease. Figure Figure

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Noris, Marina, e Giuseppe Remuzzi. "Managing and preventing atypical hemolytic uremic syndrome recurrence after kidney transplantation". Current Opinion in Nephrology and Hypertension 22, n. 6 (novembre 2013): 704–12. http://dx.doi.org/10.1097/mnh.0b013e328365b3fe.

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Avila Bernabeu, Ana Isabel, Teresa Cavero Escribano e Mercedes Cao Vilarino. "Atypical Hemolytic Uremic Syndrome: New Challenges in the Complement Blockage Era". Nephron 144, n. 11 (2020): 537–49. http://dx.doi.org/10.1159/000508920.

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Atypical hemolytic uremic syndrome (aHUS) is a rare cause of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and multisystem end organ involvement, most commonly affecting the kidney. Diagnosis is clinical, after exclusion of other TMA causes. Primary aHUS arises from genetic abnormalities, resulting in uncontrolled complement activity, while a variety of clinical scenarios cause secondary aHUS, including infection, pregnancy, malignancy, autoimmune disease, and medications. They can also induce a temporary complement deregulation with an overlap between both scenarios, which can make differential diagnosis difficult. Primary aHUS can be sporadic or familial and is associated with a high rate of progression to ESRD. Many aHUS patients relapse in the native or transplanted kidneys, leading to kidney failure. The introduction of eculizumab has changed the prognosis of aHUS, by inducing hematologic remission, improving or stabilizing kidney functions, and preventing graft failure. The early institution of appropriate therapy can prevent multiorgan damage, so is essential to recognize and differentiate the TMA syndromes. Eculizumab is considered now the first-line treatment, and it is recommended lifelong therapy. However, the high cost of therapy has led to make efforts to develop precise complement functional and genetic studies that help physicians to determine the appropriate duration of eculizumab therapy. Nowadays, more studies are needed to select candidates to adjustment of therapy.

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Winchester, Mae-Lan, Ryan Platzbecker, Megan McMahon e Marc Parrish. "Eculizumab Maintenance and the Prevention of Atypical Hemolytic Uremic Syndrome Relapse During Pregnancy: A Case Report". Journal of Medical Cases 10, n. 12 (2019): 343–44. http://dx.doi.org/10.14740/jmc3397.

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Giordano, Mario, Maria Elisabetta Baldassarre, Viviana Palmieri, Diletta D. Torres, Vincenza Carbone, Luisa Santangelo, Federico Gentile et al. "Management of STEC Gastroenteritis: Is There a Role for Probiotics?" International Journal of Environmental Research and Public Health 16, n. 9 (12 maggio 2019): 1649. http://dx.doi.org/10.3390/ijerph16091649.

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Shiga toxin-producing Escherichia Coli (STEC) infections routinely run as a common gastroenteritis, but in many cases they may evolve towards hemolytic uremic syndrome (HUS). HUS is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Gut microorganisms have a fundamental impact on human physiology, because they modulate normal intestinal functions and play a pivotal role in influencing the local and systemic immune responses. Despite surveillance established in many countries and major progresses in the understanding of STEC-HUS mechanisms, no specific treatment is currently available. Targeting the gut microbiota could represent a new potential therapeutic strategy in STEC infection. In this paper, we reviewed the current knowledge about microbiota characteristics of patients with STEC infections, as well as in vitro and in vivo evidence of probiotic supplementation in managing STEC gastroenteritis and in HUS onset prevention.

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Vallance, Bruce A., Crystal Chan, Marilyn L. Robertson e B. Brett Finlay. "Enteropathogenic and EnterohemorrhagicEscherichia coliInfections: Emerging Themes in Pathogenesis and Prevention". Canadian Journal of Gastroenterology 16, n. 11 (2002): 771–78. http://dx.doi.org/10.1155/2002/410980.

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EnteropathogenicEscherichia coli(EPEC) and enterohemorrhagicE coli(EHEC) are important causes of infectious diarrhea, particularly among pediatric populations. While EPEC is a significant health threat in the developing world, EHEC causes sporadic but deadly outbreaks of hemorrhagic colitis and hemolytic-uremic syndrome in North America and other developed areas. The present review discusses emerging themes in the pathogenesis of EPEC and EHEC, including the discovery and characterization of novel bacterial proteins that are injected by the pathogen into host cells. Recent advances have also been made in the development of relevant animal models, while bacterial virulence factors are being investigated as potential vaccination targets for humans and animals. It is hoped that these new areas of study will not only further our knowledge of the pathogenesis of EPEC- and EHEC-induced disease but also provide opportunities for reducing infection rates and improving treatment options in the future.

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Robitaille, Pierre, Marie-José Clermont, Aïcha Mérouani, Véronique Phan e Anne-Laure Lapeyraque. "Hemolytic Uremic Syndrome: Late Renal Injury and Changing Incidence—A Single Centre Experience in Canada". Scientifica 2012 (2012): 1–7. http://dx.doi.org/10.6064/2012/341860.

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Aims. To assess trends in the incidence of pediatric diarrhea-associated hemolytic uremic syndrome (D+HUS) and document long-term renal sequelae.Methods. We conducted a retrospective cohort study of children with D+HUS admitted to a tertiary care pediatric hospital in Montreal, Canada, from 1976 to 2010. In 2010, we recontacted patients admitted before 2000.Results. Of 337 cases, median age at presentation was 3.01 years (range 0.4–14). Yearly incidence peaked in 1988 and 1994-95, returning to near-1977 levels since 2003. Twelve patients (3.6%) died and 19 (5.6%) experienced long-term renal failure. Almost half (47%) The patients required dialysis. Need for dialysis was the best predictor of renal sequelae, accounting for 100% of severe complications. Of children followed ≥1 year (, mean follow-up years), 19 had severe and 18 mild-to-moderate kidney injury, a total sequelae rate, of 18.6%. Ten years or more after-HUS (, mean follow-up years), 8 (9.4%) patients demonstrated serious complications and 22 (25.9%) mild-to-moderate, including 14 (16%) microalbuminuria: total sequelae, 35.3%.Conclusions. Patients with D+HUS should be monitored at least 5 years, including microalbuminuria testing, especially if dialysis was required. The cause of the declining incidence of D+HUS is elusive. However, conceivably, improved public health education may have played an important role in the prevention of food-borne disease.

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Gonzalez Suarez, Maria L., Charat Thongprayoon, Michael A. Mao, Napat Leeaphorn, Tarun Bathini e Wisit Cheungpasitporn. "Outcomes of Kidney Transplant Patients with Atypical Hemolytic Uremic Syndrome Treated with Eculizumab: A Systematic Review and Meta-Analysis". Journal of Clinical Medicine 8, n. 7 (27 giugno 2019): 919. http://dx.doi.org/10.3390/jcm8070919.

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Background: Kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) is frequently complicated by recurrence, resulting in thrombotic microangiopathy in the renal allograft and graft loss. We aimed to assess the use of eculizumab in the prevention and treatment of aHUS recurrence after kidney transplantation. Methods: Databases (MEDLINE, EMBASE and Cochrane Database) were searched through February 2019. Studies that reported outcomes of adult kidney transplant recipients with aHUS treated with eculizumab were included. Estimated incidence rates from the individual studies were extracted and combined using random-effects, generic inverse variance method of DerSimonian and Laird. Protocol for this systematic review has been registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42018089438). Results: Eighteen studies (13 cohort studies and five case series) consisting of 380 adult kidney transplant patients with aHUS who received eculizumab for prevention and treatment of post-transplant aHUS recurrence were included in the analysis. Among patients who received prophylactic eculizumab, the pooled estimated incidence rates of recurrent thrombotic microangiopathy (TMA) after transplantation and allograft loss due to TMA were 6.3% (95%CI: 2.8–13.4%, I2 = 0%) and 5.5% (95%CI: 2.9–10.0%, I2 = 0%), respectively. Among those who received eculizumab for treatment of post-transplant aHUS recurrence, the pooled estimated rates of allograft loss due to TMA was 22.5% (95%CI: 13.6–34.8%, I2 = 6%). When the meta-analysis was restricted to only cohort studies with data on genetic mutations associated with aHUS, the pooled estimated incidence of allograft loss due to TMA was 22.6% (95%CI: 13.2–36.0%, I2 = 10%). We found no significant publication bias assessed by the funnel plots and Egger’s regression asymmetry test (p > 0.05 for all analyses). Conclusions: This study summarizes the outcomes observed with use of eculizumab for prevention and treatment of aHUS recurrence in kidney transplantation. Our results suggest a possible role for anti-C5 antibody therapy in the prevention and management of recurrent aHUS.

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Baiko, S. V. "FIRST EXPERIENCE OF USING THE BIOSIMILAR OF ORIGINAL ECULIZUMAB FOR PREVENTION OF ATYPICAL HEMOLYTIC-UREMIC SYNDROME RECURRENCE AFTER RENAL TRANSPLANTATION IN A CHILD". Pediatria. Journal named after G.N. Speransky 100, n. 1 (15 febbraio 2021): 293–96. http://dx.doi.org/10.24110/0031-403x-2021-100-1-293-296.

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The article presents a clinical case of atypical hemolytic uremic syndrome (аHUS), the debut of which proceeded under the guise of a typical HUS. After 4 months of hemodialysis, the child did not need renal replacement therapy for the next 9 months. The development of end-stage renal failure required a molecular genetic study to clarify the diagnosis. The child has mutations in the genes of the complement regulatory proteins – factor I and MCP. The risk of aHUS recurrence with these genes mutations to a renal transplant without pathogenetic prophylaxis is up to 80%. The use of the Russian biosimilar eculizumab before and after kidney transplantation allowed to prevent the activation of complement and disease recurrence to transplanted organ.

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Luz, Daniela, Maria Amaral, Flavia Sacerdoti, Alan Bernal, Wagner Quintilio, Ana Moro, Marina Palermo, Cristina Ibarra e Roxane Piazza. "Human Recombinant Fab Fragment Neutralizes Shiga Toxin Type 2 Cytotoxic Effects in vitro and in vivo". Toxins 10, n. 12 (2 dicembre 2018): 508. http://dx.doi.org/10.3390/toxins10120508.

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Shiga toxin (Stx) producing Escherichia coli (STEC) is responsible for causing hemolytic uremic syndrome (HUS), a life-threatening thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and acute renal failure after bacterially induced hemorrhagic diarrhea. Until now, there has been neither an effective treatment nor method of prevention for the deleterious effects caused by Stx intoxication. Antibodies are well recognized as affinity components of therapeutic drugs; thus, a previously obtained recombinant human FabC11:Stx2 fragment was used to neutralize Stx2 in vitro in a Vero cell viability assay. Herein, we demonstrated that this fragment neutralized, in a dose-dependent manner, the cytotoxic effects of Stx2 on human glomerular endothelial cells, on human proximal tubular epithelial cells, and prevented the morphological alterations induced by Stx2. FabC11:Stx2 protected mice from a lethal dose of Stx2 by toxin-antibody pre-incubation. Altogether, our results show the ability of a new encouraging molecule to prevent Stx-intoxication symptoms during STEC infection.

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Ahn, Christina K., Eileen Klein e Phillip I. Tarr. "Editorial Commentary:Isolation of Patients Acutely Infected withEscherichia coliO157:H7: Low‐Tech, Highly Effective Prevention of Hemolytic Uremic Syndrome". Clinical Infectious Diseases 46, n. 8 (15 aprile 2008): 1197–99. http://dx.doi.org/10.1086/587664.

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Riddell, Amy, Tim Goodship e Coralie Bingham. "Prevention of recurrence of atypical hemolytic uremic syndrome post renal transplant with the use of higher-dose eculizumab". Clinical Nephrology 86, n. 10 (1 ottobre 2016): 200–202. http://dx.doi.org/10.5414/cn108808.

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Pickering, Matthew C., Elena Goicoechea de Jorge, Rubén Martinez-Barricarte, Sergio Recalde, Alfredo Garcia-Layana, Kirsten L. Rose, Jill Moss et al. "Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains". Journal of Experimental Medicine 204, n. 6 (21 maggio 2007): 1249–56. http://dx.doi.org/10.1084/jem.20070301.

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Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype–phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS.

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Menne, Jan, Yahsou Delmas, Fadi Fakhouri, John F. Kincaid, Christoph Licht, Enrico E. Minetti, Chris Mix et al. "SO050LONG-TERM FOLLOW-UP STUDY OF ECULIZUMAB FOR PREVENTION OF THROMBOTIC MICROANGIOPATHY IN PATIENTS WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME". Nephrology Dialysis Transplantation 31, suppl_1 (maggio 2016): i84. http://dx.doi.org/10.1093/ndt/gfw153.02.

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Lüth, Stefan, Thorben W. Fründt, Thomas Rösch, Christoph Schlee e Ansgar W. Lohse. "Prevention of Hemolytic Uremic Syndrome With Daily Bowel Lavage in Patients With Shiga Toxin–Producing EnterohemorrhagicEscherichia coliO104:H4 Infection". JAMA Internal Medicine 174, n. 6 (1 giugno 2014): 1003. http://dx.doi.org/10.1001/jamainternmed.2014.1175.

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Sheth, Kruti, Raffaele Girlanda e Catherine Broome. "Long-Term Management of Atypical Hemolytic Uremic Syndrome after Non-Renal Solid Organ Transplantation with Eculizumab". Blood 126, n. 23 (3 dicembre 2015): 3466. http://dx.doi.org/10.1182/blood.v126.23.3466.3466.

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Abstract Thrombotic microangiopathy (TMA) defined as microangiopathic hemolytic anemia, thrombocytopenia and end organ damage has been described in the post transplant (PT) setting after solid organ and hematopoietic stem cell transplants (HSCT). The true incidence among non-renal solid organ transplant (NRSOT) recipients is unknown. Reported rates range from 2-30% (Verbiest 2014). Despite standard interventions such as plasma exchange and/or reduction in calcineurin inhibitor (CNI) therapy, 3-month mortality rates remain as high as 40% in NRSOT patients who develop PT-TMA. In HSCT and renal transplant recipients, it has been demonstrated that complement plays a central role in the development of PT-TMA, analogous to atypical hemolytic uremic syndrome (aHUS) (Zuber 2011; Jodele 2013). Based on similar clinical manifestations and etiology, PT-TMA should be defined by the same laboratory criteria as aHUS and treated with eculizumab (ECU), a monoclonal antibody directed against C5 (Sheth, ASH 2014). We previously reported the successful use of ECU for the acute treatment of PT-aHUS in NRSOT patients (Broome, ASH 2013). We report the long-term data on this cohort of patients here. Between January 2012-Novemeber 2013, 10 patients (8 small bowel, 2 liver), were diagnosed with PT-aHUS utilizing established clinical criteria for de novo aHUS. All patients were on CNI therapy at the time of diagnosis. The median time from transplant to TMA diagnosis was 10.5 months (range 1-53 months). All patients received standard aHUS dosing of ECU (with meningococcal vaccinations and antibiotic prophylaxis). By 1 month of ECU therapy, all patients demonstrated normalization of hematologic parameters and 4 of the 5 patients on hemodialysis (HD) at the time of ECU initiation were able to discontinue HD. At a median follow-up of 24 months, 7 patients remain on therapy (range 18-43 months). One patient had ECU discontinued at 3 months by the transplant team. Two patients have died: one at 3 months of therapy due to sepsis/multi-organ failure and the other at 6 months of therapy due to PT lymphoproliferative disorder/graft failure (GF). The 7 patients remaining on ECU had no clinical/laboratory evidence of recurrence of PT-aHUS (Table 1). No new HD has been initiated in the follow-up period. All remained on CNI therapy (tacrolimus) for prevention of transplant rejection. One patient on ECU therapy developed GF. No serious infections have been reported to date. ECU is an effective therapy for the long-term management of PT-aHUS in NRSOT recipients. Prompt initiation of ECU appears to result in an increased likelihood of reversal of end organ damage related to TMA. The 2 patients with GF (240 days, 572 days) and the 1 patient who remained on HD (180 days) had extended intervals from laboratory evidence of PT-aHUS to initiation of ECU, suggesting prolonged complement mediated TMA may contribute to irreversible organ damage. With early ECU therapy, 86% of patients have healthy graft function and 80% of patients were able to discontinue HD. Despite ongoing CNI therapy, renal function, as measured by serum creatinine, has continued to improve demonstrating the benefit of long-term ECU therapy. The observed decline in haptoglobin, an acute phase reactant, at 12 and 18 months suggests a decrease in systemic inflammation with constant complement regulation mediated by ECU, illustrating the systemic nature of PT-aHUS. All patients remained on both CNI and ECU without infectious complications, demonstrating the ability to successfully administer more than one immune mediator in NRSOT patients with PT-aHUS concurrently. The mortality rate in our cohort of NRSOT recipients with PT-aHUS is 20%, significantly less than prior reports of up to 70%. We propose treatment with ECU at the earliest clinical/laboratory signs of aHUS to prevent the morbidity and mortality associated with PT-aHUS in NRSOT patients. Future studies should prospectively evaluate ECU therapy in PT-aHUS to better define the risks and benefits of this therapy in NRSOT patients. Table 1. Median Laboratory Values Post ECU At diagnosis 1 month 3 months 6 months 12 months 18 months Platelets k/uL 86 151 p=.01 175 p=.04 177 p=.01 191 p=.04 168 p=.07 Serum Creatinine mg/dL 2.26 1.54 p=.03 1.42 p=.05 1.28 p=.04 0.97 p=.13 1.18 p=.13 LDH units/L 369 302 p=.23 206 p=.17 186 p=.17 235 p=.23 158 p=.21 Haptoglobin mg/dL <8 115 p=.00 154 p=.01 136 p=.02 67 p=.03 90 p=.04 Disclosures Broome: Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding.

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Lukyanenko, Valeriy, Irina Malyukova, Ann Hubbard, Michael Delannoy, Edgar Boedeker, Chengru Zhu, Liudmila Cebotaru e Olga Kovbasnjuk. "EnterohemorrhagicEscherichia coliinfection stimulates Shiga toxin 1 macropinocytosis and transcytosis across intestinal epithelial cells". American Journal of Physiology-Cell Physiology 301, n. 5 (novembre 2011): C1140—C1149. http://dx.doi.org/10.1152/ajpcell.00036.2011.

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Gastrointestinal infection with Shiga toxins producing enterohemorrhagic Escherichia coli causes the spectrum of gastrointestinal and systemic complications, including hemorrhagic colitis and hemolytic uremic syndrome, which is fatal in ∼10% of patients. However, the molecular mechanisms of Stx endocytosis by enterocytes and the toxins cross the intestinal epithelium are largely uncharacterized. We have studied Shiga toxin 1 entry into enterohemorrhagic E. coli-infected intestinal epithelial cells and found that bacteria stimulate Shiga toxin 1 macropinocytosis through actin remodeling. This enterohemorrhagic E. coli-caused macropinocytosis occurs through a nonmuscle myosin II and cell division control 42 (Cdc42)-dependent mechanism. Macropinocytosis of Shiga toxin 1 is followed by its transcytosis to the basolateral environment, a step that is necessary for its systemic spread. Inhibition of Shiga toxin 1 macropinocytosis significantly decreases toxin uptake by intestinal epithelial cells and in this way provides an attractive, antibiotic-independent strategy for prevention of the harmful consequences of enterohemorrhagic E. coli infection.

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Prokopenko, E. I., S. A. Pasov, A. V. Vatazin, A. Ya Tsalman, T. E. Pankratenko e G. A. Generalova. "Kidney transplantation using complement inhibitor in a patient suffering from atypical hemolytic-uremic syndrome associated with factor H antibodies: successful prevention of recurrence of the underlying disease". Russian Journal of Transplantology and Artificial Organs 22, n. 2 (12 luglio 2020): 132–38. http://dx.doi.org/10.15825/1995-1191-2020-2-132-138.

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Atypical hemolytic-uremic syndrome (aHUS) is an extremely rare complement-mediated disease that belongs to the group of thrombotic microangiopathies (TMA). It often reoccurs after kidney transplantation (KT). Previously, KT was considered contraindicated in both children and adults with aHUS due to high (up to 50% and above) incidence of early graft loss associated with post-transplant recurrent TMA. Introduction of specific complement inhibitor therapy into clinical practice has improved outcomes in patients with aHUS and has significantly reduced the risk of post-transplant recurrence of underlying disease. We describe the clinical observation of a 20-year-old female patient with aHUS associated with antibodies to factor H, a major regulator of complement activation. The patient underwent KT and eculizumab was used for prophylactic purposes. In the postoperative period, the patient developed ureteral necrosis that required reconstructive surgery, followed by graft pyelonephritis. Despite postoperative complications, which were highly likely to trigger uncontrolled complement activation, TMA recurrence was avoided due to early treatment of the complications and prophylactic use of complement inhibitor therapy.

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Zhu, George. "Retrospective Survey on the Outcome of 36 Diverse Cases of Anemia". Clinical Oncology Research and Reports 1, n. 1 (24 luglio 2020): 01–07. http://dx.doi.org/10.31579/2693-4787/004.

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Anemia is clinical common event. In this study,a retrospective study of 36 different types of anemias was place in proper interpretative review for their therapeutical outcome. By using comprehensive treatment regimen according to patients’ condition, 23 patients obtained cure or complete remission (CR), with the exception of refractory cancers and uremic anemia. Iron supplement was provided in 5 iron deficiency anemia. One megaloblastic anemia required the prescription of the supplement of vitamin B12 or folate deficiency. 2 aplastic anemia obtained complete remission with the integrated protocol of methyltestosterone,adenine,leucogen,and levamisol. Steroid hormone (e.g. prednisone) mixed traditional medicine were occasionally promising benefit in a nephrotic syndrome and renal insufficiency. Among 2 cases with dug- induced immune hemolytic anemia (DIIHA), laboratory studies a patient's serum contained paracetamol -dependent antibody that in the presence of paracetamol, agglutinated in vitro with "O" red cells with or without complement. Drug antibody titer was 1:4 positive. The reactive mechanism was attributed to both immune complex type and drug-adsorption, whereas another herba origanum vulgare- induced hemolysis secondary to drug adsorption only. In addition, regarding anemia caused by malignant tumours, the molecular genetic regulation of retinoic acid in acute promyelocytic leukemia (APL) has been further illustrated(see figure in full text). Therefore,to strengthen the active prevention and/or early interceptive treatment of anemia is our care.

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Lang, Elisabeth, e Florian Lang. "Triggers, Inhibitors, Mechanisms, and Significance of Eryptosis: The Suicidal Erythrocyte Death". BioMed Research International 2015 (2015): 1–16. http://dx.doi.org/10.1155/2015/513518.

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Suicidal erythrocyte death or eryptosis is characterized by erythrocyte shrinkage, cell membrane blebbing, and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca2+entry, ceramide formation, stimulation of caspases, calpain activation, energy depletion, oxidative stress, and dysregulation of several kinases. Eryptosis is triggered by a wide variety of xenobiotics. It is inhibited by several xenobiotics and endogenous molecules including NO and erythropoietin. The susceptibility of erythrocytes to eryptosis increases with erythrocyte age. Phosphatidylserine exposing erythrocytes adhere to the vascular wall by binding to endothelial CXC-Motiv-Chemokin-16/Scavenger-receptor for phosphatidylserine and oxidized low density lipoprotein (CXCL16). Phosphatidylserine exposing erythrocytes are further engulfed by phagocytosing cells and are thus rapidly cleared from circulating blood. Eryptosis eliminates infected or defective erythrocytes thus counteracting parasitemia in malaria and preventing detrimental hemolysis of defective cells. Excessive eryptosis, however, may lead to anemia and may interfere with microcirculation. Enhanced eryptosis contributes to the pathophysiology of several clinical disorders including metabolic syndrome and diabetes, malignancy, cardiac and renal insufficiency, hemolytic uremic syndrome, sepsis, mycoplasma infection, malaria, iron deficiency, sickle cell anemia, thalassemia, glucose 6-phosphate dehydrogenase deficiency, and Wilson’s disease. Facilitating or inhibiting eryptosis may be a therapeutic option in those disorders.

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Kallianpur, Asha R., Yuki Bradford, Rajal K. Mody, Katie N. Garman, Nicole Comstock, Sarah L. Lathrop, Carol Lyons et al. "Genetic Susceptibility to Postdiarrheal Hemolytic-Uremic Syndrome After Shiga Toxin–Producing Escherichia coli Infection: A Centers for Disease Control and Prevention FoodNet Study". Journal of Infectious Diseases 217, n. 6 (6 dicembre 2017): 1000–1010. http://dx.doi.org/10.1093/infdis/jix633.

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FRENZEN, PAUL D., ALISON DRAKE e FREDERICK J. ANGULO. "Economic Cost of Illness Due to Escherichia coli O157 Infections in the United States". Journal of Food Protection 68, n. 12 (1 dicembre 2005): 2623–30. http://dx.doi.org/10.4315/0362-028x-68.12.2623.

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Abstract (sommario):

The Centers for Disease Control and Prevention (CDC) has estimated that Shiga toxin–producing Escherichia coli O157 (O157 STEC) infections cause 73,000 illnesses annually in the United States, resulting in more than 2,000 hospitalizations and 60 deaths. In this study, the economic cost of illness due to O157 STEC infections transmitted by food or other means was estimated based on the CDC estimate of annual cases and newly available data from the Foodborne Diseases Active Surveillance Network (FoodNet) of the CDC Emerging Infections Program. The annual cost of illness due to O157 STEC was $405 million (in 2003 dollars), including $370 million for premature deaths, $30 million for medical care, and $5 million in lost productivity. The average cost per case varied greatly by severity of illness, ranging from $26 for an individual who did not obtain medical care to $6.2 million for a patient who died from hemolytic uremic syndrome. The high cost of illness due to O157 STEC infections suggests that additional efforts to control this pathogen might be warranted.

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Tanaka, Kazuki, Naoya Fujita e Satoshi Hibino. "Prophylactic amoxicillin for the prevention of meningococcal infection in infants with atypical hemolytic uremic syndrome under treatment with eculizumab: a report of two cases". CEN Case Reports 9, n. 3 (2 aprile 2020): 247–51. http://dx.doi.org/10.1007/s13730-020-00465-x.

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31

Paton, Adrienne W., Renato Morona e James C. Paton. "Neutralization of Shiga Toxins Stx1, Stx2c, and Stx2e by Recombinant Bacteria Expressing Mimics of Globotriose and Globotetraose". Infection and Immunity 69, n. 3 (1 marzo 2001): 1967–70. http://dx.doi.org/10.1128/iai.69.3.1967-1970.2001.

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Abstract (sommario):

ABSTRACT Strains of Escherichia coli producing Shiga toxins Stx1, Stx2, Stx2c, and Stx2d cause gastrointestinal disease and the hemolytic-uremic syndrome in humans. We have recently constructed a recombinant bacterium which displays globotriose (the receptor for these toxins) on its surface and adsorbs and neutralizes these Shiga toxins with very high efficiency. This agent has great potential for the treatment of humans with such infections. E. colistrains which cause edema disease in pigs produce a variant toxin, Stx2e, which has a different receptor specificity from that for the other members of the Stx family. We have now modified the globotriose-expressing bacterium such that it expresses globotetraose (the preferred receptor for Stx2e) by introducing additional genes encoding a N-acetylgalactosamine transferase and a UDP-N-acetylgalactosamine-4-epimerase. This bacterium had a reduced capacity to neutralize Stx1 and Stx2c in vitro, but remarkably, its capacity to bind Stx2e was similar to that of the globotriose-expressing construct; both constructs neutralized 98.4% of the cytotoxicity in lysates of E. coli JM109 expressing cloned stx 2e. These data suggest that either globotriose- or globotetraose-expressing constructs may be suitable for treatment and/or prevention of edema disease in pigs.

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Sheoran, Abhineet S., Susan Chapman, Pradeep Singh, Arthur Donohue-Rolfe e Saul Tzipori. "Stx2-Specific Human Monoclonal Antibodies Protect Mice against Lethal Infection with Escherichia coli Expressing Stx2 Variants". Infection and Immunity 71, n. 6 (giugno 2003): 3125–30. http://dx.doi.org/10.1128/iai.71.6.3125-3130.2003.

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Abstract (sommario):

ABSTRACT Shiga toxin-producing Escherichia coli (STEC) strains are responsible for causing hemolytic-uremic syndrome (HUS), and systemic administration of Shiga toxin (Stx)-specific human monoclonal antibodies (HuMAbs) is considered a promising approach for prevention or treatment of the disease in children. The goal of the present study was to investigate the ability of Stx2-specific HuMAbs to protect against infections with STEC strains that produce Stx2 variants. Dose-response studies on five HuMAbs, using the mouse toxicity model, revealed that only the three directed against the A subunit were protective against Stx2 variants, and 5C12 was the most effective among the three tested. Two HuMAbs directed against the B subunit, while highly effective against Stx2, were ineffective against Stx2 variants. In a streptomycin-treated mouse model, parenteral administration of 5C12 significantly protected mice up to 48 h after oral bacterial challenge. We conclude that 5C12, reactive against the Stx2 A subunit, is an excellent candidate for immunotherapy against HUS and that antibodies directed against the A subunit of Stx2 have broad-spectrum activity that includes Stx2 variants, compared with those directed against the B subunit.

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Amorim, Jaime H., Monica R. Jesus, Wilson B. Luiz, Bruna F. M. M. Porchia, Rita C. C. Ferreira, Esteban G. Servat, Pablo D. Ghiringhelli, Luis C. S. Ferreira e Leticia V. Bentancor. "Role of bacteriophages in STEC infections: new implications for the design of prophylactic and treatment approaches". F1000Research 3 (18 marzo 2014): 74. http://dx.doi.org/10.12688/f1000research.3718.1.

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Abstract (sommario):

Shiga toxin (Stx) is considered the main virulence factor in Shiga toxin-producing Escherichia coli (STEC) infections. Previously we reported the expression of biologically active Stx by eukaryotic cells in vitro and in vivo following transfection with plasmids encoding Stx under control of the native bacterial promoter. Since stx genes are present in the genome of lysogenic bacteriophages, here we evaluated the relevance of bacteriophages during STEC infection. We used the non-pathogenic E. coli K12 strain carrying a lysogenic 933W mutant bacteriophage in which the stx operon was replaced by a gene encoding the green fluorescent protein (GFP). Tracking GFP expression using an In Vivo Imaging System (IVIS), we detected fluorescence in liver, kidney, and intestine of mice infected with the recombinant E. coli strain after treatment with ciprofloxacin, which induces the lytic replication and release of bacteriophages. In addition, we showed that chitosan, a linear polysaccharide composed of D-glucosamine residues and with a number of commercial and biomedical uses, had strong anti-bacteriophage effects, as demonstrated in vitro and in vivo. These findings bring promising perspectives for the prevention and treatment of hemolytic uremic syndrome (HUS) cases.

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Ersoy Dursun, F., G. Yesil, G. Sasak e H. Dursin. "Familial atypical hemolytic uremic syndrome with positive p.S1191L (c.3572C>T) mutation on the CFH gene: A single-center experience". Balkan Journal of Medical Genetics 24, n. 1 (1 giugno 2021): 81–88. http://dx.doi.org/10.2478/bjmg-2021-0007.

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Abstract (sommario):

Abstract The atypical hemolytic uremic syndrome (aHUS) is characterized by thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury (AKI), which can exhibit a poor prognosis. Complement factor H (CFH) gene mutations play a key role in this disease, which may be sporadic or familial. We studied 13 people from the same family, investigated for gene mutations of the familial aHUS after a family member presented to our emergency clinic with the aHUS and reported a family history of chronic renal failure. The p.S1191L mutation on the CFH gene was heterozygous in six people from the patient’s family with the aHUS. One of these family members is our patient with acute kidney injury, and the other two are followed at the Nephrology Clinic, Medeniyat University, Goztepe Training and Research Hospital, Istanbul, Turkey, due to chronic renal failure. The other three family members showed no evidence of renal failure. The index case had a history of six sibling deaths; three died of chronic renal failure. Plasmapheresis and fresh frozen plasma treatment were administered to our patient. When the patient showed no response to this treatment, eculizumab (ECZ) therapy was started. The study demonstrated that thorough family history should be taken in patients with the aHUS. These patients may have the familial type of the disease, and they should be screened genetically. Eculizumab should be the first choice in the treatment with plasmapheresis. It should be kept in mind that the use of ECZ as prophylaxis in posttransplant therapy is extremely important for preventing rejection.

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López, Eduardo L., Maria M. Contrini, Eduardo Glatstein, Silvia González Ayala, Roberto Santoro, Daniel Allende, Gustavo Ezcurra et al. "Safety and Pharmacokinetics of Urtoxazumab, a Humanized Monoclonal Antibody, against Shiga-Like Toxin 2 in Healthy Adults and in Pediatric Patients Infected with Shiga-Like Toxin-Producing Escherichia coli". Antimicrobial Agents and Chemotherapy 54, n. 1 (12 ottobre 2009): 239–43. http://dx.doi.org/10.1128/aac.00343-09.

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Abstract (sommario):

ABSTRACT Shiga-like toxin-producing Escherichia coli (STEC) infection causes diarrhea, which is often bloody and which can result in potentially life-threatening hemolytic-uremic syndrome (HUS). Urtoxazumab, a humanized monoclonal antibody directed against the Shiga-like toxin 2 (Stx2) produced by STEC, has been developed as a promising agent for the prevention of HUS. Single randomized, intravenous, double-blind, placebo-controlled doses of urtoxazumab were administered to assess its safety and pharmacokinetics in healthy adults (0.1 to 3.0 mg/kg of body weight) and STEC-infected pediatric patients (1.0 and 3.0 mg/kg). No dose-related safety trends were noted, nor were antiurtoxazumab antibodies detected. The disposition of urtoxazumab showed a biexponential decline, regardless of the dose. In healthy adults, the mean terminal elimination half-life was consistent across the dose groups and ranged from 24.6 days (3.0-mg/kg dose group) to 28.9 days (0.3-mg/kg dose group). The mean maximum serum drug concentration (C max) ranged from 2.6 μg/ml at 0.1 mg/kg to 71.7 μg/ml at 3.0 mg/kg. The disposition of urtoxazumab following the administration of doses of 1.0 and 3.0 mg/kg in pediatric patients showed mean C maxs of 19.6 and 56.1 μg/ml, respectively. Urtoxazumab was well tolerated, appears to be safe at doses of up to 3.0 mg/kg, and is a potential candidate for the prevention of HUS in pediatric patients.

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Rowe, Peter C., Ruth Milner, Elaine Orrbine, Terry P. Klassen, Paul G. Goodyer, Andrew M. MacKenzie, George A. Wells et al. "A PHASE II RANDOMIZED CONTROLLED TRIAL OF SYNSORB-PK FOR THE PREVENTION OF HEMOLYTIC UREMIC SYNDROME IN CHILDREN WITH VEROTOXIN-PRODUCING E. COLI (VTEC) GASTROENTERITIS. † 1684". Pediatric Research 41 (aprile 1997): 283. http://dx.doi.org/10.1203/00006450-199704001-01703.

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Pellino, Christine A., Sayali S. Karve, Suman Pradhan e Alison A. Weiss. "AB5Preassembly Is Not Required for Shiga Toxin Activity". Journal of Bacteriology 198, n. 11 (21 marzo 2016): 1621–30. http://dx.doi.org/10.1128/jb.00918-15.

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Abstract (sommario):

ABSTRACTShiga toxin (Stx)-producingEscherichia coli(STEC) is a major cause of foodborne illness, including the life-threatening complication hemolytic-uremic syndrome. The German outbreak in 2011 resulted in nearly 4,000 cases of infection, with 54 deaths. Two forms of Stx, Stx1 and Stx2, differ in potency, and subtype Stx2a is most commonly associated with fatal human disease. Stx is considered to be an AB5toxin. The single A (enzymatically active) subunit inhibits protein synthesis by cleaving a catalytic adenine from the eukaryotic rRNA. The B (binding) subunit forms a homopentamer and mediates cellular association and toxin internalization by binding to the glycolipid globotriaosylceramide (Gb3). Both subunits are essential for toxicity. Here we report that unlike other AB5toxin family members, Stx is produced by STEC as unassembled A and B subunits. A preformed AB5complex is not required for cellular toxicity orin vivotoxicity to mice, and toxin assembly likely occurs at the cell membrane. We demonstrate that disruption of A- and B-subunit association by use of A-subunit peptides that lack enzymatic activity can protect mice from lethal doses of toxin. Currently, no treatments have been proven to be effective for hemolytic-uremic syndrome. Our studies demonstrate that agents that interfere with A- and B-subunit assembly may have therapeutic potential. Shiga toxin (Stx) produced by pathogenicEscherichia coliis considered to be an AB5heterohexamer; however, no known mechanisms ensure AB5assembly. Stx released byE. coliis not in the AB5conformation and assembles at the receptor interface. Thus, unassembled Stx can impart toxicity. This finding shows that preventing AB5assembly is a potential treatment for Stx-associated illnesses.IMPORTANCEComplications due to Shiga toxin are frequently fatal, and at present, supportive care is the only treatment option. Furthermore, antibiotic treatment is contraindicated due to the ability of antibiotics to amplify bacterial expression of Shiga toxin. We report, contrary to prevailing assumptions, that Shiga toxin produced by STEC circulates as unassembled A and B subunits at concentrations that are lethal to mice. Similar to the case for anthrax toxin, assembly occurs on receptors expressed on the surfaces of mammalian target cells. Disruption of Shiga toxin assembly by use of A-subunit peptides that lack enzymatic activity protects mice from lethal challenge with Shiga toxin, suggesting a new approach for development of therapeutics.

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Bozio, Catherine H., Cheryl Isenhour e Lucy A. McNamara. "Characteristics of and meningococcal disease prevention strategies for commercially insured persons receiving eculizumab in the United States". PLOS ONE 15, n. 11 (12 novembre 2020): e0241989. http://dx.doi.org/10.1371/journal.pone.0241989.

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Abstract (sommario):

Introduction Eculizumab is a licensed treatment for several rare, complement-mediated diseases. Eculizumab use is associated with an approximately 2,000-fold increased meningococcal disease risk. In the United States, meningococcal vaccines are recommended for eculizumab recipients but there are no recommendations on use of long-term antibiotic prophylaxis. We describe characteristics of and meningococcal vaccine and antibiotic receipt in U.S. eculizumab recipients to inform meningococcal disease prevention strategies. Methods Persons in the IBM® MarketScan® Research Databases with ≥1 claim for eculizumab injection during 2007–2017 were included. Indication for eculizumab use, meningococcal vaccine receipt, and antibiotic receipt were assessed using International Classification of Diseases-9/10 diagnosis codes, vaccine administration procedure codes, and antibiotic codes from pharmacy claims, respectively. Results Overall 696 persons met the inclusion criteria. Paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) were the most common indications for eculizumab use (41% and 37%, respectively); 20% had an undetermined indication. From June 2015 through December 2017, 28% (41/148) of continuously-enrolled patients received ≥1 serogroup B vaccine dose. For serogroup ACWY conjugate vaccine, 45% (91/201) of patients received ≥1 dose within five years of their most recent eculizumab dose, as recommended. Of eculizumab recipients with outpatient prescription data, 7% (41/579) received antibiotics for ≥50% of the period of increased risk for meningococcal disease. Conclusion Many eculizumab recipients had an undetermined indication for eculizumab use; few were up-to-date for recommended meningococcal vaccines or were prescribed antibiotics long-term. These findings can inform further investigation of how to best protect this population from meningococcal disease.

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Armstrong, G. D., P. C. Rowe, P. Goodyer, E. Orrbine, T. P. Klassen, G. Wells, A. MacKenzie et al. "A Phase I Study of Chemically Synthesized Verotoxin (Shiga-like Toxin) Pk-Trisaccharide Receptors Attached to Chromosorb for Preventing Hemolytic-Uremic Syndrome". Journal of Infectious Diseases 171, n. 4 (1 aprile 1995): 1042–45. http://dx.doi.org/10.1093/infdis/171.4.1042.

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40

Kovbasnjuk, Olga, Michael Edidin e Mark Donowitz. "Role of lipid rafts in Shiga toxin 1 interaction with the apical surface of Caco-2 cells". Journal of Cell Science 114, n. 22 (15 novembre 2001): 4025–31. http://dx.doi.org/10.1242/jcs.114.22.4025.

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Abstract (sommario):

Enterohemorrhagic Escherichia coli producing Shiga toxins 1 and/or 2 have become major foodborne pathogens. The specific binding of Shiga toxin 1 B-subunit to its receptor, a neutral glycolipid globotriaosylceramide Gb3, on the apical surface of colonic epithelium followed by toxin entry into cells are the initial steps of the process, which can result in toxin transcytosis and systemic effects of infection including hemolytic uremic syndrome. Understanding the complex mechanisms of Shiga toxin 1 binding and internalization may help to develop new strategies directed at preventing toxin internalization. Fluorescence resonance energy transfer microscopy revealed the clustering of Shiga toxin receptors Gb3 in lipid rafts with another glycosphingolipid GM1 on the apical surface of highly polarized intestinal epithelial Caco-2 cells. Lipid rafts disruption significantly decreased internalization of Shiga toxin 1 B-subunit. Although disruption of lipid rafts by cholesterol depletion did not affect the amount of bound Shiga toxin 1 B-subunit, lipid rafts are necessary for toxin uptake across the apical membrane of Caco-2 cells.

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Karmali, M. A. "Infection by verocytotoxin-producing Escherichia coli." Clinical Microbiology Reviews 2, n. 1 (gennaio 1989): 15–38. http://dx.doi.org/10.1128/cmr.2.1.15.

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Abstract (sommario):

Verocytotoxin (VT)-producing Escherichia coli (VTEC) are a newly recognized group of enteric pathogens which are increasingly being recognized as common causes of diarrhea in some geographic settings. Outbreak studies indicate that most patients with VTEC infection develop mild uncomplicated diarrhea. However, a significant risk of two serious and potentially life-threatening complications, hemorrhagic colitis and the hemolytic uremic syndrome, makes VTEC infection a public health problem of serious concern. The main reservoirs of VTEC appear to be the intestinal tracts of animals, and foods of animal (especially bovine) origin are probably the principal sources for human infection. The term VT refers to a family of subunit exotoxins with high biological activity. Individual VTEC strains elaborate one or both of at least two serologically distinct, bacteriophage-mediated VTs (VT1 and VT2) which are closely related to Shiga toxin and are thus also referred to as Shiga-like toxins. The holotoxins bind to cells, via their B subunits, to a specific receptor which is probably the glycolipid, globotriosyl ceramide (Gb3). Binding is followed by internalization of the A subunit, which, after it is proteolytically nicked and reduced to the A1 fragment, inhibits protein synthesis in mammalian cells by inactivating 60S ribosomal subunits through selective structural modification of 28S ribosomal ribonucleic acid. The mechanism of VTEC diarrhea is still controversial, and the relative roles of locally acting VT and "attaching and effacing adherence" of VTEC to the mucosa have yet to be resolved. There is increasing evidence that hemolytic uremic syndrome and possibly hemorrhagic colitis result from the systemic action of VT on vascular endothelial cells. The role of antitoxic immunity in preventing the systemic complications of VTEC infection is being explored. Antibiotics appear to be contraindicated in the treatment of VTEC infection. The most common VTEC serotype associated with human disease is O157:H7, but over 50 different VT-positive O:H serotypes have now been identified. The best strategies for diagnosing human VTEC infection include testing for the presence of free VT in fecal filtrates and examining fecal cultures for VTEC by means of deoxyribonucleic acid probes that specify genes encoding VT1 and VT2. Both methods are currently confined to specialized laboratories and await commercial development for wider use. In the meantime, most laboratories should continue to screen for the most common human VTEC serotype, O157:H7, using a sorbitol-containing MacConkey medium.

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Li, Yuling, Elizabeth Frey, Andrew M. R. Mackenzie e B. Brett Finlay. "Human Response to Escherichia coliO157:H7 Infection: Antibodies to Secreted Virulence Factors". Infection and Immunity 68, n. 9 (1 settembre 2000): 5090–95. http://dx.doi.org/10.1128/iai.68.9.5090-5095.2000.

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Abstract (sommario):

ABSTRACT Vaccination has been proposed for the prevention of disease due to enterohemorrhagic Escherichia coli (EHEC), but the immune response following human infection, including the choice of potential antigens, has not been well characterized. To study this, sera were obtained from five pediatric patients with acute diarrhea caused byE. coli O157:H7 0, 8, and 60 days after hospitalization. These sera were used to examine the immune response to four different EHEC virulence factors: Tir (translocated intimin receptor, which is inserted into the host cell membrane), intimin (bacterial outer membrane protein which binds to Tir), EspA (secreted protein which forms filamentous structures on EHEC surface), and EspB (inserted into the host membrane and cytoplasm). The response to O157:H7 lipopolysaccharide was also examined. Sera were assayed against purified recombinant proteins using immunoblot analysis and by enzyme-linked immunosorbent assay to determine the sera's titers to each of the antigens in all patients. We found that there was little reaction to EspA, EspB, and intimin in the acute-phase sera, although there was some reactivity to Tir. By day 8, titers of antibody to all four virulence factors were present in all patients, with a very strong response against Tir (up to a titer of 1:256,000), especially in hemolytic-uremic syndrome patients, and lesser strong responses to the other three antigens. The titer to the antigens 60 days after hospitalization was decreased but was still highest for Tir. These results suggest that there is a strong immune response to Tir, and to a lesser extent to the other three virulence factors, following EHEC disease, indicating that these bacterial molecules are potential vaccine candidates for preventing EHEC disease. They also suggest that bacterial virulence factors that are inserted into host cells during infection by type III secretion systems (Tir or EspB) are still recognized by the host immune response.

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Yu, Jia, Xuan Yuan, Hang Chen, Shruti Chaturvedi, Evan M. Braunstein e Robert A. Brodsky. "Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition". Blood 136, n. 18 (29 ottobre 2020): 2080–89. http://dx.doi.org/10.1182/blood.2020008248.

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Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein–treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.

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SHARAPOV, UMID M., ARTHUR M. WENDEL, JEFFREY P. DAVIS, WILLIAM E. KEENE, JEFFREY FARRAR, SAMIR SODHA, EIJA HYYTIA-TREES et al. "Multistate Outbreak of Escherichia coli O157:H7 Infections Associated with Consumption of Fresh Spinach: United States, 2006". Journal of Food Protection 79, n. 12 (1 dicembre 2016): 2024–30. http://dx.doi.org/10.4315/0362-028x.jfp-15-556.

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ABSTRACT During September to October, 2006, state and local health departments and the Centers for Disease Control and Prevention investigated a large, multistate outbreak of Escherichia coli O157:H7 infections. Case patients were interviewed regarding specific foods consumed and other possible exposures. E. coli O157:H7 strains isolated from human and food specimens were subtyped using pulsed-field gel electrophoresis and multiple-locus variable-number tandem repeat analyses (MLVA). Two hundred twenty-five cases (191 confirmed and 34 probable) were identified in 27 states; 116 (56%) case patients were hospitalized, 39 (19%) developed hemolytic uremic syndrome, and 5 (2%) died. Among 176 case patients from whom E. coli O157:H7 with the outbreak genotype (MLVA outbreak strain) was isolated and who provided details regarding spinach exposure, 161 (91%) reported fresh spinach consumption during the 10 days before illness began. Among 116 patients who provided spinach brand information, 106 (91%) consumed bagged brand A. E. coli O157:H7 strains were isolated from 13 bags of brand A spinach collected from patients' homes; isolates from 12 bags had the same MLVA pattern. Comprehensive epidemiologic and laboratory investigations associated this large multistate outbreak of E. coli O157:H7 infections with consumption of fresh bagged spinach. MLVA, as a supplement to pulsed-field gel electrophoresis genotyping of case patient isolates, was important to discern outbreak-related cases. This outbreak resulted in enhanced federal and industry guidance to improve the safety of leafy green vegetables and launched an independent collaborative approach to produce safety research in 2007.

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Svetoch, E. A., I. A. Dyatlov, N. N. Kartsev, B. V. Eruslanov, M. E. Kanashenko e N. K. Fursova. "Development of candidate vaccines against infection caused by shiga-toxin producing Escherichia coli. Part 2". Bacteriology 5, n. 3 (2020): 47–59. http://dx.doi.org/10.20953/2500-1027-2020-3-47-59.

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Prevention and treatment of hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS) caused by Shiga-toxin producing Escherichia coli (STEC) continues to be a public health concern. The main reason for the problem is the lack of vaccines and lack of evidence for using of antibacterial etiotropic drugs to treat this infection. A promising scientific approach to create specific agents against STEC infection is the development of subunit recombinant vaccines. The analysis of experimental studies presented in this review shows that effective subunit vaccines against STEC infection can be created on the basis of known immunogenic determinants of HC and HUS causative agents – EspA, EspB, and Tir proteins, intimin, as well as H7 antigen of E. coli O157:H7 and nontoxic proteins of Shiga toxins Stx1 and Stx2 A and B subunits. Using these epitopes, three types of subunit vaccines are designed: antibacterial vaccine, vaccine protecting the macroorganism from systemic intoxication caused by Shiga toxins, and vaccines that simultaneously induce the antibacterial and antitoxic immunity. Since the epitopes listed above are weak immunogenic, to increase their immunogenicity, complex chimeric antigenic structures containing protein inducers are constructed that significantly increase the immune response to target specific epitopes. Mineral adjuvants are also widely used to increase the immunogenicity of STEC epitopes. All three types of created candidate subunit vaccines, at subcutaneous, intramuscular and intranasal application induce production of specific IgG and secretory IgA antibodies in animals and protect them from the infection caused by the STEC strains. Key words: STEC, hemorrhagic colitis, immunodominant antigens, Shiga toxins, EspA, EspB, Tir, intimine, IgG, sIgA

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Tinoco, I., A. Jarrell, L. Correa, J. Bissler, J. DeVincenzo, Ivan Tinoco, Amber Jarrell, Lauren Correa, John J. Bissler e John P. DeVincenzo. "#92: What Is the Optimal Management of Patients Immunosuppressed with the Anti-compliment Monoclonal Antibody, Eculizumab? A Case Report and Review". Journal of the Pediatric Infectious Diseases Society 10, Supplement_1 (1 marzo 2021): S12. http://dx.doi.org/10.1093/jpids/piaa170.034.

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Abstract Background Patients with deficiencies of terminal components of complement are at hundreds to thousands fold increased risk of severe and fatal Neisseria spp. infections compared with the general population. Eculizumab is a newly approved monoclonal antibody C5 complement inhibitor. It is indicated for the treatment of atypical hemolytic uremic syndrome (atypical HUS), myasthenia gravis, and paroxysmal nocturnal hemoglobinuria. Because of the complement-depleting effect of Eculizumab dosing (Soliris®, Alexion Pharmaceuticals, Munich, Germany), patients are immunosuppressed for specific infectious pathogens (including Neisseria species) against which protection partially relies on normal complement activity. Because Eculizumab treatment is associated with a dramatically increased risk of Neisseria species. infections, recommendations for Neisseria meningitidis vaccination and antibiotic prophylaxis are contained in Eculizumab prescribing information. However, the most appropriate prevention of infections after Eculizumab has yet to be determined. Methods Case report and literature review. Results A previously healthy 7-year-old male was diagnosed with atypical HUS which included renal failure progressing to dialysis, persistent thrombocytopenia, hemolytic anemia, and hemoglobinuria. Stool cultures and a stool multiplex PCR panel did not detect Shiga-like producing E. coli nor E. coli O157/H7. Eculizumab dosing was therefore planned and Infectious Diseases consultation was obtained for appropriate preventions. The FDA Prescribing Information recommends Neisseria meningitidis vaccination before starting Eculizumab or, if immediate Eculizumab is necessary, to use antibiotic prophylaxis until 2 weeks after vaccination. The accepted protective titer after meningococcal vaccination is population based and uses the serum bactericidal assay (SBA). An antibody titer of >1:4 (human compliment) or 1:8 (rabbit complement) is considered protective. However, this “gold standard” assay incorporates the use of exogenous human or rabbit complement. The protective SBA titers in subjects with terminal complement component deficiencies may not be properly assessed using these same SBA titer protective thresholds. Furthermore, serious meningococcal infections have occurred after appropriate vaccination in patients receiving chronic Eculizumab treatments (ie for paroxysmal nocturnal hemoglobinuria). Finally, SBA protective levels after single Neisseria meningitidis vaccination have not been achieved in majorities of patients with renal failure receiving dialysis and or transplant immunosuppression. Conclusions The current Eculizumab prescribing information recommendations for vaccination and antimicrobial prophylaxis may be inadequate to prevent serious Neisseria infections. Repeated Neisseria meningitidis vaccination and extended antibiotic prophylaxis may afford better protection in patients chronically dosed with Eculizumab.

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Krautz-Peterson, Greice, Susan Chapman-Bonofiglio, Karen Boisvert, Hanping Feng, Ira M. Herman, Saul Tzipori e Abhineet S. Sheoran. "Intracellular Neutralization of Shiga Toxin 2 by an A Subunit-Specific Human Monoclonal Antibody". Infection and Immunity 76, n. 5 (19 febbraio 2008): 1931–39. http://dx.doi.org/10.1128/iai.01282-07.

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ABSTRACT Infection of children with Shiga toxin (Stx)-producing Escherichia coli (STEC) is the leading cause of hemolytic-uremic syndrome (HUS). Stx2, one of two toxins liberated by the bacteria, is directly linked with HUS. We have previously shown that Stx2-specific human monoclonal antibodies (HuMAbs) protect mice and piglets from fatal systemic complications of Stx2. The present study investigates the mechanisms by which our most efficacious A- and B-subunit-specific HuMAbs neutralize the cytotoxic effects of Stx2 in vitro. Whereas the B-subunit-specific HuMAb 5H8 blocked binding of Stx2 to its receptor on the cell surface, the A-subunit-specific HuMAb 5C12 did not interfere with the toxin-receptor binding. Further investigations revealed that 5C12 did not block endocytosis of Stx2 by HeLa cells as both Stx2 and 5C12 colocalized with early endosomes. However, 5C12 blocked the retrograde transport of the toxin into the Golgi and the endoplasmic reticulum, preventing the toxin from entering the cytosol where the toxin exerts its cytotoxic effect. The endocytosed 5C12/Stx2 complexes appear to be rapidly transported to the plasma membrane and/or to the slow recycling perinuclear compartments, followed by their slow recycling to the plasma membrane, and release into the extracellular environment.

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LAINE, ELLEN SWANSON, JONI M. SCHEFTEL, DAVID J. BOXRUD, KEVIN J. VOUGHT, RICHARD N. DANILA, KEVIN M. ELFERING e KIRK E. SMITH. "Outbreak of Escherichia coli O157:H7 Infections Associated with Nonintact Blade-Tenderized Frozen Steaks Sold by Door-to-Door Vendors". Journal of Food Protection 68, n. 6 (1 giugno 2005): 1198–202. http://dx.doi.org/10.4315/0362-028x-68.6.1198.

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Steaks have not been recognized as an important vehicle of Escherichia coli O157:H7 infection. During 11 to 27 June 2003, the Minnesota Department of Health (MDH) identified four O157 infection cases with the same pulsed-field gel electrophoresis (PFGE) subtype. All four case patients consumed brand A vacuum packed frozen steaks sold by door-to-door vendors. The steaks were blade tenderized and injected with marinade (i.e., nonintact). Information from single case patients in Michigan and Kansas identified through PulseNet confirmed the outbreak. The MDH issued a press release on 27 June to warn consumers, prompting a nationwide recall of 739,000 lb (335,506 kg) of frozen beef products. The outbreak resulted in six culture-confirmed cases (including one with hemolytic uremic syndrome) and two probable cases in Minnesota and single confirmed cases in four other states. The outbreak PFGE subtype of O157 was isolated from unopened brand A bacon-wrapped fillets from five affected Minnesota households. A fillet from one affected household was partially cooked in the laboratory, and the same O157 subtype was isolated from the uncooked interior. The tenderizing and injection processes likely transferred O157 from the surface to the interior of the steaks. These processing methods create new challenges for prevention of O157 infection. Food regulatory officials should reevaluate safety issues presented by nonintact steak products, such as microbiologic hazards of processing methods, possible labeling to distinguish intact from nonintact steaks, and education of the public and commercial food establishments on the increased risk associated with undercooked nonintact steaks. Information on single cases of O157 infection in individual states identified through PulseNet can be critical in solving multistate outbreaks in a timely manner.

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Mukherjee, Jean, Kerry Chios, Dianne Fishwild, Deborah Hudson, Susan O'Donnell, Stephen M. Rich, Arthur Donohue-Rolfe e Saul Tzipori. "Human Stx2-Specific Monoclonal Antibodies Prevent Systemic Complications of Escherichia coli O157:H7 Infection". Infection and Immunity 70, n. 2 (febbraio 2002): 612–19. http://dx.doi.org/10.1128/iai.70.2.612-619.2002.

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ABSTRACT Hemolytic-uremic syndrome (HUS) is a serious complication predominantly associated with infection by enterohemorrhagic Escherichia coli (EHEC), such as E. coli O157:H7. EHEC can produce Shiga toxin 1 (Stx1) and/or Shiga toxin 2 (Stx2), both of which are exotoxins comprised of active (A) and binding (B) subunits. In piglets and mice, Stx can induce fatal neurological symptoms. Polyclonal Stx2 antiserum can prevent these effects in piglets infected with the Stx2-producing E. coli O157:H7 strain 86-24. Human monoclonal antibodies (HuMAbs) against Stx2 were developed as potential passive immunotherapeutic reagents for the prevention and/or treatment of HUS. Transgenic mice bearing unrearranged human immunoglobulin (Ig) heavy and κ light chain loci (HuMAb___Mouse) were immunized with formalin-inactivated Stx2. Thirty-seven stable hybridomas secreting Stx2-specific HuMAbs were isolated: 33 IgG1κ A-subunit-specific and 3 IgG1κ and 1 IgG3κ B-subunit-specific antibodies. Six IgG1κ A-subunit-specific (1G3, 2F10, 3E9, 4H9, 5A4, and 5C12) and two IgG1κ B-subunit-specific (5H8 and 6G3) HuMAbs demonstrated neutralization of >95% activity of 1 ng of Stx2 in the presence of 0.04 μg of HuMAb in vitro and significant prolongation of survival of mice given 50 μg of HuMAb intraperitoneally (i.p.) and 25 ng of Stx2 intravenously. When administered i.p. to gnotobiotic piglets 6 or 12 h after infection with E. coli O157:H7 strain 86-24, HuMAbs 2F10, 3E9, 5H8, and 5C12 prolonged survival and prevented development of fatal neurological signs and cerebral lesions. The Stx2-neutralizing ability of these HuMAbs could potentially be used clinically to passively protect against HUS development in individuals infected with Stx-producing bacteria, including E. coli O157:H7.

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Melton-Celsa, Angela R., H. M. Carvalho, Claire Thuning-Roberson e A. D. O'Brien. "Protective Efficacy and Pharmacokinetics of Human/Mouse Chimeric Anti-Stx1 and Anti-Stx2 Antibodies in Mice". Clinical and Vaccine Immunology 22, n. 4 (25 febbraio 2015): 448–55. http://dx.doi.org/10.1128/cvi.00022-15.

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ABSTRACTIn the United States, Shiga toxin (Stx)-producingEscherichia coli(STEC) is the most frequent infectious cause of hemorrhagic colitis. Hemolytic uremic syndrome (HUS) is a serious sequela that may develop after STEC infection that can lead to renal failure and death in up to 10% of cases. STEC can produce one or more types of Stx, Stx1 and/or Stx2, and Stx1 and Stx2 are responsible for HUS-mediated kidney damage. We previously generated two monoclonal antibodies (MAbs) that neutralize the toxicity of Stx1 or Stx2. In this study, we evaluated the protective efficacy of human/mouse chimeric versions of those monoclonal antibodies, named cαStx1 and cαStx2. Mice given an otherwise lethal dose of Stx1 were protected from death when injected with cαStx1 either 1 h before or 1 h after toxin injection. Additionally, streptomycin-treated mice fed the mouse-lethal STEC strain B2F1 that produces the Stx2 variant Stx2d were protected when given a dose of 0.1 mg of cαStx2/kg of body weight administered up to 72 h post-oral bacterial challenge. Since many STEC strains produce both Stx1 and Stx2 and since either toxin may lead to the HUS, we also assessed the protective efficacy of the combined MAbs. We found that both antibodies were required to protect mice from the presence of both Stx1 and Stx2. Pharmacokinetic studies indicated that cαStx1 and cαStx2 had serum half-lives (t1/2) of about 50 and 145 h, respectively. We propose that cαStx1 and cαStx2, both of which have been tested for safety in humans, could be used therapeutically for prevention or treatment early in the development of HUS.

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