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GR.2 A deep intronic FGF14 GAA repeat expansion causes late-onset cerebellar ataxia
- D Pellerin, MC Danzi, C Wilke, M Renaud, S Fazal, M Dicaire, CK Scriba, C Ashton, C Yanick, D Beijer, A Rebelo, C Rocca, Z Jaunmuktane, JA Sonnen, R Larivière, D Genis, L Porcel, K Choquet, R Sakalla, S Provost, M Tétreault, SJ Reiling, S Nagy, V Nishadham, M Purushottam, S Vengalil, M Bardhan, A Nalini, Z Chen, J Mathieu, R Massie, CH Chalk, A Lafontaine, F Evoy, M Rioux, J Ragoussis, KM Boycott, M Dubé, A Duquette, H Houlden, G Ravenscroft, NG Laing, P Lamont, MA Saporta, R Schüle, L Schöls, R La Piana, M Synofzik, S Zuchner, B Brais
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- Journal:
- Canadian Journal of Neurological Sciences / Volume 50 / Issue s2 / June 2023
- Published online by Cambridge University Press:
- 05 June 2023, p. S46
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Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing and long-read sequencing to search for repeat expansions in patients with LOCA. We enrolled 66 French-Canadian, 228 German, 20 Australian and 31 Indian patients. Pathogenic mechanisms were studied in post-mortem cerebellum and induced pluripotent stem cell (iPSC)-derived motor neurons from 2 patients. Results: We identified 128 patients who carried an autosomal dominant GAA repeat expansion in the first intron of the FGF14 gene. The expansion was present in 61%, 18%, 15% and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. The pathogenic threshold was determined to be (GAA)≥250, although incomplete penetrance was observed in the (GAA)250-300 range. Patients developed a slowly progressive cerebellar syndrome at an average age of 59 years. Patient-derived post-mortem cerebellum and induced motor neurons both showed reduction in FGF14 RNA and protein expression compared to controls. Conclusions: This intronic, dominantly inherited GAA repeat expansion in FGF14 represents one of the most common genetic causes of LOCA uncovered to date.
3281 Management of Acute Rejection in Penile Allotransplantation
- Michael Jonczyk, Ilse M. Schol, Philipp Tratnig-Frankl, Alexandre G. Lellouch, Dicken S.C. Ko, Curtis L. Cetrulo, Jr.
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- Journal:
- Journal of Clinical and Translational Science / Volume 3 / Issue s1 / March 2019
- Published online by Cambridge University Press:
- 26 March 2019, pp. 15-16
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OBJECTIVES/SPECIFIC AIMS: Objective: To summarize the diagnosis and management of two acute rejection (AR) episodes in the first penis transplant patient in the U.S. Background: Vascularized composite allotransplantation (VCA) has been utilized for state-of-the-art reconstruction of devastating craniofacial defects, limb loss, and recently, severe genitourinary defects. To date, more than 200 VCA’s have been performed, of which four successful penis transplants have been achieved worldwide (Two in the U.S.). However, despite the technical success of VCAs in general, acute rejection episodes remain a significant postoperative management problem, with 80-85% experiencing at least one episode in the first-year post-transplantation. The incorporation of skin in VCAs, which is highly immunogenic, allows early visible recognition of rejection but requires prompt management to prevent allograft failure as well as the progression of chronic rejection, which has been associated with the frequency of acute rejection episodes in preclinical models. We present the first report of acute rejection in a penile allograft. AR episodes in VCA typically manifest with erythema of the allograft skin and/or maculopapular lesions that can be either patchy, focal or diffuse. Histopathologic assessment is essential for diagnosis and management. The Banff classification of histopathologic criteria for degree of AR is most commonly utilized to direct clinical management. METHODS/STUDY POPULATION: We reviewed the clinical course of the first American patient who underwent penis transplantation at Massachusetts General Hospital in 2016. Postoperatively, routine clinical and chemical assessment (immunosuppression levels, routine blood work) was performed, with increased frequency during AR episodes. Skin punch biopsies were obtained during (suspected) AR episodes, analyzed and graded according to the Banff 2007 classification of rejection of skin-containing composite allografts. Histopathologic tissue assessment included CD3, C4d, CD4/8, CD20 FOXP3 and cellular infiltration (hyper keratinization, lymphocytic infiltrate, dermal erosion, macrophage, eosinophilia, T-cell infiltration) and epidermal or perivascular fibrosis. RESULTS/ANTICIPATED RESULTS: The patient is a 65-year-old male with history of penile carcinoma requiring subtotal penectomy in 2012. He is currently 30-months post penile transplantation (as of 11/15/2018). First Rejection Episode: At 28 days post-transplantation, the patient noted induration, swelling and erythema of the allograft, which was diagnosed as AR clinically (Image 1A). Biopsy showed a Banff Grade III AR, with focal keratinocyte apoptosis with lymphocytic infiltration in epidermis and arteriolar endothelialitis with perivascular inflammation. Initially this episode was treated for 2 days with 2 pulse doses of methylprednisolone (500mg/d IV) with clinical improvement. However, recurrent allograft erythema was observed on postoperative day 32 and an acute rejection grade III according the Banff classification was confirmed by a second biopsy that demonstrated epidermal perivascular lymphocytic infiltrates, spongiosis and dyskeratosis, deep dermis focal lymphocytic infiltrates and focal infiltrates in arterioles as well as endothelialitis in venules. Donor specific antibodies and C4d were negative. CD3+ T cells were present in the epidermis and perivascular space. This was treated with anti-thymocyte globulin (thymoglobulin) course for 4 days (1.5mg/kg/day IV) and 3 more pulse doses of methylprednisolone (500mg/d IV.), followed by a prednisone (250mg/d) taper to baseline. This resulted in complete resolution of AR. Second Rejection Episode: At 10.8 months post VCA the patient presented with penile erythema and scrotal swelling suggestive of AR and received three doses of methylprednisolone (day 1: 500mg/d IV, day 2: 1000mg/d IV and day 3: 500mg/d IV respectively) followed by increased baseline prednisone (10mg PO daily; increased dose compared to previous AR episode). A skin biopsy confirmed Banff Grade III AR. Compared to the previous biopsy, this biopsy demonstrated an increased density of lymphocytic inflammation of the dermis with endarteritis. Prominent involvement of epidermis and adnexal structures corresponding to acute T-cell mediated rejection was also observed (Figure 1). Donor specific antibodies and C4d were again negative. Three doses of ATG (1.5mg/kg/day IV) were administered. In addition, tacrolimus was increased and local tacrolimus (1% ointment) treatment was begun. Clinical signs of rejection improved and repeat biopsy showed dramatic histopathological improvement. Current maintenance immunosuppressive regimen consists of tacrolimus, sirolimus, prednisone, mycophenolic mofetil acid (MMF), rapamycin, and tacrolimus ointment, with no new clinical or histopathological signs of rejection (Image 1B). DISCUSSION/SIGNIFICANCE OF IMPACT: We report the first described case of acute T-cell mediated rejection in penile transplantation. These rejection episodes demonstrated that, even on stringent immunosuppressive regimens, severe acute rejection episodes in VCA may still occur. Edema and acute induration preceded the development of erythema in our cases, representing a harbinger for the more severe grade of rejection that eventually developed. Our experience was consistent with other VCAs in that donor specific antibodies did not develop, despite a severe Banff Grade. Consistent use of topical calcineurin inhibitor based immunosuppression on the allograft skin may be helpful in warding off future episodes, as our patient has been rejection free now for 18 months. To date, no histologic signs of chronic rejection were present on 2-year protocol surveillance biopsy. We have added rapamycin to the current drug regimen, with concurrent reduction of tacrolimus dosing for renal protection, which has been demonstrated in cardiac transplantation to deter the intimal hyperplasia/vasculopathy associated with chronic rejection.
The piglet as a model for studying dietary components in infant diets: effects of galacto-oligosaccharides on intestinal functions
- A. Alizadeh, P. Akbari, E. Difilippo, H. A. Schols, L. H. Ulfman, M. H. C. Schoterman, J. Garssen, J. Fink-Gremmels, S. Braber
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- Journal:
- British Journal of Nutrition / Volume 115 / Issue 4 / 28 February 2016
- Published online by Cambridge University Press:
- 14 December 2015, pp. 605-618
- Print publication:
- 28 February 2016
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Prebiotic oligosaccharides, including galacto-oligosaccharides (GOS), are used in infant formula to mimic human milk oligosaccharides, which are known to have an important role in the development of the intestinal microbiota and the immune system in neonates. The maturation of the intestines in piglets closely resembles that of human neonates and infants. Hence, a neonatal piglet model was used to study the multi-faceted effect of dietary GOS in early life. Naturally farrowed piglets were separated from the mother sow 24–48 h postpartum and received a milk replacer with or without the addition of GOS for 3 or 26 d, whereafter several indicators of intestinal colonisation and maturation were measured. Dietary GOS was readily fermented in the colon, leading to a decreased pH, an increase in butyric acid in caecum digesta and an increase in lactobacilli and bifidobacteria numbers at day 26. Histomorphological changes were observed in the intestines of piglets fed a GOS diet for 3 or 26 d. In turn, differences in the intestinal disaccharidase activity were observed between control and GOS-fed piglets. The mRNA expression of various tight junction proteins was up-regulated in the intestines of piglet fed a GOS diet and was not accompanied by an increase in protein expression. GOS also increased defensin porcine β-defensin-2 in the colon and secretory IgA levels in saliva. In conclusion, by applying a neonatal piglet model, it could be demonstrated that a GOS-supplemented milk replacer promotes the balance of the developing intestinal microbiota, improves the intestinal architecture and seems to stimulate the intestinal defence mechanism.
Transmission of bovine herpesvirus 1 within and between herds on an island with a BHV1 control programme
- J. J. HAGE, Y. H. SCHUKKEN, H. SCHOLS, M. A. MARIS-VELDHUIS, F. A. M. RIJSEWIJK, C. H. L. KLAASSEN
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- Journal:
- Epidemiology & Infection / Volume 130 / Issue 3 / June 2003
- Published online by Cambridge University Press:
- 25 June 2003, pp. 541-552
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Transmission of bovine herpesvirus 1 (BHV1) within and between herds was studied on the island of Ameland, The Netherlands. There were 50 herds with 3300 head of cattle on the island. Herds were divided into three groups: (1) only containing seronegative cattle, (2) containing seronegative cattle and vaccinated seropositive cattle, and (3) containing only vaccinated cattle. All 23 herds in groups 1 and 2 were monitored. Three major outbreaks of BHV1 infections were observed due to the introduction of infectious cattle. Another major outbreak was most likely induced by reactivation of latent BHV1 in seropositive cattle. The basic reproduction ratio within these herds was estimated at least 4. Only one of these outbreaks led to three secondary outbreaks in susceptible herds in which all cattle were seronegative. These outbreaks were most likely due to respectively, direct animal contact, human transmission, and aerogenic transmission. The basic reproduction ratio between herds in this study was estimated to be 0·6.