ognizant Communication Corporation

The Regenerative Medicine Journal

VOLUME 14, NUMBERS 2/3, 2005

Cell Transplantation, Vol. 14, pp. 77-84, 2005
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Evaluation of Metabolic Control Using a Continuous Subcutaneous Glucose Monitoring System in Patients With Type 1 Diabetes Mellitus Who Achieved Insulin Independence After Islet Cell Transplantation

Milene C. Geiger,1 Jacqueline V. Ferreira,1,2 Muhammad M. Hafiz,1 Tatiana Froud,1,3 David A. Baidal,1 Luigi F. Meneghini,1,2 Camillo Ricordi,1,3 and Rodolfo Alejandro1,2

1Diabetes Research Institute, 2Department of Medicine, and 3Department of Surgery, University of Miami School of Medicine, Miami, FL 33136

This study evaluated the Medtronic MiniMed Continuous Glucose Monitoring System (CGMS) in patients with Type 1 diabetes mellitus who underwent successful islet cell transplantation (ICT). The results are compared to standardized self-monitoring (SMBG) of hyperglycemia and mean amplitude of glycemic excursions (MAGE). We studied 19 patients (mean age 40.0 ± 6.7 years) in three groups: six patients post-ICT, seven patients awaiting ICT, and six normal volunteers (controls). Continuous glucose monitoring post-ICT showed remarkable glucose stability compared with patients awaiting ICT. The CGMS group showed modestly higher glucoses (mean 111.5 mg/dl) compared with controls (88 mg/dl). Postprandial glucoses in ICT recipients rarely exceeded 180 mg/dl and were similar to controls. There was no difference in asymptomatic hypoglycemia between control and post-ICT groups. However, a higher incidence of hypoglycemia was observed in patients awaiting ICT. HbA1c and MAGE pre- and post-ICT were 8.3 ± 0.9% and 6 ± 0.3%(p < 0.001) and 109 ± 34 and 41 ± 11 (p < 0.001), respectively. No complications were associated with CGMS. This study suggests ICT significantly improves metabolic control and rate of hypoglycemia when compared with controls and patients awaiting ICT. Similar improvement in metabolic control was observed with SMBG, HbA1c, and MAGE. Although CGMS was not demonstrated to be a superior tool for routine assessment in ICT, it is very helpful in special clinical situations.

Key words: Islet; Continuous glucose monitoring; Diabetes

Address correspondence to Rodolfo Alejandro, M.D., Diabetes Research Institute (R-134), 1450 NW 10 Avenue, Miami, FL 33136. Tel: (305) 243-5324; Fax: (305) 243-1058; E-mail: ralejand@med.miami.edu

Cell Transplantation, Vol. 14, pp. 85-96, 2005
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Prolonged Allogeneic Islet Graft Survival by Protoporphyrins

Antonello Pileggi,* R. Damaris Molano,* Thierry Berney,** Hirohito Ichii, Sergio San Jose, Elsie Zahr, Raffaella Poggioli, Elina Linetsky, Camillo Ricordi, and Luca Inverardi

Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136

Transplantation of islets of Langerhans in patients with Type 1 diabetes allows for improved metabolic control and insulin independence. The need for chronic immunosuppression limits this procedure to selected patients with brittle diabetes. Definition of therapeutic strategies allowing permanent engraftment without the need for chronic immunosuppression could overcome such limitations. We tested the effect of the use of protoporphyrins (CoPP and FePP), powerful inducers of the cytoprotective protein heme-oxygenase 1 (HO-1), on allogeneic islet graft survival. Chemically induced diabetic C57BL/6 mice received DBA/2 islets. Treatment consisted in peritransplant administration of CoPP or saline. Islets were either cultured in the presence of FePP or vehicle before implant. Short-course administration of CoPP led to long-term islet allograft survival in a sizable proportion of recipients. Long-term graft-bearing animals rejected third-party islets while accepting a second set donor-specific graft permanently, without additional treatment. Preconditioning of islets with FePP by itself led to improved graft survival in untreated recipients, and provided additional advantage in CoPP-treated recipients, resulting in an increased proportion of long-term surviving grafts. Preconditioning of the graft with protoporphyrins prior to implant resulted in reduction of class II expression. Administration of protoporphyrins to the recipients of allogeneic islets also resulted in transient powerful immunosuppression with reduced lymphocyte proliferative responses, increased proportion of regulatory cells (CD4+CD25+), decreased mononuclear cell infiltrating the graft, paralleled by a systemic upregulation of HO-1 expression. All these mechanisms may have contributed to the induction of donor-specific hyporesponsiveness in a proportion of the protoporphyrin-treated animals.

Key words: Islet transplantation; Cobalt protoporphyrin (CoPP); Iron protoporphyrin (FePP, hemin); Heme oxygenase-1 (HO-1); Allograft survival; Tolerance; MHC class II; Diabetes

Address correspondence to Luca Inverardi, M.D., Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136. Tel: +1(305) 243-2954; Fax: +1(305) 243-4404; E-mail: linverar@med.miami.edu

*These authors contributed equally to this work.

**Present address: Visceral and Transplantation Surgery, Geneva University Hospital, Geneva, Switzerland.

Cell Transplantation, Vol. 14, pp. 97-108, 2005
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Encapsulation of Islets in Rough Surface, Hydroxymethylated Polysulfone Capillaries Stimulates VEGF Release and Promotes Vascularization After Transplantation

N. Lembert,1,2 J. Wesche,1 P. Petersen,2 M. Doser,3 P. Zschocke,3 H. D. Becker,2 and H. P. T. Ammon1

1Department of Pharmacology, Institute of Pharmaceutical Sciences, Auf der Morgenstelle 8, University of Tübingen, 72076 Tübingen, Germany
2Department of General Surgery, Hoppe-Seyler Straße 3, University of Tübingen, 72076 Tübingen, Germany
3Institute of Textile and Process Engineering (ITV), Stuttgart-Denkendorf, 73770 Denkendorf, Germany

The transplantation of encapsulated islets of Langerhans is one approach to treat Type 1 diabetes without the need of lifelong immunosuppression. Capillaries have been used for macroencapsulation because they have a favorable surface-to-volume ratio and because they can be refilled. It is unclear at present whether the outer surface of such capillaries should be smooth to prevent, or rough to promote, cell adhesions. In this study we tested a new capillary made of modified polysulfone (MWCO: 50 kDa) with a rough, open-porous outer surface for islet transplantation. Compared with free-floating islets, encapsulation of freshly isolated rat islets affected neither the kinetics nor the efficiency of glucose-induced insulin release in perifusion experiments. Free-floating islets maintained insulin secretion during cell culture but encapsulated islets gradually lost their glucose responsiveness and released VEGF. This indicated hypoxia in the capillary lumen. Transplantation of encapsulated rat islets into diabetic rats significantly reduced blood glucose concentrations from the first week of implantation. This hypoglycaemic effect persisted until explantation 4 weeks later. Transplantation of encapsulated porcine islets into diabetic rats reduced blood glucose concentrations depending on the islet purity. With semipurified islets a transient reduction of blood glucose concentrations was observed (2, 8, 18, 18 days) whereas with highly purified islets a sustained normoglycaemia was achieved (more than 28 days). Explanted capillaries containing rat islets were covered with blood vessels. Vascularization was also observed on capillaries containing porcine islets that were explanted from normoglycaemic rats. In contrast, on capillaries containing porcine islets that were explanted from hyperglycemic rats a fibrous capsule and lymphocyte accumulations were observed. No vascularization on the surface of transplanted capillaries was observed in the absence of islets. In conclusion, encapsulated islets can release VEGF, which appears to be an important signal for the vascularization of the capillary material. The rough, open-porous outer surface of the polysulfone capillary provides a site well suited for vascular tissue formation and may allow a prolonged islet function after transplantation.

Key words: Type 1 diabetes; Cell transplantation; Bioartificial pancreas; Macroencapsulation; Modified polysulfone; Porcine islets

Address correspondence to PD Dr. Nicolas Lembert, Department of Pharmacology, Institute of Pharmaceutical Sciences, University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. Tel: +49 7071 29 72471; E-mail: nicolas.lembert@uni-tuebingen.de

Cell Transplantation, Vol. 14, pp. 109-117, 2005
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Human Marrow Stromal Cells Enhance Connexin43 Gap Junction Intercellular Communication in Cultured Astrocytes

Qi Gao,1 Mark Katakowski,1,2 Xiaoguang Chen,3 Yi Li,1 and Michael Chopp1,2

1Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202
2Department of Physics, Oakland University, Rochester, MI 48309
3Department of Pharmacology, Institute of Materia Medica, Beijing 100050, China

Human marrow stromal cells (hMSCs) provide functional benefit in rats subjected to stroke. Astrocytes are coupled into a cellular network via gap junction channels, predominantly composed of connexin-43 (Cx43) proteins. Astrocytes are believed to play a vital role in neuroprotection by providing energy substrates to neurons and by regulating the concentrations of K+ and neurotransmitters via gap junctions. We therefore investigated the effect of factors secreted by hMSCs on gap junction intercellular communication (GJIC), expression of Cx43, and phosphorylation of Cx43 in an astrocyte cell culture system. Exposing rat cortical astrocytes to various concentrations of hMSC conditioned medium, we demonstrate that hMSCs produce soluble factors that significantly increase astrocytic GJIC, measured by the scrape-loading dye transfer method. Immunohistochemistry and Western blot showed increased Cx43 expression concomitant with altered GJIC. As the PI3K/Akt signaling pathway has been demonstrated to alter gap junction expression and GJIC, we selectively blocked phosphoinositide 3-kinase (PI3K). Addition of the PI3K inhibitor LY294002 decreased GJIC and Cx43 expression in astrocytes. These inhibitory effects of LY294002 were countered by the addition of hMSC conditioned media. Furthermore, coculturing hMSCs with rat astrocytes increased astrocyte GJIC in a manner dependent upon the hMSC/astrocyte ratio. These findings demonstrate that hMSCs secrete soluble factors that increase GJIC of astrocytes through upregulation of Cx43, and indicate a mechanistic role for PI3K.

Key words: Gap junction; Connexin-43; Astrocyte; Human marrow stromal cells; Intercellular communication; Ischemia

Address correspondence to Michael Chopp, Ph.D., Professor and Vice Chair, Department of Neurology, Henry Ford Health Sciences Center, 2799 West Grand Blvd., Detroit, MI 48202. Tel: (313) 916-2227; Fax: (313) 916-1318; E-mail: chopp@neuro.hfh.edu

Cell Transplantation, Vol. 14, pp. 119-127, 2005
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Dopaminergic Reinnervation of the Globus Pallidus by Fetal Nigral Grafts in the Rodent Model of Parkinson's Disease

L. E. Bartlett1 and I. Mendez1,2

Departments of 1Anatomy and Neurobiology and 2Surgery (Division of Neurosurgery), Dalhousie University, Halifax, Nova Scotia, B3H 4H7, Canada

The current neural transplantation strategy for Parkinson's disease (PD) involves the dopaminergic reinnervation of the striatum (STR). Although up to 85% reinnervation of the STR has been attained by neural transplantation, functional recovery in animal models and transplanted patients is incomplete. This limitation may be due to an incomplete restoration of the dopaminergic input to other basal ganglia structures such as the external segment of the globus pallidus (GPe, homologue of the rodent GP), which normally receives dopaminergic input from the substantia nigra (SN). As part of our investigation into a multiple grafting strategy for PD, we have explored the effects of dopaminergic grafts in the GP of rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. In this experiment, lesioned rats received either 300,000 fetal ventral mesencephalic (FVM) cells or a sham injection into the GP. Functional assessment consisted of rotational behavior at 3 and 6 weeks posttransplantation. A fluorogold tracer study was conducted to rule out any behavioral improvement due to striatal outgrowth of the GP graft. Sections were stained for glial fibrillary acidic protein (GFAP) to assess the degree of trauma in the GP by the graft in comparison to the sham injection.  Immunohistochemistry for tyrosine hydroxylase (TH) was performed after transplantation to assess graft survival. Animals with GP grafts demonstrated a significant improvement in rotational behavior at 3 and 6 weeks posttransplantation (p < 0.05) while sham control animals did not improve. All animals receiving FVM cells showed TH-immunoreactive grafts in the GP posttransplantation. TH-positive neurons in the GP showed no double labeling with an intrastriatal injection of fluorogold, indicating that behavioral improvement was not due to striatal innervation by the GP graft. These observations suggest that functional recovery was the result of dopaminergic reinnervation of the GP and that this nucleus may be a potential target for neural transplantation in clinical PD.

Key words: Parkinson's disease; Neural transplantation; Dopaminergic grafts; Globus pallidus; Fetal ventral mesencephalic cells; Fluorogold; Tyrosine hydroxylase; Multiple grafting strategy

Address correspondence to Dr. I. Mendez, Neural Transplantation Laboratory, Room 12-H1, Department of Anatomy and Neurobiology, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, Nova Scotia, Canada, B3H 4H7. Tel: (902) 494-8896; Fax: (902) 494-1212; E-mail mendez@is.dal.ca

Cell Transplantation, Vol. 14, pp. 129-138, 2005
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Inhibition of Chromatin Condensation Prevents Transgene Silencing in a Neural Progenitor Cell Line Transplanted to the Rat Brain

Nina Rosenqvist, Johan Jakobsson, and Cecilia Lundberg

Wallenberg Neuroscience Center, Department of Physiological Sciences, Division of Neurobiology, Lund University, Lund, Sweden

The use of ex vivo gene therapy in the central nervous system has so far suffered from transgene downregulation. Condensation of the transgenic sequences has been proposed to be a mechanism involved in this silencing. In this study we inhibited either histone deacetylation or DNA methylation in neural progenitor cell lines, transduced with a lentiviral vector carrying green fluorescent protein (GFP), prior to grafting them into the rat striatum. The expression of GFP was significantly higher in grafts pretreated with either of the inhibitors. After 1 week in vivo we detected an 11-fold increase in the number of GFP-expressing cells due to the inhibition of DNA methylation in vitro with azadeoxycytidine and a ninefold increase when inhibiting histone deacetylation with trichostatin A. This suggests that a pretreatment paradigm could be used to increase efficacy of ex vivo delivery of a therapeutic protein locally in the brain.

Key words: Histone deacetylation; DNA methylation; Ex vivo; Gene therapy; Lentiviral vector; CNS

Address correspondence to Cecilia Lundberg, BMC A11, 221 84 Lund, Sweden. Tel: +46-46 222 05 28; Fax: +46-46 222 05 61; E-mail: Cecilia.Lundberg@mphy.lu.se

Cell Transplantation, Vol. 14, pp. 139-149, 2005
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In Vivo Noninvasive Monitoring of a Tissue Engineered Construct Using H NMR Spectroscopy

C. L. Stabler,1,2 R. C. Long, Jr.,1,3 I. Constantinidis,4,5 and A. Sambanis1,2,6

1Georgia Institute of Technology/Emory University Center for the Engineering of Living Tissues, 315 Ferst Drive, Atlanta, GA 30332-0363
2Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, 313 Ferst Drive, Atlanta, GA 30332-0363
3Fredrik Philips Magnetic Resonance Research Center, Department of Radiology, Emory University, 1639 Pierce Drive, Atlanta, GA 30322
4Division of Endocrinology, Department of Medicine, University of Florida, PO Box 100226, Gainesville, FL 32610-0226
5National High Magnetic Field Laboratory, 1800 E. Paul Dirac Dr., Tallahassee, FL 32310-3706
6School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Drive, Atlanta, GA 30332-0100

Direct, noninvasive monitoring of tissue engineered substitutes containing live, functional cells would provide valuable information on dynamic changes that occur postimplantation. Such changes include remodeling both within the construct and at the interface of the implant with the surrounding host tissue, and may result in changes in the number of viable cells in the construct. This study investigated the use of H NMR spectroscopy in noninvasively monitoring the viable cell number within a tissue engineered construct in vivo. The construct consisted of mouse bTC3 insulinomas in a disk-shaped agarose gel, surrounded by a cell-free agarose gel layer. Localized H NMR spectra were acquired from within implanted constructs, and the total choline resonance was measured. Critical issues that had to be addressed in accurately quantifying total choline from the implanted cells included avoiding signal from host tissue and correcting for interfering signal from diffusing solutes. In vivo NMR measurements were correlated with MTT assays and NMR measurements performed in vitro on explanted constructs. Total choline measurements accurately and noninvasively quantified viable bTC3 cell numbers in vivo, in the range of 1 x 106 to more than 14 x 106 cells, and monitored changes in viable cell number that occurred in the same construct over time. This is the first study using NMR techniques to monitor viable cell numbers in an implanted tissue substitute. It established architectural characteristics that a construct should have to be amenable to NMR monitoring, and it set the foundation for future in vivo investigations with other tissue engineered implants.

Key words: H NMR spectroscopy; Total choline; bTC3 insulinoma cells; Pancreatic substitute; In vivo monitoring

Address correspondence to Athanassios Sambanis, Ph.D., Georgia Institute of Technology, Chemical & Biomolecular Engineering, 315 Ferst Drive, IBB Building, Room 1306, Atlanta, GA 30332. Tel: (404) 894-2869; Fax: (404) 894-2291; E-mail: athanassios.sambanis@chbe.gatech.edu

Cell Transplantation, Vol. 14, pp. 151-157, 2005
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Isolated Hepatocyte Transplantation for Crigler-Najjar Syndrome Type 1

Giovanni Ambrosino,1 Sergio Varotto,1 Stephen C. Strom,7 Graziella Guariso,2 Elisa Franchin,3 Diego Miotto,4 Luciana Caenazzo,5 Stefano Basso,1 Paolo Carraro,3 Maria Luisa Valente,6 Davide D'Amico,1 Lucia Zancan,2 and Lorenzo D'Antiga2

1Department of Surgery and Gastroenterological Science, 2Department of Paediatrics, 3Department of Laboratory Medicine, 4Department of Radiology, 5Department of Environmental Medicine and Public Health, and 6Department of Pathology,University of Padova, Padova, Italy
7Department of Pathology, University of Pittsburgh, Pittsburgh, PA

Crigler-Najjar syndrome type 1 (CN1) is an inherited disorder characterized by the absence of hepatic uridine diphosphoglucuronate glucuronosyltransferase (UDPGT), the enzyme responsible for the conjugation and excretion of bilirubin. We performed allogenic hepatocyte transplantation (AHT) in a child with CN1, aiming to improve bilirubin glucuronidation in this condition. A 9-year-old boy with CN1 was prepared with plasmapheresis and immunosuppression with prednisolone and tacrolimus. When a graft was made available, 7.5 x 109 hepatocytes were isolated and infused into the portal vein percutaneously. After 2 weeks phenobarbitone was added to promote the enzymatic activity of UDPGT of the transplanted hepatocytes. Nocturnal phototherapy was continued throughout the studied period. Total bilirubin was considered a reliable marker of allogenic cell function. There was no significant variation of vital signs nor complications during the infusion. Mean ± SD bilirubin level was 530 ± 38 mmol/L before and 359 ± 46 mmol/L after AHT (t-test, p < 0.001). However, the introduction of phenobarbitone was followed by a drop of tacrolimus level with increase of alanine aminotransferase (ALT) and increase of bilirubin. After standard treatment of cellular rejection bilirubin fell again but from then on it was maintained at a greater level. After discharge the patient experienced a further increase of bilirubin that returned to predischarge levels after readmission to the hospital. This was interpreted as poor compliance with phototherapy. Only partial correction of clinical jaundice and the poor tolerability to nocturnal phototherapy led the parents to refuse further hepatocyte infusions and request an orthotopic liver transplant. After 24 months the child is well, with good liver function on tacrolimus and prednisolone-based immunosuppression. Isolated AHT, though effective and safe, is not sufficient to correct CN1. Maintenance of adequate immunosuppression and family compliance are the main factors hampering the success of this procedure.

Key words: Hepatocyte transplantation; Crigler-Najjar syndrome; Uridine diphosphoglucuronate glucuronosyltransferase; Enzyme replacement therapy

Address correspondence to Lorenzo D'Antiga, Paediatric Department, University of Padova, Via Giustiniani 3, 35128 Padova, Italy. Tel: ++39-0498213595; Fax: ++39-0498213502; E-mail: lorenzo.dantiga@pediatria.unipd.it

Cell Transplantation, Vol. 14, pp. 159-167, 2005
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Effect of Microcapsule Composition and Short-Term Immunosuppression on Intraportal Biocompatibility

Christian Toso,1* Zoltan Mathe,1* Philippe Morel,1 José Oberholzer,1 Domenico Bosco,1 Dianelys Sainz-Vidal,2 David Hunkeler,3 Leo H. Buhler,1 Christine Wandrey,2 and Thierry Berney1

1Centre d'isolement et de transplantation cellulaire, Service de chirurgie viscérale, Hôpital Universitaire, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland
2Laboratoire de Polymères et Biomatériaux, Ecole Polytechnique Fédéral de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
3Aqua+Tech Specialties, 4,ch. du Chalet du Bac, CH-1283 La Plaine, Geneva, Switzerland

With higher nutrient and oxygen supply and close contact to blood, the portal vein is a possible alternative to the peritoneal cavity for transplantation of encapsulated cells. Data regarding intraportal biocompatibility of microcapsules are lacking. Microcapsules were built from five alginate types differing in their molar mass and mannuronic/guluronic acid ratios by complex formation with divalent cations (barium or calcium) or mixtures of divalent cations and polycations. They were injected in the portal vein of rats, and cellular and fibrotic pericapsular infiltration thickness was measured 3 and 7 days after implantation. Overgrowth was characterized using various stainings or immunohistochemistry (hematoxylin and eosin, Giemsa, ED-1 for monocyte/macrophage, a-actin for myofibroblasts, CD31 for endothelial cells). The impact of short-term immunosuppression (gadolinium-chloride IV 20 mg/kg/day on days -1 and 4 as well as 10 days of rapamycin PO 1 mg/kg/day, tacrolimus PO 3 mg/kg/day, or combinations of rapamycin/tacrolimus or gadolinium/tacrolimus) was further assessed 3, 7, and 42 days after implantation. Overall, overgrowth increased from day 3 to day 7 (p < 0.05). Three and 7 days after implantation, polycation-containing microcapsules induced more reaction than microbeads (p < 0.0001 and p < 0.01). Considering polycation-free beads, barium-alginate induced the weakest reaction. Biocompatibility of microbeads was independent of mannuronic/guluronic acid ratio and molar mass of the alginate. Infiltration was mainly a monocyte/macrophage-rich foreign body reaction, but an eosinophil-containing immunoallergic reaction was also observed. Short-term immunosuppression significantly reduced infiltration in all conditions and up to 42 days after implantation. Biocompatibility after intraportal infusion was best for barium-alginate microbeads and poorest for polycation-containing microcapsules. Short- and long-term overgrowth could be significantly reduced by short-term immunosuppression.

Key words: Microcapsule; Intraporal biocompatibility; Immunosuppression

Address correspondence to Christian Toso, Centre d'isolement et de transplantation cellulaire, Service de chirurgie viscérale, Hôpital Universitaire, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. Tel: 00 41 22 37 27 702; Fax: 00 41 22 37 27 755; E-mail: christian.toso@hcuge.ch

*These authors contributed equally to this work.