Publications by authors named "Pascal Furrer"

12 Publications

  • Page 1 of 1

Patient-specific statistical shape modeling for optimal spinal sagittal alignment in lumbar spinal fusion.

Eur Spine J 2021 08 2;30(8):2333-2341. Epub 2021 May 2.

Department of Orthopedic Surgery, Balgrist University Hospital, University of Zurich, Forchstrasse 340, 8008, Zurich, Switzerland.

Purpose: The present study compared patients developing ASD after L4/5 spinal fusion with a control group using a patient-specific statistical shape model (SSM) to find alignment-differences between the groups.

Methods: This study included patients who had undergone spinal fusion at L4/5 and either remained asymptomatic (control group; n = 25, follow-up of > 4 years) or required revision surgery for epifusional ASD (n = 22). Landmarks on preoperative and postoperative lateral radiographs were annotated, and the optimal spinal sagittal alignment was calculated for each patient. The two-dimensional distance from the SSM-calculated optimum to the actual positions before and after fusion surgery was compared.

Results: Postoperatively, the additive mean distance from the SSM-calculated optimum was 86.8 mm in the ASD group and 67.7 mm in the control group (p = 0.119). Greater differences were observed between the groups with a larger distance to the ideal in patients with ASD at more cranial levels. Significant difference between the groups was seen postoperatively in the vertical distance of the operated segment L4. The patients with ASD (5.69 ± 3.0 mm) had a significant greater distance from the SSM as the control group (3.58 ± 3.5 mm, p = 0.034).

Conclusion: Patients with ASD requiring revision after lumbar spinal fusion have greater differences from the optimal spinal sagittal alignment as an asymptomatic control group calculated by patient-specific statistical shape modeling. Further research might help to understand the value of SSM, in conjunction with already established indexes, for preoperative planning with the aim of reducing the risk of ASD.

Level Of Evidence I: Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding.
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http://dx.doi.org/10.1007/s00586-021-06852-xDOI Listing
August 2021

Unplanned Return Visits to a Pediatric Emergency Department.

Pediatr Emerg Care 2019 Mar 1. Epub 2019 Mar 1.

From the Pediatric Emergency Department.

Objectives: Unplanned return visits (URVs) to emergency departments (EDs) account internationally for 2.5% to 5.2% of all consultations. ED crowding is an increasing challenge, and URVs seem to contribute to this problem. This study aimed to assess factors for URVs at the ED of a tertiary children's hospital to analyze if they are jointly responsible for the steadily rising amount of treated patients.

Methods: All patients with an URV to a pediatric ED in Switzerland between January and December 2013 were included in the study. Data were taken retrospectively from the electronic patient files, and different variables were defined and analyzed.

Results: URVs occurred at an incidence of 4.6%, and mostly concerned infants and toddlers (46%). URVs were independent of weekdays and mostly occurred between 10 AM and 10 PM. In 84.2% of the cases, the URVs were judged as unnecessary, and in 15.8%, a hospitalization was indicated, mainly for children with a worsening respiratory illness.

Conclusions: The occurrence of URVs in our ED was within the incidence reported in the literature. While URVs lead to hospitalization in some patients, the majority of URVs were unnecessary from a medical point of view. These results indicate that a correct evaluation of the child's health state by parents is often challenging and requires repeated medical attendance following a first ED visit, especially in infants with airway diseases and infections. Intensive counseling and scheduled short-term follow-up consultation at the pediatrician's office could prevent URVs to the ED.
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http://dx.doi.org/10.1097/PEC.0000000000001764DOI Listing
March 2019

Antileishmanial Activity of Dimeric Flavonoids Isolated from .

Molecules 2018 Dec 20;24(1). Epub 2018 Dec 20.

Laboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz), Avenida Waldemar Falcão, 121, Candeal⁻Salvador-BA 40296-710, Brazil.

Leishmaniasis are diseases caused by parasites belonging to genus. The treatment with pentavalent antimonials present high toxicity. Secondary line drugs, such as amphotericin B and miltefosine also have a narrow therapeutic index. Therefore, there is an urgent need to develop new drugs to treat leishmaniasis. Here, we present the in vitro anti-leishmanial activity of unusual dimeric flavonoids purified from . Three compounds were tested against sp. Compound 2 was the most active against promastigotes. Quantifying the in vitro infected macrophages revealed that compound 2 was also the most active against intracellular amastigotes of , without displaying host cell toxicity. Drug combinations presented an additive effect, suggesting the absence of interaction between amphotericin B and compound 2. Amastigotes treated with compound 2 demonstrated alterations in the Golgi and accumulation of vesicles inside the flagellar pocket. Compound 2-treated amastigotes presented a high accumulation of cytoplasmic vesicles and a myelin-like structure. When administered in -infected mice, neither the oral nor the topical treatments were effective against the parasite. Based on the high in vitro activity, dimeric flavonoids can be used as a lead structure for the development of new molecules that could be useful for structure-active studies against .
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http://dx.doi.org/10.3390/molecules24010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337281PMC
December 2018

Intranasal administration of resveratrol successfully prevents lung cancer in A/J mice.

Sci Rep 2018 09 24;8(1):14257. Epub 2018 Sep 24.

School of pharmaceutical sciences, University of Geneva, University of Lausanne, Rue Michel-Servet 1, CH-1211, Geneva 4, Switzerland.

Lung cancer is the most lethal cancer in the world. About 80% of lung cancer deaths are linked to tobacco use. As a complement to tobacco control, efficient chemoprevention strategies are needed to tackle lung cancer epidemic. Resveratrol is one of the most studied natural products, notably for its cancer chemoprevention properties. However, its low oral bioavailability has often limited the translation of in vitro activities to in vivo effects. While oral administration of resveratrol effectively inhibited colorectal carcinogenesis, it failed to protect mice from chemically-induced lung carcinogenesis. Therefore, non-invasive parenteral routes must be considered to bring resveratrol to the lungs. In the present study, intranasal administration of a concentrated formulation proved to be a valid method to expose the lungs to a sufficient amount of resveratrol. This formulation was administered three times a week for 25 weeks to A/J mice having 4-[methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone-induced lung carcinogenesis. Resveratrol-treated mice showed a 27% decrease in tumour multiplicity, with smaller tumours, resulting in 45% decrease in tumour volume/mouse. In vitro investigations highlighted apoptosis as a potential mechanism of action. This study presents an effective way to overcome resveratrol low oral bioavailability, encouraging a reevaluation of its use in future clinical trials.
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http://dx.doi.org/10.1038/s41598-018-32423-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155121PMC
September 2018

Identification and Mode of Action of a Plant Natural Product Targeting Human Fungal Pathogens.

Antimicrob Agents Chemother 2017 09 24;61(9). Epub 2017 Aug 24.

Institute of Microbiology, University of Lausanne, and Lausanne University Hospital, Lausanne, Switzerland

is a major cause of fungal diseases in humans, and its resistance to available drugs is of concern. In an attempt to identify novel antifungal agents, we initiated a small-scale screening of a library of 199 natural plant compounds (i.e., natural products [NPs]). susceptibility profiling experiments identified 33 NPs with activity against (MICs ≤ 32 μg/ml). Among the selected NPs, the sterol alkaloid tomatidine was further investigated. Tomatidine originates from the tomato () and exhibited high levels of fungistatic activity against species (MICs ≤ 1 μg/ml) but no cytotoxicity against mammalian cells. Genome-wide transcriptional analysis of tomatidine-treated cells revealed a major alteration (upregulation) in the expression of ergosterol genes, suggesting that the ergosterol pathway is targeted by this NP. Consistent with this transcriptional response, analysis of the sterol content of tomatidine-treated cells showed not only inhibition of Erg6 (C-24 sterol methyltransferase) activity but also of Erg4 (C-24 sterol reductase) activity. A forward genetic approach in coupled with whole-genome sequencing identified 2 nonsynonymous mutations in (amino acids D249G and G132D) responsible for tomatidine resistance. Our results therefore unambiguously identified Erg6, a C-24 sterol methyltransferase absent in mammals, to be the main direct target of tomatidine. We tested the efficacy of tomatidine in a mouse model of systemic infection. Treatment with a nanocrystal pharmacological formulation successfully decreased the fungal burden in infected kidneys compared to the fungal burden achieved by the use of placebo and thus confirmed the potential of tomatidine as a therapeutic agent.
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http://dx.doi.org/10.1128/AAC.00829-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571344PMC
September 2017

A novel cyclosporin a aqueous formulation for dry eye treatment: in vitro and in vivo evaluation.

Invest Ophthalmol Vis Sci 2012 Apr 30;53(4):2292-9. Epub 2012 Apr 30.

School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.

Purpose: The aim of the present study was the in vitro and in vivo evaluation of a novel aqueous formulation based on polymeric micelles for the topical delivery of cyclosporine A for dry eye treatment.

Methods: In vitro experiments were carried out on primary rabbit corneal cells, which were characterized by immunocytochemistry using fluorescein-labeled lectin I/isolectin B4 for the endothelial cells and mouse monoclonal antibody to cytokeratin 3+12 for the epithelial ones. Living cells were incubated for 1 hour or 24 hours with a fluorescently labeled micelle formulation and analyzed by fluorescence microscopy. In vivo evaluations were done by Schirmer test, osmolarity measurement, CyA kinetics in tears, and CyA ocular distribution after topical instillation. A 0.05% CyA micelle formulation was compared to a marketed emulsion (Restasis).

Results: The in vitro experiments showed the internalization of micelles in the living cells. The Schirmer test and osmolarity measurements demonstrated that micelles did not alter the ocular surface properties. The evaluation of the tear fluid gave similar CyA kinetics values: AUC = 2339 ± 1032 min*μg/mL and 2321 ± 881.63; Cmax = 478 ± 111 μg/mL and 451 ± 74; half-life = 36 ± 9 min and 28 ± 9 for the micelle formulation and Restasis, respectively. The ocular distribution investigation revealed that the novel formulation delivered 1540 ± 400 ng CyA/g tissue to the cornea.

Conclusions: The micelle formulation delivered active CyA into the cornea without evident negative influence on the ocular surface properties. This formulation could be applied for immune-related ocular surface diseases.
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http://dx.doi.org/10.1167/iovs.11-8829DOI Listing
April 2012

Ocular biocompatibility of novel Cyclosporin A formulations based on methoxy poly(ethylene glycol)-hexylsubstituted poly(lactide) micelle carriers.

Int J Pharm 2011 Sep 8;416(2):515-24. Epub 2011 Jan 8.

School of Pharmaceutical Sciences, Pharmaceutics, University of Geneva, University of Lausanne, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland.

Topical ocular drug delivery has always been a challenge for pharmaceutical technology scientists. In the last two decades, many nano-systems have been studied to find ways to overcome the typical problems of topical ocular therapy, such as difficult corneal penetration and poor drug availability. In this study, methoxy poly(ethylene glycol)-hexylsubstituted poly(lactides) (MPEG-hexPLA) micelle formulations, which are promising nanocarriers for poorly water soluble drugs, were investigated for the delivery of Cyclosporin A (CsA) to the eye. As a new possible pharmaceutical excipient, the ocular compatibility of MPEG-hexPLA micelle formulations was evaluated. An in vitro biocompatibility assessment on human corneal epithelial cells was carried out using different tests. Cytotoxicity was studied by using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT), and clonogenic tests and revealed that the CsA formulations and copolymer solutions were not toxic. After incubation with MPEG-hexPLA micelle formulations, the activation of caspase-dependent and -independent apoptosis as well as autophagy was evaluated using immunohistochemistry by analyzing the localization of four antibodies: (1) anti-caspase 3; (2) anti-apoptotic inducing factor (AIF); (3) anti-IL-Dnase II and (4) anti-microtubule-associated protein 1 light chain 3 (LC3). No apoptosis was induced when the cells were treated with the micelle solutions that were either unloaded or loaded with CsA. The ocular tolerance was assessed in vivo on rabbit eyes by Confocal Laser Scanning Ophthalmoscopy (CLSO), and very good tolerability was seen. The observed corneal surface was comparable to a control surface that was treated with a 0.9% NaCl solution. In conclusion, these results demonstrate that MPEG-hexPLA micelles are promising drug carriers for ocular diseases involving the activation of cytokines, such as dry eye syndrome and autoimmune uveitis, or for the prevention of corneal graft rejection.
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http://dx.doi.org/10.1016/j.ijpharm.2011.01.004DOI Listing
September 2011

Recent advances in confocal microscopy for studying drug delivery to the eye: concepts and pharmaceutical applications.

Eur J Pharm Biopharm 2010 Jan 13;74(1):33-40. Epub 2009 Sep 13.

School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Switzerland.

Since its seminal introduction 50years ago, confocal microscopy has been applied in numerous fields in life sciences. This review presents the different key elements of confocal microscopes, in particular scanning techniques, light sources and especially laser sources are described in this review. Furthermore, an overview of the different image processing systems coupled with confocal microscopy is provided. The chapter closes with the applications of confocal microscopy in drug delivery to the eye.
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http://dx.doi.org/10.1016/j.ejpb.2009.09.002DOI Listing
January 2010

Comparative studies of various hyaluronic acids produced by microbial fermentation for potential topical ophthalmic applications.

J Biomed Mater Res A 2010 Mar;92(4):1421-30

Novozymes Biopolymer A/S, Krogshoejvej 36, DK-2880 Bagsvaerd, Denmark.

This work presents a comparative study of various hyaluronic acids (HA) produced by fermentation of either Bacillus subtilis or Streptococcus towards the selection of an optimal molecular weight (MW) HA for the preparation of topical ophthalmic formulations. The influence of HA MW on water binding capacity, sterile filtration, rheological properties, precorneal residence time and ocular tolerance of ophthalmic solutions was investigated. Molecular weight did not affect hydration of hyaluronic acid according to differential scanning calorimetry (DSC). In general, medium MW HA (0.6-1 MDa) resulted in solutions that were superior in terms of sterile filtration and kinematic viscosity requirements compared to high MW HA (>1 MDa). Moreover, all HA-based solutions exhibited well-defined viscoelastic properties that depend on MW. Gamma scintigraphic data indicated that HA MW at 0.1% concentration (w/v) and HA origin did not significantly affect the corneal residence time on rabbit eyes. A 0.3% solution of high MW HA had a prolonged residence time in the precorneal area compared to a medium MW HA at the same concentration. Finally, an in vivo ocular irritation test based on confocal laser scanning ophthalmoscopy (CLSO) conclusively showed the excellent tolerance of both Bacillus-derived HA and Streptococcus-derived HA after topical instillation onto the corneal surface. Overall, this comprehensive work highlights the superiority of medium MW hyaluronic acid for topical ophthalmic formulations based on their physico-chemical and biological properties, tolerance and handling. Such solutions are expected to enhance tear film stability, to allow for maximum comfort, and to exhibit high residence times, while being biocompatible and easy to sterile filter.
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http://dx.doi.org/10.1002/jbm.a.32481DOI Listing
March 2010

New surface-active polymers for ophthalmic formulations: evaluation of ocular tolerance.

Eur J Pharm Biopharm 2004 Jul;58(1):169-75

Institut für Pharmazeutische Technologie, Technische Universität Braunschweig, Braunschweig, Germany.

Two n-octenylsuccinate starch (AS) types of unknown molecular weights were assessed for ocular tolerance. Irritation potential of different solutions (containing 2 and 15% (w/w) AS) and AS stabilized emulsions (containing 15% (w/w) AS) was evaluated in vivo in rabbit eyes, using a confocal laser scanning microscope, and in vitro on treated excised pig corneas by light microscopy of histological cross sections. Both AS types were previously characterized by viscosity, osmolality and surface tension measurements. All tested solutions and emulsions showed good eye tolerance regardless of concentration and emulsifying properties suggesting AS to be a good alternative to commonly used solubilizing or emulsifying agents in ophthalmic formulations.
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http://dx.doi.org/10.1016/j.ejpb.2004.03.005DOI Listing
July 2004

Ocular tolerance of absorption enhancers in ophthalmic preparations.

AAPS PharmSci 2002 ;4(1):E2

School of Pharmacy, Institute of Medicinal Chemistry; University of Lausanne, CH-1015 Lausanne, Switzerland.

The use of absorption promoters is a way to improve the bioavailability and therapeutic response of topically applied ophthalmic drugs. The ocular tolerance of 9 potential absorption promoters was investigated as well as the influence of the enhancers' concentration on the ocular tolerance. The substances tested were instillated repetitively (4 times per day, during 3 days, and once just before examination) as aqueous solutions onto rabbit corneas. Fluorescein dyeing enabled us to specifically mark corneal damage that was observed by confocal microscopy. The degree of corneal injury was assessed with an image-processing system that calculated the total fluorescent areas. Confocal microscopy results showed the relatively good tolerance of permeation enhancers like dimethyl sulfoxide (DMSO), decamethonium, edetate, glycocholate, and cholate in contrast to the poorly tolerated saponin and fusidate. Increasing the promoters' concentration led generally to an increase in corneal lesions.
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http://dx.doi.org/10.1208/ps040102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751287PMC
July 2002

Ocular tolerance of preservatives and alternatives.

Eur J Pharm Biopharm 2002 May;53(3):263-80

School of Pharmacy, Institute of Medical Chemistry, University of Lausanne, Switzerland.

Eye drops are multiple dosage forms protected against microbial contamination by means of preservatives. However, the ocular tolerance of these chemicals can vary and this may result in adverse toxic or allergic reactions. This overview presents the pharmacopoeial requirements for the preservation of eye drops, the factors affecting ocular tolerance as well as the adverse external ocular effects induced by preservatives. The alternatives to the use of preservatives are also discussed, including the recent progress in eye drops packaging.
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http://dx.doi.org/10.1016/s0939-6411(01)00246-6DOI Listing
May 2002
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