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2.  Safety of concurrent treatment of cats with fluralaner and emodepsid–praziquantel 
Parasites & Vectors  2016;9:322.
Background
Fluralaner is a novel systemic ectoparasiticide for cats providing immediate and persistent flea- and tick-control after a single topical dose. Emodepsid and praziquantel are routinely used to control intestinal worm infections in cats. The safety of concurrent use of fluralaner and a commercially available emodepsid-praziquantel combination topical solution was investigated using topical administrations at the maximum recommended dose rates.
Findings
Few mild and transient clinical findings like erythema at the administration site and single incidences of salivation or vomiting were observed. All of which were consistent with the individual product leaflets. There were no findings suggesting an increased safety risk associated with the concurrent treatment of cats with fluralaner and emodepsid-praziquantel.
Conclusions
Concurrent treatment with fluralaner, emodepsid and praziquantel is well tolerated in cats.
doi:10.1186/s13071-016-1618-y
PMCID: PMC4896020  PMID: 27267592
Cat; Fluralaner; Bravecto™; Emodepsid; Praziquantel; Profender™; Safety
3.  Plasma pharmacokinetic profile of fluralaner (Bravecto™) and ivermectin following concurrent administration to dogs 
Parasites & Vectors  2015;8:508.
Background
Fluralaner is a novel systemic ectoparasiticide for dogs providing immediate and persistent flea, tick and mite control after a single oral dose. Ivermectin has been used in dogs for heartworm prevention and at off label doses for mite and worm infestations. Ivermectin pharmacokinetics can be influenced by substances affecting the p-glycoprotein transporter, potentially increasing the risk of ivermectin neurotoxicity. This study investigated ivermectin blood plasma pharmacokinetics following concurrent administration with fluralaner.
Findings
Ten Beagle dogs each received a single oral administration of either 56 mg fluralaner (Bravecto™), 0.3 mg ivermectin or 56 mg fluralaner plus 0.3 mg ivermectin/kg body weight. Blood plasma samples were collected at multiple post-treatment time points over a 12-week period for fluralaner and ivermectin plasma concentration analysis.
Ivermectin blood plasma concentration profile and pharmacokinetic parameters Cmax, tmax, AUC∞ and t½ were similar in dogs administered ivermectin only and in dogs administered ivermectin concurrently with fluralaner, and the same was true for fluralaner pharmacokinetic parameters.
Conclusions
Concurrent administration of fluralaner and ivermectin does not alter the pharmacokinetics of either compound. Based on the plasma pharmacokinetic profile and the clinical observations, there is no evident interaction between fluralaner and ivermectin, and co-administration does not increase the risk of ivermectin associated neurotoxicity.
doi:10.1186/s13071-015-1123-8
PMCID: PMC4595236  PMID: 26438338
Fluralaner; Bravecto™; Ivermectin; Dog; Pharmacokinetic; P-glycoprotein; MDR1
4.  Safety of concurrent treatment of dogs with fluralaner (Bravecto™) and milbemycin oxime - praziquantel 
Parasites & Vectors  2014;7:481.
Background
Fluralaner (Bravecto™; Merck/MSD Animal Health) is a novel systemic ectoparasiticide for dogs providing long-acting flea and tick control after a single oral dose. Milbemycin oxime and praziquantel are routinely used to control Dirofilaria immitis and intestinal worm infections in dogs. The safety of concurrent use of fluralaner and a commercially available milbemycin oxime plus praziquantel combination tablet, in particular with regard to gastrointestinal symptoms, was investigated using oral doses at or above the maximum recommended rates.
Findings
Some minor and transient clinical findings were observed during the study period; however, none of these was considered to be related to concurrent treatment with fluralaner and milbemycin oxime plus praziquantel, or to the use of either product alone.
Conclusions
Concurrent treatment with fluralaner, milbemycin oxime and praziquantel is well tolerated in dogs.
doi:10.1186/s13071-014-0481-y
PMCID: PMC4198702  PMID: 25315498
Bravecto™; Fluralaner; Dog; Safety; Milbemycin oxime; Praziquantel
5.  Safety of the concurrent treatment of dogs with Bravecto™ (fluralaner) and Scalibor™ protectorband (deltamethrin) 
Parasites & Vectors  2014;7:105.
Background
Bravecto™ (fluralaner; MSD Animal Health) is a novel systemic ectoparasiticide for dogs providing long-acting flea- and tick-control after a single oral dose. Scalibor™ Protectorband (deltamethrin; MSD Animal Health) is a collar often used to reduce sandfly feeding for leishmaniasis prevention. This study investigated the safety of the concurrent use of BravectoTM and ScaliborTM Protectorband at the recommended dosage regimens.
Findings
Throughout the study period of 24 weeks, there were no clinical findings related to the concurrent treatment with Bravecto™ in dogs fitted with Scalibor™ Protectorband at the recommended dosage regimen.
Conclusions
Concurrent treatment with Bravecto™ in dogs fitted with Scalibor™ Protectorband is well tolerated.
doi:10.1186/1756-3305-7-105
PMCID: PMC3972964  PMID: 24646450
BravectoTM; Fluralaner; Dog; Safety; Scalibor™; Deltamethrin
6.  Safety of fluralaner chewable tablets (BravectoTM), a novel systemic antiparasitic drug, in dogs after oral administration 
Parasites & Vectors  2014;7:87.
Background
Fluralaner is a novel systemic insecticide and acaricide that provides long acting efficacy in dogs after a single oral treatment. This study investigated the safety of oral administration of fluralaner in chewable tablets to dogs at the highest recommended treatment dose and at multiples of this dose.
Methods
Thirty-two (16 male and 16 female) healthy 8-week old Beagle dogs weighing 2.0 - 3.6 kg at first administration were included in the study. Fluralaner was administered on three occasions at 8-week intervals at doses of up to 56, 168, and 280 mg fluralaner/kg body weight, equivalent to 1, 3, and 5 times the highest recommended treatment dose of fluralaner; sham dosed dogs served as controls.
During the study, all dogs were clinically observed, and their health was carefully monitored including body weight development, food consumption and measurement of hematology, coagulation, clinical chemistry (including measurement of levels of ACTH and C-reactive protein) and urinalysis. Following euthanasia of the dogs, complete gross post mortem examination, including organ weight determination, and histopathological examination of multiple tissues were conducted.
Results
There were no clinical findings related to fluralaner treatment. Statistically significant differences between the treated groups and the control group were observed for some clinical pathology parameters and organ weights; none of these findings were considered to be of clinical relevance.
Conclusions
Oral administration of fluralaner at the highest recommended treatment dose (56 mg/kg) at 8-week intervals is well tolerated and has a safety margin of more than five in healthy dogs eight weeks of age or older and weighing at least 2 kg.
doi:10.1186/1756-3305-7-87
PMCID: PMC3975339  PMID: 24606886
Fluralaner; Dog; Safety; Bravecto™
7.  Safety of fluralaner, a novel systemic antiparasitic drug, in MDR1(-/-) Collies after oral administration 
Parasites & Vectors  2014;7:86.
Background
Fluralaner is a novel systemic ectoparasiticide for dogs providing long-acting flea- and tick-control after a single oral dose. This study investigated the safety of oral administration of fluralaner at 3 times the highest expected clinical dose to Multi Drug Resistance Protein 1 (MDR1(-/-)) gene defect Collies.
Methods
Sixteen Collies homozygous for the MDR1 deletion mutation were included in the study. Eight Collies received fluralaner chewable tablets once at a dose of 168 mg/kg; eight sham dosed Collies served as controls. All Collies were clinically observed until 28 days following treatment.
Results
No adverse events were observed subsequent to fluralaner treatment of MDR1(-/-) Collies at three times the highest expected clinical dose.
Conclusions
Fluralaner chewable tablets are well tolerated in MDR1(-/-) Collies following oral administration.
doi:10.1186/1756-3305-7-86
PMCID: PMC3975640  PMID: 24602342
Fluralaner; Bravecto™; Dog; Safety; MDR1
8.  The effect of food on the pharmacokinetics of oral fluralaner in dogs 
Parasites & Vectors  2014;7:84.
Background
Fluralaner is a novel systemic ectoparasiticide for dogs providing long-acting flea- and tick-control after a single oral dose. The pharmacokinetics of orally administered drugs may be influenced by feeding. This study investigated the influence of concurrent feeding on fluralaner pharmacokinetics.
Methods
Twelve fasted or fed beagles received a single oral administration of 25 mg fluralaner/kg body weight in a chewable tablet. Plasma samples were collected at multiple post-treatment time points for fluralaner concentration analysis. Clinical observations were performed on all dogs at regular intervals throughout the study.
Results
Fluralaner was readily absorbed in fasted and fed dogs administered at a dose of 25 mg/kg BW with a similar mean tmax for both groups. In fed dogs, AUC and Cmax were increased compared to fasted dogs by a factor of 2.5 and 2.1 respectively. The difference in AUC and Cmax between the fed and fasted groups was statistically significant. No adverse events were observed following oral fluralaner administration to fasted and fed dogs.
Conclusions
Fluralaner is absorbed to a considerable extent in fasted and fed dogs. Administration of fluralaner chewable tablets with food significantly increases bioavailability.
doi:10.1186/1756-3305-7-84
PMCID: PMC3975707  PMID: 24598049
Fluralaner; Dog; Pharmacokinetics; Food effect; Fasted
9.  HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children 
PLoS Pathogens  2012;8(3):e1002579.
Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients.
Author Summary
HO-1 is an important anti-inflammatory enzyme induced by several stimuli associated with critical illness. In humans, the amount of HO-1 produced is influenced by a genetic polymorphism in the gene promoter region. Using Plasmodium falciparum malaria that can cause a sepsis-like syndrome as an example, we characterize the associations between the (GT)n polymorphism, HO-1 protein levels and HMOX1-mRNA expression with severity of malaria in 307 Gambian children. Our results support the functionality of this polymorphism, demonstrate that P. falciparum infections increase HO-1 levels, and indicate that a genetic predisposition to strongly upregulate HO-1 is associated with severe forms of malaria and increased risk of dying. We identify neutrophils as the main HO-1-producing blood cells, and provide evidence that hemin-mediated induction of HMOX1 in neutrophils in vitro enhances the oxidative burst. In this way sequestered neutrophils may contribute to oxidative damage of endothelial cells, which may be part of a causal pathway explaining the association between short (GT)n repeats and increased disease severity. Our findings imply that the beneficial effects of HO-1 may be limited to a narrow window of concentrations, which should be born in mind when considering the therapeutic potential of manipulating HO-1 induction in critically ill patients.
doi:10.1371/journal.ppat.1002579
PMCID: PMC3305414  PMID: 22438807
10.  Arthrodesis in the treatment of hallux rigidus 
International Orthopaedics  2003;27(6):382-385.
We reviewed 34 patients (38 joints) with hallux rigidus treated from 1989 to 1999 with arthrodesis of the first metatarsophalangeal joint. Average patient age at time of surgery was 52 (24–71) years, and the mean follow-up was 54 (18–116) months. There were six superficial infections, and all arthrodeses united. There was a good functional result with a significant pain reduction. The mean postoperative American Orthopaedic Foot and Ankle Society (AOFAS) score was 53 (5–84) points.
doi:10.1007/s00264-003-0492-3
PMCID: PMC3461880  PMID: 12942194
11.  Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer 
Journal of Medical Genetics  2005;43(1):18-27.
Background
Hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839) is the predisposition to develop smooth muscle tumours of the skin and uterus and/or renal cancer and is associated with mutations in the fumarate hydratase gene (FH). Here we characterise the clinical and genetic features of 21 new families and present the first report of two African‐American families with HLRCC.
Methods
Using direct sequencing analysis we identified FH germline mutations in 100% (21/21) of new families with HLRCC.
Results
We identified 14 germline FH mutations (10 missense, one insertion, two nonsense, and one splice site) located along the entire length of the coding region. Nine of these were novel, with six missense (L89S, R117G, R190C, A342D, S376P, Q396P), one nonsense (S102X), one insertion (111insA), and one splice site (138+1G>C) mutation. Four unrelated families had the R58X mutation and five unrelated families the R190H mutation. Of families with HLRCC, 62% (13/21) had renal cancer and 76% (16/21) cutaneous leiomyomas. Of women FH mutation carriers from 16 families, 100% (22/22) had uterine fibroids. Our study shows that expression of cutaneous manifestations in HLRCC ranges from absent to mild to severe cutaneous leiomyomas. FH mutations were associated with a spectrum of renal tumours. No genotype‐phenotype correlations were identified.
Conclusions
In combination with our previous report, we identify 31 different germline FH mutations in 56 families with HLRCC (20 missense, eight frameshifts, two nonsense, and one splice site). Our FH mutation detection rate is 93% (52/56) in families suspected of HLRCC.
doi:10.1136/jmg.2005.033506
PMCID: PMC2564499  PMID: 15937070
fumarate hydratase; germline mutations; HLRCC; leiomyomas; renal cancer
12.  ESICM LIVES 2016: part two 
Sivakumar, S. | Taccone, F. S. | Desai, K. A. | Lazaridis, C. | Skarzynski, M. | Sekhon, M. | Henderson, W. | Griesdale, D. | Chapple, L. | Deane, A. | Williams, L. | Strickland, R. | Lange, K. | Heyland, D. | Chapman, M. | Rowland, M. J. | Garry, P. | Westbrook, J. | Corkill, R. | Antoniades, C. A. | Pattinson, K. T. | Fatania, G. | Strong, A. J. | Myers, R. B. | Lazaridis, C. | Jermaine, C. M. | Robertson, C. S. | Rusin, C. G. | Hofmeijer, J. | Sondag, L. | Tjepkema-Cloostermans, M. C. | Beishuizen, A. | Bosch, F. H. | van Putten, M. J. A. M. | Carteron, L. | Patet, C. | Solari, D. | Oddo, M. | Ali, M. A. | Dias, C. | Almeida, R. | Vaz-Ferreira, A. | Silva, J. | Monteiro, E. | Cerejo, A. | Rocha, A. P. | Elsayed, A. A. | Abougabal, A. M. | Beshey, B. N. | Alzahaby, K. M. | Pozzebon, S. | Ortiz, A. Blandino | Cristallini, S. | Lheureux, O. | Brasseur, A. | Vincent, J. L. | Creteur, J. | Taccone, F. S. | Hravnak, M. | Yousef, K. | Chang, Y. | Crago, E. | Friedlander, R. M. | Abdelmonem, S. A. | Tahon, S. A. | Helmy, T. A. | Meligy, H. S. | Puig, F. | Dunn-Siegrist, I. | Pugin, J. | Gupta, S. | Govil, D. | Srinivasan, S. | Patel, S. J. | N, J. K. | Gupta, A. | Tomar, D. S. | Shafi, M. | Harne, R. | Arora, D. P. | Talwar, N. | Mazumdar, S. | Papakrivou, E. E. | Makris, D. | Manoulakas, E. | Tsolaki, B. | Karadodas, B. | Zakynthinos, E. | Garcia, I. Palacios | Martin, A. Diaz | Encinares, V. Sanchez | Ibañez, M. Pachón | Montero, J. Garnacho | Labrador, G. | Cangueiro, T. Cebrero | Poulose, V. | Koh, J. | Kam, J. W. | Yeter, H. | Kara, A. | Aktepe, O. | Topeli, A. | Tsolakoglou, I. | Intas, G. | Stergiannis, P. | Kolaros, A. A. | Chalari, E. | Athanasiadou, E. | Martika, A. | Fildisis, G. | Faivre, V. | Mengelle, C. | Favier, B. | Payen, D. | Poppe, A. | Winkler, M. S. | Mudersbach, E. | Schreiber, J. | Wruck, M. L. | Schwedhelm, E. | Kluge, S. | Zöllner, C. | Tavladaki, T. | Spanaki, A. M. | Dimitriou, H. | Kondili, E. | Choulaki, C. | Meleti, E. | Kafetzopoulos, D. | Georgopoulos, D. | Briassoulis, G. | la Torre, A. García-de | de la Torre-Prados, M. V. | Tsvetanova-Spasova, T. | Nuevo-Ortega, P. | Rueda-Molina, C. | Fernández-Porcel, A. | Camara-Sola, E. | Salido-Díaz, L. | García-Alcántara, A. | Tavladaki, T. | Spanaki, A. M. | Dimitriou, H. | Kondili, E. | Choulaki, C. | Meleti, D. E. | Kafetzopoulos, D. | Georgopoulos, D. | Briassoulis, G. | Suberviola, B. | Riera, J. | Rellan, L. | Sanchez, M. | Robles, J. C. | Lopez, E. | Vicente, R. | Miñambres, E. | Santibañez, M. | Le Guen, M. | Moore, J. | Mason, N. | Windpassinger, M. | Plattner, O. | Mascha, E. | Sessler, D. I. | Research, Outcomes | Melia, U. | Fontanet, J. | van den Berg, J. P. | Struys, M. M. R. F. | Vereecke, H. E. M. | Jensen, E. W. | Rood, P. J. T. | van de Schoor, F. | van Tertholen, K. | Pickkers, P. | van den Boogaard, M. | Beardow, Z. J. | Redhead, H. | Paramasivam, K. | Numan, T. | van den Boogaard, M. | Kamper, A. M. | Rood, P. | Peelen, L. M. | Zeman, P. M. | Slooter, A. J. | van Ewijk, C. E. | Jacobs, G. E. | Girbes, A. R. J. | Myatra, S. N. | Harish, M. M. | Prabu, N. R. | Siddiqui, S. | Kulkarni, A. P. | Divatia, J. V. | Murbach, L. D. | Leite, M. A. | Osaku, E. F. | Costa, C. R. L. M. | Pelenz, M. | Neitzke, N. M. | Moraes, M. M. | Jaskowiak, J. L. | Silva, M. M. M. | Zaponi, R. S. | Abentroth, L. R. L. | Ogasawara, S. M. | Jorge, A. C. | Duarte, P. A. D. | Hernández-Sánchez, N. | Sánchez-Hurtado, L. A. | García-Guillen, F. J. | Ñamendys-Silva, S. A. | Maghsoudi, B. | Emami, M. | Khosravi, M. B. | Zand, F. | Tabatabaie, H. R. | Masjedi, M. | Sabetiyan, G. | Mokri, A. | Troubleyn, J. | Diltoer, M. | Jacobs, R. | Nguyen, D. N. | De Waele, E. | De Regt, J. | Honoré, P. M. | Van Gorp, V. | Spapen, H. D. | Contreras, R. S. | Toapanta, N. 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doi:10.1186/s40635-016-0099-9
PMCID: PMC5042923
13.  The Breadth, but Not the Magnitude, of Circulating Memory B Cell Responses to P. falciparum Increases with Age/Exposure in an Area of Low Transmission 
PLoS ONE  2011;6(10):e25582.
Background
Malaria caused by Plasmodium falciparum remains a major cause of death in sub-Saharan Africa. Immunity against symptoms of malaria requires repeated exposure, suggesting either that the parasite is poorly immunogenic or that the development of effective immune responses to malaria may be impaired.
Methods
We carried out two age-stratified cross-sectional surveys of anti-malarial humoral immune responses in a Gambian village where P. falciparum malaria transmission is low and sporadic. Circulating antibodies and memory B cells (MBC) to four malarial antigens were measured using ELISA and cultured B cell ELISpot.
Findings and Conclusions
The proportion of individuals with malaria-specific MBC and antibodies, and the average number of antigens recognised by each individual, increased with age but the magnitude of these responses did not. Malaria-specific antibody levels did not correlate with either the prevalence or median number of MBC, indicating that these two assays are measuring different aspects of the humoral immune response. Among those with immunological evidence of malaria exposure (defined as a positive response to at least one malarial antigen either by ELISA or ELISPOT), the median number of malaria-specific MBC was similar to median numbers of diphtheria-specific MBC, suggesting that the circulating memory cell pool for malaria antigens is of similar size to that for other antigens.
doi:10.1371/journal.pone.0025582
PMCID: PMC3186790  PMID: 21991321
14.  Therapeutic time window for angiotensin‐(1–7) in acute lung injury 
British Journal of Pharmacology  2016;173(10):1618-1628.
Background and Purpose
There is presently no proven pharmacological therapy for the acute respiratory distress syndrome. Recently, we and others discovered that the heptapeptide angiotensin‐(1–7) [Ang‐(1–7)] shows significant beneficial effects in preclinical models of acute lung injury (ALI). Here, we aimed to identify the best time window for Ang‐(1–7) administration to protect rats from oleic acid (OA) induced ALI.
Experimental Approach
The effects of i.v. infused Ang‐(1–7) were examined over four different time windows before or after induction of ALI in male Sprague–Dawley rats. Haemodynamic effects were continuously monitored, and loss of barrier function, inflammation and lung peptidase activities were measured as experimental endpoints.
Key Results
Ang‐(1–7) infusion provided the best protection against experimental ALI when administered by continuous infusion starting immediately after 30 min OA infusion till the end of the experiment (30–240 min). Both pretreatment (−60 to 0 min before OA) and short‐term therapy (30–90 min) also had beneficial effects although less pronounced than the effects achieved with the optimal therapy window. Starting infusion of Ang‐(1–7) 60 min after the end of OA treatment (90–240 min) did not protect barrier function or haemodynamics but still reduced myeloperoxidase activity and increased ACE2/ACE activity ratio respectively.
Conclusions and Implications
Our findings indicate that early initiation of therapy after ALI and continuous drug delivery are most beneficial for optimal therapeutic efficiency of Ang‐(1–7) treatment in experimental ALI and, presumably accordingly, in clinical acute respiratory distress syndrome.
doi:10.1111/bph.13462
PMCID: PMC4842919  PMID: 26895462
15.  Preclinical study on combined chemo‐ and nonviral gene therapy for sensitization of melanoma using a human TNF‐alpha expressing MIDGE DNA vector†  
Molecular Oncology  2014;8(3):609-619.
Nonviral gene therapy represents a realistic option for clinical application in cancer treatment. This preclinical study demonstrates the advantage of using the small‐size MIDGE® DNA vector for improved transgene expression and therapeutic application. This is caused by significant increase in transcription efficiency, but not by increased intracellular vector copy numbers or gene transfer efficiency. We used the MIDGE‐hTNF‐alpha vector for high‐level expression of hTNF‐alpha in vitro and in vivo for a combined gene therapy and vindesine treatment in human melanoma models. The MIDGE vector mediated high‐level hTNF‐alpha expression leads to sensitization of melanoma cells towards vindesine. The increased efficacy of this combination is mediated by remarkable acceleration and increase of initiator caspase 8 and 9 and effector caspase 3 and 7 activation. In the therapeutic approach, the nonviral intratumoral in vivo jet‐injection gene transfer of MIDGE‐hTNF‐alpha in combination with vindesine causes melanoma growth inhibition in association with increased apoptosis in A375 cell line or patient derived human melanoma xenotransplant (PDX) models. This study represents a proof‐of‐concept for an anticipated phase I clinical gene therapy trial, in which the MIDGE‐hTNF‐alpha vector will be used for efficient combined chemo‐ and nonviral gene therapy of malignant melanoma.
Highlights
The minimalistic MIDGE‐vector improves transcription compared to plasmid vectors.This vector achieved high‐level hTNF‐alpha expression for melanoma sensitization.This sensitization is mediated by accelerated and increased caspase activation.Nonviral in vivo MIDGE‐vector gene transfer leads to efficient TNF‐expression.Combined gene‐ and chemotherapy improves melanoma growth inhibition in vivo.
doi:10.1016/j.molonc.2013.12.019
PMCID: PMC5528640  PMID: 24503218
Cancer; Gene therapy; Melanoma; Nonviral gene transfer; TNF‐alpha
16.  In vivo imaging of virological synapses 
Nature communications  2012;3:1320.
Retroviruses such as the human immunodeficiency virus, human T-cell lymphotropic virus and murine leukaemia virus are believed to spread via sites of cell–cell contact designated virological synapses. Support for this model is based on in vitro evidence in which infected cells are observed to specifically establish long-lived cell–cell contact with uninfected cells. Whether virological synapses exist in vivo is unknown. Here we apply intravital microscopy to identify a subpopulation of B cells infected with the Friend murine leukaemia virus that form virological synapses with uninfected leucocytes in the lymph node of living mice. In vivo virological synapses are, like their in vitro counterpart, dependent on the expression of the viral envelope glycoprotein and are characterized by a prolonged polarization of viral capsid to the cell–cell interface. Our results validate the concept of virological synapses and introduce intravital imaging as a tool to visualize retroviral spreading directly in living mice.
doi:10.1038/ncomms2338
PMCID: PMC3784984  PMID: 23271654
17.  Comparison of parasite sequestration in uncomplicated and severe childhood Plasmodium falciparum malaria☆ 
The Journal of Infection  2013;67(3):220-230.
Summary
Objectives
To determine whether sequestration of parasitized red blood cells differs between children with uncomplicated and severe Plasmodium falciparum malaria.
Methods
We quantified circulating-, total- and sequestered-parasite biomass, using a mathematical model based on plasma concentration of P. falciparum histidine rich protein 2, in Gambian children with severe (n = 127) and uncomplicated (n = 169) malaria.
Results
Circulating- and total-, but not sequestered-, parasite biomass estimates were significantly greater in children with severe malaria than in those with uncomplicated malaria. Sequestered biomass estimates in children with hyperlactataemia or prostration were similar to those in uncomplicated malaria, whereas sequestered biomass was higher in patients with severe anaemia, and showed a trend to higher values in cerebral malaria and fatal cases. Blood lactate concentration correlated with circulating- and total-, but not sequestered parasite biomass. These findings were robust after controlling for age, prior antimalarial treatment and clonality of infection, and over a realistic range of variation in model parameters.
Conclusion
Extensive sequestration is not a uniform requirement for severe paediatric malaria. The pathophysiology of hyperlactataemia and prostration appears to be unrelated to sequestered parasite biomass. Different mechanisms may underlie different severe malaria syndromes, and different therapeutic strategies may be required to improve survival.
doi:10.1016/j.jinf.2013.04.013
PMCID: PMC3744804  PMID: 23623771
Cerebral malaria; Microcirculation; Lactic acid; Sequestration; HRP2; Anaemia; Parasite Biomass
18.  Prolonged Neutrophil Dysfunction Following Plasmodium falciparum Malaria is Related to Hemolysis and Heme Oxygenase-1 Induction1 
It is not known why people are more susceptible to bacterial infections such as non-Typhoid Salmonella (NTS) during and after a malaria infection but, in mice, malarial hemolysis impairs resistance to NTS by impairing the neutrophil oxidative burst. This acquired neutrophil dysfunction is a consequence of induction of the cytoprotective, heme degrading enzyme heme oxygenase-1 (HO-1) in neutrophil progenitors in bone marrow. In this study, we assessed whether neutrophil dysfunction occurs in humans with malaria and how this relates to hemolysis. We evaluated neutrophil function in 58 Gambian children with Plasmodium falciparum malaria (55 (95%) with uncomplicated disease), and examined associations with erythrocyte count, haptoglobin, hemopexin, plasma heme, expression of receptors for heme uptake, and HO-1 induction. Malaria caused the appearance of a dominant population of neutrophils with reduced oxidative burst activity, which gradually normalized over 8 weeks of follow-up. The degree of neutrophil impairment correlated significantly with markers of hemolysis and HO-1 induction. HO-1 expression was increased in blood during acute malaria, but at a cellular level HO-1 expression was modulated by changes in surface expression of the haptoglobin receptor (CD163). These findings demonstrate that neutrophil dysfunction occurs in P. falciparum malaria and support the relevance of the mechanistic studies in mice. Furthermore, they suggest the presence of a regulatory pathway to limit HO-1 induction by hemolysis in the context of infection, and indicate new targets for therapeutic intervention to abrogate the susceptibility to bacterial infection in the context of hemolysis in humans.
doi:10.4049/jimmunol.1201028
PMCID: PMC3504608  PMID: 23100518
19.  Evaluation of 13C isotopic tracers for metabolic flux analysis in mammalian cells 
Journal of biotechnology  2009;144(3):167-174.
13C metabolic flux analysis (MFA) is the most comprehensive means of characterizing cellular metabolic states. Uniquely labeled isotopic tracers enable more focused analyses to probe specific reactions within the network. As a result, the choice of tracer largely determines the precision with which one can estimate metabolic fluxes, especially in complex mammalian systems that require multiple substrates. Here we have experimentally determined metabolic fluxes in a tumor cell line, successfully recapitulating the hallmarks of cancer cell metabolism. Using these data, we computationally evaluated specifically labeled 13C glucose and glutamine tracers for their ability to precisely and accurately estimate fluxes in central carbon metabolism. These methods enabled us to to identify the optimal tracer for analyzing individual fluxes, specific pathways, and central carbon metabolism as a whole. [1,2-13C2]glucose provided the most precise estimates for glycolysis, the pentose phosphate pathway, and the overall network. Tracers such as [2-13C]glucose and [3-13C]glucose also outperformed the more commonly used [1-13C]glucose. [U-13C5]glutamine emerged as the preferred isotopic tracer for analysis of the tricarboxylic acid (TCA) cycle. These results provide valuable, quantitative information on the performance of 13C-labeled substrates and can aid in the design of more informative MFA experiments in mammalian cell culture.
doi:10.1016/j.jbiotec.2009.07.010
PMCID: PMC3026314  PMID: 19622376
Metabolic flux analysis; confidence intervals; isotopic tracers; tumor cells
20.  A Complex-based Reconstruction of the Saccharomyces cerevisiae Interactome *S⃞ 
Most cellular processes are performed by proteomic units that interact with each other. These units are often stoichiometrically stable complexes comprised of several proteins. To obtain a faithful view of the protein interactome we must view it in terms of these basic units (complexes and proteins) and the interactions between them. This study makes two contributions toward this goal. First, it provides a new algorithm for reconstruction of stable complexes from a variety of heterogeneous biological assays; our approach combines state-of-the-art machine learning methods with a novel hierarchical clustering algorithm that allows clusters to overlap. We demonstrate that our approach constructs over 40% more known complexes than other recent methods and that the complexes it produces are more biologically coherent even compared with the reference set. We provide experimental support for some of our novel predictions, identifying both a new complex involved in nutrient starvation and a new component of the eisosome complex. Second, we provide a high accuracy algorithm for the novel problem of predicting transient interactions involving complexes. We show that our complex level network, which we call ComplexNet, provides novel insights regarding the protein-protein interaction network. In particular, we reinterpret the finding that “hubs” in the network are enriched for being essential, showing instead that essential proteins tend to be clustered together in essential complexes and that these essential complexes tend to be large.
doi:10.1074/mcp.M800490-MCP200
PMCID: PMC2690481  PMID: 19176519
22.  Human CASK/LIN-2 Binds Syndecan-2 and Protein 4.1 and Localizes to the Basolateral Membrane of Epithelial Cells  
The Journal of Cell Biology  1998;142(1):129-138.
In Caenorhabditis elegans, mutations in the lin-2 gene inactivate the LET-23 receptor tyrosine kinase/Ras/MAP kinase pathway required for vulval cell differentiation. One function of LIN-2 is to localize LET-23 to the basal membrane domain of vulval precursor cells. LIN-2 belongs to the membrane-associated guanylate kinase family of proteins. We have cloned and characterized the human homolog of LIN-2, termed hCASK, and Northern and Western blot analyses reveal that it is ubiquitously expressed. Indirect immunofluorescence localizes CASK to distinct lateral and/or basal plasma membrane domains in different epithelial cell types. We detect in a yeast two-hybrid screen that the PDZ domain of hCASK binds to the heparan sulfate proteoglycan syndecan-2. This interaction is confirmed using in vitro binding assays and immunofluorescent colocalization. Furthermore, we demonstrate that hCASK binds the actin-binding protein 4.1. Syndecans are known to bind extracellular matrix, and to form coreceptor complexes with receptor tyrosine kinases. We speculate that CASK mediates a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with protein 4.1. Like other membrane-associated guanylate kinases, its multidomain structure enables it to act as a scaffold at the membrane, potentially recruiting multiple proteins and coordinating signal transduction.
PMCID: PMC2133028  PMID: 9660868
CASK; LIN-2; syndecan; protein 4.1; MAGUK
23.  Postoperative leg vein thrombosis. 
British Medical Journal  1970;4(5726):56.
PMCID: PMC1820573  PMID: 5470452
24.  Half-Saline versus Combined Normal Saline and 1/3–2/3 Intravenous Fluid Therapy in Kidney Transplantation 
Background: Sufficient intravascular volume should be established for optimal graft function after renal transplantation. However, there is no recommendation for the type of fluid therapy post-operatively. We compared half-saline vs. normal saline and 1/3–2/3 intravenous fluid replacement after renal transplantation.
Methods: We enrolled all patients who underwent kidney transplantation between June 2008 and March 2010 in Golestan Hospital, Ahwaz, southwestern Iran. Patients were randomly divided into two groups using a blinded allocation technique. Group A patients (Case) received half saline, and group B patients (Control) received normal saline and 1/3–2/3 intravenous fluid. According to our protocol, we replaced as much as 100% of hourly urine output in the first day, followed by 90% and 70% of every 2-hour urine output in the 2nd and 3rd days, respectively. Blood pressure and pulse rate were recorded hourly. Serum sodium, potassium, creatinine and pH were assessed twice a day.
Results: There were 34 and 36 eligible patients in the case and control groups, respectively. The mean±SD 6-hour urine output in the first 5 days after surgery was 2586±725 mL in the control group and 2764±758 mL in the case group (p=0.31). The mean±SD serum creatinine level at the end of the 5th post-operative day was 1.3±0.5 and 1.4±0.7 mg/dL in the case and control groups, respectively (p=0.56). Serum creatinine level did not reduce to 1.5 mg/dL or lower in 6 of 36 control subjects and in 4 of 34 cases at the end of the 5th day (p=0.558). The mean±SD time to creatinine level <1.5 mg/dL was 1.3±1 days in the control group and 1.7±0.8 days in the case group (p=0.635). Hyperkalemia occurred in 3 of 36 patients in the control group and in 2 of 34 patients in the case group (p=0.318). The incidence of hyponatremia in the control group was 11% (4 of 36 patients) vs no patients in the case group (p=0.115).
Conclusion: Either half-saline or normal saline and 1/3–2/3 intravenous solution can be safely used as fluid replacement therapy after kidney transplantation.
PMCID: PMC4089258  PMID: 25013601
Renal transplantation; Intravenous fluid therapy; Renal function
25.  A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder 
Molecular Psychiatry  2015;21(10):1342-1350.
Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant—associated with reduced SNX7 expression—to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.
doi:10.1038/mp.2015.186
PMCID: PMC4965332  PMID: 26666201

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