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5. Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes the TRIGR randomized clinical trial

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Knip M., Akerblom H. K., Altaji E., Becker D., Bruining J., Castano L., Danne T., De Beaufort C., Dosch H. -M., Dupre J., Fraser W. D., Howard N., Ilonen J., Konrad D., Kordonouri O., Krischer J. P., Lawson M. L., Ludvigsson J., Madacsy L., Mahon J. L., Ormisson A., Palmer J. P., Pozzilli P., Savilahti E., Serrano-Rios M., Songini M., Taback S., Vaarala O., White N. H., Virtanen S. M., Wasikowa R., Mandrup-Poulsen T., Arjas E., Lernmark A., Laara E., Schmidt B., Hyytinen M., Koski K., Koski M., Merentie K., Pajakkala E., Reunanen A., Salonen M., Terhonen T., Virkkunen S., Cuthbertson D., Gainer B., Hadley D., Malloy J., Nallamshetty L., Shanker L., Bradley B., Lough G., Fraser W., Sermer M., Taback S. P., Franciscus M., Nucci A., Palmer J., Alahuhta K., Barlund S., Korhonen T., Kovanen L., Lehtonen E., Niinisto S., Pekkala M., Sorkio S., Toivanen L., Vahatalo L., Uusitalo U., Ohman T., Bongiorno R., Catteau J., Fraser G., Lloyd M., Crock P., Giles M., Siech K., See D. W., Brown C., Craig M., Johnston A., Bere L. J., Clarson C. L., Jenner M., McManus R., Renato N., Lovell M., Higo D., Kent N., Kwan J., Marshall C., Metzger D., Chanoine J. -P., Stewart L., Thompson D., Edwards A., Lange I., Mercer J., Pacaud D., Josephine H., Schwarz W., Stephure D. K., Boer J., Chatur T., Chick C., Couch B., Demianczuk N., Girgis R., Marks S., Ryan E., Thompson M., Dean H. J., Grant L., Hamelin K., LaForte J., Murphy L., Catte D., Schneider C., Sellers E. A. C., Woo V., Boland A., Clark H. D., Cooper T., Gruslin A., Karovitch A., Keely E., Malcolm J. C., Sauro V., Tawagi G. F., Andrighetti S., Arnold G., Barrett J., Blumer I., Daneman D., Donat D., Ehrlich R., Feig D., Gottesman I., Gysler M., Karkanis S., Kenshole A., Knight B., Lackie E., Lewis V., Martin M. J., Maxwell C., Oliver G., Panchum P., Shilletto N., Simone A., Skidmore M., Turrini T., Wong S., Allen C., Belanger L., Bouchard I., Ferland S., Frenette L., Garrido-Russo M., Leblanc M., Imbeault J., Morin V., Olivier G., Weisnagell J., Costain G., Dornan J., Heath K., MacSween M. -C., McGibbon A., Ramsay C., Sanderson F., Sanderson S., Benabdesselam L., Gonthier M., Huot C., Thibeault M., Laforte D., Legault L., Perron P., Armson A., Canning P., Cummings E. A., Ivanko V., McLeod L., Mokashi A., Scott K., Bridger T., Crane J., Crummell C., Curtis J. C., Dawson C., Joyce C., Newhook L. A., Newman S., Druken E., Begum-Hasan J., Breen A., Houlden R., Woods M., Carrson G., Kelly S., Martel M. J., Penner M., Sankaran K., Hardy-Brown K., King N., White R. A., Park M., Popkin J., Robson L., Coles K., Al Taji E., Cerna M., Cerny M., Francova H., Hainerova I., Kothankova H., Koukalova R., Krakorova V., Mendlova P., Sitova R., Stechova K., Vavrinec J., Vosahlo J., Zlatohlavkova B., Brazdova L., Faksova P., Gregorova D., Kantor L., Malkova K., Venhacova J., Venhacova P., Cipra A., Skvor J., Budejovice C., Tomsikova Z., Botkova-Krauseova H., Mockova A., Paterova P., Gogelova P., Kandrnalova J., Einberg U., Jakovlev U., Posiadlo S., Rannaste E., Raukas R., Riikjarv M. -A., Valla K., Astover V., Kirss A., Retpap J., Taht E., Tillmann V., Vahtra S., Heikkila M., Hirvasniemi M., Luopajarvi K., Johansson S., Kleemola P., Laukkanen E., Parkkola A., Pigg H. -M., Puttonen H., Renlund M., Salonen K., Suomalainen H., Tenkula T., Teramo K., Jarvenpaa A. -L., Hamalainen A. -M., Jussila R., Kiiveri S., Haavisto H., Holopainen S., Kupiainen H., Leeve T., Lumme K., Nironen T., Tenhola S., Tiilikainen T., Keinonen H., Lautala P., Salonen P., Vesanto M., Aspholm A. S., Asunta P., Ikavalko H., Jason E., Jaminki S., Kekki P., Koskinen M., Lehtimaki S., Lahde J., Makela M., Peltoniemi S., Poutiainen L., Ranta K., Salonsaari T., Sarviharju-Tujula S. -L., Selvenius J., Siljander H., Haanpaa P. -L., Holm C., Juutilainen A., Jarvelainen V., Kangaskolkka-Keskilohko A. -M., Laino E., Marjamaki L., Suominen E., Ylitalo S., Hokkanen M., Lounamaa R., Matikainen M., Nuuja A., Paalanen I., Puupponen A. R., Salo-Edwards H., Alanne S., Kultti T., Linjama H., Muhonen K., Vaaraniemi M., Talvitie T., Backman M., Hanhijarvi R., Koivula P., Lindstrom K., Martikainen A., Nurmi P., Bjork A., Huopio H., Komulainen J., Lehtomaki S., Muikku E., Pesola J., Sankilampi U., Arkkola T., Hekkala A., Jurvakainen S., Koivikko M. -L., Kahonen M., Leinonen E., Mykkanen T., Pohjola H., Riikonen K., Niittyvuopio A., Stenius A., Tapanainen P., Veijola R., Alar A., Jovio S., Korpela P., Makinen E., Hietanen L., Kivisto J., Kaar M. -L., Lehtimaki P., Mustila T., Popov E., Saatela S., Taittonen L., Ahtiainen K., Laaksonen N., Luoto M., Viitala J., Virransalo R., Nykanen P., Paajanen S., Parkkinen S., Pyrhonen H., Sarkka T., Aschemeier B., Bektas S., Biester T., Datz N., Deiss D., Fath M., Lupke K., Muller B., Nestoris C., Rothes S., Sadeghian E., Semler K., Arato A., Krikovszky D., Nobilis A., Szenasi J., Benevento D., Anguissola G. B., Biagioni M., Bizzarri C., Cherubini V., Ferrito L., Giordano C., Giorgetti C., Khazrai Y. M., Kyanvash S., Maddaloni E., Napoli A., Piergiovanni F., Pitocco D., Suraci T., Tabacco G., Valente L., Visalli N., Carboni M. B., Cavallo R., Cau V., Isola C., Ledda A., Loddo M., Mannu C., Pettinau M., Pisano S., Porceddu M., Putzu C., Rita A., Peters D., Schierloh U., Bisschoff M., Blonk L., Lappenschaar T., Manai B., Seesink M., Sperling-Conrad M., Verhagen M., Zoethout J. A., Basiak A., Chalas M., Chesiak M., Gramza A., Iwankiewicz J., Sieradzan E., Wikiera B., Ciechanowska M., Dziatkowiak H., Futona B., Gorska A., Glowacka-Wony M., Kaim I., Klich B., Starzyk J., Wolanin M., Tokarska L., Chucherco D., Deja G., Firek-Pedras M., Jarosz-Chobot P., Kalina M., Kutrowska-Adamusiak K., Minkina-Pedras M., Muchaka-Bianga M., Bodalski J., Mlynarski W., Szadkowska A., Cieslak A., Cypryk K., Dziatosz K., Jastzebowska J., Krysiak A., Szymanska U., Wilcznski J., Zawodniak-Szalapska M., Aguay A., Bilbao J. R., Chueca M., Cortazar A., Echarte G., Frutos T. G., Jimenez P., Martul P., Moreno A., Oyarzabal M., Rica I., Salgado Y., Martinez-Larrad M. T., Hawkins F. G., Hernandez R., Herranz L., Pallardo L. F., Deibarra L. S., Fernandez B. H., Luis J. L., Ortiz-Quintana L., Recarte P. P., Arnau D. R., Aronsson L., Boden S., Fredriksson J., Isacsson E., Johansson I., Karlsson E., Lock C., Sandstrom A. -M., Konefal M. S., Andreasson C., Dahlstrom U., Hanas R., Lundqvist K., Windell L., Jansson I., Karlsson A. -K., Lindbladh B., Odenman I., Pettersson C., Sundberg F., Sundqvist M., Aronsson S., Bellman I., Bengtsson A. -B., Lyden G. -B., Nilsson N. -O., Soderblom M., Unt C., Augustsson M., Bengtsson M., Fors H., Helmrich A., Johansson T. O., Andersson A. -C., Boiard-Stomlid A., Hellgren G., Kallsholm H., Lindqvist J., Nilsson M., Nordwall M., Stromstedt C., Ahsberg C., Lindh A., Lindhe C., Samuelsson C., Wiik A., Edenwall H., Ljumgcrantz M., Persson I. -B., Strigard E., Svensson B. -L., Aman J., Breivik G. -E., Detlofsson I. -L., Kroon M., Sarnblad S., Johansson C., Ilvered R., Lundberg A., Akesson K., Beccarelli A., Gadient M., Rappold-Amrein C., Schoenle E., Daftary A., Damagro-Elias M. E., Gilmour C., Klein M. B., Lain C., Salerno D., Smith M. E., Vats K., Pfaff D. J., Malone P., Mansfield P., Munns M., Nickel K., Pompilio K., Siemion W., Taculad R., Van Horn K., Zdanadewic M., Chambliss C., Jones J., Sadler M., Tanner-Blasiar M., Bell C., Camper N., Devaskar S., Devaskar U., Horowitz H., Rogers L., Shannahan R., Silk K., Bermudez Z., Colon R., Frazer T., Martinez-Nieves B., Torres J., Vega J., Chan M., Cook S., Goland R., Greenberg E., Jules N., Montes J., Nelson M., Parra-Valencia Z., Schachner H., Softness B., Kiviniemi M., Suomenin R., Alexander A., Hyrckowian E., Nichol L., Trucco M., Karjalainen E., Louhio T., Sarnesto A., Valtonen E., Davydova B., Helander S., Hamalainen J., Harkonen T., Joutsjoki L., Kararic M., Latva-Koivisto M., Lonn E., Nurmi T., Ollila I., Rinkinen J., Ronkainen M., Tukiainen H., Cederlof A., Kiikeri M., Tsupari S., Cheng R., Bryant K., Chan Y., Maezawa Y., Paltser G., Rasavi R., Tsui H., Winer S., Wu P., Yantha J., Pediatrics, Knip M., Akerblom H.K., Altaji E., Becker D., Bruining J., Castano L., Danne T., De Beaufort C., Dosch H.-M., Dupre J., Fraser W.D., Howard N., Ilonen J., Konrad D., Kordonouri O., Krischer J.P., Lawson M.L., Ludvigsson J., Madacsy L., Mahon J.L., Ormisson A., Palmer J.P., Pozzilli P., Savilahti E., Serrano-Rios M., Songini M., Taback S., Vaarala O., White N.H., Virtanen S.M., Wasikowa R., Mandrup-Poulsen T., Arjas E., Lernmark A., Laara E., Schmidt B., Hyytinen M., Koski K., Koski M., Merentie K., Pajakkala E., Reunanen A., Salonen M., Terhonen T., Virkkunen S., Cuthbertson D., Gainer B., Hadley D., Malloy J., Nallamshetty L., Shanker L., Bradley B., Lough G., Fraser W., Sermer M., Taback S.P., Franciscus M., Nucci A., Palmer J., Alahuhta K., Barlund S., Korhonen T., Kovanen L., Lehtonen E., Niinisto S., Pekkala M., Sorkio S., Toivanen L., Vahatalo L., Uusitalo U., Ohman T., Bongiorno R., Catteau J., Fraser G., Lloyd M., Crock P., Giles M., Siech K., See D.W., Brown C., Craig M., Johnston A., Bere L.J., Clarson C.L., Jenner M., McManus R., Renato N., Lovell M., Higo D., Kent N., Kwan J., Marshall C., Metzger D., Chanoine J.-P., Stewart L., Thompson D., Edwards A., Lange I., Mercer J., Pacaud D., Josephine H., Schwarz W., Stephure D.K., Boer J., Chatur T., Chick C., Couch B., Demianczuk N., Girgis R., Marks S., Ryan E., Thompson M., Dean H.J., Grant L., Hamelin K., LaForte J., Murphy L., Catte D., Schneider C., Sellers E.A.C., Woo V., Boland A., Clark H.D., Cooper T., Gruslin A., Karovitch A., Keely E., Malcolm J.C., Sauro V., Tawagi G.F., Andrighetti S., Arnold G., Barrett J., Blumer I., Daneman D., Donat D., Ehrlich R., Feig D., Gottesman I., Gysler M., Karkanis S., Kenshole A., Knight B., Lackie E., Lewis V., Martin M.J., Maxwell C., Oliver G., Panchum P., Shilletto N., Simone A., Skidmore M., Turrini T., Wong S., Allen C., Belanger L., Bouchard I., Ferland S., Frenette L., Garrido-Russo M., Leblanc M., Imbeault J., Morin V., Olivier G., Weisnagell J., Costain G., Dornan J., Heath K., MacSween M.-C., McGibbon A., Ramsay C., Sanderson F., Sanderson S., Benabdesselam L., Gonthier M., Huot C., Thibeault M., Laforte D., Legault L., Perron P., Armson A., Canning P., Cummings E.A., Ivanko V., McLeod L., Mokashi A., Scott K., Bridger T., Crane J., Crummell C., Curtis J.C., Dawson C., Joyce C., Newhook L.A., Newman S., Druken E., Begum-Hasan J., Breen A., Houlden R., Woods M., Carrson G., Kelly S., Martel M.J., Penner M., Sankaran K., Hardy-Brown K., King N., White R.A., Park M., Popkin J., Robson L., Coles K., Al Taji E., Cerna M., Cerny M., Francova H., Hainerova I., Kothankova H., Koukalova R., Krakorova V., Mendlova P., Sitova R., Stechova K., Vavrinec J., Vosahlo J., Zlatohlavkova B., Brazdova L., Faksova P., Gregorova D., Kantor L., Malkova K., Venhacova J., Venhacova P., Cipra A., Skvor J., Budejovice C., Tomsikova Z., Botkova-Krauseova H., Mockova A., Paterova P., Gogelova P., Kandrnalova J., Einberg U., Jakovlev U., Posiadlo S., Rannaste E., Raukas R., Riikjarv M.-A., Valla K., Astover V., Kirss A., Retpap J., Taht E., Tillmann V., Vahtra S., Heikkila M., Hirvasniemi M., Luopajarvi K., Johansson S., Kleemola P., Laukkanen E., Parkkola A., Pigg H.-M., Puttonen H., Renlund M., Salonen K., Suomalainen H., Tenkula T., Teramo K., Jarvenpaa A.-L., Hamalainen A.-M., Jussila R., Kiiveri S., Haavisto H., Holopainen S., Kupiainen H., Leeve T., Lumme K., Nironen T., Tenhola S., Tiilikainen T., Keinonen H., Lautala P., Salonen P., Vesanto M., Aspholm A.S., Asunta P., Ikavalko H., Jason E., Jaminki S., Kekki P., Koskinen M., Lehtimaki S., Lahde J., Makela M., Peltoniemi S., Poutiainen L., Ranta K., Salonsaari T., Sarviharju-Tujula S.-L., Selvenius J., Siljander H., Haanpaa P.-L., Holm C., Juutilainen A., Jarvelainen V., Kangaskolkka-Keskilohko A.-M., Laino E., Marjamaki L., Suominen E., Ylitalo S., Hokkanen M., Lounamaa R., Matikainen M., Nuuja A., Paalanen I., Puupponen A.R., Salo-Edwards H., Alanne S., Kultti T., Linjama H., Muhonen K., Vaaraniemi M., Talvitie T., Backman M., Hanhijarvi R., Koivula P., Lindstrom K., Martikainen A., Nurmi P., Bjork A., Huopio H., Komulainen J., Lehtomaki S., Muikku E., Pesola J., Sankilampi U., Arkkola T., Hekkala A., Jurvakainen S., Koivikko M.-L., Kahonen M., Leinonen E., Mykkanen T., Pohjola H., Riikonen K., Niittyvuopio A., Stenius A., Tapanainen P., Veijola R., Alar A., Jovio S., Korpela P., Makinen E., Hietanen L., Kivisto J., Kaar M.-L., Lehtimaki P., Mustila T., Popov E., Saatela S., Taittonen L., Ahtiainen K., Laaksonen N., Luoto M., Viitala J., Virransalo R., Nykanen P., Paajanen S., Parkkinen S., Pyrhonen H., Sarkka T., Aschemeier B., Bektas S., Biester T., Datz N., Deiss D., Fath M., Lupke K., Muller B., Nestoris C., Rothes S., Sadeghian E., Semler K., Arato A., Krikovszky D., Nobilis A., Szenasi J., Benevento D., Anguissola G.B., Biagioni M., Bizzarri C., Cherubini V., Ferrito L., Giordano C., Giorgetti C., Khazrai Y.M., Kyanvash S., Maddaloni E., Napoli A., Piergiovanni F., Pitocco D., Suraci T., Tabacco G., Valente L., Visalli N., Carboni M.B., Cavallo R., Cau V., Isola C., Ledda A., Loddo M., Mannu C., Pettinau M., Pisano S., Porceddu M., Putzu C., Rita A., Peters D., Schierloh U., Bisschoff M., Blonk L., Lappenschaar T., Manai B., Seesink M., Sperling-Conrad M., Verhagen M., Zoethout J.A., Basiak A., Chalas M., Chesiak M., Gramza A., Iwankiewicz J., Sieradzan E., Wikiera B., Ciechanowska M., Dziatkowiak H., Futona B., Gorska A., Glowacka-Wony M., Kaim I., Klich B., Starzyk J., Wolanin M., Tokarska L., Chucherco D., Deja G., Firek-Pedras M., Jarosz-Chobot P., Kalina M., Kutrowska-Adamusiak K., Minkina-Pedras M., Muchaka-Bianga M., Bodalski J., Mlynarski W., Szadkowska A., Cieslak A., Cypryk K., Dziatosz K., Jastzebowska J., Krysiak A., Szymanska U., Wilcznski J., Zawodniak-Szalapska M., Aguay A., Bilbao J.R., Chueca M., Cortazar A., Echarte G., Frutos T.G., Jimenez P., Martul P., Moreno A., Oyarzabal M., Rica I., Salgado Y., Martinez-Larrad M.T., Hawkins F.G., Hernandez R., Herranz L., Pallardo L.F., Deibarra L.S., Fernandez B.H., Luis J.L., Ortiz-Quintana L., Recarte P.P., Arnau D.R., Aronsson L., Boden S., Fredriksson J., Isacsson E., Johansson I., Karlsson E., Lock C., Sandstrom A.-M., Konefal M.S., Andreasson C., Dahlstrom U., Hanas R., Lundqvist K., Windell L., Jansson I., Karlsson A.-K., Lindbladh B., Odenman I., Pettersson C., Sundberg F., Sundqvist M., Aronsson S., Bellman I., Bengtsson A.-B., Lyden G.-B., Nilsson N.-O., Soderblom M., Unt C., Augustsson M., Bengtsson M., Fors H., Helmrich A., Johansson T.O., Andersson A.-C., Boiard-Stomlid A., Hellgren G., Kallsholm H., Lindqvist J., Nilsson M., Nordwall M., Stromstedt C., Ahsberg C., Lindh A., Lindhe C., Samuelsson C., Wiik A., Edenwall H., Ljumgcrantz M., Persson I.-B., Strigard E., Svensson B.-L., Aman J., Breivik G.-E., Detlofsson I.-L., Kroon M., Sarnblad S., Johansson C., Ilvered R., Lundberg A., Akesson K., Beccarelli A., Gadient M., Rappold-Amrein C., Schoenle E., Daftary A., Damagro-Elias M.E., Gilmour C., Klein M.B., Lain C., Salerno D., Smith M.E., Vats K., Pfaff D.J., Malone P., Mansfield P., Munns M., Nickel K., Pompilio K., Siemion W., Taculad R., Van Horn K., Zdanadewic M., Chambliss C., Jones J., Sadler M., Tanner-Blasiar M., Bell C., Camper N., Devaskar S., Devaskar U., Horowitz H., Rogers L., Shannahan R., Silk K., Bermudez Z., Colon R., Frazer T., Martinez-Nieves B., Torres J., Vega J., Chan M., Cook S., Goland R., Greenberg E., Jules N., Montes J., Nelson M., Parra-Valencia Z., Schachner H., Softness B., Kiviniemi M., Suomenin R., Alexander A., Hyrckowian E., Nichol L., Trucco M., Karjalainen E., Louhio T., Sarnesto A., Valtonen E., Davydova B., Helander S., Hamalainen J., Harkonen T., Joutsjoki L., Kararic M., Latva-Koivisto M., Lonn E., Nurmi T., Ollila I., Rinkinen J., Ronkainen M., Tukiainen H., Cederlof A., Kiikeri M., Tsupari S., Cheng R., Bryant K., Chan Y., Maezawa Y., Paltser G., Rasavi R., Tsui H., Winer S., Wu P., Yantha J., University of Zurich, and Knip, Mikael

Subjects
Male, Risk, medicine.medical_specialty, Casein, Breastfeeding, 030209 endocrinology & metabolism, 610 Medicine & health, 2700 General Medicine, Endocrinology and Diabetes, Disease-Free Survival, law.invention, Follow-Up Studie, Nutrition Policy, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, SDG 3 - Good Health and Well-being, law, Internal medicine, Diabetes mellitus, medicine, Humans, Cumulative incidence, 030212 general & internal medicine, Child, Infant Nutritional Physiological Phenomena, Original Investigation, 2. Zero hunger, Type 1 diabetes, business.industry, Hazard ratio, Absolute risk reduction, Infant, Newborn, Caseins, General Medicine, ta3121, medicine.disease, Infant Formula, 3. Good health, Diabetes Mellitus, Type 1, Infant formula, 10036 Medical Clinic, Endokrinologi och diabetes, Female, business, Human, Follow-Up Studies
Abstract

IMPORTANCE Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas. OBJECTIVE To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children. DESIGN, SETTING, AND PARTICIPANTS An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017. INTERVENTIONS The participants received either a casein hydrolysate or a conventional adapted cows milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age. MAIN OUTCOMES AND MEASURES Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events). RESULTS Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8%[95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group). CONCLUSIONS AND RELEVANCE Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes. Funding Agencies|Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD); National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [HD040364, HD042444, HD051997]; Canadian Institutes of Health Research; Commission of the European Communities [QLK1-2002-00372]; European Foundation for the Study of Diabates/JDRF/Novo Nordisk; Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research) [250114]; Dutch Diabetes Research Foundation; Finnish Diabetes Research Foundation; JDRF

Published
2018

6. Myocardial performance index in term appropriate and small for gestational age neonates - a cross sectional study.

Author

Vats, K., Choudhary, S.K., Kumar, D., Maria, A., and Bandopadhyay, T.

Subjects
*SMALL for gestational age, *NEWBORN infants, *CARDIOVASCULAR diseases risk factors, *BIRTH weight, *ABSOLUTE value
Abstract

BACKGROUND: It is known that small for gestational age (SGA) babies may be at an increased risk of cardiovascular diseases during adulthood. There is paucity of literature regarding comparative cardiac functions of SGA and appropriate for gestational age (AGA) babies in neonatal period. The present study was conceived to compare the cardiac function of term small and appropriate for gestational age (AGA) babies through a relatively novel echocardiographic index in early neonatal period. OBJECTIVES: To compare values of myocardial performance index (MPI) index (MPI = IVCT + IVRT/ET) at 48–72 hours of age among AGA and SGA babies. METHODS: Morphological and anthropometric assessment of serially born term babies was done at time of birth to recruit hundred each of AGA and SGA babies. Tissue Doppler Imaging (TDI) was done between 48–72 hours for each enrolled baby to assess both right and left ventricle MPI in each group. RESULTS: Mean±SD values for right ventricular MPI in AGA and SGA groups were 0.268 + 0.007 and 0.30 + 0.026 respectively (p < 0.001). Mean±SD values for left ventricular MPI in AGA and SGA groups were 0.25 + 0.012 and 0.30 + 0.017 respectively (p < 0.001). There was significant negative correlation between MPI values for either ventricles and the birth weight (spearmen's rho of –0.66) (p < 0.001). Mean±SD values for LVET in AGA and SGA group were 0.304 + 0.026 and 0.266 + 0.032 respectively (p < 0.001). CONCLUSION: MPI had a higher absolute value in the SGA babies as compared to AGA babies. These observations point towards suboptimal cardiac performance among SGA babies as compared to AGA babies on the basis of myocardial performance index. [ABSTRACT FROM AUTHOR]

Published
2021
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9. P.139 Cerebral toxoplasmosis in an HIV-negative patient

Author

Liu, E, Kakodkar, P, Toyota, P, Pendleton, N, Persad, A, Zherebitskiy, V, Hamula, C, Auer, RN, Vats, K, Hnenny, L, and Radic, J

Abstract

Background: Toxoplasma gondii is a protozoan parasite with the ability to infect any nucleated cell in humans. Most immunocompetent infected individuals are asymptomatic. Latent toxoplasma can become reactivated in immunocompromised individuals though this is exceptionally rare in HIV-negative individuals. Methods: We present the case of a 47-year-old male with chronic immunosuppression secondary to marginal zone lymphoma and steroid therapy. Results: The patient presented to hospital with a 1-week history of word-finding difficulties, intermittent right facial numbness and leg weakness, and tonic-clonic seizures. CT head showed a left temporal heterogenous mass measuring 2.8 × 2.8 × 3.5 cm. Biopsy of the lesion showed Multiple tachyzoites and rare bradyzoites with strong positivity for the toxoplasma specific immunostain. The patient was treated with trimethoprim/sulfamethoxazole which resulted in complete neurologic recovery. Conclusions: Our literature review included 32 cases of cerebral toxoplasmosis in HIV-negative patients with an overall mortality rate of 48%. Cerebral toxoplasmosis has a predilection for immunosuppressed patients with an underlying hematologic malignancy (74%, n= 23). Successful treatment requires early recognition of the disease and prompt treatment with sulfamethoxazole and trimethoprim, pyrimethamine, or sulfadiazine. Patients who recover from acute toxoplasmosis should remain on lifelong suppressive antibiotic therapy to prevent relapse.

Published
2023
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11. Ferroptosis of select skin epithelial cells initiates and maintains chronic systemic immune-mediated psoriatic disease.

Author

Vats K, Tian H, Singh K, Tyurina YY, Sparvero LJ, Tyurin VA, Kruglov O, Chang A, Wang J, Green F, Samovich SN, Zhang J, Chattopadhyay A, Murray N, Shah VK, Mathers AR, Chandran UR, Pilewski JM, Kellum JA, Wenzel SE, Bayir H, Kagan VE, and Bunimovich YL

Abstract

Dysregulations of epithelial-immune interactions frequently culminate in chronic inflammatory diseases of the skin, lungs, kidneys, and gastrointestinal tract. Yet, the intraepithelial processes which initiate and perpetuate inflammation in these organs are poorly understood. Here, by utilizing redox lipidomics we identified ferroptosis-associated peroxidation of polyunsaturated phosphatidylethanolamines in the epithelia of patients with asthma, cystic fibrosis, psoriasis and renal failure. Focusing on psoriasis as a disease model, we used high-resolution mass spectrometry imaging and identified keratin 14 (K14)-expressing keratinocytes executing a ferroptotic death program in human psoriatic skin. Psoriatic phenotype with characteristic Th1/Th17 skin and extracutaneous immune responses was initiated and maintained in a murine model designed to actuate ferroptosis in a fraction of K14+ glutathione peroxidase 4 (Gpx4)-deficient epidermal keratinocytes. Importantly, an anti-ferroptotic agent, Liproxstatin-1, was as effective as clinically relevant biologic IL-12/IL-23/TNFα-targeting therapies or the depletion of T cells in completely abrogating molecular, biochemical and morphologic features of psoriasis. As ferroptosis in select epidermal keratinocytes triggers and sustains a pathologic psoriatic multi-organ inflammatory circuit, we suggest that strategies targeting ferroptosis, or its causes, may be effective in preventing or ameliorating a variety of chronic inflammatory diseases.

Published
2024
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12. Impact of COVID-19 on Antibiotic Stewardship, Antimicrobial Resistance, and Prescribing Habits at Two General Hospitals in Abu Dhabi: A Retrospective Analysis.

Author

Vats K, Singh K, and Oommen S

Abstract

Introduction The COVID-19 pandemic has overwhelmingly affected healthcare systems, particularly in the area of antibiotic management. The surge in antimicrobial use to address secondary bacterial infections in COVID-19 patients has heightened concerns about overuse and antimicrobial resistance (AMR). This study examined the pandemic's effect on the antibiotic stewardship program (ASP) at two general hospitals in Abu Dhabi, focusing on changes in prescribing practices, adherence to stewardship guidelines, resistance trends, and overall health system impact. The present retrospective study evaluated shifts in antibiotic consumption, compliance with stewardship practices, and broader healthcare implications. The aim is to assess the pandemic's impact, identify improvement areas, and provide insights to enhance the ASP in addressing the global AMR crisis. Methods This retrospective review assessed electronic medical records from two general hospitals in Abu Dhabi over a 24-month period, from January 2019 to December 2020. It included pre-COVID-19 data from 2019 and data from 2020 during the COVID-19 surge. The study focused on patients aged 25 to 40 years with respiratory tract infections, urinary tract infections, ventilator-associated pneumonia, and nosocomial infections, identified using predefined ICD-10-CM (International Classification of Diseases, Tenth Revision, Clinical Modification) codes. Patients with COVID-19 diagnoses and those undergoing surgical procedures were excluded. Key metrics compared data from 2019 and 2020 to assess changes in clinicians' prescribing practices, antibiotic usage, ASP interventions, and their impact on the healthcare system. Results The COVID-19 pandemic influenced antibiotic use and resistance trends, leading to longer hospital stays (3.86 days in 2019 vs. 4.29 days in 2020) and increased use of duplicate anaerobic therapy (4.58% in 2019 vs. 5.71% in 2020). From 2019 to 2020, the average duration of antibiotic therapy decreased from 6.23 days to 5.24 days, but empirical therapy without sufficient evidence rose. The average length of treatment increased (2.87 days in 2019 vs. 3.28 days in 2020), and there was a rise in the use of antibiotics for viral and fungal infections, with cases growing from 17.08% in 2019 to 22.38% in 2020. Despite modest improvements in stewardship practices in 2020, AMR challenges persisted. These results underscore the need for enhanced stewardship programs and continued research to address the ongoing impact on antibiotic prescribing and resistance. Conclusion The COVID-19 pandemic increased antibiotic use and altered resistance patterns. Although stewardship practices improved, AMR challenges remained. Enhanced stewardship programs and ongoing research are essential to mitigate these effects and improve antibiotic management. Recommendation To address changes in antibiotic use and resistance during the COVID-19 pandemic, it is recommended to strengthen ASPs to adapt to new prescribing trends, ensure adherence to evidence-based practices, provide ongoing education for clinicians, invest in research on long-term resistance impacts, and enhance data tracking and monitoring systems., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board of Burjeel Holdings and Department of Health - Abu Dhabi Health Research and Technology Ethics Committee issued approval BH/REC/039/22 and DOH/CVDC/2023/512. This is a retrospective study. Subjects who had consented to the collection of data for research purposes were included in the study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Vats et al.)

Published
2024
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13. Antibiotic Stewardship Program in a General Hospital in Abu Dhabi, UAE: Preparedness for the COVID-19 Pandemic.

Author

Vats K, Singh K, and Oommen S

Abstract

Introduction The COVID-19 pandemic has highlighted the critical need for resilient healthcare systems capable of swift response and adaptation, particularly in light of the ongoing global threat of antibiotic resistance. Hospitals in Abu Dhabi, UAE, are not exempted and must establish robust antibiotic stewardship programs capable of navigating any pandemic, ensuring judicious antibiotic use while maintaining high standards of care and optimal patient outcomes. This study seeks to evaluate the maturity levels of antibiotic stewardship programs in a general hospital to assess preparedness for such health crises. By analyzing data from non-surgical hospitalized patients in a specific age bracket, the study examines prescribing practices, program efficacy, and the hospital's overall readiness to manage infectious disease outbreaks. The findings will guide efforts to strengthen antibiotic stewardship and improve pandemic readiness across healthcare settings. Methods The retrospective observational study focused on non-surgical hospitalized patients aged 25-40 from January to December 2019. Data were collected from electronic medical records between March 2023 and February 2024, using a predefined set of International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes related to respiratory tract infections, urinary tract infections, ventilator-associated pneumonia, and nosocomial infections. The study evaluated clinicians' prescribing habits, antibiotic consumption, stewardship interventions, and the overall impact on the healthcare system to assess the implementation and maturity levels of the antibiotic stewardship program. Results A study of 240 cases involving 229 patients revealed significant findings in antibiotic use and resistance patterns based on predefined criteria. The average duration of antibiotic use per patient was 6.23 days. Duplicate anaerobic therapy was identified in 4.58% of cases. Escherichia coli , Klebsiella pneumoniae , Enterobacter spp., and Proteus spp. showed reduced susceptibility to multiple antibiotics. Citrobacter spp. were fully resistant to one antibiotic and had low susceptibility to another. Haemophilus influenzae , Salmonella spp., Staphylococcus spp., Streptococcus  spp., and Enterococcus spp.   displayed varying degrees of reduced susceptibility. Of the cases, 91.66% (n = 220) received antibiotics within 24 hours of admission, with 98.63% (n = 217) receiving empirical therapy. Inaccurate empirical decisions correlated with longer hospital stays (4.45 versus 3.36 days). Appropriate antibiotic stewardship was observed in only 2.35% of cases during stays exceeding three days and 16.47% at discharge. Recommendation A further longitudinal study is recommended to compare how these results contribute to our understanding of the impact of the COVID-19 pandemic on antibiotic stewardship practices, resistance trends, and clinicians' prescribing habits in non-surgical hospitals in Abu Dhabi. Conclusion The review highlighted key aspects of existing stewardship practices. While most patients received empirical therapy, issues such as duplicate anaerobic therapy and a concerning decline in antibiotic susceptibility were identified. Inaccurate empirical decisions were associated with longer hospital stays. The limited instances of appropriate stewardship conduct suggest a need for better adherence to antibiotic management practices and enhanced preparedness for future healthcare challenges., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Institutional Review Board of Burjeel Holdings and the Department of Health Abu Dhabi Health Research and Technology Ethics Committee issued approval BH/REC/039/22 and DOH/CVDC/2023/512, respectively. Approval was issued by the Institutional Review Board of Burjeel Holdings on 20/01/2023 and by the Department of Health Abu Dhabi Health Research and Technology Ethics Committee on 02/03/2023. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Vats et al.)

Published
2024
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14. Manufacturing and preclinical toxicity of GLP grade gene deleted attenuated Leishmania donovani parasite vaccine.

Author

Avishek K, Beg MA, Vats K, Singh AK, Dey R, Singh KP, Singh RK, Gannavaram S, Ramesh V, Mulla MSA, Bhatnagar U, Singh S, Nakhasi HL, Salotra P, and Selvapandiyan A

Subjects
Animals, Humans, Dogs, Cricetinae, Leishmaniasis Vaccines immunology, Leishmaniasis Vaccines genetics, Protozoan Proteins genetics, Protozoan Proteins immunology, Leukocytes, Mononuclear immunology, Female, Leishmania donovani immunology, Leishmania donovani genetics, Vaccines, Attenuated immunology, Leishmaniasis, Visceral prevention & control, Leishmaniasis, Visceral immunology, Leishmaniasis, Visceral parasitology, Gene Deletion
Abstract

Centrin1 gene deleted Leishmania donovani parasite (LdCen1 -/- ) was developed and extensively tested experimentally as an intracellular stage-specific attenuated and immunoprotective live parasite vaccine candidate ex vivo using human PBMCs and in vivo in animals. Here we report manufacturing and pre-clinical evaluation of current Good-Laboratory Practice (cGLP) grade LdCen1 -/- parasites, as a prerequisite before proceeding with clinical trials. We screened three batches of LdCen1 -/- parasites manufactured in bioreactors under cGLP conditions, for their consistency in genetic stability, attenuation, and safety. One such batch was preclinically tested using human PBMCs and animals (hamsters and dogs) for its safety and protective immunogenicity. The immunogenicity of the CGLP grade LdCen1 -/- parasites was similar to one grown under laboratory conditions. The cGLP grade LdCen1 -/- parasites were found to be safe and non-toxic in hamsters and dogs even at 3 times the anticipated vaccine dose. When PBMCs from healed visceral leishmaniasis (VL) cases were infected with cGLP LdCen1 -/- , there was a significant increase in the stimulation of cytokines that contribute to protective responses against VL. This effect, measured by multiplex ELISA, was greater than that observed in PBMCs from healthy individuals. These results suggest that cGLP grade LdCen1 -/- manufactured under cGMP complaint conditions can be suitable for future clinical trials., (© 2024. The Author(s).)

Published
2024
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15. A New Source of Opioid and Lead Toxicity on the Block-Kamini: An Emerging Health Hazard-A Case Series.

Author

Abhilasha P, Vats K, Gautam N, Kaur V, Singla M, Pavitra Ds, Gupta M, Chaudhary V, Joyal W, and John MJ

Abstract

Introduction: Illicit drug abuse with opioids can inadvertently lead to refractory anemia and lead poisoning. 1 The absence of adequate regulations for Ayurvedic herbal products has led to the adulteration of opioid-containing drugs with lead. 2 As a result, lead toxicity has become a concern within this seldom-addressed population of opioid users. In this report, we present a collection of cases where individuals developed lead toxicity while being dependent on opioids due to their use of a little-known herbal product called Kamini, which contains Papaver somniferum . This retrospective case series aims to raise awareness about and foster broader recognition of opioid dependence linked to herbal products like Kamini, along with the associated risks associated with its usage., Methods: We retrospectively analyzed the records of three patients who were opioid abusers and presented with symptoms and signs of lead poisoning., Results: All three patients were male and presented with complaints of abdominal pain and generalized weakness. Laboratory examinations showed high lead levels and low hemoglobin as well as basophilic stippling. Urine porphyrins were falsely positive in two patients. All three patients showed symptomatic improvement with a decrease in lead levels after chelation therapy., Discussion and Conclusion: This case series highlights the need for awareness regarding opioid dependence syndrome and potential lead toxicity stemming from the use of Ayurvedic preparations over the counter, such as Kamini. A low threshold should be kept for testing for lead poisoning in patients who present with anemia and/or abdominal pain with a history of opioid dependence., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2024 The Author(s).)

Published
2024
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16. Utility of Postnatal Chest X-Ray in Newborns for the Evaluation of Prenatally Suspected Congenital Pulmonary Airway Malformation: A Single-Center Experience.

Author

Jackson LE, Yanowitz TD, Waltz P, and Vats K

Subjects
Humans, Infant, Newborn, Retrospective Studies, Female, Pregnancy, Male, Radiography, Thoracic, Cystic Adenomatoid Malformation of Lung, Congenital diagnostic imaging
Abstract

Objective: The aim of the study is to assess the necessity of chest X-ray (CXR) during the newborn hospitalization for all patients with prenatally suspected congenital pulmonary airway malformation (CPAM)., Study Design: This is a retrospective chart review of all infants delivered with prenatally suspected CPAM at our high-risk delivery hospital from January 2013 through April 2020 ( n  = 44). Nonparametric tests assessed the association between postnatal CXR findings, prescribed follow-up timeline, and neonatal outcomes., Results: Mean follow-up period recommended was 6.4 weeks regardless of CXR findings in the neonatal period ( p  = 0.81). Additionally, patients who required respiratory support at or after birth were not more likely to have a lesion identified on chest X-ray (odds ratio [OR] = 0.72, 95% confidence interval [CI], 0.18-2.64, p  = 0.71)., Conclusion: Neonatal hospital course and future follow-up plan of patients with prenatally suspected CPAM were not altered by information from the CXR obtained in the immediate neonatal period, suggesting that this CXR may not be necessary in the asymptomatic patient., Key Points: · Immediate postnatal X-ray of prenatally diagnosed CPAM does not alter planned follow-up interval.. · Immediate postnatal X-ray does not alter surgical plan for CPAM.. · Postnatal X-ray is not absolutely required for asymptomatic newborns with CPAM.., Competing Interests: None declared., (Thieme. All rights reserved.)

Published
2024
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17. Navigating the Digital Landscape: Embracing Innovation, Addressing Challenges, and Prioritizing Patient-Centric Care.

Author

Vats K

Abstract

In the digital era, healthcare customer feedback plays a pivotal role in shaping the reputation of healthcare organizations. The study explores how digital advancements are integrated into modern healthcare, offering both transformative insights and addressing the challenges they present. It investigates how technologies such as artificial intelligence (AI), digital platforms, and patient feedback systems impact patient care, operational efficiency, and customer satisfaction in healthcare settings. The study emphasizes the importance of balancing both capitalizing on the opportunities presented by innovations and addressing the inherent difficulties associated with digitalization in healthcare, underlining the need for a comprehensive approach to navigating the opportunities and challenges in healthcare digitalization. AI is recognized for its role in reshaping value creation in healthcare, fostering collaboration among stakeholders, and improving patient care. Additionally, the study identifies key areas of research essential for effectively navigating the digital transformation in healthcare, including operational efficiency, patient-centric strategies, and organizational factors. However, along with the potential benefits come challenges, such as the need for regulatory frameworks to validate new technologies and address privacy concerns surrounding patient data. Managing reputation and customer relationships in the digital sphere also emerges as critical for healthcare organizations. In summary, the study underscores the importance of healthcare institutions prioritizing patient-centric care, adopting digital innovations, and adeptly navigating regulatory and ethical challenges. By doing so, they can enhance patient outcomes, and satisfaction, and drive innovation in today's dynamic healthcare landscape., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Vats et al.)

Published
2024
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18. A quality improvement initiative standardizing the antibiotic treatment and feeding practices in patients with medical necrotizing enterocolitis.

Author

Mahmood Z, O'Donnell B, Brozanski BS, Vats K, Kloesz J, Jackson LE, Shenk J, Miller M, Pasqualicchio MB, Schmidt H, Azzuqa A, and Yanowitz TD

Subjects
Infant, Newborn, Humans, Infant, Premature, Quality Improvement, Enteral Nutrition, Anti-Bacterial Agents therapeutic use, Infant, Very Low Birth Weight, Enterocolitis, Necrotizing drug therapy, Infant, Newborn, Diseases
Abstract

Objective: Evaluate the impact of a multidisciplinary guideline standardizing antibiotic duration and enteral feeding practices following medical necrotizing enterocolitis (mNEC)., Study Design: For preterm infants with Bell Stage 2 A mNEC and negative blood culture, antibiotic treatment was standardized to 7 days. Trophic feeds of unfortified human milk began 72 h after resolution of pneumatosis. Feeds were advanced by 20 cc/kg/day starting on the last day of antibiotics. Primary outcomes were antibiotic days and days to full feeds, defined as 120 cc/kg/day of enteral nutrition. Secondary outcomes included central line days and length of stay (LOS)., Results: Antibiotic duration decreased 23%. Time to start trophic feeds and time to full feeds decreased 33 and 16% respectively. Central line use dropped (98 to 72% of infants) and central line days were reduced by 59%., Conclusion: Implementation of a mNEC QI package reduced antibiotic duration, time to full feeds, central line use and CL days., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2024
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19. Functional consequences of familial ALS-associated SOD1 L84F in neuronal and muscle cells.

Author

Verma S, Vats A, Ahuja V, Vats K, Khurana S, Vats Y, Gourie-Devi M, Wajid S, Ganguly NK, Chakraborti P, and Taneja V

Subjects
Animals, Mice, Disease Models, Animal, Mice, Transgenic, Muscle Cells metabolism, Mutation, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Superoxide Dismutase-1 genetics
Abstract

Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder characterized by progressive skeletal muscle denervation and loss of motor neurons that results in muscle atrophy and eventual death due to respiratory failure. Previously, we identified a novel SOD1 L84F variation in a familial ALS case. In this study, we examined the functional consequences of SOD1 L84F overexpression in the mouse motor neuron cell line (NSC-34). The cells expressing SOD1 L84F showed increased oxidative stress and increased cell death. Interestingly, SOD1 L84F destabilized the native dimer and formed high molecular weight SDS-resistant protein aggregates. Furthermore, SOD1 L84F also decreased the percentage of differentiated cells and significantly reduced neurite length. A plethora of evidence suggested active involvement of skeletal muscle in disease initiation and progression. We observed differential processing of the mutant SOD1 and perturbations of cellular machinery in NSC-34 and muscle cell line C2C12. Unlike neuronal cells, mutant protein failed to accumulate in muscle cells probably due to the activated autophagy, as evidenced by increased LC3-II and reduced p62. Further, SOD1 L84F altered mitochondrial dynamics only in NSC-34. In addition, microarray analysis also revealed huge variations in differentially expressed genes between NSC-34 and C2C12. Interestingly, SOD1 L84F hampered the endogenous FUS autoregulatory mechanism in NSC-34 by downregulating retention of introns 6 and 7 resulting in a two-fold upregulation of FUS. No such changes were observed in C2C12. Our findings strongly suggest the differential processing and response towards the mutant SOD1 in neuronal and muscle cell lines., (© 2024 Federation of American Societies for Experimental Biology.)

Published
2024
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20. Comparison of wear on articular cartilage by titanium alloy, ultra-high-molecular-weight polyethylene, and carbon fibre reinforced polyether-ether-ketone: A pilot study.

Author

Sun R, Vats K, Jn Baptiste J, Adeeb S, Jomha N, and Westover L

Subjects
Animals, Swine, Carbon Fiber, Pilot Projects, Biocompatible Materials pharmacology, Materials Testing, Polyethylene Glycols, Polyethylenes, Ketones, Alloys, Ethers, Titanium, Cartilage, Articular
Abstract

Artificial implant materials may articulate against native articular cartilage in certain clinical scenarios and the selection of an implant material that results in the least wear on articular cartilage is preferred to maintain normal joint architecture and function. This project compared the wear on porcine femoral condyles induced by articulation against porcine patellae, titanium alloy (Ti6Al4V), ultra high molecular weight polyethylene (UHMWPE), and carbon fibre reinforced polyether-ether-ketone (CFR-PEEK) through an ex vivo experimental setup. A sinusoidal compressive load of 30-160 N, representing an approximate joint pressure of 0.19-1 MPa at a frequency of 3 Hz coupled with a rotational displacement of +/- 10⁰ at 3 Hz was used to simulate physiological joint motion. Wear was characterized via gross examination and histologically using the OARSI scoring system after 43,200 cycles. CFR-PEEK resulted in the most significant wear on articular cartilage compared to titanium alloy and UHMWPE whereas titanium alloy and UHMWPE resulted in similar levels of wear. All materials caused more wear compared to cartilage-on-cartilage testing. The wear mechanism was characterized by progressive loss of proteoglycan content in cartilage in histology samples., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Ltd.)

Published
2023
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21. Melanoma-associated repair-like Schwann cells suppress anti-tumor T-cells via 12/15-LOX/COX2-associated eicosanoid production.

Author

Kruglov O, Vats K, Soman V, Tyurin VA, Tyurina YY, Wang J, Williams L, Zhang J, Donahue Carey C, Jaklitsch E, Chandran UR, Bayir H, Kagan VE, and Bunimovich YL

Subjects
Mice, Animals, Cyclooxygenase 2 metabolism, Schwann Cells metabolism, Schwann Cells pathology, Eicosanoids metabolism, T-Lymphocytes, Tumor Microenvironment, Arachidonate 15-Lipoxygenase metabolism, Melanoma
Abstract

Peripheral glia, specifically the Schwann cells (SCs), have been implicated in the formation of the tumor microenvironment (TME) and in cancer progression. However, in vivo and ex vivo analyses of how cancers reprogram SC functions in different organs of tumor-bearing mice are lacking. We generated Plp1-CreERT/tdTomato mice which harbor fluorescently labeled myelinated and non-myelin forming SCs. We show that this model enables the isolation of the SCs with high purity from the skin and multiple other organs. We used this model to study phenotypic and functional reprogramming of the SCs in the skin adjacent to melanoma tumors. Transcriptomic analyses of the peritumoral skin SCs versus skin SCs from tumor-free mice revealed that the former existed in a repair-like state typically activated during nerve and tissue injury. Peritumoral skin SCs also downregulated pro-inflammatory genes and pathways related to protective anti-tumor responses. In vivo and ex vivo functional assays confirmed immunosuppressive activities of the peritumoral skin SCs. Specifically, melanoma-reprogrammed SCs upregulated 12/15-lipoxygenase (12/15-LOX) and cyclooxygenase (COX)-2, and increased production of anti-inflammatory polyunsaturated fatty acid (PUFA) metabolites prostaglandin E2 (PGE2) and lipoxins A4/B4. Inhibition of 12/15-LOX or COX2 in SCs, or EP4 receptor on lymphocytes reversed SC-dependent suppression of anti-tumor T-cell activation. Therefore, SCs within the skin adjacent to melanoma tumors demonstrate functional switching to repair-like immunosuppressive cells with dysregulated lipid oxidation. Our study suggests the involvement of the melanoma-associated repair-like peritumoral SCs in the modulation of locoregional and systemic anti-tumor immune responses., Competing Interests: No potential conflict of interest was reported by the authors., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Published
2023
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22. [ 99m Tc]Tc-HYNIC-RM2: A potential SPECT probe targeting GRPR expression in prostate cancers.

Author

Vats K, Chakraborty A, Rakshit S, Damle A, Sarma HD, and Satpati D

Subjects
Male, Humans, Animals, Mice, Tissue Distribution, Mice, SCID, Tomography, Emission-Computed, Single-Photon methods, Peptides metabolism, Cell Line, Tumor, Receptors, Bombesin metabolism, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology
Abstract

Introduction: Elevated density of gastrin releasing peptide receptors (GRPR) in prostate cancer has led to exploration of several radiolabeled peptides for imaging and staging of the disease. The GRPR antagonist peptide RM2 has been successfully conjugated with several chelators and radiolabeled with gallium-68. The goal of this study was to synthesize a 99m Tc-labeled probe and investigate its potential for SPECT imaging of prostate cancer. Towards this HYNIC-RM2 peptide conjugate was synthesized, radiolabeled with 99m Tc and evaluated in GRPR-positive PC3 tumor xenografts., Methods: HYNIC-RM2 was manually synthesized by standard Fmoc solid phase strategy and radiolabeled with 99m Tc. In vitro cell studies were performed in GRPR-positive human prostate carcinoma (PC3) cells. Metabolic stability studies of [ 99m Tc]Tc-HYNIC-RM2 were performed in normal mice in the presence as well as absence of neutral endopeptidase (NEP) inhibitor, phosphoramidon (PA). Biodistribution and imaging studies of [ 99m Tc]Tc-HYNIC-RM2 were performed in SCID mice bearing PC3-xenograft., Results: [ 99m Tc]Tc-HYNIC-RM2 exhibited high binding affinity in low nanomolar range (K d  = 1.83 ± 0.31 nM). Metabolic stability studies in mice indicated that in the absence of PA, radiolabeled peptide was about 65 % intact in the blood at 15 min p.i., whereas proportion of intact radiolabeled peptide was enhanced to 90 % on co-administration of PA. Biodistribution studies in PC3 tumor bearing mice demonstrated high tumor uptake (8.02 ± 0.9%ID/g and 6.13 ± 0.44%ID/g at 1 h and 3 h p.i.). Co-administration of PA with the radiolabeled peptide resulted in further enhancement of tumor uptake (14.24 ± 0.76 % ID/g and 11.71 ± 0.59%ID/g at 1 h and 3 h p.i.). SPECT/CT images of [ 99m Tc]Tc-HYNIC-RM2 could clearly visualize the tumor. Significant (p < 0.001) reduction in the tumor uptake with a co-injected blocking dose of unlabeled peptide ascertained the GRPR specificity of [ 99m Tc]Tc-HYNIC-RM2., Conclusion: Encouraging results obtained in biodistribution and imaging studies indicate the potential of [ 99m Tc]Tc-HYNIC-RM2 for further exploration as GRPR targeting agent., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Published
2023
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23. Interaction of novel proteins, centrin4 and protein of centriole in Leishmania parasite and their effects on the parasite growth.

Author

Vats K, Tandon R, Roshanara, Beg MA, Corrales RM, Yagoubat A, Reyaz E, Wani TH, Baig MS, Chaudhury A, Krishnan A, Puri N, Salotra P, Sterkers Y, and Selvapandiyan A

Subjects
Animals, Humans, Centrioles genetics, Centrioles metabolism, Cell Division, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Parasites metabolism, Leishmania donovani genetics
Abstract

Centrins are cytoskeletal proteins associated with the centrosomes or basal bodies in the eukaryotes. We previously reported the involvement of Centrin 1-3 proteins in cell division in the protozoan parasites Leishmania donovani and Trypanosoma brucei. Centrin4 and 5, unique to such parasites, had never been characterized in Leishmania parasite. In the current study, we addressed the function of centrin4 (LdCen4) in Leishmania. By dominant-negative study, the episomal expression of C-terminal truncated LdCen4 in the parasite reduced the parasite growth. LdCen4 double allele gene deletion by either homologous recombination or CRISPR-Cas9 was not successful in L. donovani. However, CRISPR-Cas9-based deletion of the homologous gene was possible in L. mexicana, which attenuated the parasite growth in vitro, but not ex vivo in the macrophages. LdCen4 also interacts with endogenous and overexpressed LdPOC protein, a homolog of centrin reacting human POC (protein of centriole) in a calcium sensitive manner. LdCen4 and LdPOC binding has also been confirmed through in silico analysis by protein structural docking and validated by co-immunoprecipitation. By immunofluorescence studies, we found that both the proteins share a common localization at the basal bodies. Thus, for the first time, this article describes novel centrin4 and its binding protein in the protozoan parasites., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2022. Published by Elsevier B.V.)

Published
2023
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24. History of Neonatal Resuscitation: From Uncivilized to Evidence-based Practices.

Author

Ibrahim J and Vats K

Subjects
Humans, Infant, Newborn, Resuscitation, Evidence-Based Practice
Abstract

Neonatal resuscitation, an early and critical intervention in human life, has dramatically evolved. This procedure has gone through phases from uncivilized practices that were sometimes based on myths to the current evidence-based approaches. In this review, we will shed light on the evolution of neonatal resuscitation from early centuries to the current day. Our goal is to highlight the value of clinical research and its role in invalidating hazardous practices and establishing evidence-based guidelines., (Copyright © 2023 by the American Academy of Pediatrics.)

Published
2023
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25. Tumor-Induced T Cell Polarization by Schwann Cells.

Author

Shurin GV, Vats K, Kruglov O, Bunimovich YL, and Shurin MR

Subjects
Humans, Lymphocyte Activation, Transforming Growth Factor beta metabolism, Prostaglandins metabolism, Schwann Cells metabolism, Neoplasms metabolism
Abstract

Nerve-cancer crosstalk resulting in either tumor neurogenesis or intratumoral neurodegeneration is critically controlled by Schwann cells, the principal glial cells of the peripheral nervous system. Though the direct stimulating effect of Schwann cells on malignant cell proliferation, motility, epithelial-mesenchymal transition, and the formation of metastases have been intensively investigated, the ability of Schwann cells to affect the effector and regulatory immune cells in the tumor environment is significantly less studied. Here, we demonstrated that tumor cells could stimulate Schwann cells to produce high levels of prostaglandin E, which could be blocked by COX-2 inhibitors. This effect was mediated by tumor-derived TGF-β as neutralization of this cytokine in the tumor-conditioned medium completely blocked the inducible prostaglandin E production by Schwann cells. Similar protective effects were also induced by the Schwann cell pretreatment with TGF-βR1/ALK4/5/7 and MAPK/ERK kinase inhibitors of the canonical and non-canonical TGF-β signaling pathways, respectively. Furthermore, prostaglandin E derived from tumor-activated Schwann cells blocked the proliferation of CD3/CD28-activated T cells and upregulated the expression of CD73 and PD-1 on both CD4+ and CD8+ T cells, suggesting T cell polarization to the exhausted phenotype. This new pathway of tumor-induced T cell inhibition via the activation of neuroglial cells represents new evidence of the importance of nerve-cancer crosstalk in controlling tumor development and progression. A better understanding of the tumor-neuro-immune axis supports the development of efficient targets for harnessing this axis and improving the efficacy of cancer therapy.

Published
2022
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27. Moving towards the optimization of diagnosis for patients with sarcoma: A 10-year review of externally consulted sarcoma cases in a general anatomical pathology service.

Author

Vats K, Spafford M, Groot G, Graham P, Banerjee T, Deobald R, and Osmond A

Subjects
Delayed Diagnosis, Humans, Referral and Consultation, Sarcoma diagnosis, Sarcoma pathology, Soft Tissue Neoplasms diagnosis
Abstract

Introduction: Soft tissue sarcomas (STS) are rare, diagnostically challenging, malignant tumors with diverse histomorphologic, immunohistochemical and molecular features. In our practice, STS are reported in a general anatomical pathology practice with no formal subspecialized training in reporting these complex specimens. Our study was performed to look at the rate of external consultation (EC), along with other parameters including discordance rate, associated diagnostic delay with EC and extent of secondary work-up performed by the consultant for correct diagnosis., Methods: The reports from 880 soft tissue sarcomas cases in the province of Saskatchewan between January 1, 2010, and December 31, 2020, were analyzed descriptively., Results: Of the 880 cases reviewed in our database, 51.9% (n = 457) cases were sent to 35 different North American institutions for expert opinion. The initial diagnosis and expert opinion were in full agreement for 182 cases (39.8%), while 194 cases (42.5%) had partial agreement and 66 cases (14.4%) had zero agreement. Of the cases that had zero agreement, 20 cases (4.4%) were initially diagnosed as malignant, with a benign opinion given by the expert; and 10 cases (2.2%) were initially diagnosed as benign, which were malignant upon expert review., Conclusion: Soft tissue sarcomas are complex tumors that frequently require expert opinion and integration of ancillary techniques with histomorphologic features for definitive classification. A multidisciplinary, subspecialized approach to STS and availability of necessary ancillary tests would improve diagnostic accuracy. In centers where the case load would not support the full-time expertise of an STS multidisciplinary team, criteria should be developed to effectively utilize EC practices., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Published
2022
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28. Antenatal Milk Expression as a Lactation Support Intervention for Parents of Infants With Severe Birth Defects: A Case Series.

Author

Davis JA, Glasser M, Clemens M, Eichhorn B, Vats K, and Demirci JR

Subjects
Infant, Female, Humans, Pregnancy, Animals, Pilot Projects, Breast Feeding, Parents, Lactation, Milk
Abstract

Background: A diet high in parent's own milk (parental milk) is a lifesaving intervention for critically ill infants. Lactating parents whose infants are born with birth defects that require surgical repair (surgical infants) shortly after birth often struggle to initiate and maintain a milk supply that meets their infant's nutritional needs. Antenatal milk expression has been identified as a safe, feasible, and potentially effective strategy that promotes parents' direct chest/breastfeeding or milk expression (lactation) confidence and helps parents attain their lactation goals. Two cases are presented to illustrate the potential for using antenatal milk expression as a lactation support intervention for parents of surgical infants., Case Presentation: Cases were drawn from a pilot study exploring the feasibility of implementing antenatal milk expression among pregnant parents of surgical infants. Participants were healthy women recruited after 30 weeks of gestation who received a fetal diagnosis of a complex congenital heart defect. Despite variability in clinical course and length of stay, parental milk was provided for the duration of each infant's hospitalization. Participant perceptions of antenatal milk expression varied., Conclusion: More research is needed to evaluate the feasibility, efficacy, and parent or provider perceptions of antenatal milk expression as a lactation support intervention for parents of surgical infants., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Published
2022
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29. Synthesis and comparative evaluation of 177 Lu-labeled PEG and non-PEG variant peptides as HER2-targeting probes.

Author

Sharma AK, Sharma R, Vats K, Sarma HD, Mukherjee A, Das T, and Satpati D

Subjects
Female, Humans, Peptides, Polyethylene Glycols, Radioisotopes therapeutic use, Radiopharmaceuticals therapeutic use, Breast Neoplasms diagnostic imaging, Breast Neoplasms drug therapy, Lutetium therapeutic use
Abstract

Highest global cancer incidence of female breast cancer is a matter of great concern. HER2-positive breast cancers have high mortality rate hence detection at an early stage is vital for successful treatment, improved cancer care and survival rate. Radiolabeled peptides have emerged as new alternatives to radiolabeled antibodies to overcome the limitations of slow clearance and uptake in non-target tissues. Herein, DOTA-A9 peptide and its pegylated variant were constructed on solid phase and radiolabeled with [ 177 Lu]LuCl 3 . [ 177 Lu]DOTA-A9 and [ 177 Lu]DOTA-PEG 4 -A9 displayed high binding affinity (K d  = 48.4 ± 1.4 and 55.7 ± 12.3 nM respectively) in human breast carcinoma SKBR3 cells. Two radiopeptides exhibited renal excretion and rapid clearance from normal organs. Uptake in SKBR3 tumor and tumor-to-background ratios were significantly higher (p < 0.05) for [ 177 Lu]DOTA-PEG 4 -A9 at the three time points investigated. Xenografts could be clearly visualized by [ 177 Lu]DOTA-PEG 4 -A9 in SPECT images at 3, 24 and 48 h p.i. indicating the potential for further exploration as HER2-targeting probe. The encouraging in vivo profile of PEG construct, [ 177 Lu]DOTA-PEG 4 -A9 incentivizes future studies for clinical applications., (© 2022. The Author(s).)

Published
2022
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30. Sensory Nerves Impede the Formation of Tertiary Lymphoid Structures and Development of Protective Antimelanoma Immune Responses.

Author

Vats K, Kruglov O, Sahoo B, Soman V, Zhang J, Shurin GV, Chandran UR, Skums P, Shurin MR, Zelikovsky A, Storkus WJ, and Bunimovich YL

Subjects
Humans, Immunity, Tumor Microenvironment, Melanoma, Skin Neoplasms, Tertiary Lymphoid Structures
Abstract

Peripheral neurons comprise a critical component of the tumor microenvironment (TME). The role of the autonomic innervation in cancer has been firmly established. However, the effect of the afferent (sensory) neurons on tumor progression remains unclear. Utilizing surgical and chemical skin sensory denervation methods, we showed that afferent neurons supported the growth of melanoma tumors in vivo and demonstrated that sensory innervation limited the activation of effective antitumor immune responses. Specifically, sensory ablation led to improved leukocyte recruitment into tumors, with decreased presence of lymphoid and myeloid immunosuppressive cells and increased activation of T-effector cells within the TME. Cutaneous sensory nerves hindered the maturation of intratumoral high endothelial venules and limited the formation of mature tertiary lymphoid-like structures containing organized clusters of CD4+ T cells and B cells. Denervation further increased T-cell clonality and expanded the B-cell repertoire in the TME. Importantly, CD8a depletion prevented denervation-dependent antitumor effects. Finally, we observed that gene signatures of inflammation and the content of neuron-associated transcripts inversely correlated in human primary cutaneous melanomas, with the latter representing a negative prognostic marker of patient overall survival. Our results suggest that tumor-associated sensory neurons negatively regulate the development of protective antitumor immune responses within the TME, thereby defining a novel target for therapeutic intervention in the melanoma setting., (©2022 American Association for Cancer Research.)

Published
2022
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32. Primary epithelioid angiosarcoma of the mediastinum, cytomorphologic features of a rare entity-A case report and literature review.

Author

Vats K, Al-Nourhji O, Wang H, and Wang C

Subjects
Aged, Biopsy, Fine-Needle, Humans, Immunohistochemistry, Mediastinum pathology, Hemangioendothelioma, Epithelioid diagnosis, Hemangiosarcoma diagnostic imaging, Hemangiosarcoma pathology
Abstract

Epithelioid angiosarcoma (EA) is a highly aggressive vascular neoplasm. Primary mediastinal EA is extremely rare with only few cases reported in the English literature. We herein present a case of a 78-year-old patient, who was found to have a right superior mediastinal mass associated with mediastinal and hilar lymphadenopathy. Endobronchial ultrasound guided fine needle aspiration cytology of a station 4R lymph node revealed a cellular, discohesive malignant neoplasm displaying primarily epithelioid morphology with occasional spindled, plasmacytoid, and tumor giant cells. The tumor cells had ample eosinophilic cytoplasm with pleomorphic nuclei and prominent nucleoli. Vasoformative features were noted, exemplified by widespread cytoplasmic vacuoles containing neutrophils and rare red blood cells (hemophagocytosis) and vascular channels identified solely in the cell block. By immunohistochemistry, the tumor cells stained strongly positive for vimentin, positive for ERG, CD-31, FLI-1, and focally positive for pan-cytokeratin. The cytomorphological features and immunostaining patterns were diagnostic of EA. No history of malignancy was reported, and no other lesions were identified on imaging. The diagnosis of primary mediastinal EA on cytology and small biopsy specimens may be challenging due to the rarity of this tumor, limited diagnostic material, and overlapping morphologic features with other entities in the differential diagnosis. A high index of suspicion, especially in cases with vasoformative features, and utilization of ancillary studies can help establish the diagnosis., (© 2022 Wiley Periodicals LLC.)

Published
2022
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33. Assessment of 177 Lu-labeled carboxyl-terminated polyamidoamine (PAMAM) dendrimer-RGD peptide conjugate.

Author

Vats K, Sharma R, Sharma AK, Sarma HD, and Satpati D

Subjects
Animals, Mice, Oligopeptides metabolism, Polyamines, Tissue Distribution, Dendrimers
Abstract

Structurally unique polyamidoamine (PAMAM) dendrimers implanted with targeting biological moiety along with complexed radiometal constitute a favorable nano-system for diagnosis and therapy of targeted tumor sites. In the present study, carboxyl functionalities of PAMAM- generation 4 dendrimer (PAMAM-G4-COOH) were conjugated with ε-amino group of lysine of cRGDfK peptide to impart integrin α v β 3 targeting capability. Reaction of p-NH 2 -Bn-DOTA with PAMAM was accomplished via acid-amine coupling using EDC/NHS for 177 Lu-complexation. 177 Lu-labeled nano-system, 177 Lu-PAMAM-DOTA-cRGDfK demonstrated receptor-mediated uptake in murine melanoma B16F10 cells during in vitro cell uptake studies. In vivo biodistribution studies demonstrated low tumor uptake and retention of 177 Lu-PAMAM-DOTA-cRGDfK which may be attributed to rapid blood clearance. However, fast clearance from non-target organs resulted in higher target to background ratio. Tumor uptake of targeted nano-system, 177 Lu-PAMAM-DOTA-cRGDfK was observed to be significantly (p < 0.05) higher in comparison to 177 Lu-PAMAM-DOTA without the targeting peptide. Inhibition studies with unlabeled cRGDfK resulted in 60% reduction in tumor uptake of 177 Lu-PAMAM-DOTA-cRGDfK, indicating specificity of the developed nano-system towards integrin α v β 3 receptors., (© 2021 European Peptide Society and John Wiley & Sons, Ltd.)

Published
2022
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34. Histiocytic Glomerulopathy Associated With Hemophagocytic Lymphohistiocytosis.

Author

Dokouhaki P, Van der Merwe DE, Vats K, Said SM, D'Agati VD, and Nasr SH

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a systemic inflammatory syndrome characterized by heightened activation and proliferation of nonmalignant macrophages and excessive cytokine release. Whereas acute kidney injury is common in this syndrome, direct glomerular involvement by activated histiocytes is very rare. We present the case of a man in his 20s who presented with fevers, malaise, flank pain, anemia, thrombocytopenia, severe acute kidney injury, and proteinuria. A kidney biopsy revealed histiocytic glomerulopathy and subacute thrombotic microangiopathy, and he was diagnosed with HLH. Recovery of kidney function occurred following steroid therapy. A review of kidney involvement by HLH is provided., (© 2021 The Authors.)

Published
2021
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35. Keratinocyte death by ferroptosis initiates skin inflammation after UVB exposure.

Author

Vats K, Kruglov O, Mizes A, Samovich SN, Amoscato AA, Tyurin VA, Tyurina YY, Kagan VE, and Bunimovich YL

Subjects
Animals, Apoptosis, Inflammation, Keratinocytes, Mice, Skin, Ultraviolet Rays adverse effects, Ferroptosis
Abstract

The ultraviolet B radiation (UVB) causes skin inflammation, which contributes to the causality and the exacerbation of a number of cutaneous diseases. However, the mechanism of UVB-driven inflammation in the skin remains poorly understood. We show that ferroptosis, a non-apoptotic programmed cell death pathway that is promoted by an excessive phospholipid peroxidation, is activated in the epidermal keratinocytes after their exposure to UVB. The susceptibility of the keratinocytes to UVB-induced ferroptosis depends on the extent of pro-ferroptosis death signal generation and the dysregulation of the glutathione system. Inhibition of ferroptosis prevents the release of HMGB1 from the human epidermal keratinocytes, and blocks necroinflammation in the UVB-irradiated mouse skin. We show that while apoptosis and pyroptosis are also detectable in the keratinocytes after UVB exposure, ferroptosis plays a significant role in initiating UVB-induced inflammation in the skin. Our results have important implications for the prevention and the treatment of a broad range of skin diseases which are fostered by UVB-induced inflammation., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2021
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36. Intra-arterial Stem Cell Therapy Diminishes Inflammasome Activation After Ischemic Stroke: a Possible Role of Acid Sensing Ion Channel 1a.

Author

Vats K, Sarmah D, Datta A, Saraf J, Kaur H, Pravalika K, Wanve M, Kalia K, Borah A, Dave KR, Yavagal DR, and Bhattacharya P

Subjects
Amiloride therapeutic use, Animals, Brain Damage, Chronic etiology, Brain Damage, Chronic prevention & control, Female, Infarction, Middle Cerebral Artery complications, Infarction, Middle Cerebral Artery immunology, Infarction, Middle Cerebral Artery metabolism, Injections, Intra-Arterial, Mesenchymal Stem Cells physiology, Ovariectomy, Rats, Rats, Sprague-Dawley, Rotarod Performance Test, Somatosensory Disorders etiology, Somatosensory Disorders prevention & control, Acid Sensing Ion Channels physiology, Infarction, Middle Cerebral Artery therapy, Inflammasomes metabolism, Mesenchymal Stem Cell Transplantation methods, Nerve Tissue Proteins physiology
Abstract

Studies from our lab demonstrated that 1 × 10 5 intra-arterial mesenchymal stem cells (IA MSCs) at 6 h following ischemic stroke are efficacious owing to its maximum homing due to elevated stromal derived factor 1 (SDF1) in the tissue. Further, IA MSCs could abate the infarct progression, improve functional outcome, and decrease expression of calcineurin by modifying neuronal Ca 2+ channels following ischemic stroke. Since stroke pathology also encompasses acidosis that worsens the condition; hence, the role of acid sensing ion channels (ASICs) in this context could not be overlooked. ASIC1a being the major contributor towards acidosis triggers Ca 2+ ions overload which progressively contributes towards exacerbation of neuronal injury following ischemic insult. Inflammasome involvement in ischemic stroke is well reported as activated ASIC1a increases the expression of inflammasome in a pH-dependent manner to trigger inflammatory cascade. Hence, the current study aimed to identify if IA MSCs can decrease the production of inflammasome by attenuating ASIC1a expression to render neuroprotection. Ovariectomized Sprague Dawley (SD) rats exposed to middle cerebral artery occlusion (MCAo) for 90 min were treated with phosphate-buffered saline (PBS) or 1 × 10 5 MSCs IA at 6 h to check for the expression of ASIC1a and inflammasome in different groups. Inhibition studies were carried out to explore the underlying mechanism. Our results demonstrate that IA MSCs improves functional outcome and oxidative stress parameters, and decreases the expression of ASIC1a and inflammasomes in the cortical brain region after ischemic stroke. This study offers a preliminary evidence of the role of IA MSCs in regulating inflammasome by modulating ASIC1a.

Published
2021
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38. Group Sessions or Home Visits for Early Childhood Development in India: A Cluster RCT.

Author

Grantham-McGregor S, Adya A, Attanasio O, Augsburg B, Behrman J, Caeyers B, Day M, Jervis P, Kochar R, Makkar P, Meghir C, Phimister A, Rubio-Codina M, and Vats K

Subjects
Child, Female, Humans, India, Male, Child Development, Counseling methods, Health Education methods, House Calls statistics & numerical data, Mothers education, Nutritional Status
Abstract

Objectives: Poor early childhood development in low- and middle-income countries is a major public health problem. Efficacy trials have shown the potential of early childhood development interventions but scaling up is costly and challenging. Guidance on effective interventions' delivery is needed. In an open-label cluster-randomized control trial, we compared the effectiveness of weekly home visits and weekly mother-child group sessions. Both included nutritional education, whose effectiveness was tested separately., Methods: In Odisha, India, 192 villages were randomly assigned to control, nutritional education, nutritional education and home visiting, or nutritional education and group sessions. Mothers with children aged 7 to 16 months were enrolled ( n = 1449). Trained local women ran the two-year interventions, which comprised demonstrations and interactions and targeted improved play and nutrition. Primary outcomes, measured at baseline, midline (12 months), and endline (24 months), were child cognition, language, motor development, growth and morbidity., Results: Home visiting and group sessions had similar positive average (intention-to-treat) impacts on cognition (home visiting: 0.324 SD, 95% confidence interval [CI]: 0.152 to 0.496, P = .001; group sessions: 0.281 SD, 95% CI: 0.100 to 0.463, P = .007) and language (home visiting: 0.239 SD, 95% CI: 0.072 to 0.407, P = .009; group sessions: 0.302 SD, 95% CI: 0.136 to 0.468, P = .001). Most benefits occurred in the first year. Nutrition-education had no benefit. There were no consistent effects on any other primary outcomes., Conclusions: Group sessions cost $38 per child per year and were as effective on average as home visiting, which cost $135, implying an increase by a factor of 3.5 in the returns to investment with group sessions, offering a more scalable model. Impacts materialize in the first year, having important design implications., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Published
2020
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39. Spectral evidence for generic charge → acceptor interactions in carbamates and esters.

Author

Prabhakaran EN, Tumminakatti S, Vats K, and Ghosh S

Abstract

The correlations of the 1 H NMR, 13 C NMR and FT-IR spectral data from the R-O-C[double bond, length as m-dash]O groups in the alkyl carbamates and esters of homologous alcohols reveal R-group-dependent negative charge stabilization at the carbonyl oxygen and their donation to generic acceptors at C α of even alkyl alcohols (R), which explains several of their apparently anomalous properties., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Published
2020
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40. 68 Ga-labeling of internalizing RGD (iRGD) peptide functionalized with DOTAGA and NODAGA chelators.

Author

Satpati D, Vats K, Sharma R, Sarma HD, and Dash A

Subjects
Acetates chemistry, Administration, Intravenous, Anhydrides chemistry, Animals, Cell Line, Tumor, Heterocyclic Compounds, 1-Ring chemistry, Integrins chemistry, Mice, Neuropilin-1 chemistry, Peptides administration & dosage, Peptides chemistry, Chelating Agents chemistry, Gallium Radioisotopes chemistry, Melanoma, Experimental metabolism, Peptides pharmacokinetics
Abstract

The dual interaction with integrins and neuropilin-1 receptor is the peculiar feature of iRGD peptide. Hence, in the present study, two iRGD peptide analogs were synthesized with DOTAGA and NODAGA as bifunctional chelator and aminohexanoic acid as a spacer for radiometalation with 68 GaCl 3 . Negatively charged 68 Ga-DOTAGA-iRGD and neutral 68 Ga-NODAGA-iRGD radiotracers were investigated through in vitro cell uptake studies and in vivo biodistribution studies. Significant internalization of radiotracers in murine melanoma B16F10 cells was observed during in vitro studies. During in vivo studies, tumor uptake was higher for neutral 68 Ga-NODAGA-iRGD, but 68 Ga-DOTAGA-iRGD exhibited better tumor-to-blood ratio due to faster blood clearance. High kidney uptake of the two radiotracers was the limitation, which needs to be resolved through modification either in the peptide backbone or spacer/chelator., (© 2020 European Peptide Society and John Wiley & Sons, Ltd.)

Published
2020
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41. Preparation and clinical translation of 99m Tc-PSMA-11 for SPECT imaging of prostate cancer.

Author

Vats K, Agrawal K, Sharma R, Sarma HD, Satpati D, and Dash A

Abstract

This study explores the feasibility of radiolabeling the HBED-CC-PSMA (PSMA-11) ligand with Tc-99m for SPECT imaging of prostate cancer patients. 68 Ga-HBED-CC-PSMA (PSMA-11) is used clinically for PET/CT imaging of prostate cancer (PCa) patients. However, a PET/CT facility may not be affordable and/or accessible to remotely located health centers. Thus, economic considerations require development of a SPECT-based tracer to provide low cost effective health care to the entire global population. Hence, radiochemical parameters were varied and optimized to obtain the maximum radiochemical yield of 99m Tc-PSMA-11. 99m Tc-PSMA-11 could be prepared in 60 ± 5% radiochemical yield and >98% radiochemical purity with a specific activity of 15 ± 5 GBq μmol -1 . The radiotracer exhibited high stability in vitro in human serum after 24 h. A cell uptake of 15.2 ± 1.2% was observed for 99m Tc-PSMA-11 in PSMA-positive prostate carcinoma LNCaP cells. Rapid clearance from blood, liver, intestine, lungs and other major organs was observed during normal biodistribution studies. The radiotracer, 99m Tc-PSMA-11, exhibited physiological distribution in salivary and lacrimal glands similar to that of 68 Ga-PSMA-11 in mice and successfully identified primary tumors as well as metastatic lesions in human patients. This study thus highlights successful radiolabeling of HBED-CC-PSMA with Tc-99m and the potential of 99m Tc-PSMA-11 as a SPECT imaging agent for PCa., (This journal is © The Royal Society of Chemistry 2019.)

Published
2019
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42. Coordinating Care Across the Perinatal Continuum in Hemolytic Disease of the Fetus and Newborn: The Timely Handoff of a Positive Maternal Anti-Erythrocyte Antibody Screen.

Author

Vats K and Watchko JF

Subjects
Adult, Erythroblastosis, Fetal immunology, Female, Hematologic Diseases blood, Hematologic Diseases immunology, Humans, Infant, Newborn, Male, Pregnancy, Autoantibodies analysis, Erythroblastosis, Fetal diagnosis, Erythrocytes immunology, Hematologic Diseases diagnosis, Patient Handoff standards, Perinatal Care organization & administration, Prenatal Diagnosis methods
Published
2019
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43. Intra-arterial stem cell therapy modulates neuronal calcineurin and confers neuroprotection after ischemic stroke.

Author

Saraf J, Sarmah D, Vats K, Kaur H, Pravalika K, Wanve M, Kalia K, Borah A, Dave KR, Yavagal DR, and Bhattacharya P

Subjects
Animals, Brain Ischemia therapy, Female, Infusions, Intra-Arterial, Ovariectomy adverse effects, Ovariectomy trends, Rats, Rats, Sprague-Dawley, Stroke therapy, Brain Ischemia metabolism, Calcineurin biosynthesis, Mesenchymal Stem Cell Transplantation methods, Neurons metabolism, Neuroprotection physiology, Stroke metabolism
Abstract

Aim: Calcineurin (CaN) is a threonine/phosphatase which play roles in neuronal homeostasis. Ischemic stroke induces hyperactivation of CaN which further triggers apoptotic signaling. CaN inhibition has limited therapeutic output and neurotoxicity due to its intricate roles in the neuronal network and requires a strategic modulation. Intra-arterial (IA) mesenchymal stem cells (MSCs) have shown to interact with the milieu in a paracrine manner as compared to CaN inhibitors to ameliorate the neuronal damage triggered by ischemia/reperfusion injury. The present study investigates the role of IA MSCs in modulating neuronal CaN after stroke onset. Materials and methods: To validate, middle-aged ovariectomized female rats exposed to MCAo (90 min) were treated with IA MSCs (1 × 10 5 MSCs) or phosphate-buffered saline (PBS) at 6 hours to check CaN expression in different groups.Tests for assessing functional and motor coordination were performed along with biochemical estimations. Furthermore, an inhibition study by non-selective inhibitor of neuronal calcium channel, flunarizine, was performed to explore the possible underlying mechanism by which IA MSCs may interact with CaN. Results: The study suggests that IA MSCs seemingly reduce the expression of CaN after ischemic stroke. IA MSCs have shown to improve the functional outcome and normalize oxidative parameters. Conclusion: Our study provides a preliminary evidence of role of IA MSCs in modulating CaN expression.

Published
2019
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44. Synthesis, radiolabeling, and evaluation of gastrin releasing peptide receptor antagonist 68 Ga-HBED-CC-RM26.

Author

Satpati D, Vats K, Sharma R, Kameswaran M, Sarma HD, and Dash A

Subjects
Chemistry Techniques, Synthetic, Edetic Acid chemical synthesis, Edetic Acid chemistry, Edetic Acid pharmacology, Humans, Hydrophobic and Hydrophilic Interactions, Isotope Labeling, PC-3 Cells, Radiochemistry, Edetic Acid analogs & derivatives, Gallium Radioisotopes chemistry, Receptors, Bombesin antagonists & inhibitors
Abstract

The acyclic chelator HBED-CC has attained huge clinical significance owing to high thermodynamic and kinetic stability of 68 Ga-HBED-CC chelate. It provides an excellent platform for quick preparation of 68 Ga-based radiotracers in high yield. Thus, the present study aimed at conjugation of gastrin releasing peptide receptor (GRPr) antagonist, RM26, with HBED-CC chelator for 68 Ga-labeling. In vitro and vivo behavior of the peptide tracer, 68 Ga-HBED-CC-PEG 2 -RM26, was assessed and compared with 68 Ga-NODAGA-PEG 2 -RM26. The peptide tracers, 68 Ga-HBED-CC-PEG 2 -RM26 and 68 Ga-NODAGA-PEG 2 -RM26, prepared either by wet chemistry or formulated using freeze-dried kits exhibited excellent radiochemical yield and in vitro stability. The two peptide tracers cleared rapidly from the blood. Biodistribution studies in normal mice demonstrated slightly higher or comparable uptake of 68 Ga-HBED-CC-PEG 2 -RM26 in GRPr-expressing organs pancreas, stomach, and intestine. The preliminary studies suggest high potential of 68 Ga-HBED-CC-PEG 2 -RM26 for further investigation as a GRPr imaging agent and the wide scope of HBED-CC chelator in development of 68 Ga-based peptide tracers., (© 2019 John Wiley & Sons, Ltd.)

Published
2019
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45. Design, synthesis, and comparative evaluation of 99m Tc(CO) 3 -labeled N-terminal and C-terminal modified asparagine-glycine-arginine peptide constructs.

Author

Vats K, Sharma R, Kameswaran M, Sarma HD, Satpati D, and Dash A

Subjects
Animals, Cell Line, Tumor, HT29 Cells, Humans, Mice, Mice, Inbred C57BL, Molecular Structure, Oligopeptides chemistry, Oligopeptides pharmacokinetics, Tissue Distribution, Carbon Monoxide chemistry, Drug Design, Oligopeptides chemical synthesis, Radiopharmaceuticals chemistry, Technetium chemistry
Abstract

The present study describes modification of asparagine-glycine-arginine (NGR) peptide at N-terminally and C-terminally by introduction of a tridentate chelating scaffold via click chemistry reaction. The N-terminal and C-terminal modified peptides were radiometalated with [ 99m Tc(CO) 3 ] + precursor. The influence of these moieties at the two termini on the targeting properties of NGR peptide was determined by in vitro cell uptake studies and in vivo biodistribution studies. The two radiolabeled constructs did not exhibit any significant variation in uptake in murine melanoma B16F10 cells during in vitro studies. In vivo studies revealed nearly similar tumor uptake of N-terminally modified peptide construct 5 and C-terminally construct 6 at 2 h p.i. (1.9 ± 0.1 vs 2.4 ± 0.2% ID/g, respectively). The tumor-to-blood (T/B) and tumor-to-liver (T/L) ratios of the two radiometalated peptides were also quite similar. The two constructs cleared from all the major organs (heart, lungs, spleen, stomach, and blood) at 4 h p.i. (<1% ID/g). Blocking studies carried out by coinjection of cCNGRC peptide led to approximately 50% reduction in the tumor uptake at 2 h p.i. This work thus illustrates the possibility of convenient modification/radiometalation of NGR peptide at either N- or C-terminus without hampering tumor targeting and pharmacokinetics., (© 2019 European Peptide Society and John Wiley & Sons, Ltd.)

Published
2019
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46. Co-Delivery of Eugenol and Dacarbazine by Hyaluronic Acid-Coated Liposomes for Targeted Inhibition of Survivin in Treatment of Resistant Metastatic Melanoma.

Author

Mishra H, Mishra PK, Iqbal Z, Jaggi M, Madaan A, Bhuyan K, Gupta N, Gupta N, Vats K, Verma R, and Talegaonkar S

Abstract

While melanoma remains a challenge for oncologists, possibilities are being continuously explored to fight resistant metastatic melanoma more effectively. Eugenol is reported to inhibit survivin protein in breast cancer cells. Survivin is also overexpressed by melanoma cells, and is known to impart resistance to them against chemotherapy-induced apoptosis. To be able to fight resistant melanoma, we formulated hyaluronic acid (HA)-coated liposomes loaded with an effective combination of anti-melanoma agents (Dacarbazine and Eugenol), using a solvent injection method. Quality-by-Design (QbD) was applied to optimize and obtain a final formulation with the desired quality attributes, and within an acceptable size range. The optimized formulation was then subjected to performance analysis in cell lines. Coated-Dacarbazine Eugenol Liposomes were found to possess 95.08% cytotoxicity at a dacarbazine concentration of 0.5 µg/mL, while Dacarbazine Solution showed only 10.20% cytotoxicity at the same concentration. The number of late apoptotic cells was also found to be much higher (45.16% vs. 8.43%). Furthermore, migration assay and proliferation study also revealed significantly higher inhibition of cell migration and proliferation by Coated-Dacarbazine Eugenol Liposomes, signifying its potential against metastasis. Thus, surface-functionalized dacarbazine- and eugenol-loaded liposomes hold great promise against resistant and aggressive metastatic melanoma, with much less unwanted cytotoxicity and reduced doses of the chemotherapeutic agent., Competing Interests: The authors declare no conflict of interest.

Published
2019
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47. Preparation and evaluation of 99m Tc-labeled porphyrin complexes prepared using PNP and HYNIC cores: studying the effects of core selection on pharmacokinetics and tumor uptake in a mouse model.

Author

Guleria M, Das T, Vats K, Amirdhanayagam J, Mathur A, Sarma HD, and Dash A

Abstract

Porphyrins are tetrapyrrolic macrocyclic ligands known for their affinity towards neoplastic tissues and once radiolabeled with a suitable diagnostic radioisotope could potentially be used for the imaging of tumorous lesions. In the present study, an unsymmetrically substituted porphyrin derivative namely 5-( p -amino-propyloxyphenyl)-10,15,20-tris(carboxymethyleneoxyphenyl)-porphyrin was synthesized and modified further to enable radiolabeling with 99m Tc using two different 99m Tc-cores viz. 99m Tc-HYNIC (hydrazino nicotinic acid) and 99m Tc(N)PNP2 (PNP2 = bis-[(2-dimethylphosphino)ethyl]-methoxy-ethylamine) in order to study the effect of employing different 99m Tc-cores on tumor affinity and pharmacokinetic behavior of the resultant 99m Tc-labeled porphyrin complexes. 99m Tc-Porphyrin complexes were characterized by reversed phase HPLC studies and could be prepared with >95% radiochemical purity under optimized radiolabeling conditions. Both 99m Tc-complexes were found to be adequately stable in human blood serum till 3 h post-preparation. Bio-distribution studies, carried out in Swiss mice bearing fibrosarcoma tumors, revealed relatively higher tumor uptake for the 99m Tc-HYNIC-porphyrin complex (3.95 ± 1.42 and 3.28 ± 0.27% IA per g) compared to that exhibited by the 99m Tc(N)PNP-DTC-porphyrin complex (1.52 ± 0.53 and 1.56 ± 0.10% IA per g) at 1.5 and 3 h post-administration, although the former complex exhibited comparatively lower lipophilicity in the octanol-water system. Higher uptake and longer retention in the blood were observed for the 99m Tc-HYNIC-porphyrin complex (6.63 ± 0.75 and 4.36 ± 0.25% IA per g) compared to that exhibited by the 99m Tc(N)PNP-DTC-porphyrin complex (2.41 ± 0.54 and 2.30 ± 0.16% IA per g) at both 1.5 and 3 h post-administration. However, relatively lower liver uptake was observed for the former complex (19.26 ± 3.48 and 18.45 ± 1.05% IA per g) than that exhibited by the latter one (39.37 ± 3.88 and 34.15 ± 8.25% IA per g) at both 1.5 and 3 h post-administration. This study indicates that the in vivo behavior exhibited by the 99m Tc-labeled porphyrins not only depends on their lipophilicity/hydrophilicity but is also governed by the Tc-cores employed for radiolabeling.

Published
2019
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48. Therapeutic spectrum of interferon-β in ischemic stroke.

Author

Wanve M, Kaur H, Sarmah D, Saraf J, Pravalika K, Vats K, Kalia K, Borah A, Yavagal DR, Dave KR, and Bhattacharya P

Subjects
Animals, Brain Ischemia metabolism, Humans, Interferon-beta classification, Interferon-beta metabolism, Stroke metabolism, Brain Ischemia physiopathology, Interferon-beta physiology, Stroke physiopathology
Abstract

Ischemic stroke is devastating and a major cause of morbidity and mortality worldwide. To date, only clot retrieval devices and/or intravenous tissue plasminogen activators (tPA) have been approved by the US-FDA for the treatment of acute ischemic stroke. Therefore, there is an urgent need to develop an effective treatment for stroke that can have limited shortcomings and broad spectrum of applications. Interferon-beta (IFN-β), an endogenous cytokine and a key anti-inflammatory agent, contributes toward obviating deleterious stroke outcomes. Therefore, exploring the role of IFN-β may be a promising alternative approach for stroke intervention in the future. In the present review, we have discussed about IFN-β along with its different mechanistic roles in ischemic stroke. Furthermore, therapeutic approaches targeting the inflammatory cascade with IFN-β therapy that may be helpful in improving stroke outcome are also discussed., (© 2018 Wiley Periodicals, Inc.)

Published
2019
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49. Single vial cold kits optimized for preparation of gastrin releasing peptide receptor (GRPR)-radioantagonist 68 Ga-RM2 using three different 68 Ge/ 68 Ga generators.

Author

Vats K, Sharma R, Kameswaran M, Satpati D, and Dash A

Subjects
Cell Line, Tumor, Cold Temperature, Drug Compounding instrumentation, Drug Storage, Humans, Male, Positron-Emission Tomography, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology, Receptors, Bombesin metabolism, Drug Compounding methods, Oligopeptides chemical synthesis, Radionuclide Generators, Radiopharmaceuticals chemical synthesis, Receptors, Bombesin antagonists & inhibitors
Abstract

68 Ga-RM2 is a gastrin releasing peptide receptor (GRPR) antagonist PET (positron emission tomography) radiotracer which is being investigated in clinical trials as a potential prostate cancer imaging agent. Simple, one-step kit formulation of 68 Ga-RM2 would facilitate multicentre trials and allow easier integration in hospital radiopharmacy. Herein we report development of three sets of single-vial RM2 cold kits validated for formulation with three respective 68 Ge/ 68 Ga generators eluted in 0.6 M, 0.1 M and 0.05 M HCl (hydrochloric acid). Cold kits of varied pH (2, 3, 4 and 5) were prepared using 2 M sodium acetate for three different 68 Ge/ 68 Ga generators to determine influence of pH on the radiochemical yield of 68 Ga-RM2. Buffer content was optimized with respect to volume of 68 GaCl 3 eluate to be added (1 mL/2 mL/ 5 mL). Sterility, apyrogenicity and long term stability of cold kits; in vitro and serum stability of 68 Ga-RM2 were investigated. In vitro cellular uptake and inhibition studies were performed to demonstrate the specificity of kit-formulated 68 Ga-RM2. The radiochemical yield of 68 Ga-RM2 formulated from three different generators was observed to be maximum at pH 3 (99 ± 0.5%). Cold kits stored for 6 months at 0 °C also resulted in high radiochemical yield. 68 Ga-RM2 exhibited excellent in vitro stability (1 h) and serum stability (1 h). In vitro cellular uptake of 5 ± 0.8% in PC3 cells with >85% inhibition was observed for the 68 Ga-RM2 radiotracer indicating its specificity towards GRPR expression. These simple, robust kits shall allow hospitals with different generators to participate in clinical studies of 68 Ga-RM2 for screening of GRPR-expressing prostate tumors., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Published
2019
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50. Trigonelline therapy confers neuroprotection by reduced glutathione mediated myeloperoxidase expression in animal model of ischemic stroke.

Author

Pravalika K, Sarmah D, Kaur H, Vats K, Saraf J, Wanve M, Kalia K, Borah A, Yavagal DR, Dave KR, and Bhattacharya P

Subjects
Alkaloids administration & dosage, Aniline Compounds pharmacology, Animals, Antioxidants metabolism, Blotting, Western, Brain Ischemia pathology, Cerebral Infarction drug therapy, Cerebral Infarction pathology, Disease Models, Animal, Dose-Response Relationship, Drug, Glutathione metabolism, Male, Neuroprotective Agents administration & dosage, Rats, Rats, Sprague-Dawley, Stroke pathology, Alkaloids pharmacology, Brain Ischemia drug therapy, Neuroprotective Agents pharmacology, Peroxidase metabolism, Stroke drug therapy
Abstract

Aim: Stroke is devastating with a limited choice of intervention. Many pharmacological entities are available but none of them have evolved successfully in counteracting the multifaceted molecular alterations following stroke. Myeloperoxidase (MPO) has been reported to play an important role in neuroinflammation following neurodegenerative diseases. Therefore, using it as a therapeutic target may be a strategy to confer neuroprotection in stroke. Trigonelline (TG), a plant alkaloid has shown neuroprotective effects in the past. Here we explore its neuroprotective effects and its role in glutathione mediated MPO inhibition in ischemic stroke., Methods: An in silico study was performed to confirm effective TG and MPO interaction. An in vitro evaluation of toxicity with biochemical estimations was performed. Further, in vivo studies were undertaken where rats were treated with 25, 50 and 100 mg/kg TG or standard MPO inhibiting drug4‑Aminobenzoic hydrazide (4‑ABH) at 60 min prior, post immediate and an hour post 90 min of middle cerebral artery occlusion (MCAo) followed by 24 h reperfusion. Rats were evaluated for neurodeficit and motor function tests. Brains were further harvested for infarct size evaluation, biochemical analysis, and western blot experiments., Key Findings: TG at 100 mg/kg dose i.p. administered immediately post ischemia confers neuroprotection by reducing cerebral infarct with improvement in motor and neurodeficit scores. Furthermore, elevated nitrite and MDA levels were also found to be reduced in brain regions in the treated group. TG also potentiated intrinsic antioxidant status and markedly inhibited reduced glutathione mediated myeloperoxidase expression in the cortical brain region., Significance: TG confers neuroprotection by reduced glutathione mediated myeloperoxidase inhibition in ischemic stroke., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Published
2019
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