Ethnomedicinal uses of plants for various diseases in the remote areas of Changa Manga Forest, Pakistan / Usos etnomedicinais de plantas para várias doenças nas áreas remotas da Floresta Changa Manga, Paquistão

This study aims at reporting the indigenous knowledge of the medicinal flora from the inhabitants of surroundings of the World's largest artificial planted forest "Changa Manga", Pakistan. Data were collected by direct interviews and group meetings from 81 inhabitants including 32 local healers having information regarding the use of indigenous medicinal plants over a period of one year. Different statistical tools were applied to analyze the data including Frequency citation (FC), Relative frequency citation (RFC), Use Value, Factor of informants consensus and fidelity level. This study reported 73 plant species belonging to 37 plant families and 46 genera. The majority of plant species belong to compositae family. The most commonly used medicinal plants were P. hysterophorus L., P. dactylifera L., S. indicum L, P. harmala L., P. emblica L., and A. indica A.Juss. The greatest number of species was used to cure gastrointestinal disorders. The highest fidelity level (68.18%) was of E. helioscopia to cure gastrointestinal disorders. Maximum fresh uses (17) were reported by C. dactylon (L.) Pars. While the highest number of species reporting fresh uses in similar number was 13. In this study, five novel plants are being reported for the first time in Pakistan for their ethnomedicinal worth. Our data reflect unique usage of the medicinal plants in the study area. The statistical tools used in the study proved useful in pointing the most important and disease category specific plants. High use value plant and the new reported medicinal plants might prove an important source of the isolation of pharmacologically active compounds.

Este estudo tem como objetivo relatar o conhecimento indígena sobre a flora medicinal dos habitantes do entorno da maior floresta artificial plantada do mundo, a Changa Manga, no Paquistão. Os dados foram coletados por meio de entrevistas diretas e reuniões em grupo de 81 habitantes, incluindo 32 curandeiros locais, com informações sobre o uso de plantas medicinais indígenas durante o período de um ano. Diferentes ferramentas estatísticas foram aplicadas para analisar os dados, incluindo citação de frequência (FC), citação de frequência relativa (RFC), valor de uso, fator de consenso dos informantes e nível de fidelidade. Este estudo relatou 73 espécies de plantas pertencentes a 37 famílias de plantas e 46 gêneros. A maioria das espécies de plantas pertence à família Compositae. As plantas medicinais mais utilizadas foram P. hysterophorus L., P. dactylifera L., S. indicum L., P. harmala L., P. emblica L. e A. indica A. Juss. O maior número de espécies foi usado para curar distúrbios gastrointestinais. O maior nível de fidelidade (68,18%) foi de E. helioscopia para cura de distúrbios gastrointestinais. Os usos máximos em fresco (17) foram relatados por C. dactylon (L.) Pars. enquanto o maior número de espécies relatando usos frescos em número semelhante foi de 13. Neste estudo, cinco novas plantas estão sendo relatadas pela primeira vez no Paquistão por seu valor etnomedicinal. Nossos dados refletem o uso exclusivo das plantas medicinais na área de estudo. As ferramentas estatísticas utilizadas no estudo mostraram-se úteis para apontar as plantas mais importantes e específicas da categoria de doença. Plantas de alto valor de uso e as novas plantas medicinais relatadas podem ser uma importante fonte de isolamento de compostos farmacologicamente ativos.

Microvascular dysfunction following cardiopulmonary bypass plays a central role in postoperative organ dysfunction.

Despite significant advances in surgical technique and strategies for tissue/organ protection, cardiac surgery involving cardiopulmonary bypass is a profound stressor on the human body and is associated with numerous intraoperative and postoperative collateral effects across different tissues and organ systems. Of note, cardiopulmonary bypass has been shown to induce significant alterations in microvascular reactivity. This involves altered myogenic tone, altered microvascular responsiveness to many endogenous vasoactive agonists, and generalized endothelial dysfunction across multiple vascular beds. This review begins with a survey of in vitro studies that examine the cellular mechanisms of microvascular dysfunction following cardiac surgery involving cardiopulmonary bypass, with a focus on endothelial activation, weakened barrier integrity, altered cell surface receptor expression, and changes in the balance between vasoconstrictive and vasodilatory mediators. Microvascular dysfunction in turn influences postoperative organ dysfunction in complex, poorly understood ways. Hence the second part of this review will highlight in vivo studies examining the effects of cardiac surgery on critical organ systems, notably the heart, brain, renal system, and skin/peripheral tissue vasculature. Clinical implications and possible areas for intervention will be discussed throughout the review.

Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic Myocardium.

We have previously shown that normoxia serum-starved extracellular vesicle (EV) therapy improves myocardial function, perfusion, and angiogenesis in a swine model of chronic myocardial ischemia. Hypoxia-modified EVs have increased abundance of anti-oxidant, pro-angiogenic, and pro-survival proteins. The purpose of this study is to investigate the differential effects of normoxia serum-starved EVs and hypoxia-modified EVs on myocardial function, perfusion, and microvascular density in chronically ischemic myocardium. Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, the pigs underwent intramyocardial injection of either normoxia serum-starved EVs (NOR, n = 10) or hypoxia-modified EVs (HYP, n = 7). Five weeks later, pigs were euthanized, and ischemic myocardium was harvested. Hypoxia EV treatment was associated with improved contractility compared to NOR, as well as improved capillary density, without changes in arteriolar density. There were trends towards improved perfusion at rest and during pacing in the HYP group compared to NOR. Ischemic myocardium in the HYP group had increased pro-angiogenic Akt and ERK signaling and decreased expression of anti-angiogenic markers compared to the NOR group. In the setting of chronic myocardial ischemia, hypoxia-modified EVs may enhance contractility, capillary density, and angiogenic signaling pathways compared to normoxia serum-starved EVs.

Partial replacement of fish meal with Moringa oleifera leaf meal in practical diets of Cirrhinus mrigala fingerlings / Substituição parcial da refeição de peixe com farinha de folha de Moringa oleifera em dietas práticas de dedos Cirrhinus mrigala

Fish protein is serving as a source of nutrition for protein starving world. However, sustainable aquaculture products require inexpensive plant by-products due to finite sources of fish meal. Therefore, this study was conducted to examine nutrient utilization, growth performance and hematological indices of Cirrhinus mrigala fingerlings fed on Moringa oleifera leaf meal (MOLM) based diets. Fish were fed with six isonitrogenous and isoenergetic diets having MOLM as a substitute of fish meal (FM) at the levels of 0%, 10%, 20%, 30%, 40% and 50% for the period of 90 days. Fingerlings having initial weight 6.35±0.04g were reared in triplicate tanks at the stocking density of 15 and hand fed at the rate of 5% of total biomass twice regularly. Chromic oxide inclusion level was 1% in diets. After analysis, maximum growth performance and improved digestibility of nutrients were found in fish fed with diet at 10% replacement level as compared to fish fed on control diet and other test diets. Additionally, it was found that the red blood cells, white blood cells, hemoglobin and mean corpuscular hemoglobin concentration of fish showed a significantly (p<0.05) inverse correlation with the increase in MOLM. In present research, it was concluded that MOLM has good potential to be used as a FM substitute in C. mrigala diet with maximum effect at 10% showing positive hematological indices.(AU)

A proteína do peixe está servindo como fonte de nutrição para o mundo faminto por proteína. No entanto, produtos de aquicultura sustentáveis requerem subprodutos vegetais baratos devido às fontes finitas de farinha de peixe. Portanto, este estudo foi conduzido para examinar a utilização de nutrientes, o desempenho do crescimento e os índices hematológicos de alevinos de Cirrhinus mrigala alimentados com dietas à base de farelo de folhas de Moringa oleifera (MOLM). Os peixes foram alimentados com seis dietas isonitrogênicas e isoenergéticas contendo MOLM como substituto da farinha de peixe (FM) nos níveis de 0%, 10%, 20%, 30%, 40% e 50% pelo período de 90 dias. Os alevinos com peso inicial de 6,35 ± 0,04g foram criados em tanques triplicados com densidade de 15 animais e alimentados à mão a uma taxa de 5% da biomassa total duas vezes regularmente. O nível de inclusão de óxido crômico foi de 1% nas dietas. Após análise, desempenho máximo de crescimento e melhor digestibilidade de nutrientes foram encontrados em peixes alimentados com dieta em nível de reposição de 10% em comparação com peixes alimentados com dieta controle e outras dietas teste. Além disso, verificou-se que as concentrações de hemácias, leucócitos, hemoglobina e hemoglobina corpuscular média dos peixes apresentaram correlação inversa significativa (p < 0,05) com o aumento do MOLM. Na presente pesquisa, concluiu-se que o MOLM tem bom potencial para ser utilizado como substituto do FM na dieta de C. mrigala com efeito máximo a 10% apresentando índices hematológicos positivos.(AU)

Efficacy of acidified phytase supplemented cottonseed meal based diets on growth performance and proximate composition of Labeo rohita fingerlings / Eficácia de dietas à base de algodão com fitase acidificada suplementada no desempenho do crescimento e na composição proximada de dedos de Labeo rohita

The growth of aquaculture sector is strongly dependent upon the continuous supply of inexpensive fish feed with balanced nutritional profile. However, fish meal (FM) is unable to satisfy this demand due to its scarce supply and high cost. In order to test the potential of cottonseed meal (CSM) as a fish meal replacer, a feeding trial of 12 weeks was conducted to check growth performance and proximate composition of Labeo rohita fingerlings. The protein ration of the test feed was satisfied by replacing FM with CSM at 0, 25, 50 and 75%. Sixteen test diets viz., TD1 (control), TD2, TD3, TD4, TD5, TD6, TD7, TD8, TD9, TD10, TD11, TD12, TD13, TD14, TD15 and TD16 were supplemented with citric acid (CA; 0 and 2.5%) and phytase (PHY; 0 and 750 FTU/kg) in a completely randomized design with 3×3 factorial arrangement. The highest weight gain (11.03g), weight gain% (249.21%), specific growth rate (1.39) and best feed conversion ratio (1.20) were recorded by fish fed with TD12. Furthermore, the same level increased the crude protein (59.26%) and fat (16.04%) being significantly different (p<0.05) than that of control. Conclusively, the addition of acidified phytase (CA; 2.5%, PHY; 750 FTU/kg) in TD12 (CSM=50%) led to the improved growth and proximate composition of L. rohita fingerlings.(AU)

O crescimento do setor de aquicultura é fortemente dependente do fornecimento contínuo de rações baratas para peixes com perfil nutricional equilibrado. Porém, a farinha de peixe (FM) não consegue atender a essa demanda devido à sua escassa oferta e alto custo. Com o objetivo de testar o potencial da farinha de semente de canola (MSC) como substituto da farinha de peixe, um ensaio alimentar de 12 semanas foi conduzido para verificar o desempenho de crescimento e a composição centesimal de alevinos de Labeo rohita. A ração de proteína da ração teste foi satisfeita substituindo FM por CSM em 0, 25, 50 e 75%. Dezesseis dietas de teste, viz., TD1 (controle), TD2, TD3, TD4, TD5, TD6, TD7, TD8, TD9, TD10, TD11, TD12, TD13, TD14, TD15 e TD16 foram suplementadas com ácido cítrico (CA; 0 e 2,5%) e fitase (PHY; 0 e 750 FTU / kg) em um delineamento inteiramente casualizado com arranjo fatorial 3 × 3. O maior ganho de peso (11,03g), % de ganho de peso (249,21%), taxa de crescimento específico (1,39) e melhor taxa de conversão alimentar (1,20) foram registrados por peixes alimentados com TD12. Além disso, o mesmo nível aumentou a proteína bruta (59,26%) e a gordura (16,04%), sendo significativamente diferente (p <0,05) do controle. Conclusivamente, a adição de fitase acidificada (CA; 2,5%, PHY; 750 FTU / kg) em TD12 (CSM = 50%) levou a um melhor crescimento e composição próxima de alevinos de L. rohita.(AU)

Use of phytase and citric acid supplementation on growth performance and nutrient digestibility of Cirrhinus mrigala fingerlings fed on canola meal based diet / Uso de suplementação de fitase e ácido cítrico no desempenho do crescimento e digestibilidade de nutrientes de dedos Cirrhinus mrigala alimentados em dieta à base de refeição de canola

Fishmeal; being a limited and costly feed ingredient is continuously been substituted with locally available plant proteins. However, the occurrence of anti-nutritional factors in plant meal suppresses its potential to be fully replaced. Therefore, in this study we aimed to study the synergistic effects of dietary additives like citric acid and phytase enzyme supplementation on growth performance and nutrient digestibility of Cirrhinus mrigala fingerlings. Canola meal (CM) was used as a test ingredient to replace fishmeal (FM) as; 0%, 25%, 50% and 75%. These four diets were further supplemented by varying levels of phytase (0 and 750 FTU kg-1) and citric acid (0% and 2.5%) to formulate total sixteen test diets as T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, T13, T14, T15 and T16. Each treatment contained three replicates; applied to fish groups having 15 fingerlings each; following 3×3 factorial arrangement. 1% of chromic oxide was added as an inert marker. Maximum weight gain% (288%) and the lowest value of FCR (1.07) were recorded when fish was fed on diet T12 as compared to fish fed control diet (T1). Similarly, optimum nutrient digestibility values such as crude protein (77%), crude fat (84%) and gross energy (70%) were noted on same level. It was concluded that 50% canola meal can optimally replace fishmeal when supplemented with phytase and citric acid at the levels of 750 FTU kg-¹ and 2.5%, respectively.(AU)

A farinha de peixe, por ser um ingrediente alimentar limitado e caro, é continuamente substituída por proteínas vegetais disponíveis localmente. No entanto, a ocorrência de fatores antinutricionais na farinha de plantas suprime seu potencial de ser totalmente substituída. Portanto, neste estudo objetivamos estudar os efeitos sinérgicos de aditivos dietéticos como ácido cítrico e suplementação com enzima fitase sobre o desempenho de crescimento e digestibilidade de nutrientes de alevinos de Cirrhinus mrigala. A farinha de canola (CM) foi usada como ingrediente de teste para substituir a farinha de peixe (FM) como: 0%, 25%, 50% e 75%. Essas quatro dietas foram suplementadas por níveis variados de fitase (0 e 750 FTU kg-1) e ácido cítrico (0% e 2,5%) para formular um total de 16 dietas de teste como T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, T13, T14, T15 e T16. Cada tratamento continha três repetições; aplicado a grupos de peixes com 15 alevinos cada; seguindo o arranjo fatorial 3 × 3. 1% de óxido crômico foi adicionado como um marcador inerte. % de ganho de peso máximo (288%) e o valor mais baixo de FCR (1,07) foram registrados quando os peixes foram alimentados com dieta T12 em comparação com peixes alimentados com dieta controle (T1). Da mesma forma, valores ótimos de digestibilidade de nutrientes, como proteína bruta (77%), gordura bruta (84%) e energia bruta (70%) foram anotados no mesmo nível. Concluiu-se que 50% da farinha de canola pode substituir de forma ideal a farinha de peixe quando suplementada com fitase e ácido cítrico nos níveis de 750 FTU kg-¹ e 2,5%, respectivamente.(AU)

Use of phytase and citric acid supplementation on growth performance and nutrient digestibility of Cirrhinus mrigala fingerlings fed on canola meal based diet / Uso de suplementação de fitase e ácido cítrico no desempenho do crescimento e digestibilidade de nutrientes de dedos Cirrhinus mrigala alimentados em dieta à base de refeição de canola

Abstract Fishmeal; being a limited and costly feed ingredient is continuously been substituted with locally available plant proteins. However, the occurrence of anti-nutritional factors in plant meal suppresses its potential to be fully replaced. Therefore, in this study we aimed to study the synergistic effects of dietary additives like citric acid and phytase enzyme supplementation on growth performance and nutrient digestibility of Cirrhinus mrigala fingerlings. Canola meal (CM) was used as a test ingredient to replace fishmeal (FM) as; 0%, 25%, 50% and 75%. These four diets were further supplemented by varying levels of phytase (0 and 750 FTU kg-1) and citric acid (0% and 2.5%) to formulate total sixteen test diets as T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, T13, T14, T15 and T16. Each treatment contained three replicates; applied to fish groups having 15 fingerlings each; following 3×3 factorial arrangement. 1% of chromic oxide was added as an inert marker. Maximum weight gain% (288%) and the lowest value of FCR (1.07) were recorded when fish was fed on diet T12 as compared to fish fed control diet (T1). Similarly, optimum nutrient digestibility values such as crude protein (77%), crude fat (84%) and gross energy (70%) were noted on same level. It was concluded that 50% canola meal can optimally replace fishmeal when supplemented with phytase and citric acid at the levels of 750 FTU kg-1 and 2.5%, respectively.

Resumo A farinha de peixe, por ser um ingrediente alimentar limitado e caro, é continuamente substituída por proteínas vegetais disponíveis localmente. No entanto, a ocorrência de fatores antinutricionais na farinha de plantas suprime seu potencial de ser totalmente substituída. Portanto, neste estudo objetivamos estudar os efeitos sinérgicos de aditivos dietéticos como ácido cítrico e suplementação com enzima fitase sobre o desempenho de crescimento e digestibilidade de nutrientes de alevinos de Cirrhinus mrigala. A farinha de canola (CM) foi usada como ingrediente de teste para substituir a farinha de peixe (FM) como: 0%, 25%, 50% e 75%. Essas quatro dietas foram suplementadas por níveis variados de fitase (0 e 750 FTU kg-1) e ácido cítrico (0% e 2,5%) para formular um total de 16 dietas de teste como T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, T13, T14, T15 e T16. Cada tratamento continha três repetições; aplicado a grupos de peixes com 15 alevinos cada; seguindo o arranjo fatorial 3 × 3. 1% de óxido crômico foi adicionado como um marcador inerte. % de ganho de peso máximo (288%) e o valor mais baixo de FCR (1,07) foram registrados quando os peixes foram alimentados com dieta T12 em comparação com peixes alimentados com dieta controle (T1). Da mesma forma, valores ótimos de digestibilidade de nutrientes, como proteína bruta (77%), gordura bruta (84%) e energia bruta (70%) foram anotados no mesmo nível. Concluiu-se que 50% da farinha de canola pode substituir de forma ideal a farinha de peixe quando suplementada com fitase e ácido cítrico nos níveis de 750 FTU kg-1 e 2,5%, respectivamente.

Efficacy of acidified phytase supplemented cottonseed meal based diets on growth performance and proximate composition of Labeo rohita fingerlings / Eficácia de dietas à base de algodão com fitase acidificada suplementada no desempenho do crescimento e na composição proximada de dedos de Labeo rohita

Abstract The growth of aquaculture sector is strongly dependent upon the continuous supply of inexpensive fish feed with balanced nutritional profile. However, fish meal (FM) is unable to satisfy this demand due to its scarce supply and high cost. In order to test the potential of cottonseed meal (CSM) as a fish meal replacer, a feeding trial of 12 weeks was conducted to check growth performance and proximate composition of Labeo rohita fingerlings. The protein ration of the test feed was satisfied by replacing FM with CSM at 0, 25, 50 and 75%. Sixteen test diets viz., TD1 (control), TD2, TD3, TD4, TD5, TD6, TD7, TD8, TD9, TD10, TD11, TD12, TD13, TD14, TD15 and TD16 were supplemented with citric acid (CA; 0 and 2.5%) and phytase (PHY; 0 and 750 FTU/kg) in a completely randomized design with 3×3 factorial arrangement. The highest weight gain (11.03g), weight gain% (249.21%), specific growth rate (1.39) and best feed conversion ratio (1.20) were recorded by fish fed with TD12. Furthermore, the same level increased the crude protein (59.26%) and fat (16.04%) being significantly different (p<0.05) than that of control. Conclusively, the addition of acidified phytase (CA; 2.5%, PHY; 750 FTU/kg) in TD12 (CSM=50%) led to the improved growth and proximate composition of L. rohita fingerlings.

Resumo O crescimento do setor de aquicultura é fortemente dependente do fornecimento contínuo de rações baratas para peixes com perfil nutricional equilibrado. Porém, a farinha de peixe (FM) não consegue atender a essa demanda devido à sua escassa oferta e alto custo. Com o objetivo de testar o potencial da farinha de semente de canola (MSC) como substituto da farinha de peixe, um ensaio alimentar de 12 semanas foi conduzido para verificar o desempenho de crescimento e a composição centesimal de alevinos de Labeo rohita. A ração de proteína da ração teste foi satisfeita substituindo FM por CSM em 0, 25, 50 e 75%. Dezesseis dietas de teste, viz., TD1 (controle), TD2, TD3, TD4, TD5, TD6, TD7, TD8, TD9, TD10, TD11, TD12, TD13, TD14, TD15 e TD16 foram suplementadas com ácido cítrico (CA; 0 e 2,5%) e fitase (PHY; 0 e 750 FTU / kg) em um delineamento inteiramente casualizado com arranjo fatorial 3 × 3. O maior ganho de peso (11,03g), % de ganho de peso (249,21%), taxa de crescimento específico (1,39) e melhor taxa de conversão alimentar (1,20) foram registrados por peixes alimentados com TD12. Além disso, o mesmo nível aumentou a proteína bruta (59,26%) e a gordura (16,04%), sendo significativamente diferente (p <0,05) do controle. Conclusivamente, a adição de fitase acidificada (CA; 2,5%, PHY; 750 FTU / kg) em TD12 (CSM = 50%) levou a um melhor crescimento e composição próxima de alevinos de L. rohita.

Fungal conversion of chicken-feather waste into biofortified compost / Conversão fungosa de resíduos de pena de frango em composto biofortificado

Poultry industry is amongst highly developed industries of Pakistan, fulfilling the protein demand of rapidly increasing population. On the other hand, the untreated poultry waste is causing several health and environmental problems. The current study was designed to check the potential of keratinolytic fungal species for the conversion of chicken-feather waste into biofortified compost. For the purpose, three fungal species were isolated from soil samples. These strains were pure cultured and then characterized phenotypically and genotypically. BLAST searches of 18S rDNA nucleotide sequence of the fungal isolates revealed that the two fungal isolates belonged to genus Aspergillus and one belonged to genus Chrysosporium. Optimum temperature for Aspergillus flavus, Aspergillus niger and Chrysosporium queenslandicum was 29, 26 and 25 oC, respectively. A. flavus showed maximum (53%) feather degradation, A. niger degraded feather waste up to 37%, while C. queenslandicum showed 21% keratinolytic activity on chicken feathers at their respective temperature optima. The degradation potential of these fungal species showed their ability to form compost that has agro-industrial importance.

A indústria avícola está entre as indústrias altamente desenvolvidas do Paquistão, atendendo a demanda de proteína da população em rápido crescimento. Por outro lado, os resíduos de aves não tratados estão causando diversos problemas de saúde e ambientais. O presente estudo foi desenhado para verificar o potencial de espécies de fungos queratinolíticos para a conversão de resíduos de penas de frango em composto biofortificado. Para tanto, três espécies de fungos foram isoladas de amostras de solo. Essas cepas foram cultivadas puramente e, em seguida, caracterizadas fenotipicamente e genotipicamente. As pesquisas do BLAST da sequência de nucleotídeos do rDNA 18S dos isolados de fungos revelaram que os dois isolados de fungos pertenciam ao gênero Aspergillus e um pertencia ao gênero Chrysosporium. A temperatura ótima para Aspergillus flavus, Aspergillus niger e Chrysosporium queenslandicum foi de 29, 26 e 25 oC, respectivamente. A. flavus apresentou degradação máxima de penas (53%), A. niger degradou resíduos de penas em até 37%, enquanto C. queenslandicum apresentou 21% de atividade queratinolítica em penas de frango em suas respectivas temperaturas ótimas. O potencial de degradação dessas espécies de fungos mostrou sua capacidade de formar composto de importância agroindustrial.

Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia.

Background Sodium-glucose cotransporter-2 inhibitors are cardioprotective independent of glucose control, as demonstrated in animal models of acute myocardial ischemia and clinical trials. The functional and molecular mechanisms of these benefits in the setting of chronic myocardial ischemia are poorly defined. The purpose of this study is to determine the effects of canagliflozin therapy on myocardial perfusion, fibrosis, and function in a large animal model of chronic myocardial ischemia. Methods and Results Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (n=8) or 300 mg sodium-glucose cotransporter-2 inhibitor canagliflozin orally, daily (n=8). Treatment continued for 5 weeks, followed by hemodynamic measurements, harvest, and tissue analysis. Canagliflozin therapy was associated with increased stroke volume and stroke work and decreased left ventricular stiffness compared with controls. The canagliflozin group had improved perfusion to ischemic myocardium compared with controls, without differences in arteriolar or capillary density. Canagliflozin was associated with decreased interstitial and perivascular fibrosis in chronically ischemic tissue, with reduced Jak/STAT (Janus kinase/signal transducer and activator of transcription) signaling compared with controls. In ischemic myocardium of the canagliflozin group, there was increased expression and activation of adenosine monophosphate-activated protein kinase, decreased activation of endothelial nitric oxide synthase, and unchanged total endothelial nitric oxide synthase. Canagliflozin therapy reduced total protein oxidation and increased expression of mitochondrial antioxidant superoxide dismutase 2 compared with controls. Conclusions In the setting of chronic myocardial ischemia, canagliflozin therapy improves myocardial function and perfusion to ischemic territory, without changes in collateralization. Attenuation of fibrosis via reduced Jak/STAT signaling, activation of adenosine monophosphate-activated protein kinase, and antioxidant signaling may contribute to these effects.

Extracellular vesicle therapy attenuates antiangiogenic signaling in ischemic myocardium of swine with metabolic syndrome.

OBJECTIVE: Our recent studies using a porcine model of metabolic syndrome (MS) and chronic myocardial ischemia show that extracellular vesicle (EV) therapy improves blood flow and arteriogenesis in ischemic myocardium, although mechanisms of these changes are unclear. We hypothesized that in the setting of MS, EV therapy would decrease antiangiogenic signaling to mediate increased blood flow to chronically ischemic myocardium. METHODS: Yorkshire swine were fed a high-fat diet for 4 weeks to induce MS, then underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs underwent intramyocardial injection of vehicle (control, n = 6) or human bone marrow-derived EVs (n = 8). Five weeks later, left ventricular myocardium in ischemic territory was harvested. Protein expression was measured using immunoblot analysis, and data were analyzed using Wilcoxon rank sum test. Myocardial perfusion was measured with isotope-labeled microspheres, and correlation data were analyzed using Spearman rank correlation coefficient. RESULTS: EV treatment was associated with decreased expression of antiangiogenic proteins, angiostatin (P < .001) and endostatin (P = .043) in ischemic myocardium compared with control. In EV-treated pigs, there was a negative correlation between blood flow to ischemic myocardium and angiostatin (rs = -0.76; P = .037), but not endostatin expression (rs = .02; P = .98). EV treatment was also associated with decreased cathepsin D, which cleaves precursors to produce angiostatin and endostatin, in ischemic myocardium (P = .020). CONCLUSIONS: In the setting of MS and chronic myocardial ischemia, EV therapy is associated with decreased expression of antiangiogenic proteins, which might contribute to increased blood flow to chronically ischemic myocardium.

Strengthening vaccination delivery system resilience in the context of protracted humanitarian crisis: a realist-informed systematic review.

BACKGROUND: Childhood vaccination is among the most effective public health interventions available for the prevention of communicable disease, but coverage in many humanitarian settings is sub-optimal. This systematic review critically evaluated peer-review and grey literature evidence on the effectiveness of system-level interventions for improving vaccination coverage in protracted crises, focusing on how they work, and for whom, to better inform preparedness and response for future crises. METHODS: Realist-informed systematic review of peer-reviewed and grey literature. Keyword-structured searches were performed in MEDLINE, EMBASE and Global Health, CINAHL, the Cochrane Collaboration and WHOLIS, and grey literature searches performed through the websites of UNICEF, the Global Polio Eradication Initiative (GPEI) and Technical Network for Strengthening Immunization Services. Results were independently double-screened for inclusion on title and abstract, and full text. Data were extracted using a pre-developed template, capturing information on the operating contexts in which interventions were implemented, intervention mechanisms, and vaccination-related outcomes. Study quality was assessed using the MMAT tool. Findings were narratively synthesised. RESULTS: 50 studies were included, most describing interventions applied in conflict or near-post conflict settings in sub-Saharan Africa, and complex humanitarian emergencies. Vaccination campaigns were the most commonly addressed adaptive mechanism (n = 17). Almost all campaigns operated using multi-modal approaches combining service delivery through multiple pathways (fixed and roving), health worker recruitment and training and community engagement to address both vaccination supply and demand. Creation of collaterals through service integration showed generally positive evidence of impact on routine vaccination uptake by bringing services closer to target populations and leveraging trust that had already been built with communities. Robust community engagement emerged as a key unifying mechanism for outcome improvement across almost all of the intervention classes, in building awareness and trust among crisis-affected populations. Some potentially transformative mechanisms for strengthening resilience in vaccination delivery were identified, but evidence for these remains limited. CONCLUSION: A number of interventions to support adaptations to routine immunisation delivery in the face of protracted crisis are identifiable, as are key unifying mechanisms (multi-level community engagement) apparently irrespective of context, but evidence remains piecemeal. Adapting these approaches for local system resilience-building remains a key challenge.

Extracellular vesicles modulate inflammatory signaling in chronically ischemic myocardium of swine with metabolic syndrome.

OBJECTIVE: Extracellular vesicle (EV) therapy has been shown to mitigate inflammation in animal models of acute myocardial ischemia/reperfusion. This study evaluates the effect of EV therapy on inflammatory signaling in a porcine model of chronic myocardial ischemia and metabolic syndrome. METHODS: Yorkshire swine were fed a high-cholesterol diet for 4 weeks to induce metabolic syndrome, then underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received intramyocardial injection of either saline (control) (n = 6) or EVs (n = 8). Five weeks later, pigs were put to death and left ventricular myocardial tissue in ischemic and nonischemic territories were harvested. Protein expression was measured with immunoblotting, and macrophage count was determined by immunofluorescent staining of cluster of differentiation 68. Data were statistically analyzed via Wilcoxon rank-sum test. RESULTS: EV treatment was associated with decreased expression of proinflammatory markers nuclear factor kappa B (P = .002), pro-interleukin (IL) 1ß (P = .020), and cluster of differentiation 11c (P = .001) in ischemic myocardium, and decreased expression of nuclear factor kappa B in nonischemic myocardium (P = .03) compared with control. EV treatment was associated with increased expression of anti-inflammatory markers IL-10 (P = .020) and cluster of differentiation 163 (P = .043) in ischemic myocardium compared with control. There were no significant differences in expression of IL-6, tumor necrosis factor alpha, arginase, HLA class II histocompatibility antigen DR alpha chain, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha, or phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha in ischemic myocardium or pro-IL1ß, IL-6, tumor necrosis factor alpha, IL-10, or nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha in nonischemic myocardium of EV-treated pigs compared with control. There were no differences in macrophage count in ischemic myocardium between EV-treated pigs and control. CONCLUSIONS: In the setting of metabolic syndrome and chronic myocardial ischemia, intramyocardial EV therapy attenuates proinflammatory signaling.

Poorly controlled hypertension is associated with increased coronary myogenic tone in patients undergoing cardiac surgery with cardiopulmonary bypass.

OBJECTIVE: Cardioplegia and cardiopulmonary bypass dysregulate coronary vasomotor tone, which can be further affected by common comorbidities in patients undergoing cardiac surgery. This study investigates differences in coronary myogenic tone and vasomotor responses to phenylephrine before and after cardioplegia and cardiopulmonary bypass based on hypertension history. METHODS: Coronary arterioles before and after cardioplegia and cardiopulmonary bypass were dissected from atrial tissue samples in patients with no hypertension, well-controlled hypertension, or uncontrolled hypertension, as determined by documented history of hypertension, antihypertensive agent use, and clinical blood pressure measurements averaged over 1 year. Myogenic tone in response to stepwise increases in intraluminal pressure was studied between pressure steps. Microvascular reactivity in response to phenylephrine was assessed via vessel myography. Protein expression was measured with immunoblotting. RESULTS: Coronary myogenic tone was significantly increased in the uncontrolled hypertension group compared with the no hypertension and well-controlled hypertension groups before cardioplegia and cardiopulmonary bypass at higher intraluminal pressures, and after cardioplegia and cardiopulmonary bypass across all intraluminal pressures (P < .05). Contractile responses to phenylephrine were significantly enhanced in patients in the uncontrolled hypertension group compared with the well-controlled hypertension group before cardioplegia and cardiopulmonary bypass, and in the uncontrolled hypertension group compared with the no hypertension and well-controlled hyertension groups after cardioplegia and cardiopulmonary bypass (P < .05). There were no differences in myogenic tone or phenylephrine-induced reactivity between the no hypertension and well-controlled hypertension groups (P > .05). There was increased expression of phosphorylated protein kinase C alpha in the uncontrolled hypertension group after cardiopulmonary bypass compared with before cardiopulmonary bypass and increased phosphorylated extracellular signal-regulated kinase 1/2 in the uncontrolled hypertension compared with the no hypertension group after cardiopulmonary bypass (P < .05). CONCLUSIONS: Uncontrolled hypertension is associated with increased coronary myogenic tone and vasoconstrictive response to phenylephrine that persists after cardioplegia and cardiopulmonary bypass.

A Rare Case of COVID-19 Associated With Autoimmune Hemolytic Anemia, Thrombocytopenia and Acute Kidney Injury.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has numerous effects on different systemic organs other than the lungs. In this case report, we look at the presentation of a young female who was diagnosed with autoimmune hemolytic anemia (AIHA), kidney injury and thrombocytopenia during coronavirus disease 2019 (COVID-19) infection. She recovered well without the need for steroids. As demonstrated by this case, COVID-19 infection can be associated with the development of AIHA. The purpose of this report is to indicate that COVID-19 can present unusually with different clinical manifestations enough to require hospitalization.

The influence of candidates' physical attributes on patient ratings in simulated assessments of clinical practice.

BACKGROUND: We have previously shown that clinical examiners' scoring is not negatively impacted when a candidate has a tattoo, unnatural hair colour, or a regional accent. We investigated whether these physical attributes in exam candidates impact patient scoring. METHODS: Simulated/real patients were randomly assigned to watch five videos of simulated candidate performances of a cranial nerve examination: clear fail, borderline, good, 'clear pass' without an attribute, and 'clear pass' with one of the attributes (tattoo, purple hair, accent). Participants scored domains of communication and professionalism. We compared scores for the clear pass candidates with and without attributes. RESULTS: One hundred and eighty three patients participated. The total scores for the candidates with tattoos and purple hair were higher than the candidate with no physical attribute (p < 0.001). For the candidate with a Liverpool English accent no difference was identified (p = 0.120). CONCLUSIONS: The presence of certain physical attributes (tattoos or purple hair) was associated with higher scores given by patients to candidates in a simulated physical examination station.

Fungal conversion of chicken-feather waste into biofortified compost.

Poultry industry is amongst highly developed industries of Pakistan, fulfilling the protein demand of rapidly increasing population. On the other hand, the untreated poultry waste is causing several health and environmental problems. The current study was designed to check the potential of keratinolytic fungal species for the conversion of chicken-feather waste into biofortified compost. For the purpose, three fungal species were isolated from soil samples. These strains were pure cultured and then characterized phenotypically and genotypically. BLAST searches of 18S rDNA nucleotide sequence of the fungal isolates revealed that the two fungal isolates belonged to genus Aspergillus and one belonged to genus Chrysosporium. Optimum temperature for Aspergillus flavus, Aspergillus niger and Chrysosporium queenslandicum was 29, 26 and 25 oC, respectively. A. flavus showed maximum (53%) feather degradation, A. niger degraded feather waste up to 37%, while C. queenslandicum showed 21% keratinolytic activity on chicken feathers at their respective temperature optima. The degradation potential of these fungal species showed their ability to form compost that has agro-industrial importance.

Phase I Trial Characterizing the Pharmacokinetic Profile of N-803, a Chimeric IL-15 Superagonist, in Healthy Volunteers.

The oncotherapeutic promise of IL-15, a potent immunostimulant, is limited by a short serum t 1/2 The fusion protein N-803 is a chimeric IL-15 superagonist that has a >20-fold longer in vivo t 1/2 versus IL-15. This phase 1 study characterized the pharmacokinetic (PK) profile and safety of N-803 after s.c. administration to healthy human volunteers. Volunteers received two doses of N-803, and after each dose, PK and safety were assessed for 9 d. The primary endpoint was the N-803 PK profile, the secondary endpoint was safety, and immune cell levels and immunogenicity were measures of interest. Serum N-803 concentrations peaked 4 h after administration and declined with a t 1/2 of ∼20 h. N-803 did not cause treatment-emergent serious adverse events (AEs) or grade ≥3 AEs. Injection site reactions, chills, and pyrexia were the most common AEs. Administration of N-803 was well tolerated and accompanied by proliferation of NK cells and CD8+ T cells and sustained increases in the number of NK cells. Our results suggest that N-803 administration can potentiate antitumor immunity.

Ethnomedicinal uses of plants for various diseases in the remote areas of Changa Manga Forest, Pakistan.

This study aims at reporting the indigenous knowledge of the medicinal flora from the inhabitants of surroundings of the World's largest artificial planted forest "Changa Manga", Pakistan. Data were collected by direct interviews and group meetings from 81 inhabitants including 32 local healers having information regarding the use of indigenous medicinal plants over a period of one year. Different statistical tools were applied to analyze the data including Frequency citation (FC), Relative frequency citation (RFC), Use Value, Factor of informants consensus and fidelity level. This study reported 73 plant species belonging to 37 plant families and 46 genera. The majority of plant species belong to compositae family. The most commonly used medicinal plants were P. hysterophorus L., P. dactylifera L., S. indicum L, P. harmala L., P. emblica L., and A. indica A.Juss. The greatest number of species was used to cure gastrointestinal disorders. The highest fidelity level (68.18%) was of E. helioscopia to cure gastrointestinal disorders. Maximum fresh uses (17) were reported by C. dactylon (L.) Pars. While the highest number of species reporting fresh uses in similar number was 13. In this study, five novel plants are being reported for the first time in Pakistan for their ethnomedicinal worth. Our data reflect unique usage of the medicinal plants in the study area. The statistical tools used in the study proved useful in pointing the most important and disease category specific plants. High use value plant and the new reported medicinal plants might prove an important source of the isolation of pharmacologically active compounds.