Gastrointestinal injury following cardiopulmonary bypass

The gastrointestinal (GI) tract may be the source of a number of bacterial and non-bacterial mediators, which may contribute to the development of morbidity and mortality following episodes of gut hypoperfusion/ ischaemia. The aim of this thesis has been to identify the changes in gut blood flow, oxygenation and function following cardiopulmonary bypass (CPB) and their relationship to the development of post-CPB morbidity. The findings are summarised below: The retrospective study identified age (>65 yr) and CPB time as risk factors for the development of post-CPB intra-abdominal complications . Tonometrically determined values for intramucosal pH (pHi) need temperature correction to avoid calculation of erroneously high values during hypothermic CPB. Considerable hypoperfusion occurs during hypothermic CPB, with laser Doppler flowmetry (LDF) falling to approximately 45% of pre-CPB values. The gastric and colonic pHi becomes acidotic (<7.35) during the re-warming and immediate post-CPB period. Intramucosal acidosis occurs at a time when mucosal LDF blood flow is normal or supranormal. CPB increases gut permeability and reduces the absorption of the monosaccharides, 3-O-m-D-glucose, D-xylose & L-rhamnose. Post-CPB gut permeability has a temporal relationship with the CPB time. Pulsatile flow attenuates the increase in post-CPB gut permeability. Endotoxaemia occurs during CPB but is not associated with the production of TNFα; pulsatile flow attenuates this endotoxaemia. When examining perfusion and patient factors, the best predictor for a protracted ventilation & ICU stay for patients was a low gastric pHi (<7.35). A canine model of CPB supported the clinical findings, but also found that: (a) changes in large vessel blood flow do not indicate more dynamic alterations in small vessel blood flow (b) blood flow is prioritised to the mucosa at the expense of the serosal aspects of the bowel wall (c) in the re-warming phase of hypothermic CPB & the immediate post-CPB period, when intramucosal acidosis occurs, there is a disparity between gut oxygen consumption & delivery (b) increased expression of vasoactive intestinal peptide was found in the neural plexus of the submucosa post-CPB, which may indicate a role in preserving mucosal blood flow during periods of hypoperfusion

Organic cultivation of Ashwagandha with improved biomass and high content of active Withanolides: Use of Vermicompost

<div><p><i>Withania somnifera</i> (Ashwagandha) has recently been studied extensively for its health-supplementing and therapeutic activities against a variety of ailments. Several independent studies have experimentally demonstrated pharmaceutical potential of its active Withanolides, Withaferin A (Wi-A), Withanone (Wi-N) and Withanolide A (Wil-A). However, to promote its use in herbal industry, an environmentally sustainable cultivation and high yield are warranted. In modern agriculture strategies, there has been indiscriminate use of chemical fertilizers to boost the crop-yield, however the practice largely ignored its adverse effect on the quality of soil and the environment. In view of these, we attempted to recruit Vermicompost (Vcom, 20–100%) as an organic fertilizer of choice during the sowing and growing phases of Ashwagandha plants. We report that (i) pre-soaking of seeds for 12 h in Vermicompost leachate (Vcom-L) and Vermicompost tea (Vcom-T) led to higher germination, (ii) binary combination of pre-soaking of seeds and cultivation in Vcom (up to 80%) resulted in further improvement both in germination and seedling growth, (iii) cultivated plants in the presence of Vcom+Vcom-L showed higher leaf and root mass, earlier onset of flowering and fruiting and (iv) leaves from the Vcom+Vcom-L cultivated plants showed higher level of active Withanolides, Withanone (Wi-N), Withanolide A (Wil-A) and Withaferin A (Wi-A) and showed anticancer activities in cell culture assays. Taken together, we report a simple and inexpensive method for improving the yield and pharmaceutical components of Ashwagandha leaves.</p></div

Effect of Vcom and Vcom+Vcom-L on <i>W</i>. <i>somnifera</i> growth.

<p>Figure showing effect Vcom and Vcom+Vcom-L application on plant growth (A), shoot length (B), shoot diameter (C), and number of branches (D) of <i>W</i>. <i>somnifera</i>. Letters (a, b, c, d) marked statistical significance (HSD, P≤0.05) within various pre-soaking treatments; whereas letters (p, q, r, s) represented statistical significance (HSD, P≤0.05) between various concentrations (%) of Vcom performed by ANOVA test.</p

Effect of Vcom and Vcom+Vcom-L on <i>W</i>. <i>somnifera</i> fruiting and analysis of cell cytotoxicity treated with leave extracts.

<p>Effect of Vcom and Vcom+Vcom-Lon flowering and fruiting of <i>W</i>. <i>somnifera</i> (A). Cytotoxicity of leaf extracts (β-cyclodextrin assisted water extract, β-CD, and its residual fraction dissolved in DMSO, β-DM) in human cancer and normal cells is shown (B-C). Whereas the extracts from plants pre-soaked with Vcom-L and treated with Vcom (up to 60%) showed cytotoxicity, the extracts from plants treated with 100% Vcom were inactive. Furthermore, β-CD leaf extracts showed somewhat equal cytotoxicity to both human cancer and normal cells; β-DM extracts from plants treated with 40% Vcom showed highest selectivity to human cancer cells (B-C).</p

Effect of Vcom and Vcom+Vcom-L on <i>W</i>. <i>somnifera</i> vegetative extension.

<p>Effect of pre-soaking, Vcom and Vcom-L on fresh and dry weight of shoot (A, B) and root (C, D) of <i>W</i>. <i>somnifera</i>. Whereas, size of the roots of <i>W</i>. <i>somnifera</i> grown with Vcom and Vcom+Vcom-L is shown below (E). Letters (a, b, c, d) marked statistical significance (HSD, P≤0.05) within various pre-soaking treatments; whereas letters (p, q, r, s) represented statistical significance (HSD, P≤0.05) between various concentrations (%) of Vcom performed by ANOVA test.</p

Effect of pre-soaking on <i>W</i>. <i>somnifera</i> vegetation and biomass.

<p>Effect of pre-soaking and Vcom application on root number (A), number of leaves (B) and seedling biomass (C). Letters (a, b, c, d) marked statistical significance (HSD, P≤0.05) within various pre-soaking treatments; whereas letters (p, q, r, s) represented statistical significance (HSD, P≤0.05) between various concentrations (%) of Vcom performed by ANOVA test.</p

Effect of Vcom and Vcom+Vcom-L on <i>W</i>. <i>somnifera</i> vegetative development.

<p>Effect of pre-soaking, Vcom and Vcom-L on number of leaves (A), leaf area (B) of <i>W</i>. <i>somnifera</i>. Whereas, size of the leaves of <i>W</i>. <i>somnifera</i> grown with Vcom and Vcom+Vcom-L is shown below (C). Letters (a, b, c, d) marked statistical significance (HSD, P≤0.05) within various pre-soaking treatments; whereas letters (p, q, r, s) represented statistical significance (HSD, P≤0.05) between various concentrations (%) of Vcom performed by ANOVA test.</p

Effect of pre-soaking, Vcom and Vcom-L application on the content of Withaferin A, Withanolide A and Withanone in leaves of <i>W</i>. <i>somnifera</i>.

<p>Effect of pre-soaking, Vcom and Vcom-L application on the content of Withaferin A, Withanolide A and Withanone in leaves of <i>W</i>. <i>somnifera</i>.</p

Effect of pre-soaking on <i>W</i>. <i>somnifera</i> growth.

<p>Figure showing the effect of pre-soaking and Vcom application on seed germination (A-B), shoot length (C), shoot diameter (D) and root length (E) of the seedlings of <i>W</i>. <i>somnifera</i>. DW: distilled water; KN: KNO₃, Vcom: Vermicompost; Vcom-L: Vermicompost leachate; Vcom-T: Vermicompost tea. Letters (a, b, c, d) marked statistical significance (HSD, P≤0.05) within various pre-soaking treatments (DW, KN, Vcom-L and Vcom-T); whereas letters (p, q, r, s) represented statistical significance (HSD, P≤0.05) between various concentrations of Vcom (0, 20, 40, 60, 80 and 100%) performed by ANOVA test.</p

Effect of transcatheter aortic valve implantation vs surgical aortic valve replacement on all-cause mortality in patients with aortic stenosis

Importance: Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to surgical aortic valve replacement and is the treatment of choice for patients at high operative risk. The role of TAVI in patients at lower risk is unclear. Objective: To determine whether TAVI is noninferior to surgery in patients at moderately increased operative risk. Design, Setting, and Participants: In this randomized clinical trial conducted at 34 UK centers, 913 patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk due to age or comorbidity were enrolled between April 2014 and April 2018 and followed up through April 2019. Interventions: TAVI using any valve with a CE mark (indicating conformity of the valve with all legal and safety requirements for sale throughout the European Economic Area) and any access route (n = 458) or surgical aortic valve replacement (surgery; n = 455). Main Outcomes and Measures: The primary outcome was all-cause mortality at 1 year. The primary hypothesis was that TAVI was noninferior to surgery, with a noninferiority margin of 5% for the upper limit of the 1-sided 97.5% CI for the absolute between-group difference in mortality. There were 36 secondary outcomes (30 reported herein), including duration of hospital stay, major bleeding events, vascular complications, conduction disturbance requiring pacemaker implantation, and aortic regurgitation. Results: Among 913 patients randomized (median age, 81 years [IQR, 78 to 84 years]; 424 [46%] were female; median Society of Thoracic Surgeons mortality risk score, 2.6% [IQR, 2.0% to 3.4%]), 912 (99.9%) completed follow-up and were included in the noninferiority analysis. At 1 year, there were 21 deaths (4.6%) in the TAVI group and 30 deaths (6.6%) in the surgery group, with an adjusted absolute risk difference of −2.0% (1-sided 97.5% CI, −∞ to 1.2%; P &lt; .001 for noninferiority). Of 30 prespecified secondary outcomes reported herein, 24 showed no significant difference at 1 year. TAVI was associated with significantly shorter postprocedural hospitalization (median of 3 days [IQR, 2 to 5 days] vs 8 days [IQR, 6 to 13 days] in the surgery group). At 1 year, there were significantly fewer major bleeding events after TAVI compared with surgery (7.2% vs 20.2%, respectively; adjusted hazard ratio [HR], 0.33 [95% CI, 0.24 to 0.45]) but significantly more vascular complications (10.3% vs 2.4%; adjusted HR, 4.42 [95% CI, 2.54 to 7.71]), conduction disturbances requiring pacemaker implantation (14.2% vs 7.3%; adjusted HR, 2.05 [95% CI, 1.43 to 2.94]), and mild (38.3% vs 11.7%) or moderate (2.3% vs 0.6%) aortic regurgitation (adjusted odds ratio for mild, moderate, or severe [no instance of severe reported] aortic regurgitation combined vs none, 4.89 [95% CI, 3.08 to 7.75]). Conclusions and Relevance: Among patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk, TAVI was noninferior to surgery with respect to all-cause mortality at 1 year. Trial Registration: isrctn.com Identifier: ISRCTN57819173