Effect of geography on the use of ultrafiltration during cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Ultrafiltration (UF) is a common practice during cardiopulmonary bypass (CPB) where it is used as a blood management strategy to reduce red blood cell (RBC) transfusion, minimize adverse effects of hemodilution, and reduce proinflammatory mediators. However, its clinical utilization has been shown to vary throughout the continents. PURPOSE: The purpose of this investigation was to assess the distribution of UF use across the United States. DATA COLLECTION: Data on UF use during cardiac surgery was obtained from a national (United States) perfusion database for adult cardiac procedures performed from January 2016 through December 2018. STUDY SAMPLE: Four geographical regions were established: Northeast (NE), South (SO), Midwest (MW) and West (WE). The primary endpoint was the use of UF with secondary endpoints UF volume, CPB and anesthesia asanguineous volumes, intraoperative allogeneic RBC transfusion, nadir hematocrit and urine output (UO). 92,859 adult cardiac cases from 191 hospitals were reviewed. RESULTS: The NE and the WE had similar usages of UF (59.9% and 59.7% respectively), which were higher than the MW and the SO (38.6% and 34.9%, p < .001). When UF was utilized, the median [IQR] volume removed was highest in the NE (1900 [1200-2800]mL), and similar in all other regions (WE 1500 [850-2400 mL, MW 1500 [900-2300]mL and SO 1500 [950-2200]mL, p < .001. Median total UO was lowest in the NE 400 [210,650]mL vs all other regions (p < .001), and remained so when indexed by patient weight and operative time (NE-0.8 [0.5, 1.3]mL/kg/hour, MW-1.1 [0.7, 1.8] mL/kg/hour, SO-1.3 [0.8, 2.0]mL/kg/hour, WE-1.1 [0.7, 1.3]mL/kg/hour, p < .001. Intraoperative RBC transfusion rate was highest in the SO (21.3%) and WE (20.5%), while similar rates seen in the NE (16.2%) and MW (17.6%), p < .001. CONCLUSIONS: Across the United States there is geographic variation on the use of UF. Further research is warranted to investigate why these practice variations exist and to better understand and determine their reasons for use.

Establishment of a national quality improvement process on oxygen delivery index during cardiopulmonary bypass.

Targeted oxygen delivery during cardiopulmonary bypass (CPB) has received significant attention due to its influence on patient outcomes, especially in mitigating acute kidney injury. While it has gained popularity in select institutions, there remains a gap in establishing it globally across multiple centers. The purpose of this investigation was to describe the development of a quality improvement process of targeted oxygen delivery during CPB across hospitals throughout the United States. A systematic approach to utilize oxygen delivery index (DO2i) as a key performance indicator within hospitals serviced by a national provider of perfusion services. The process included a review of the current literature on DO2i, which yielded a target nadir value (272 mL/min/m2) and an area under the curve (DO2i272AUC) cut off of 632. All data is displayed on a dashboard with results categorized across multiple levels from system-wide to individual clinician performance. From January 2020 through December 2022, DO2i data from 91 hospitals and 11,165 coronary artery bypass graft procedures were collected. During this period the monthly proportion of DO2i measurements above the target nadir DO2i272 ranged from 60.5% to 78.4% with a mean+/-SD of 70.8 +/- 4.2%. Binary logistic regression for the first 7 months following monthly DO2i performance reporting has shown a statistically significant positive linear trend in the probability of achieving the target DO2i272 (p < .001), with a crude increase of approximately 7.8% for DO2i272AUC, and a 73.8% success rate (p < .001). A survey was sent to all individuals measuring oxygen delivery during CPB to assess why a target DO2i272 could not be reached. The two most common responses were an 'inability to improve CPB flow rates' and 'restrictive allogeneic red blood cell transfusion policies'. This study demonstrates that targeting a minimum level of oxygen delivery can serve as a key performance indicator during CPB using a structured quality improvement process.

Multi-institutional Analysis of 505 Patients With Coronavirus Disease-2019 Supported With Extracorporeal Membrane Oxygenation: Predictors of Survival.

BACKGROUND: We reviewed our experience with 505 patients with confirmed coronavirus disease-2019 (COVID-19) supported with extracorporeal membrane oxygenation (ECMO) at 45 hospitals and estimated risk factors for mortality. METHODS: A multi-institutional database was created and used to assess all patients with COVID-19 who were supported with ECMO. A Bayesian mixed-effects logistic regression model was estimated to assess the effect on survival of multiple potential risk factors for mortality, including age at cannulation for ECMO as well as days between diagnosis of COVID-19 and intubation and days between intubation and cannulation for ECMO. RESULTS: Median time on ECMO was 18 days (interquartile range, 10-29 days). All 505 patients separated from ECMO: 194 patients (38.4%) survived and 311 patients (61.6%) died. Survival with venovenous ECMO was 184 of 466 patients (39.5%), and survival with venoarterial ECMO was 8 of 30 patients (26.7%). Survivors had lower median age (44 vs 51 years, P < .001) and shorter median time interval from diagnosis to intubation (7 vs 11 days, P = .001). Adjusting for several confounding factors, we estimated that an ECMO patient intubated on day 14 after the diagnosis of COVID-19 vs day 4 had a relative odds of survival of 0.65 (95% credible interval, 0.44-0.96; posterior probability of negative effect, 98.5%). Age was also negatively associated with survival: relative to a 38-year-old patient, we estimated that a 57-year-old patient had a relative odds of survival of 0.43 (95% credible interval, 0.30-0.61; posterior probability of negative effect, >99.99%). CONCLUSIONS: ECMO facilitates salvage and survival of select critically ill patients with COVID-19. Survivors tend to be younger and have shorter time from diagnosis to intubation. Survival of patients supported with only venovenous ECMO was 39.5%.

The assessment of patients undergoing cardiac surgery for Covid-19: Complications occurring during cardiopulmonary bypass.

The outbreak of the novel coronavirus pandemic (COVID-19) has resulted in dramatic changes to the conduct of surgery both from a patient management perspective and in protecting healthcare providers. The current study reports on the status of COVID-19 infections in patients presenting for cardiac surgery with cardiopulmonary bypass (CPB) on circuit complications. A tracking process for monitoring the presence of COVID-19 in adult cardiac surgery patients was integrated into a case documentation system across United States hospitals where out-sourced perfusion services were provided. Assessment included infection status, testing technique employed, surgery status and CPB complications. Records from 5612 adult patients who underwent cardiac surgery between November 1, 2020 and January 18, 2021 from 176 hospitals were reviewed. A sub-cohort of coronary artery bypass graft patients (3283) was compared using a mixed effect binary logistic regression analysis. 4297 patients had negative test results (76.6%) while 49 (0.9%) tested positive for COVID-19, and unknown or no results were reported in 693 (12.4%) and 573 (10.2%) respectively. Coagulation complications were reported at 0.2% in the negative test results group versus 4.1% in the positive test result group (p < 0.001). Oxygenator gas exchange complications were 0.2% in the negative test results group versus 2.0% in the positive test results group (p = 0.088). Coronary artery bypass graft patients with a positive test had significantly higher risk for any CPB complication (p = 0.003) [OR 10.38, CI 2.18-49.53] then negative test patients [OR 0.01, CI 0.00-0.20]. The present study has shown that patients undergoing cardiac surgery with CPB who test positive for COVID-19 have higher CPB complication rate than those who test negative.

Multi-institutional Analysis of 200 COVID-19 Patients Treated With Extracorporeal Membrane Oxygenation: Outcomes and Trends.

BACKGROUND: The role of extracorporeal membrane oxygenation (ECMO) in the management of patients with COVID-19 continues to evolve. The purpose of this analysis is to review our multi-institutional clinical experience involving 200 consecutive patients at 29 hospitals with confirmed COVID-19 supported with ECMO. METHODS: This analysis includes our first 200 COVID-19 patients with complete data who were supported with and separated from ECMO. These patients were cannulated between March 17 and December 1, 2020. Differences by mortality group were assessed using χ2 tests for categoric variables and Kruskal-Wallis rank sum tests and Welch's analysis of variance for continuous variables. RESULTS: Median ECMO time was 15 days (interquartile range, 9 to 28). All 200 patients have separated from ECMO: 90 patients (45%) survived and 110 patients (55%) died. Survival with venovenous ECMO was 87 of 188 patients (46.3%), whereas survival with venoarterial ECMO was 3 of 12 patients (25%). Of 90 survivors, 77 have been discharged from the hospital and 13 remain hospitalized at the ECMO-providing hospital. Survivors had lower median age (47 versus 56 years, P < .001) and shorter median time from diagnosis to ECMO cannulation (8 versus 12 days, P = .003). For the 90 survivors, adjunctive therapies on ECMO included intravenous steroids (64), remdesivir (49), convalescent plasma (43), anti-interleukin-6 receptor blockers (39), prostaglandin (33), and hydroxychloroquine (22). CONCLUSIONS: Extracorporeal membrane oxygenation facilitates survival of select critically ill patients with COVID-19. Survivors tend to be younger and have a shorter duration from diagnosis to cannulation. Substantial variation exists in drug treatment of COVID-19, but ECMO offers a reasonable rescue strategy.

Zero-Balance Ultrafiltration during Cardiopulmonary Bypass Is Associated with Decreased Urine Output.

Zero-balance ultrafiltration (ZBUF) during cardiopulmonary bypass (CPB) has been purported to reduce pro-inflammatory mediators during cardiac surgery. However, its clinical benefit is equivocal and its effect on renal function unknown. The purpose of this study was to examine the effect of ZBUF on urine output in adult patients undergoing CPB. Following institutional review board approval, 98,953 records from a national registry of adult patients at 215 U.S. hospitals between January 2016 and September 2019 were reviewed. Groups were stratified according to ZBUF use. Anuric patients were excluded from the study as they were patients with missing data on urine output, ultrafiltration use, or ZBUF volume. The primary endpoint was intraoperative urine output normalized to body weight and procedure duration (total operative time). Final analysis of this endpoint was carried out using a linear mixed-effects regression model adjusting for patient and procedural characteristics, as well as practice patterns associated with surgeons and perfusionists. There was a significant 16.1% reduction in median urine output for ZBUF patients (.94 [.54, 1.47] mL/kg/h) vs. the non-ZBUF group (1.12 [.70,-1.73] mL/kg/h), p < .001. After statistically adjusting for patient and procedural characteristics, each liter of ZBUF volume was associated with an estimated change in intraoperative urine output of -.03 mL/kg/h (95% CI: [-.04 to -.02], p < .001). The median ZBUF volume was 1,550 [1,000, 2,600] mL, and when ZBUF was used, conventional ultrafiltration (CUF) was more likely to be used as well (88.4% vs. 44.8%, p < .001). ZBUF patients had median asanguineous volume and crystalloid cardioplegia nearly two times more than non-ZBUF patients, and had slightly higher red blood cell transfusions (17.6% vs. 16.3%, p < .05). The application of ZBUF during CPB was associated with patients having lower urine output and significantly higher use of CUF. Further research is required to determine if these results are reproducible in prospective clinical studies.

The Effect of Antifibrinolytic Use on Intraoperative Cell Salvage: Results from a National Registry of Surgical Procedures.

Intraoperative cell salvage (ICS) is a critical component of any blood management program involving surgery with a high potential for blood loss. The introduction of antifibrinolytics (AF) may reduce blood loss. The purpose of this study was to evaluate the use of AF on ICS in non-cardiac surgical procedures. Following institutional review board approval, 69,935 consecutive case records between January 2016 and September 2019 from a national registry of adult surgical patients were reviewed. Procedure types were stratified into one of nine surgical categories: general (GN, n = 1,525), neurosurgical (NS, n = 479), obstetric (OB, n = 1,563), cervical spine (CS, n = 2,701), lumbar spine (LS, n = 38,383), hip arthroplasty (HA, n = 13,327), knee arthroplasty (KA, n = 596), vascular (VA, n = 9,845), or orthopedic other (OO, n = 1,516). The primary endpoint was the use of AF with the secondary endpoints ICS shed blood volume and volume available for return. The overall use of AF across all surgical procedures increased from 21.4% in 2016 to 25.4% in 2019. The greatest increases were seen in NS (4.4% to 16.2%), LS (13.7% to 23.1%), and HA (55.8% to 61.9%). For several procedure types, there was an initial increase then either a leveling off or a decline in AF use: OB initially increased from 6.2% to 10.8% in 2018, whereas GN (9.4% to 7.2%) and VA surgery declined slightly (9.9% to 5.7%). When comparing patients who did not receive AF with those who did, there were similar volumes of ICS available for return in all groups, except for LS, GN, and VA, where lower volumes were seen in the No-AF groups. The use of AF has increased each year over the 4-year period in most of the surgical categories, but several have declined. There may be a beneficial effect of AF with lower ICS volumes available for return in a few groups.

Strengthening antioxidant defense & cardio protection by Piper betle: An in-vitro study.

INTRODUCTION: The purpose of this research work was to evaluate Piper betle ethyl acetate extract (PBEA) for its free radical scavenging, antioxidant, anti-apoptotic activities and its role in protecting against oxidative cardiac cell injury. METHODS: The Free radical scavenging activity and antioxidant potential of PBEA were evaluated using various non-cellular methods (1,1-Diphenyl-2-picrylhydrazyl, ß-carotene bleaching, superoxide anion, hydroxyl radical, hydrogen peroxide, Reducing power, Total phenolics and Total flavonoids). PBEA was standardized with Eugenol by GC-FID analysis. Furthermore, PBEA was also assessed for its cytotoprotective effect against 100µM H2O2 in H9c2 cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Intracellular reactive oxygen species scavenging and anti-apoptoic activity of PBEA was assessed by using 2', 7'-Dichlorofluorescein diacetate and Annexin- Propidium Iodide, respectively. RESULTS: PBEA exhibited radical scavenging and antioxidant defense response at different magnitudes of potency. Eugenol, a cardiac protective bioactive molecule in PBEA was found to be 43.43 ± 1.46 mg/g of PBEA extract. Further, pre-incubation of H9c2 cells with 10 µg/ml PBEA for 24 h exhibited remarkable cytoprotective effect against H2O2 induced oxidative stress. PBEA at 10 µg/ml dose with 24 h contact with H9c2 cells significantly enhanced the activity of cellular defense system and significantly decreased intracellular ROS (P < 0.001) and apoptosis (P < 0.01) thereby protecting against the cytotoxic effects of H2O2. CONCLUSION: These outcomes indicated that PBEA could shield against oxidative and apoptotic cardiac cell injury in invitro studies. Thus, PBEA might be a desirable antioxidant of natural origin that has future clinical implications in both health care and food industry.

Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents.

The multifaceted nature of Alzheimer's disease (AD) demands treatment with multitarget-directed ligands (MTDLs) to confront the key pathological aberrations. A novel series of triazinoindole derivatives were designed and synthesized. In vitro studies revealed that all the compounds showed moderate to good anticholinesterase activity; the most active compound 23e showed an IC50 value of 0.56 ± 0.02 µM for AChE and an IC50 value of 1.17 ± 0.09 µM for BuChE. These derivatives are also endowed with potent antioxidant activity. To understand the plausible binding mode of the compound 23e, molecular docking studies and molecular dynamics simulation studies were performed, and the results indicated significant interactions of 23e within the active sites of AChE as well as BuChE. Compound 23e successfully diminished H2O2-induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2 as well as Aß-induced toxicity in SH-SY5Y cells in a concentration dependent manner. Furthermore, it did not show any significant toxicity in neuronal SH-SY5Y cells in the cytotoxicity assay. Compound 23e did not show any acute toxicity in rats at doses up to 2000 mg/kg, and it significantly reversed scopolamine-induced memory deficit in mice model. Additionally, compound 23e showed notable in silico ADMET properties. Taken collectively, these findings project compound 23e as a potential balanced MTDL in the evolution process of novel anti-AD drugs.

Hyaluronic acid tethered pH-responsive alloy-drug nanoconjugates for multimodal therapy of glioblastoma: An intranasal route approach.

In the present investigation, FePt alloy nanoparticles were synthesized with controlled size and elemental composition followed by surface modification using (3-Aminopropyl) triethoxysilane (APTES). Lenalidomide was covalently bound to FePt-NH2 by pH sensitive hydrazone bonding. Hyaluronic acid was conjugated to amino groups of APTES while lactoferrin (Lf) was directly conjugated to excess carboxylic group present on hyaluronic acid (HA) to form surface modified pH sensitive alloy-drug nanoconjugates (SPANs). The multifunctional nanoconjugates were characterized and evaluated using extensive in vitro and in vivo techniques. The nanoconjugates demonstrated excellent heating ability on exposure to alternating magnetic field and near-infrared laser irradiation. The acidic microenvironment of lysozome triggered release of LND from SPANs. Owing to leaching of Fe and Pt contents, SPANs demonstrated ability to generate reactive oxygen species (ROS) in U87MG cell line which further enhanced therapeutic effect of SPANs. Significant difference in cell viability suppression was observed in in vitro photothermal, chemo-photothermal and chemo-magnetophotothermal killing of cancer cells using SPANs in U87MG cell lines. Significant difference in heating ability and cell cytotoxicity of SPANs in comparison to alternative magnetic field and NIR irradiation was observed for DUAL-mode exposure of SPANs. The results of cellular internalization study showed efficient internalization of SPANs inside U87MG cells. The in vivo results (both qualitative and quantitative) confirmed enhanced uptake of SPANs in brain after intranasal administration with enhanced nasal and mucus penetration owing to presence of Lf. No significant interaction was observed with ECM and mucin due to presence of carboxyl group on SPANs.

Breast cancer amelioration by Butea monosperma in-vitro and in-vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Butea monosperma belonging to family Fabaceae is used in the Indian traditional medicine (Ayurveda) for various ailments including abdominal tumors and possess anti-estrogenic activity. AIM OF THE STUDY: The present study is aimed at investigating the chemo-preventive potential of Butea monosperma in breast cancer and elucidating it's mechanism of action by assessing its effect on key processes like apoptosis, angiogenesis and metastasis. METHODS: Cytotoxic potential of methanol extract of Butea monosperma flower (MEBM) was tested in MCF-7 (estrogen receptor positive), MDA-MB-231 (triple negative) and MDA-MB-453 (HER2 positive) human breast cancer cells by MTT assay. Chemo-preventive potential was evaluated in-vivo in Methylnitrosourea (MNU) induced mammary cancer in nulliparous Sprague-Dawley rats. The mechanism for anticancer potential was screened by in-vitro studies involving Annexin V- FITC assay (apoptosis), Chick Chorioallantoic Membrane assay (angiogenesis) and Migration assay (metastasis). Statistical analysis was done by one way and two way ANOVA (for Growth Rate and feed consumption efficiency) followed by post hoc Bonferroni's test with P value < 0.05. RESULTS: It is observed that the exposure of MEBM, at various concentrations and time intervals to different cell lines, resulted in decreased cell proliferation. The IC50 value of MCF-7 cells was found significantly less than that of MDA-MB-231 and MDA-MB-453 cells, which indicated that the extract of said medicinal plant were more potent inhibitors of estrogen positive breast cancer cells than other types of breast cancer cells in vitro. Corroborative evidences were acquired in MNU actuated mammary carcinogenesis where MEBM constricted tumor parameters, decreased expression of estrogen and progesterone, nucleic acid content and increased latency period. MEBM also induced apoptosis, inhibited angiogenesis and metastasis in-vitro. CONCLUSION: Selective cytotoxic activity in MCF-7 estrogen positive breast cancer cells and inhibition of growth of mammary carcinoma in-vivo by methanol extract of Butea monosperma flowers (MEBM) suggests chemo-prevention through modulation of estrogen and progesterone receptor, apoptotic, anti-angiogenesis and anti-metastatic activity.

Low-Flow Extracorporeal Carbon Dioxide Removal Using the Hemolung Respiratory Dialysis System® to Facilitate Lung-Protective Mechanical Ventilation in Acute Respiratory Distress Syndrome.

Extracorporeal carbon dioxide removal (ECCO2R) permits reductions in alveolar ventilation requirements that the lungs would otherwise have to provide. This concept was applied to a case of hypercapnia refractory to high-level invasive mechanical ventilator support. We present a case of an 18-year-old man who developed post-pneumonectomy acute respiratory distress syndrome (ARDS) after resection of a mediastinal germ cell tumor involving the left lung hilum. Hypercapnia and hypoxemia persisted despite ventilator support even at traumatic levels. ECCO2R using a miniaturized system was instituted and provided effective carbon dioxide elimination. This facilitated establishment of lung-protective ventilator settings and lung function recovery. Extracorporeal lung support increasingly is being applied to treat ARDS. However, conventional extracorporeal membrane oxygenation (ECMO) generally involves using large cannulae capable of carrying high flow rates. A subset of patients with ARDS has mixed hypercapnia and hypoxemia despite high-level ventilator support. In the absence of profound hypoxemia, ECCO2R may be used to reduce ventilator support requirements to lung-protective levels, while avoiding risks associated with conventional ECMO.

Synthesis and Biological Evaluation of Novel Multi-target-Directed Benzazepines Against Excitotoxicity.

Excitotoxicty, a key pathogenic event is characteristic of the onset and development of neurodegeneration. The glutamatergic neurotransmission mediated through different glutamate receptor subtypes plays a pivotal role in the onset of excitotoxicity. The role of NMDA receptor (NMDAR), a glutamate receptor subtype, has been well established in the excitotoxicity pathogenesis. NMDAR overactivation triggers excessive calcium influx resulting in excitotoxic neuronal cell death. In the present study, a series of benzazepine derivatives, with the core structure of 3-methyltetrahydro-3H-benzazepin-2-one, were synthesised in our laboratory and their NMDAR antagonist activity was determined against NMDA-induced excitotoxicity using SH-SY5Y cells. In order to assess the multi-target-directed potential of the synthesised compounds, Aß1-42 aggregation inhibitory activity of the most potent benzazepines was evaluated using thioflavin T (ThT) and Congo red (CR) binding assays as Aß also imparts toxicity, at least in part, through NMDAR overactivation. Furthermore, neuroprotective, free radical scavenging, anti-oxidant and anti-apoptotic activities of the two potential test compounds (7 and 14) were evaluated using primary rat hippocampal neuronal culture against Aß1-42-induced toxicity. Finally, in vivo neuroprotective potential of 7 and 14 was assessed using intracerebroventricular (ICV) rat model of Aß1-42-induced toxicity. All of the synthesised benzazepines have shown significant neuroprotection against NMDA-induced excitotoxicity. The most potent compound (14) showed relatively higher affinity for the glycine binding site as compared with the glutamate binding site of NMDAR in the molecular docking studies. 7 and 14 have been shown experimentally to abrogate Aß1-42 aggregation efficiently. Additionally, 7 and 14 showed significant neuroprotective, free radical scavenging, anti-oxidant and anti-apoptotic properties in different in vitro and in vivo experimental models. Finally, 7 and 14 attenuated Aß1-42-induced tau phosphorylation by abrogating activation of tau kinases, i.e. MAPK and GSK-3ß. Thus, the results revealed multi-target-directed potential of some of the synthesised novel benzazepines against excitotoxicity.

Evaluation of the effect of Punica granatum juice and punicalagin on NFκB modulation in inflammatory bowel disease.

Punica granatum L. (Lythraceae) inhibits cancer cell proliferation and apoptosis through the modulation of cellular transcription factors and signaling proteins. No pharmacological work is reported on the effects of P. granatum juice on the cellular signaling pathways involved in initiation and progression of inflammation. The present investigation evaluates the effect of P. granatum juice (PJ) and purified punicalagin (PW) on nuclear factor kappa B (NFκB) and the signaling pathways leading to its expression in colon inflammation. Male Sprague-Dawley rats were divided into six groups: positive and negative control, vehicle (50 % ethanol), standard (5-ASA 100 mg/kg, p.o.), PJ (400 mg/kg, p.o.), PW (4 mg/kg, p.o.). Colitis was induced with 2,4-dinitrobenzene sulfonic acid and animals were euthanized on 18th day. Colon samples collected were subjected to various histological assessment (CMDI, DAI), and biochemical parameters (MPO, MDA, SOD, NO). Gene expression study was carried out using RT-PCR for cytokines (TNF-α, IL-1ß, IL-18 and NF-κß). Pretreatment with PJ and PW significantly (p < 0.05) lowered the disease extent and severity as indicated by reduction in CMDI (2 ± 0.31) and DAI (1.83(#) ± 0.22) when compared with DNBS-treated rats (3.83* ± 0.17). Gene expression studies showed decreased mRNA levels of TNF-α, IL-18, and IL-1ß in PJ and PW-treated groups. NF-κß mRNA levels were found to be reduced 84 and 64 % by PJ and PW, respectively. These results suggest that P. granatum juice is more biologically active over punicalagin alone and can be potentially used for the treatment of inflammatory bowel disease.

Characterisation of volatile profiles in 50 native Peruvian chili pepper using solid phase microextraction-gas chromatography mass spectrometry (SPME-GCMS).

The volatiles were characterised by headspace solid phase micro extraction (HS-SPME), gas chromatography mass spectrometry (GC-FID/MS). A total of 127 compounds were identified with terpenes (including mono terpenes and sesquiterpenes - a total of 45 compounds), esters (31 compounds) and hydrocarbons (20 compounds) were the predominant volatile compounds. Principal component analysis (PCA) of the volatile compounds yielded 2 significant PC's, which together accounted for 90.3% of the total variance in the data set and the scatter plot generated between PC1 and PC2 successfully segregated the 50 chili pepper samples into 7 groups. Clusters of hydrocarbons, esters, terpenes, aldehyde and ketones formed the major determinants of the difference.

A qualitative investigation of the effects of psycho-spiritual integrative therapy on breast cancer survivors' experience of paradox.

This study is an exploratory, qualitative investigation of breast cancer survivors' experiences of paradox, following psycho-spiritual integrative therapy (PSIT). Previous studies examined the role of paradox in spiritual development among women diagnosed with cancer; this study investigated a psycho-spiritual intervention for multicultural cancer survivors. Twelve multicultural breast cancer survivors, from a sample of 30 women participants in an 8-week PSIT group intervention, were recruited from oncologists, hospitals, support groups, outpatient oncology centers, surgeons, radiation therapy centers, cancer events, and websites. We conducted semi-structured, open-ended interviews lasting 1-2 h regarding participants' experiences coping with cancer and their experience of PSIT. We transcribed interviews and conducted blind searches for both new and previously identified paradoxes and themes. Two previously identified themes emerged: (1) attempting to maintain coherence in new and old ways and (2) letting go of ultimate control in life. Additionally, three novel themes emerged: (1) interconnection between helpers and hinderers, (2) spiritual edges and tensions, and (3) new paths to empowerment. Results of this qualitative analysis indicate participants experienced previously identified themes and experienced an expanded range of paradoxes. After learning compassionate acceptance through PSIT, breast cancer survivors develop greater access to the multidimensionality of paradoxes, which can go beyond a binary (either/or) construction to a more interdependent (both/and) relationship. Devoting greater attention to investigating and understanding how diverse participants engage with and move through paradoxical change processes could enhance the effectiveness of existential and spiritual interventions.

Combination of omeprazole with GLP-1 agonist therapy improves insulin sensitivity and antioxidant activity in liver in type 1 diabetic mice.

BACKGROUND: Combination with suitable pharmacological agents can improve the antiobesity and antidiabetic actions of glucagon like peptide-1 (GLP-1) based therapies. GLP-1 agonist exendin-4 may have insulin-independent effects on amelioration of insulin resistance and hepatic steatosis by virtue of its action on hepatic GLP-1 receptors, and these effects can be improved by combination with proton pump inhibitors. However, it was not assessed whether omeprazole can improve the peripheral actions of exendin-4 in the state of insulin deficiency. METHODS: We investigated the effects of combination of omeprazole with GLP-1 agonist exendin-4 in multiple low-dose streptozotocin (STZ)-induced diabetes in C57BL/KsJ mice, a model of type 1 diabetes. Male diabetic mice were treated with exendin-4 and/or omeprazole for a period of 4 weeks. RESULTS: Omeprazole treatment had no significant effect on lowering the blood glucose levels of diabetic mice, when compared to control, although it improved the antihyperglycemic actions of exendin-4. Similarly, serum triglycerides and total cholesterols levels were significantly lower in the combination treated mice compared to either exendin-4 and omeprazole alone. In addition, the combination treatment significantly ameliorated lipid peroxidation and hepatic triglycerides in diabetic mice compared to either exendin-4 and omeprazole alone. The improvement in hepatic insulin sensitivity, as indicated by insulin tolerance test (ITT) and pyruvate tolerance test (IPPTT), was correlated with the expression of nuclear factor erythroid-related factor 2 (Nrf2) and insulin receptor substrate-1 (IRS-1) and the combination treatment significantly improved the insulin sensitivity in comparison to vehicle control. CONCLUSION: We conclude that combination with omeprazole improves the insulin sensitizing actions of GLP-1 therapy and these effects are partially mediated through the decrease in hepatic steatosis and improvement in antioxidant status in the liver.

Omeprazole improves the anti-obesity and antidiabetic effects of exendin-4 in db/db mice (-4 db/db)*.

BACKGROUND: In addition to its glucoregulatory actions, exendin-4, a stable glucagon-like peptide-1 receptor agonist, exhibits protective effects in the pancreas and anti-obesity effects. Suitable combination treatment with other anti-obesity or pancreas protective agents would be an effective approach to optimize these additional effects. In the present study, we investigated the effects of the addition of omeprazole, a proton pump inhibitor, to exendin-4 in db/db mice, an experimental model of obesity and type 2 diabetes. METHODS: The effects repeated dose treatment for 14 days with exendin-4 (8 µg/kg, s.c.) and omeprazole (30 mg/kg, s.c.) on glycemic control, food intake, and body weight were determined in obese and hyperglycemic db/db mice. The effects of these treatments on plasma gastrin, ghrelin, and leptin levels were determined, along with effects on nausea-like symptoms. The pancreatic effects of the repeated dose treatment were assessed by measuring %HbA1c in the circulation as well as pancreatic insulin and glucagon content and glucokinase activity. RESULTS: Combination treatment resulted in significant decreases in plasma leptin and ghrelin levels after repeated dosing. Omeprazole improved the anorectic and body weight-lowering effects and reversed the inhibitory effect of exendin-4 on gastrin levels after repeated dose treatment. The 14-day combination treatment significantly reduced glucose excursion and improved insulin levels, with a concomitant decrease in %HbA1c levels. It also improved glucokinase activity and pancreatic insulin content, with a significant decrease in glucagon content. CONCLUSIONS: Combined treatment with omeprazole with exendin-4 reduces food intake and body weight gain, most likely through changes in plasma ghrelin and leptin levels, and improves pancreatic insulin and glucagon content by improving glucokinase activity.

Clinical utility of serum interleukin-8 and interferon-alpha in thyroid diseases.

Serum interleukin-8 (IL-8) and interferon-alpha (IFN-α) levels have been estimated from a total of 88 individuals of which 19 were disease-free healthy individuals, and 69 were patients with thyroid diseases: goitre (N = 21), autoimmune diseases (N = 16), and carcinomas (N = 32). Both IL-8 and IFN-α were significantly higher in all the patients as compared to healthy individuals. Serum IL-8 levels showed significant positive correlation with disease stage in thyroid cancer patients. Higher serum IL-8 levels were associated with advanced disease stage while no significant correlation was observed between serum IFN-α levels and any of the clinicopathological parameters. IL-8 and IFN-α significantly correlated with each other in anaplastic carcinoma patients. Finally concluding, monitoring the serum IL-8 and IFN-α levels can help differentiate patients with thyroid diseases from healthy individuals, and IL-8 seems to have a role in the pathogenesis of thyroid diseases and may represent a target for innovative diagnostic and therapeutic strategies.

Cured of "stickiness", poly-L ß-hairpin is promoted with LL-to-DD mutation as a protein and a hydrolase mimic.

The planar ribbon of the poly-L ß-hairpin is modified to a local ~90° bend by mutating a cross-strand pair of residues from LL to DD structure. The bend is furnished aromatic side chains in proximity of acid-base-nucleophile side chains, toward the possibility of catalyzed hydrolysis of an active-site-anchored substrate. Six sequences permuted in putative catalytic side chains are evaluated for activity and variability as hydrolase enzymes. Studies using CD, NMR, spectorofluorometry, ITC, and molecular dynamics establish that the sequences over the bent ß-hairpin are by and large aggregation-free folds soluble to at least millimolar concentration, and thus remarkably contrasted with "stickiness" of the canonical poly-L ß-hairpin. The heterochiral fold displays cooperative ordering and affinity for acetylcholine, p-nitrophenylacetate, and p-nitrophenylphosphate, presumably as the ligands in its aromatic pocket as a bent hairpin. The fold displays hydrolytic activity against p-nitrophenylacetate and manifests saturation kinetics with respect to substrate concentration. However, the catalysis power is feeble, which remains unaffected by repositioning acid-base-nucleophile side chains. Stereochemistry is proven to be critical in the balance between mutually competitive forces of polypeptide structure involved in guidance of folding or aggregation of the structure. Residue stereochemistry is confirmed in its value as the alphabet for design of protein folds to desired molecular shapes.