Overexpression of Human Soluble Epoxide Hydrolase Exacerbates Coronary Reactive Hyperemia Reduction in Angiotensin-II-Treated Mouse Hearts.

ABSTRACT: Coronary reactive hyperemia (CRH) is impaired in cardiovascular diseases, and angiotensin-II (Ang-II) exacerbates it. However, it is unknown how Ang-II affects CRH in Tie2-sEH Tr (human-sEH-overexpressed) versus wild-type (WT) mice. sEH-overexpression resulted in CRH reduction in Tie2-sEH Tr versus WT. We hypothesized that Ang-II exacerbates CRH reduction in Tie2-sEH Tr versus WT. The Langendorff system measured coronary flow in Tie2-sEH Tr and WT. The hearts were exposed to 15-second ischemia, and CRH was assessed in 10 mice each. Repayment volume was reduced by 40.50% in WT treated with Ang-II versus WT (7.42 ± 0.8 to 4.49 ± 0.8 mL/g) and 48% in Tie2-sEH Tr treated with Ang-II versus Tie2-sEH Tr (5.18 ± 0.4 to 2.68 ± 0.3 mL/g). Ang-II decreased repayment duration by 50% in WT-treated with Ang-II versus WT (2.46 ± 0.5 to 1.24 ± 0.4 minutes) and 54% in Tie2-sEH Tr treated with Ang-II versus Tie2-sEH Tr (1.66 ± 0.4 to 0.76 ± 0.2 minutes). Peak repayment flow was reduced by 11.2% in WT treated with Ang-II versus WT (35.98 ± 0.7 to 32.11 ± 1.4 mL/g) and 4% in Tie2-sEH Tr treated with Ang-II versus Tie2-sEH Tr (32.18 ± 0.6 to 30.89 ± 1.5 mL/g). Furthermore, coronary flow was reduced by 43% in WT treated with Ang-II versus WT (14.2 ± 0.5 to 8.15 ± 0.8 mL/min/g) and 32% in Tie2-sEH Tr treated with Ang-II versus Tie2-sEH Tr (12.1 ± 0.8 to 8.3 ± 1.2 mL/min/g). Moreover, the Ang-II-AT 1 -receptor and CYP4A were increased in Tie2-sEHTr. Our results demonstrate that Ang-II exacerbates CRH reduction in Tie2-sEH Tr mice.

Using the social cognitive theory to examine spontaneous attempts to quit illicit substance use.

Rural areas in the US exhibit high rates of illicit substance use. This study aimed to investigate the Social Cognitive Theory factors associated with spontaneous attempts to quit illicit substance use in a sample of users. A cross-sectional survey was administered through face-to-face interviews. Data was collected from adult (≥ 18 years of age) current illicit substance users who were not receiving professional addiction treatment. Binary logistic regression analyses were utilized to answer the research question. Data from 230 illicit substance users met the eligibility criteria. The mean age was 38 years, whereas the average history of illicit substance use was 14 years. Users with a higher perceived value of quitting illicit substance use were significantly more likely to attempt to quit use spontaneously. Health behavior interventions that incorporate the perceived value of quitting illicit substance use can be effective in encouraging spontaneous attempts to quit illicit substance use.

Comparison of anal dilatation versus no dilatation with a standardized dilator in reducing pain after hemorrhoidectomy: a randomized control trial.

BACKGROUND: Post-operative pain is the main problem of hemorrhoidectomy. An adequate pain management can promote early mobilization, fast recovery, and reduce hospitalization costs. This study aimed to investigate the role of preoperative anal dilatation using a standardized anal dilator in reducing post-operative pain. METHOD: This study was conducted using randomized prospective trial with a total of 40 subjects, who were divided into 2 groups. The first group received preoperative anal dilatation using a 33 mm anal dilator for 20 min, while the second group did not. The post-operative anal pain, edema, bleeding, and incontinence were observed in the first, second, and seventh day. RESULT: The post-operative pain was significantly lower in the preoperative anal dilatation group for all days of observation (p < 0.05). The difference of post-operative bleeding and edema between groups were not significant. Fecal incontinence was initially significantly higher in the preoperative anal dilatation group, but the difference was insignificant at the seventh day (p = 0.500). CONCLUSION: Preoperative anal dilatation significantly reduced post-operative pain. The side effect of fecal incontinence was only temporary until the seventh day after surgery. Trial Registration This trial was registered on Thai Clinical Trials Registry (TCTR) with TCTR identification number TCTR20220314002, on 14/03/2022 (retrospectively registered).

Effectiveness and predictors of conversion in mini-laparotomy cholecystectomy in developing country: a cohort retrospective study.

BACKGROUND: Mini laparotomy cholecystectomy (MLC) is an alternative surgical procedure in conditions where laparoscopic cholecystectomy (LC) is not feasible. MLC is a simpler and easier technique compared to LC. MLC involves smaller skin incision, low morbidity rate, and early return to oral diet. MLC has the potential to be the preferred surgical technique in developing countries due to its low cost and availability. METHOD: A cohort retrospective study was performed on 44 patients who underwent mini laparotomy cholecystectomy due to ineligibility for LC. Patients were documented for successful mini laparotomy or conversion to laparotomy cholecystectomy. There are pre-operative aspects recorded and analyzed to formulate predictor factors for conversion surgery, as well as intra-operative and post-operative aspects. Patients also filled evaluation questionnaire based on Likert Scale about their satisfaction towards result of MLC. RESULT: MLC is performed in 31 (70.5%) patients while 13 (29.5%) patients underwent conversion to open cholecystectomy. There were no complications nor mortalities observed during and after the surgery. Greater BMI, higher leucocyte count, higher bilirubin level, increasing severity of adhesion, and chronic cholecystitis were found to be statistically significant (p < 0.05) in the conversion surgery group. MLC also resulted in shorter post-operative hospitalization compared to conversion surgery. Patients showed great satisfaction towards the cosmetic aspect and recovery period after MLC procedure. CONCLUSION: MLC is an effective surgery procedure for cholelithiasis and can be safely performed in patients with complication such as cholecystitis and gallbladder adhesion although these conditions increase the risk of conversion surgery.

Adenosine A2A receptor and vascular response: role of soluble epoxide hydrolase, adenosine A1 receptor and angiotensin-II.

Previously, we have reported that the coronary reactive hyperemic response was reduced in adenosine A2A receptor-null (A2AAR-/-) mice, and it was reversed by the soluble epoxide hydrolase (sEH) inhibitor. However, it is unknown in aortic vascular response, therefore, we hypothesized that A2AAR-gene deletion in mice (A2AAR-/-) affects adenosine-induced vascular response by increase in sEH and adenosine A1 receptor (A1AR) activities. A2AAR-/- mice showed an increase in sEH, AI AR and CYP450-4A protein expression but decrease in CYP450-2C compared to C57Bl/6 mice. NECA (adenosine-analog) and CCPA (adenosine A1 receptor-agonist)-induced dose-dependent vascular response was tested with t-AUCB (sEH-inhibitor) and angiotensin-II (Ang-II) in A2AAR-/- vs. C57Bl/6 mice. In A2AAR-/-, NECA and CCPA-induced increase in dose-dependent vasoconstriction compared to C57Bl/6 mice. However, NECA and CCPA-induced dose-dependent vascular contraction in A2AAR-/- was reduced by t-AUCB with NECA. Similarly, dose-dependent vascular contraction in A2AAR-/- was reduced by t-AUCB with CCPA. In addition, Ang-II enhanced NECA and CCPA-induced dose-dependent vascular contraction in A2AAR-/- with NECA. Similarly, the dose-dependent vascular contraction in A2AAR-/- was also enhanced by Ang-II with CCPA. Further, t-AUCB reduced Ang-II-enhanced NECA and CCPA-induced dose-dependent vascular contraction in A2AAR-/- mice. Our data suggest that the dose-dependent vascular contraction in A2AAR-/- mice depends on increase in sEH, A1AR and CYP4A protein expression.

Thrombotic complications and anticoagulation in COVID-19 pneumonia: a New York City hospital experience.

Infection with SARS-CoV-2 (COVID-19) can cause prothrombotic complications. We aim to study the frequency of thrombotic complications and impact of anticoagulation on outcomes in hospitalized patients. We conducted a retrospective chart review of 921 consecutive patients admitted to our hospital with COVID-19. Patients were divided into four groups depending on whether they were on anticoagulation prior to admission, started anticoagulation during the admission, received prophylactic anticoagulation, or did not receive any anticoagulation. At the time of analysis, 325 patients (35.3%) had died, while 544 patients (59%) had been discharged resulting in inpatient mortality of 37.3%. Male sex, age > 65 years, and high D-dimer at admission were associated with higher mortality. Sixteen patients (1.7%) had venous thromboembolism confirmed with imaging, 11 patients had a stroke, and 2 patients developed limb ischemia. Treatment with therapeutic anticoagulation was associated with improved inpatient mortality compared with prophylactic anticoagulation alone (63% vs 86.2%, p < 0.0001) in patients requiring mechanical ventilation. Other outcomes such as rates of liberation from mechanical ventilation and duration of mechanical ventilation were not significantly impacted by the type of anticoagulation.

Ephx2-gene deletion affects acetylcholine-induced relaxation in angiotensin-II infused mice: role of nitric oxide and CYP-epoxygenases.

Previously, we showed that adenosine A2A receptor induces relaxation independent of NO in soluble epoxide hydrolase-null mice (Nayeem et al. in Am J Physiol Regul Integr Comp Physiol 304:R23-R32, 2013). Currently, we hypothesize that Ephx2-gene deletion affects acetylcholine (Ach)-induced relaxation which is independent of A2AAR but dependent on NO and CYP-epoxygenases. Ephx2-/- aortas showed a lack of sEH (97.1%, P < 0.05) but an increase in microsomal epoxide hydrolase (mEH, 37%, P < 0.05) proteins compared to C57Bl/6 mice, and no change in CYP2C29 and CYP2J protein (P > 0.05). Ach-induced response was tested with nitro-L-arginine methyl ester (L-NAME) NO-inhibitor; 10-4 M), N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH) (CYP-epoxygenase inhibitor; 10-5 M), 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, an epoxyeicosatrienoic acid-antagonist; 10-5 M), SCH-58261 (A2AAR-antagonist; 10-6 M), and angiotensin-II (Ang-II, 10-6 M). In Ephx2-/- mice, Ach-induced relaxation was not different from C57Bl/6 mice except at 10-5 M (92.75 ± 2.41 vs. 76.12 ± 3.34, P < 0.05). However, Ach-induced relaxation was inhibited with L-NAME (Ephx2-/-: 23.74 ± 3.76% and C57Bl/6: 11.61 ± 2.82%), MS-PPOH (Ephx2-/-: 48.16 ± 6.53% and C57Bl/6: 52.27 ± 7.47%), and 14,15-EEZE (Ephx2-/-: 44.29 ± 8.33% and C57Bl/6: 39.27 ± 7.47%) vs. non-treated (P < 0.05). But, it did not block with SCH-58261 (Ephx2-/-: 68.75 ± 11.41% and C57Bl/6: 66.26 ± 9.43%, P > 0.05) vs. non-treated (P > 0.05). Interestingly, Ang-II attenuates less relaxation in Ehx2-/- vs. C57Bl/6 mice (58.80 ± 7.81% vs. 45.92 ± 7.76, P < 0.05). Our data suggest that Ach-induced relaxation in Ephx2-/- mice depends on NO and CYP-epoxygenases but not on A2A AR, and Ephx2-gene deletion attenuates less Ach-induced relaxation in Ang-II-infused mice.

Determination of optimum harvest maturity and non-destructive evaluation of pod development and maturity in cacao (Theobroma cacao L.) using a multiparametric fluorescence sensor.

BACKGROUND: A series of fluorescence indices (anthocyanin, flavonol, chlorophyll and nitrogen balance) were deployed to detect the pigments and colourless flavonoids in cacao pods of three commercial cacao (Theobroma cacao L.) genotypes (QH1003, KKM22 and MCBC1) using a fast and non-destructive multiparametric fluorescence sensor. The aim was to determine optimum harvest periods (either 4 or 5 months after pod emergence) of commercial cacao based on fluorescence indices of cacao development and bean quality. RESULTS: As pod developed, cacao exhibited a rise with the peak of flavonol occurring at months 4 and 5 after pod maturity was initiated while nitrogen balance showed a decreasing trend during maturity. Cacao pods contained high chlorophyll as they developed but chlorophyll content declined significantly on pods that ripened at month 5. CONCLUSION: Cacao pods harvested at months 4 and 5 can be considered as commercially-ready as the beans have developed good quality and comply with the Malaysian standard on cacao bean specification. Thus, cacao pods can be harvested earlier when they reach maturity at month 4 after pod emergence to avoid germinated beans and over fermentation in ripe pods harvested at month 5. © 2018 Society of Chemical Industry.

Does Progesterone Receptor Matter in the Risk of Recurrence for Patients With Ductal Carcinoma in Situ?

BACKGROUND: Local recurrence is a major concern in patients diagnosed with ductal carcinoma in situ (DCIS). In invasive breast cancers, estrogen receptor (ER) (+)/progesterone receptor (PR) (-) subtype is considered more aggressive with poorer prognosis as compared to ER+/PR+ tumors. It is unclear whether this holds true in DCIS. METHODS: Six hundred ninety-three patients diagnosed and treated for DCIS at Froedtert and Medical College of Wisconsin Cancer Center (February 2002 to March 2015) were studied to determine if the recurrence rates were significantly different between ER+/PR- and ER+/PR+ tumors. Recurrence was defined as either noninvasive or invasive ipsilateral, contralateral, or distant disease. Probabilities of recurrences were calculated using Kaplan-Meier estimator. Cox proportional hazards model was used to evaluate the effect of prognostic factors on DCIS recurrence. RESULTS: Median follow-up was 5.2 years. The 5-year recurrence-free survival (RFS) was 91% (95% CI, 88.2-93.3) while estimated 7-year RFS was 86% (95% CI, 81.9-89.2). Seventy-five patients had a recurrence during their follow-up. Patients with ER-/PR- tumors (n = 118) had a significantly higher risk of recurrence (Hazard Ratio 3.7, 95% CI, 1.9-7.2, P = 0.0001) whereas those with ER+/PR- subtype (n = 77) did not have a significant difference in recurrence risk (HR 1.75, 95% CI, 0.92-3.32, P = 0.085) when compared to ER+/PR+ tumors (n = 482). No endocrine therapy for ER+ DCIS and lumpectomy alone were also significant predictors of recurrence (P = 0.0073 and P = 0.005, respectively). CONCLUSIONS: ER+/PR- subtype was not a significant predictor of recurrence in DCIS patients. This finding is in contrast to the recurrence risk seen in invasive breast cancers. Mastectomy and postlumpectomy radiation were associated with improved outcomes as was adjuvant endocrine therapy.

Reduced coronary reactive hyperemia in mice was reversed by the soluble epoxide hydrolase inhibitor (t-AUCB): Role of adenosine A2A receptor and plasma oxylipins.

Coronary reactive hyperemia (CRH) protects the heart against ischemia. Adenosine A2AAR-deficient (A2AAR-/-) mice have increased expression of soluble epoxide hydrolase (sEH); the enzyme responsible for breaking down the cardioprotective epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs). sEH-inhibition enhances CRH, increases EETs, and modulates oxylipin profiles. We investigated the changes of oxylipins and their impact on CRH in A2AAR-/- and wild type (WT) mice. We hypothesized that the attenuated CRH in A2AAR-/- mice is mediated by changes in oxylipin profiles, and that it can be reversed by either sEH- or ω-hydroxylases-inhibition. Compared to WT mice, A2AAR-/- mice had attenuated CRH and changed oxylipin profiles, which were consistent between plasma and heart perfusate samples, including decreased EET/DHET ratios, and increased hydroxyeicosatetraenoic acids (HETEs). Plasma oxylipns in A2AAR-/- mice indicated an increased proinflammatory state including increased ω-terminal HETEs, decreased epoxyoctadecaenoic/dihydroxyoctadecaenoic acids (EpOMEs/DiHOMEs) ratios, increased 9-hydroxyoctadecadienoic acid, and increased prostanoids. Inhibition of either sEH or ω-hydroxylases reversed the reduced CRH in A2AAR-/- mice. In WT and sEH-/- mice, blocking A2AAR decreased CRH. These data demonstrate that A2AAR-deletion was associated with changes in oxylipin profiles, which may contribute to the attenuated CRH. Also, inhibition of sEH and ω-hydroxylases reversed the reduction in CRH.

Exploring Adenosine Receptor Ligands: Potential Role in the Treatment of Cardiovascular Diseases.

Cardiovascular diseases remain the number one diseases affecting patients' morbidity and mortality. The adenosine receptors are G-protein coupled receptors which have been of interest for drugs target for the treatment of multiple diseases ranging from cardiovascular to neurological. Adenosine receptors have been connected to several biological pathways affecting the physiology and pathology of the cardiovascular system. In this review, we will cover the different adenosine receptor ligands that have been identified to interact with adenosine receptors and affect the vascular system. These ligands will be evaluated from clinical as well as medicinal chemistry perspectives with more emphasis on how structural changes in structure translate into ligand potency and efficacy. Adenosine receptors represent a novel therapeutic target for development of treatment options treating a wide variety of diseases, including vascular disease and obesity.

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors.

The impact of Janus kinase (JAK) 1/2 inhibitor therapy before allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into 5 groups: (1) clinical improvement (n = 23), (2) stable disease (n = 31), (3) new cytopenia/increasing blasts/intolerance (n = 15), (4) progressive disease: splenomegaly (n = 18), and (5) progressive disease: leukemic transformation (LT) (n = 13). Overall survival (OS) at 2 years was 61% (95% confidence interval [CI], 49% to 71%). OS was 91% (95% CI, 69% to 98%) for those who experienced clinical improvement and 32% (95% CI, 8% to 59%) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (P = .03), dynamic international prognostic scoring system score (P = .003), and donor type (P = .006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, 2 patients developed serious adverse events necessitating delay of HCT and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days before conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplantation outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy before HCT were particularly encouraging, and need further prospective validation.

Deletion of soluble epoxide hydrolase enhances coronary reactive hyperemia in isolated mouse heart: role of oxylipins and PPARγ.

The relationship between soluble epoxide hydrolase (sEH) and coronary reactive hyperemia (CRH) response to a brief ischemic insult is not known. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia/reperfusion injury. sEH converts EETs into dihydroxyeicosatrienoic-acids (DHETs). Therefore, we hypothesized that knocking out sEH enhances CRH through modulation of oxylipin profiles, including an increase in EET/DHET ratio. Compared with sEH+/+, sEH-/- mice showed enhanced CRH, including greater repayment volume (RV; 28% higher, P < 0.001) and repayment/debt ratio (32% higher, P < 0.001). Oxylipins from the heart perfusates were analyzed by LC-MS/MS. The 14,15-EET/14,15-DHET ratio was 3.7-fold higher at baseline (P < 0.001) and 5.6-fold higher post-ischemia (P < 0.001) in sEH-/- compared with sEH+/+ mice. Likewise, the baseline 9,10- and 12,13-EpOME/DiHOME ratios were 3.2-fold (P < 0.01) and 3.7-fold (P < 0.001) higher, respectively in sEH-/- compared with sEH+/+ mice. 13-HODE was also significantly increased at baseline by 71% (P < 0.01) in sEH-/- vs. sEH+/+ mice. Levels of 5-, 11-, 12-, and 15-hydroxyeicosatetraenoic acids were not significantly different between the two strains (P > 0.05), but were decreased postischemia in both groups (P = 0.02, P = 0.04, P = 0.05, P = 0.03, respectively). Modulation of CRH by peroxisome proliferator-activated receptor gamma (PPARγ) was demonstrated using a PPARγ-antagonist (T0070907), which reduced repayment volume by 25% in sEH+/+ (P < 0.001) and 33% in sEH-/- mice (P < 0.01), and a PPARγ-agonist (rosiglitazone), which increased repayment volume by 37% in both sEH+/+ (P = 0.04) and sEH-/- mice (P = 0.04). l-NAME attenuated CRH in both sEH-/- and sEH+/+ These data demonstrate that genetic deletion of sEH resulted in an altered oxylipin profile, which may have led to an enhanced CRH response.

Multivariate statistical techniques for the assessment of seasonal variations in surface water quality of pasture ecosystems.

This study investigates the applicability of multivariate statistical techniques including cluster analysis (CA), discriminant analysis (DA), and factor analysis (FA) for the assessment of seasonal variations in the surface water quality of tropical pastures. The study was carried out in the TPU catchment, Kuala Lumpur, Malaysia. The dataset consisted of 1-year monitoring of 14 parameters at six sampling sites. The CA yielded two groups of similarity between the sampling sites, i.e., less polluted (LP) and moderately polluted (MP) at temporal scale. Fecal coliform (FC), NO3, DO, and pH were significantly related to the stream grouping in the dry season, whereas NH3, BOD, Escherichia coli, and FC were significantly related to the stream grouping in the rainy season. The best predictors for distinguishing clusters in temporal scale were FC, NH3, and E. coli, respectively. FC, E. coli, and BOD with strong positive loadings were introduced as the first varifactors in the dry season which indicates the biological source of variability. EC with a strong positive loading and DO with a strong negative loading were introduced as the first varifactors in the rainy season, which represents the physiochemical source of variability. Multivariate statistical techniques were effective analytical techniques for classification and processing of large datasets of water quality and the identification of major sources of water pollution in tropical pastures.

Role of cytochrome P450-epoxygenase and soluble epoxide hydrolase in the regulation of vascular response.

The role of cytochrome P450-epoxygenase has been seen in cardiovascular physiology and pathophysiology. The aberration in CYP450-epoxygenase genes occur due to genetic polymorphisms, aging, or environmental factors, that increase susceptibility to cardiovascular diseases (CVDs). The actual role played by the CYP450-epoxygenases is the metabolism of arachidonic acid (AA) and linoleic acid (LA) into epoxyeicosatrienoic acids (EETs) and epoxyoctadecaenoic acid (EpOMEs) metabolites (oxylipins) and others, which is involved in vasodilation and myocardial-protection. But the genetic polymorphisms in CYP450-epoxygenases lose their beneficial cardiovascular effects of oxylipins, and the soluble epoxide hydrolase (sEH) antagonizes beneficial oxylipins into diols. Like sEH converts EETs into dihydroxyeicosatrienoic acid (DHETs), EpOMEs into dihydroxyoctadecaenoic acid (DiHOMEs), and reverses its beneficial effects, and the sEH gene (Ephx2) polymorphisms cause the enzyme to become overactive and convert epoxy-fatty acids into diols, making them vulnerable to CVDs, including hypertension. Other, enzymes like ω-hydroxylases (CYP450-4A11 & CYP450-4F2)-derived oxylipins from AA, ω-terminal-hydroxyeicosatetraenoic acids (19-, 20-HETE), lipoxygenase-derived oxylipins, mid-chain hydroxyeicosatetraenoic acids (5-, 11-, 12-, 15-HETEs), and the cyclooxygenase-derived prostanoids (prostaglandins: PGD2, PGF2α; thromboxane: Txs, oxylipins) are involved in vasoconstriction, hypertension, inflammation, and cardiac toxicity. Also, there are significant interactions were seen between adenosine receptors [adenosine A2A receptor (A2AAR) and adenosine A1 receptor (A1AR)] with CYP450-epoxygenases, ω-hydroxylases, sEH, and their derived oxylipins in the regulation of the cardiovascular response. Moreover, polymorphisms exist in CYP450-epoxygenases, ω-hydroxylases, sEH, and the adenosine receptor genes in populations associated with CVDs. This chapter will discuss the role of oxylipins' interactions with adenosine receptors in cardiovascular function/dysfunction in mice and humans.

Rectovaginal fistula surgery with horizontal mattress and running suture after unsuccessful first repair: a report of two cases.

Rectovaginal fistula (RVF) repair after failed primary repair is uncommon. Patients with RVF experience physiological and sexual dysfunction with a significantly high risk of intravaginal infection and sepsis. There are many surgical procedures available for RVF repair. We performed an improvised transvaginal repair technique. Methods: We report two cases of recurring RVF after failed primary repair. Patient 1 developed RVF because of a failed vaginoplasty due to cosmetic reasons, while patient 2 developed RVF because of a fourth-degree perineal rupture repair post-delivery. We used a combination of horizontal mattress and running suture with the addition of diverting colostomy. Both surgeries went successfully and there were no complications. Outcomes: RVF repair using a combination of horizontal mattress and running suture went successfully and there were no complications. Both patients were able to be discharged after a short stay. Long-term evaluation was done by physical and supporting examinations for 2-3 months. Both patients showed excellent wound healing and physiological function. Conclusions: The combination of a transvaginal horizontal mattress and running suture in the posterior to anterior fashion with diverting colostomy is a safe and effective procedure for recurring RVF repair.

Combination of Cattell-Braasch and Kocher maneuver in laparotomy for diverticular resection in the third part of the duodenum: a case report.

A duodenal diverticulum is an outpouching of all or partial layers of the duodenal wall. Duodenal diverticulum complications such as bleeding, diverticulitis, pancreatitis, choledochal occlusion, and perforation can develop. Localization of the diverticulum in the third part of the duodenum is rare. Surgical intervention with a combination of Cattell-Braasch and Kocher maneuvers in laparotomy is currently emerging as a viable option. Case presentation: The authors report a case of a 68-year-old male with chief complaints of black stool and recurring epigastric pain. Barium follow-through showed diverticulum at the third part of the duodenum. Surgery with a combination of Cattell-Braasch and Kocher's maneuvers using a linear stapler was successful, and there were no intraoperative or postoperative complications. Postoperative barium follow-through showed no diverticulum residue. The patient had no more complaints of black stools nor epigastric pain. Clinical discussion: Symptomatic duodenal diverticulum is a rare case with a very small chance of complications. Due to its lack of specific symptoms, imaging examinations play a better role in diagnosis. Surgical intervention is also rarely performed due to the small chance of complications. Diverticulectomy with the use of Cattell-Braasch and the extended Kocher maneuver results in better duodenum exposure, and the usage of a linear stapler also made the surgery safer and quicker to perform. Conclusion: The authors propose that a diverticulectomy of the third part of the duodenum performed with a combination of the Cattell-Braasch and Kocher maneuvers with the use of a linear stapler as a safe procedure.

Crosstalk between adenosine receptors and CYP450-derived oxylipins in the modulation of cardiovascular, including coronary reactive hyperemic response.

Adenosine is a ubiquitous endogenous nucleoside or autacoid that affects the cardiovascular system through the activation of four G-protein coupled receptors: adenosine A1 receptor (A1AR), adenosine A2A receptor (A2AAR), adenosine A2B receptor (A2BAR), and adenosine A3 receptor (A3AR). With the rapid generation of this nucleoside from cellular metabolism and the widespread distribution of its four G-protein coupled receptors in almost all organs and tissues of the body, this autacoid induces multiple physiological as well as pathological effects, not only regulating the cardiovascular system but also the central nervous system, peripheral vascular system, and immune system. Mounting evidence shows the role of CYP450-enzymes in cardiovascular physiology and pathology, and the genetic polymorphisms in CYP450s can increase susceptibility to cardiovascular diseases (CVDs). One of the most important physiological roles of CYP450-epoxygenases (CYP450-2C & CYP2J2) is the metabolism of arachidonic acid (AA) and linoleic acid (LA) into epoxyeicosatrienoic acids (EETs) and epoxyoctadecaenoic acid (EpOMEs) which generally involve in vasodilation. Like an increase in coronary reactive hyperemia (CRH), an increase in anti-inflammation, and cardioprotective effects. Moreover, the genetic polymorphisms in CYP450-epoxygenases will change the beneficial cardiovascular effects of metabolites or oxylipins into detrimental effects. The soluble epoxide hydrolase (sEH) is another crucial enzyme ubiquitously expressed in all living organisms and almost all organs and tissues. However, in contrast to CYP450-epoxygenases, sEH converts EETs into dihydroxyeicosatrienoic acid (DHETs), EpOMEs into dihydroxyoctadecaenoic acid (DiHOMEs), and others and reverses the beneficial effects of epoxy-fatty acids leading to vasoconstriction, reducing CRH, increase in pro-inflammation, increase in pro-thrombotic and become less cardioprotective. Therefore, polymorphisms in the sEH gene (Ephx2) cause the enzyme to become overactive, making it more vulnerable to CVDs, including hypertension. Besides the sEH, ω-hydroxylases (CYP450-4A11 & CYP450-4F2) derived metabolites from AA, ω terminal-hydroxyeicosatetraenoic acids (19-, 20-HETE), lipoxygenase-derived mid-chain hydroxyeicosatetraenoic acids (5-, 11-, 12-, 15-HETEs), and the cyclooxygenase-derived prostanoids (prostaglandins: PGD2, PGF2α; thromboxane: Txs, oxylipins) are involved in vasoconstriction, hypertension, reduction in CRH, pro-inflammation and cardiac toxicity. Interestingly, the interactions of adenosine receptors (A2AAR, A1AR) with CYP450-epoxygenases, ω-hydroxylases, sEH, and their derived metabolites or oxygenated polyunsaturated fatty acids (PUFAs or oxylipins) is shown in the regulation of the cardiovascular functions. In addition, much evidence demonstrates polymorphisms in CYP450-epoxygenases, ω-hydroxylases, and sEH genes (Ephx2) and adenosine receptor genes (ADORA1 & ADORA2) in the human population with the susceptibility to CVDs, including hypertension. CVDs are the number one cause of death globally, coronary artery disease (CAD) was the leading cause of death in the US in 2019, and hypertension is one of the most potent causes of CVDs. This review summarizes the articles related to the crosstalk between adenosine receptors and CYP450-derived oxylipins in vascular, including the CRH response in regular salt-diet fed and high salt-diet fed mice with the correlation of heart perfusate/plasma oxylipins. By using A2AAR-/-, A1AR-/-, eNOS-/-, sEH-/- or Ephx2-/-, vascular sEH-overexpressed (Tie2-sEH Tr), vascular CYP2J2-overexpressed (Tie2-CYP2J2 Tr), and wild-type (WT) mice. This review article also summarizes the role of pro-and anti-inflammatory oxylipins in cardiovascular function/dysfunction in mice and humans. Therefore, more studies are needed better to understand the crosstalk between the adenosine receptors and eicosanoids to develop diagnostic and therapeutic tools by using plasma oxylipins profiles in CVDs, including hypertensive cases in the future.

Perceived stress, academic self-concept, and coping mechanisms among pharmacy students following a curricular revision.

INTRODUCTION: Pharmacy students experience high levels of perceived stress. Data regarding the impact of curricular revision on students' stress level are lacking. The primary objective of this study was to compare perceived stress, academic self-concept, and coping strategies between pharmacy students prior to and following a curricular revision. Secondary objectives included determining university resources used by students to deal with stress. METHODS: Students in the first, second, and third years of the pharmacy curriculum were asked to complete a survey, including the 14-item Perceived Stress Scale (PSS-14), Brief COPE, and Academic Self-Concept Scale (ASCS), and questions regarding use of university resources. Responses to the PSS-14, Brief COPE, and ASCS were compared to a student cohort prior to the curricular revision. RESULTS: Perceived stress was reduced to a small, statistically significant degree following a curricular revision. In both cohorts, increased stress was statistically significantly correlated with decreased academic self-concept. Students reported increased use of self-distraction, along with decreased use of active coping, substance abuse, and planning, as coping strategies when compared to the previous cohort. Approximately half of the student cohort reported no use of university resources. The most commonly used resources were financial aid and mental health services. CONCLUSIONS: Perceived stress decreased following the revision of a Doctor of Pharmacy curriculum. The most common coping strategies were positive and comparable with strategies reported by students in the former curriculum. The impact of curricular changes on student stress and the use of university resources in health professions students warrant further study.

Lymphoplasmacytic Lymphoma with Only Lambda Light Chain Monoclonal Paraprotein Expression.

Introduction: Lymphoplasmacytic lymphoma (LPL) is a rare low-grade B-cell neoplasm that accounts for approximately 2% of all haematological malignancies. Most patients have the clinical syndrome of Waldenstrom macroglobulinemia (WM), which is defined as LPL with an associated immunoglobulin M (IgM) serum monoclonal protein. Roughly 5% of LPL patients secrete non-IgM paraproteins (e.g., IgG, IgA, kappa, lambda) or are non-secretory. Case description: We report the case of a 41-year-old woman who was diagnosed with non-IgM LPL with lambda light chain monoclonal paraprotein production and normal serum immunoglobulin levels. The MYD88 L265P mutation was detected on fluorescence in-situ hybridization (FISH) analysis of the bone marrow. The patient underwent treatment with a combination of ibrutinib and rituximab. There was an initial response but she died 8 months after diagnosis. Discussion: Non-IgM LPL poses diagnostic and therapeutic challenges to clinicians as it is an exceptionally rare malignancy with a heterogeneous clinicopathological presentation and scarce literature. Among non-IgM LPL cases, those with lambda light chain production are even more rare. To the best of our knowledge, none have been reported to date. The addition of MYD88 L265P testing to the diagnostic armamentarium of non-IgM LPL cases is advisable for potential therapeutic reasons. LEARNING POINTS: Our case report and literature review provide insight into non-IgM lymphoplasmacytic lymphoma (LPL), an extremely rare malignancy.Our case report highlights the importance of the need for new treatments for non-IgM LPL.