Hypoxia-inducible factor hydroxylase inhibition enhances the protective effects of cyclosporine in colitis.

Inflammatory bowel disease (IBD) is characterized by epithelial barrier dysfunction with resultant inflammation as the mucosal immune system becomes exposed to luminal antigens. The hydroxylase inhibitor dimethyloxalylglycine (DMOG) reduces symptoms in experimental colitis through the upregulation of genes promoting barrier function and inhibition of epithelial cell apoptosis. The immunosuppressive drug cyclosporine reduces inflammation associated with IBD via suppression of immune cell activation. Given the distinct barrier protective effect of DMOG and the anti-inflammatory properties of cyclosporine, we hypothesized that combining these drugs may provide an enhanced protective effect by targeting both barrier dysfunction and inflammation simultaneously. We used the dextran sulfate sodium model of colitis in C57BL/6 mice to determine the combinatorial efficacy of cyclosporine and DMOG. While cyclosporine and DMOG ameliorated disease progression, in combination they had an additive protective effect that surpassed the level of protection afforded by either drug alone. The ability of DMOG to augment the anti-inflammatory effects of cyclosporine was largely due to preservation of barrier function and at least in part due to zonula occludens-1 regulation. We propose that combining the barrier protective effects of a hydroxylase inhibitor with the anti-inflammatory effects of cyclosporine provides added therapeutic benefit in colitis.NEW & NOTEWORTHY Inflammatory bowel disease is the result of decreased intestinal epithelial barrier function leading to exposure of the mucosal immune system to luminal antigens causing inflammation, which in turn further decreases epithelial barrier function. We demonstrate for the first time that strengthening the epithelial barrier with a hydroxylase inhibitor in combination with the administration of the immunosuppressive cyclosporine provides additive therapeutic advantage in a murine model of colitis.

Albumin nano-encapsulation of caffeic acid phenethyl ester and piceatannol potentiated its ability to modulate HIF and NF-kB pathways and improves therapeutic outcome in experimental colitis.

Hypoxia inducible factor and nuclear factor-kappa beta pathways have been proposed as therapeutic targets for several inflammatory diseases. Caffeic acid phenethyl ester (CAPE) and piceatannol (PIC) are natural anti-inflammatory compounds; however, poor bioavailability and limited understanding of biomolecular mechanistic limits its clinical use. The aims of this study are to enhance bioavailability and investigate their impact on nuclear p65 and HIF-1α for the first time in experimental colitis.Dextran sulphate sodium was used to induce colitis in mice and effect of either free CAPE/PIC or CAPE/PIC loaded albumin nanoparticles treatment was observed on disease development and levels of cellular p65 and HIF-1α.Our results indicate that albumin nano-encapsulation of CAPE/PIC not only enhances its anti-inflammatory potential but also potentiates its ability to effectively modulate inflammation related biomolecular pathways. Hence, combining nanotechnology with natural compounds could result in development of new therapeutic options for IBD.

Polymeric Nano-Encapsulation of Curcumin Enhances its Anti-Cancer Activity in Breast (MDA-MB231) and Lung (A549) Cancer Cells Through Reduction in Expression of HIF-1α and Nuclear p65 (Rel A).

BACKGROUND: The anti-cancer potential of curcumin, a natural NFκß inhibitor, has been reported extensively in breast, lung and other cancers. In vitro and in vivo studies indicate that the therapeutic efficacy of curcumin is enhanced when formulated in a nanoparticulate carrier. However, the mechanism of action of curcumin at the molecular level in the hypoxic tumour micro-environment is not fully understood. Hence, the aim of our study was to investigate the mechanism of action of curcumin formulated as nanoparticles in in vitro models of breast and lung cancer under an hypoxic microenvironment. METHODS: Biodegradable poly(lactic-co-glycolic acid) PLGA nanoparticles (NP), loaded with curcumin (cur-PLGA-NP), were fabricated using a solvent evaporation technique to overcome solubility issues and to facilitate intracellular curcumin delivery. Cytotoxicity of free curcumin and cur-PLGA-NP was evaluated in MDA-MB-231 and A549 cell lines using migration, invasion and colony formation assays. All treatments were performed under an hypoxic micro-environment and whole cell lysates from controls and test groups were used to determine the expression of HIF-1α and p65 levels using ELISA assays. RESULTS: A ten-fold increase in solubility, three-fold increase in anti-cancer activity and a significant reduction in the levels of cellular HIF-1α and nuclear p65 (Rel A) were observed for cur-PLGA-NP, when compared to free curcumin. CONCLUSION: Our findings indicate that curcumin can effectively lower the elevated levels of HIF-1α and nuclear p65 (Rel A) in breast and lung cancer cells under an hypoxic tumour micro-environment when delivered in nanoparticulate form. This applied means of colloidal delivery could explain the improved anti-cancer efficacy of curcumin and has further potential applications in enhancing the activity of anti-cancer agents of low solubility.

Caffeic acid phenethyl ester is protective in experimental ulcerative colitis via reduction in levels of pro-inflammatory mediators and enhancement of epithelial barrier function.

BACKGROUND: Inhibition of the nuclear factor kappa beta (NF-κß) pathway has been proposed as a therapeutic target due to its key role in the expression of pro-inflammatory genes, including pro-inflammatory cytokines, chemokines, and adhesion molecules. Caffeic acid phenethyl ester (CAPE) is a naturally occurring anti-inflammatory agent, found in propolis, and has been reported as a specific inhibitor of NF-κß. However, the impact of CAPE on levels of myeloperoxidases (MPO) and pro-inflammatory cytokines during inflammation is not clear. The aims of this study were to investigate the protective efficacy of CAPE in the mouse model of colitis and determine its effect on MPO activity, pro-inflammatory cytokines levels, and intestinal permeability. METHOD: Dextran sulphate sodium was administered in drinking water to induce colitis in C57/BL6 mice before treatment with intraperitoneal administration of CAPE (30 mg kg-1 day-1). Disease activity index (DAI) score, colon length and tissue histology levels of MPO, pro-inflammatory cytokines, and intestinal permeability were observed. RESULTS: CAPE-treated mice had lower DAI and tissue inflammation scores, with improved epithelial barrier protection and significant reduction in the level of MPO and pro-inflammatory cytokines. CONCLUSION: Our results show that CAPE is effective in suppressing inflammation-triggered MPO activity and pro-inflammatory cytokines production while enhancing epithelial barrier function in experimental colitis. Thus, we conclude that CAPE could be a potential therapeutic agent for further clinical investigations for treatment of inflammatory bowel diseases in humans.

Mobile Devices and Insomnia: Understanding Risks and Benefits.

Mobile devices (smartphones and tablet computers) have become widely prevalent due to rapid improvements in function and decreasing costs. As of 2014, 90 % of US adults have a mobile phone, with 58 % having a smartphone, 32 % owning some type of e-reader, and 42 % of US adults owning a tablet computer. Mobile devices are particularly well-suited for the study of common conditions such as sleep difficulties because of their ubiquity. Around 35 to 49 % of the US adult population have problems falling asleep or have daytime sleepiness. These sleep disorders are often under-recognized because of patient-physician communication difficulties, low rates of medical awareness resulting in underreporting of insomnia symptoms, and limited primary care physician (PCP) training in insomnia recognition. Mobile devices have the potential to bridge some of these gaps, but they can also lead to sleep difficulties when used inappropriately.

Underweight and overweight men have greater exercise-induced dyspnoea than normal weight men.

INTRODUCTION: Persons with high or low body mass index (BMI), involved in clinical or mechanistic trials involving exercise testing, might estimate dyspnoea differently from persons with a normal BMI. AIMS: Our objective was to investigate the relationship between BMI and dyspnoea during exercise in normal subjects with varying BMI. MATERIAL AND METHODS: A total of 37 subjects undertook progressive exercise testing. Subjects were divided into three groups: underweight (UW), normal weight (NW), and overweight (OW). Dyspnoea was estimated using the visual analogue scale (VAS). Spirometry, maximum voluntary ventilation (MVV), and respiratory muscle strength (RMS) were measured. RESULTS AND DISCUSSION: The intercept of the VAS/ventilation relationship was significantly higher in NW subjects compared to UW (P = 0.029) and OW subjects (P = 0.040). Relative to the OW group, FVC (P = 0.020), FEV(1) (P = 0.024), MVV (P = 0.019), and RMS (P = 0.003) were significantly decreased in the UW group. The greater levels of dyspnoea in UW subjects could possibly be due to decreased RMS. Healthy persons should aim to achieve an optimum BMI range to have the lowest exercise-induced dyspnoea.

An isolated fistula between the right pulmonary artery and the right pulmonary vein: an unusual cause of stroke in a young female.

We describe the case of a 29 year-old female who presented with right sided hemiparesis with global aphasia. She had a history of transient ischemic attack with migraine headaches. Diagnostic workup revealed a right to left cardiac shunt. An isolated right pulmonary artery to left pulmonary vein fistula was diagnosed on pulmonary angiogram. The fistula was occluded successfully by cardiac catheterization. Early recognition and intervention is indicated to prevent further complications.

Higher rate of recurrent atrial flutter and atrial fibrillation following atrial flutter ablation after cardiac surgery.

INTRODUCTION: Atrial flutter (AFL) is common after cardiac surgery. However, the types of post-cardiac surgery AFL, its response to catheter-based radiofrequency ablation, and its relationship to atrial fibrillation (AF) are unknown. METHODS AND RESULTS: We retrospectively studied all patients who underwent mapping and ablation for AFL after cardiac surgery from January 1990 to July 2004. One hundred randomly selected patients without prior cardiac surgery (PCS) who underwent mapping and ablation of AFL served as the control population. A total of 236 patients formed the study population (mean age 62 + 13 years, 22% female) and 100 patients formed the control population (mean age 60 + 13 years, 25% female). The majority of patients without PCS had cavo-tricuspid isthmus (CTI)-dependent AFL when compared to patients with PCS (93% vs 72%, respectively, P < 0.0001). In contrast, scar-related AFL was more common in patients with PCS as compared to patients without PCS (22% vs 3%, P < 0.0001). Predictors of scar related AFL in multivariable regression analysis included PCS and left-sided AFL. Acute success rates and complications were similar between the groups. When compared to patients with AFL ablation without PCS, those that had AFL after PCS had higher rates of recurrence of both AFL (1% vs 12%, P < 0.0001; mean time to recurrence 1.85 years) and AF (16% vs 28%, P = 0.02; mean time to recurrence 2.67 years). CONCLUSION: Despite ablation of AFL, patients with PCS have a higher rate of AFL and AF when compared to patients without PCS who underwent ablation of atrial flutter during long-term follow-up.

Pulmonary-vein isolation for atrial fibrillation in patients with heart failure.

BACKGROUND: Pulmonary-vein isolation is increasingly being used to treat atrial fibrillation in patients with heart failure. METHODS: In this prospective, multicenter clinical trial, we randomly assigned patients with symptomatic, drug-resistant atrial fibrillation, an ejection fraction of 40% or less, and New York Heart Association class II or III heart failure to undergo either pulmonary-vein isolation or atrioventricular-node ablation with biventricular pacing. All patients completed the Minnesota Living with Heart Failure questionnaire (scores range from 0 to 105, with a higher score indicating a worse quality of life) and underwent echocardiography and a 6-minute walk test (the composite primary end point). Over a 6-month period, patients were monitored for both symptomatic and asymptomatic episodes of atrial fibrillation. RESULTS: In all, 41 patients underwent pulmonary-vein isolation, and 40 underwent atrioventricular-node ablation with biventricular pacing; none were lost to follow-up at 6 months. The composite primary end point favored the group that underwent pulmonary-vein isolation, with an improved questionnaire score at 6 months (60, vs. 82 in the group that underwent atrioventricular-node ablation with biventricular pacing; P<0.001), a longer 6-minute-walk distance (340 m vs. 297 m, P<0.001), and a higher ejection fraction (35% vs. 28%, P<0.001). In the group that underwent pulmonary-vein isolation, 88% of patients receiving antiarrhythmic drugs and 71% of those not receiving such drugs were free of atrial fibrillation at 6 months. In the group that underwent pulmonary-vein isolation, pulmonary-vein stenosis developed in two patients, pericardial effusion in one, and pulmonary edema in another; in the group that underwent atrioventricular-node ablation with biventricular pacing, lead dislodgment was found in one patient and pneumothorax in another. CONCLUSIONS: Pulmonary-vein isolation was superior to atrioventricular-node ablation with biventricular pacing in patients with heart failure who had drug-refractory atrial fibrillation. (ClinicalTrials.gov number, NCT00599976.)

A methoxylated fatty acid isolated from the brown seaweed Ishige okamurae inhibits bacterial phospholipase A2.

A methoxylated fatty acid that inhibits phospholipase A(2) (PLA(2); EC 3.1.1.4) was purified from the brown seaweed Ishige okamurae. Approximately 8.1 mg of the inhibitory compound, 7-methoxy-9-methylhexadeca-4,8-dienoic acid, was isolated from 1 kg of I. okamurae powder. Recombinant PLA(2) derived from the pathogenic bacterium Vibrio mimicus was used as the target enzyme. The methoxylated fatty acid compound competitively inhibited PLA(2) with a Ki value of 3.9 microg/mL. The concentrations required for 50% inhibition of PLA(2), oedema and erythema were 1.0 microg/mL, 3.6 mg/mL and 4.6 mg/mL, respectively. The compound strongly inhibited PLA(2) activity in vitro and had potent antiinflammatory activity in vivo.

Low incidence of left atrial or left atrial appendage thrombus in patients with paroxysmal atrial fibrillation and normal EF who present for pulmonary vein antrum isolation procedure.

INTRODUCTION: The incidence of left atrial appendage (LAA) thrombus in patients with paroxysmal atrial fibrillation (PAF) who present for pulmonary vein antrum isolation procedure (PVAI) is unknown. METHODS AND RESULTS: All consecutive patients from January 2000 to June 2004 who underwent a PVAI received a computed tomography (CT) to evaluate LAA thrombus before the procedure and 3 months post-PVAI. All patients were followed prospectively. One thousand two hundred twenty-one patients received a PVAI during the study dates. All patients received a CT pre-PVAI at 3 months, and 601 (49%) received a transesophageal echocardiography (TEE) pre-PVAI. Per protocol, all patients who had CT scans that were positive for LAA thrombus received a TEE. There were 9 patients who had LAA thrombus on CT scan, but only 3 had LAA thrombus on TEE. Using TEE as the gold standard, only 3 patients had an LAA thrombus before PVAI; of these patients, 2 had chronic AF with average ejection fraction (EF) of 48% and 1 patient had PAF with EF 25%. No patients with PAF and normal EF had LAA thrombus. Patients with LAA thrombus pre-PVAI had lower EF than patients without LAA thrombus (40% vs. 53%, P = 0.007) but had similar LA size (5.0 vs. 4.5 cm, P = 0.77). No other differences in baseline characteristics were noted. CONCLUSIONS: In this registry of 1,221 patients, we did not observe LA thrombus in PAF patients with normal EF who present for PVAI. Prescreening CT alone is likely to be sufficient in paroxysmal AF patients with normal EF, and the use of TEE may not be needed.

Anti-inflammatory activities of methanol extracts from various seaweed species.

Thirty-seven species of common seaweeds from the coast of Korea were screened for anti-inflammatory activity Methanol extracts of the seaweeds were tested against mouse ear edema and erythema induced by phorbol myristate acetate. At 40 mg ml(-1) of extract, edema was strongly suppressed by the seaweeds Undaria pinnatifida and Ulva linza, with relative inhibition of 85 and 84%, respectively These two seaweeds also showed the greatest suppression of erythema, with inhibition of 78 and 70%, respectively IC50 values of U. pinnatifida were 10, 15, and 18 mg ml(-1) when inflammation symptoms of edema, erythema, and blood flow, respectively were measured. The IC50 of U. linza was 20, 26, and 31 mg ml(-1) when edema, erythema, and blood flow, respectively, were measured. A linear correlation among inhibition rates of edema, erythema, and blood flow was observed with high confidence.

Does Ramadan fasting affect expiratory flow rates in healthy subjects?

OBJECTIVE: To assess whether Ramadan fasting affects the expiratory flow rates in healthy subjects, and to know if these effects correlate to a change in other variables. METHODS: This unmatched case-control longitudinal study includes 46 non-smoking healthy subjects who undertook lung function testing at the Aga Khan University, Pakistan. Expiratory flow rates and body mass were measured in 3 Islamic months, corresponding to November 2001 to January 2002. RESULTS: There was a significant reduction in body mass in Ramadan compared to pre and post Ramadan. No significant changes in expiratory flows were seen during Ramadan as compared to the pre Ramadan period. However, forced expiratory flow rates at 75% of vital capacity (FEF(75)) and between 75% and 85% of vital capacity (FEF(75-85)) showed a significant increase in the post Ramadan period compared to Ramadan. Changes in FEF(75) were negatively correlated to changes in body mass between Ramadan and post Ramadan. CONCLUSION: This study shows that Ramadan fasting will not affect expiratory flow rates in healthy subjects. Post Ramadan values did show an increase in FEF(75) and FEF(75-85), possibly due to changes in body water and fat content. The reductions in body mass were most probably due to lack of nutrition and not dehydration as the fasts were performed in winter. Collection of reference values or early phase clinical trials measuring expiratory flow rates should not be affected by Ramadan fasting.

Chronotropic incompetence as a predictor of death among patients with normal electrograms taking beta blockers (metoprolol or atenolol).

Chronotropic incompetence, or an inability to increase heart rate during exercise, independently predicts death in patients not taking beta blockers. Whether it predicts death in patients taking beta blockers is not known. Consecutive patients (n = 3,736; mean age 58 +/- 11 years; 68% men), who were taking either metoprolol tartrate or atenolol and were referred for symptom-limited exercise testing from 1990 to 2002 at a major academic medical center, formed the prospective study cohort. None had heart failure, pacemakers, atrial fibrillation, or any electrocardiographic abnormalities. Patients were followed for a median of 4.5 years for all-cause mortality. Chronotropic response was defined as the percentage of heart rate reserve used. A value of < or =62%, which was noted in 813 patients (22%), was considered abnormal, meaning that chronotropic incompetence was present. There were 173 deaths. After adjusting for age, gender, heart rate at rest, standard risk factors, other medications, Duke treadmill score, and heart rate recovery, chronotropic incompetence predicted death (adjusted hazard ratio 1.94, 95% confidence interval 1.43 to 2.64, p <0.0001). The association of chronotropic incompetence with death was present, irrespective of which drug was taken or the number of half-lives that had elapsed since the last dose. In conclusion, in patients taking beta blockers, chronotropic incompetence is independently predictive of death.

Delayed lead perforation: a disturbing trend.

BACKGROUND: Delayed lead perforation (occurring more than 1 month after implantation) is a rare complication. Its pathophysiology and optimal management are currently unclear. METHODS: Three cases of delayed lead perforation (6-10 month) were identified in patients with low-profile active fixation leads. RESULTS: All cases presented in a subacute fashion with pleuritic chest pain with confirmatory chest x-ray and device interrogation. Given the potential complications of a perforated lead, all cases had the lead extracted under TEE observation with cardiac surgery backup in the operating room. All patients tolerated extraction without complication. CONCLUSION: Based on these cases, we recommend a management scheme for patients who present with delayed lead perforation.

Usefulness of the pediatric electrocardiogram in detecting left ventricular hypertrophy: results from the Prospective Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2 HIV) multicenter study.

BACKGROUND: A shortcoming of the pediatric electrocardiogram (ECG) appears to be its inability to accurately detect left ventricular hypertrophy (LVH). This study prospectively assesses the usefulness of the pediatric ECG as a screening modality for LVH. METHODS: Concomitant echocardiograms and ECGs from a large cohort of children who were exposed to the human immunodeficiency virus (HIV; uninfected) and children who were infected with HIV were compared. By use of the values of Davignon et al, qualitative determination of LVH and quantitative criteria for LVH (RV6, SV1, RV6+SV1, QV6, and Q(III) >98% for age, R/SV1 <98% for age, and [-]TV6) were compared to body surface area adjusted for left ventricular (LV) mass z score. Results were then stratified according to weight and weight-for-height z scores. New age-adjusted predicted values were then constructed from children of a mixed race who were HIV-uninfected, < or =6 years old, and similarly assessed. RESULTS: The sensitivity rate was <20% for detecting increased LV mass, irrespective of HIV status; the specificity rate was 88% to 92%. The sensitivity rate of the individual criteria ranged from 0 to 35%; the specificity rate was 76% to 99%. Test sensitivities remained low when stratified by weight and weight-for-height z scores. Areas under the receiver operator characteristic curves were between 0.59 and 0.70, also suggesting poor accuracy of the ECG criteria. By use of new age-adjusted predicted values, the sensitivity rate decreased to <17%, and the specificity rate increased to 94% to 100%. CONCLUSION: The ECG is a poor screening tool for identifying LVH in children. Sensitivity is not improved with revision of current criteria.