The early history and development of functional endoscopic sinus surgery.

BACKGROUND: The concept of endoscopic diagnosis and procedures on the nasal cavity had been investigated for several decades in Europe in the early part of the twentieth century. It was Prof Walter Messerklinger and his assistant, Heinz Stammberger, with US colleague, David Kennedy, who brought the science and technique of functional endoscopic sinus surgery to the wider world. METHODS: The author, an English-speaking surgeon, was present at this movement from the commencement of its propagation, and has recorded the remarkable ascendency of this technique throughout the world. CONCLUSION: The technique revolutionised the diagnosis and management of intranasal, sinus and intracranial conditions.

Racial Differences in Eating Patterns and Food Purchasing Behaviors among Urban Older Women.

OBJECTIVE: To examine differences in diet and food purchasing behaviors between Black and White older women living in urban neighborhoods. DESIGN: Cross-sectional observational study. SETTING: Urban neighborhoods in Washington, DC, USA. PARTICIPANTS: Community-dwelling White and Black women of age 65 and older. MEASUREMENTS: Participants were queried on diet via 24-hour recalls, food purchasing habits, their use of neighborhood resources and local travel patterns. Frequency and location of self-reported food purchasing and consumption were compared by race. RESULTS: In 2014 and 2015, 49 White and 44 Black older women were enrolled in the study. Compared to Whites, Blacks reported lower daily caloric intake (mean (SD) 1314 (404) vs. 1529 (448), p=0.02), with a higher percent of calories from protein and fat 1.8 (7.0), p=0.03), and a slightly higher polyunsaturated to saturated fat ratio (p=0.05). Blacks had substantially lower alternate healthy eating index (AHEI) (33.5 (10.2) vs. 43.9 (10.8) of 80 possible points, p<0.001), daily intake (grams) of total fiber (15.3 (8.1) vs. 22.9 (8.5), p<0.001), insoluble fiber (10.8 (6.9) vs. 15.9 (6.5), p<0.001), and soluble fiber (4.5 (2.0) vs. 6.9 (2.8), p<0.001). Blacks had lower intake of micronutrients, alcohol and caffeine. Blacks shopped for groceries less often (4.4 (3.0) vs. 6.2 (3.0) monthly; p=0.006) and spent a longer time traveling to stores (15.8 (9.1) vs. 11.5 (7.2) minutes per trip, p=0.02). A lower percent of Blacks walked to stores (14% vs. 40%, p=0.003) and a higher percent of Blacks rode in a car with someone else (33% vs. 6%, p<0.001). CONCLUSIONS: In an urban setting, food consumption and purchasing behaviors differed substantially between older Black and White women, which should be further investigated and considered to promote healthy eating in older populations.

Racial Differences in Misclassification of Healthy Eating Based on Food Frequency Questionnaire and 24-Hour Dietary Recalls.

OBJECTIVES: To examine the agreement in nutrient intake and alternate healthy eating indices (AHEI) between a self-administered Food Frequency Questionnaire (FFQ) and 24-hour recall (24HR) measurements of diet by race, among urban older women. DESIGN: Cross-sectional observational study. SETTING: Urban neighborhoods in Washington, DC, USA. PARTICIPANTS: Community-dwelling White and Black women aged 65 and older. MEASUREMENTS: In 2014 and 2015, 49 White and 44 Black older women were queried on diet using both FFQ and 24-hour recalls. The correlation coefficients of 55 nutrient intake measures and agreements on healthy eating classification between the two instruments were compared overall and by race. RESULTS: The mean correlation coefficient (rho) was 0.46 for Whites and 0.23 for Blacks. For 47 measures, rho was lower for Blacks. Whites had a strong correlation of ≥0.5 for 28 items, while Blacks had strong correlations for only 3 items. Based on FFQ, the mean (SD) of AHEI were 54.0 (10.3) for Whites and 45.9 (8.8) for Blacks (p<0.001). Based on 24HR, the mean (SD) were 43.9 (10.8) for Whites and 33.2 (9.6) for Blacks (p<0.001). Using 32 as the cutoff (40% of maximum AHEI score), 50% of Blacks and 14% of Whites were classified as eating unhealthy based on the 24HR, versus 2.6% and 0% based on the FFQ. CONCLUSION: The FFQ has limited ability to accurately assess nutrient intake among older Black women, and tends to underestimate racial differences in healthy eating. The FFQ should be further improved for use in racial disparities research of healthy eating in older age, using a larger sample of older women with racial and geographic diversities.

Gender and Age Differences in Levels, Types and Locations of Physical Activity among Older Adults Living in Car-Dependent Neighborhoods.

BACKGROUND: A thorough understanding of gender differences in physical activity is critical to effective promotion of active living in older adults. OBJECTIVES: To examine gender and age differences in levels, types and locations of physical activity. DESIGN: Cross-sectional observation. SETTING: Car-dependent urban and rural neighborhoods in Worcester County, Massachusetts, USA. PARTICIPANTS: 111 men and 103 women aged 65 years and older. MEASUREMENTS: From 2012 to 2014, participants were queried on type, frequency and location of physical activity. Participants wore an accelerometer for 7 consecutive days. RESULTS: Compared to women, men had a higher mean daily step count (mean (SD) 4385 (2122) men vs. 3671(1723) women, p=0.008). Men reported higher frequencies of any physical activity and moderate-to-vigorous physical activity, and a lower frequency of physical activity inside the home. Mean daily step counts and frequency of physical activity outside the home decreased progressively with age for both men and women. Women had a sharper decline in frequencies of self-reported physical activity. Men had a significant decrease in utilitarian walking, which women did not (p=0.07). Among participants who reported participation in any physical activity (n=190), more women indicated exercising indoors more often (59% vs. 44%, p=0.04). The three most commonly cited locations for physical activity away from home for both genders were streets or sidewalks, shopping malls, and membership-only facilities (e.g., YMCA or YWCA). The most common types of physical activity, performed at least once in a typical month, with over 40% of both genders reporting, included light housework, brisk walking, leisurely walking, and stretching. CONCLUSION: Levels, types and location preferences of physical activity differed substantially by gender. Levels of physical activity decreased progressively with age, with greater decline among women. Consideration of these gender differences is necessary to improve the effectiveness of active living promotion programs among older adults.

Inhibition of chemokine (C-X-C motif) receptor four (CXCR4) at the fetal-maternal interface during early gestation in sheep: alterations in expression of chemokines, angiogenic factors and their receptors.

Chemokine (C-X-C motif) ligand 12 (CXCL12) and its receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), are involved in significant biological processes associated with early pregnancy including increasing trophoblast invasion and stimulating placental vascularization. To further elucidate functions of CXCL12-CXCR4 signaling during early gestation, our objective was to inhibit CXCR4 in vivo using a CXCR4 antagonist, AMD3100. We hypothesized that inhibition of CXCR4 would negatively affect chemokine and angiogenic factor regulation imperative for placental development in sheep. Osmotic pumps containing PBS (control) or AMD3100 (CXCR4 antagonist) were surgically installed ipsilateral to the corpus luteum on d 12 of gestation and administered treatments directly into the uterine lumen. Maternal (caruncle and intercaruncle) and fetal membrane tissues were collected on d 23 of gestation and mRNA and protein expression were analyzed for vascular endothelial growth factor (VEGF), kinase insert domain receptor (KDR), fms related tyrosine kinase 1 (FLT1), fibroblast growth factor 2 (FGF2), angiopoietin 1 (ANGPT1), hypoxia inducible factor 1 ɑ subunit (HIF1A), CXCL12, and its corresponding receptors (CXCR4 and CXCR7). Immunohistochemical procedures were performed for analysis of CXCL12 and cell proliferation. In caruncle tissue ipsilateral to the pump, mRNA for KDR, ANGPT1, HIF1A, and CXCL12 increased (P < 0.05) in treated ewes compared to control, whereas caruncle tissue contralateral to the pump had increased expression (P < 0.05) of KDR, and CXCL12 in treated ewes. In fetal membrane, CXCR4 mRNA and protein decreased (P < 0.05), while VEGF protein decreased (P < 0.05) in caruncle and fetal membrane tissue from treated ewes. Results from this study highlight the importance of CXCL12-CXCR4 signaling at the fetal-maternal interface. Inhibiting this axis may disrupt typical regulation of angiogenic factors needed for placental development and embryo growth.

'New to me': changing patient understanding of psoriasis and identifying mechanisms of change. The Pso Well® patient materials mixed-methods feasibility study.

BACKGROUND: Psoriasis is an inflammatory long-term condition involving comorbidities, unhealthy lifestyle and significant life impact. Patients' understanding of psoriasis is limited and support lacking. The Common-Sense Model of Self-Regulation of Health and Illness emphasizes the role of illness and treatment beliefs on coping and self-management. New 'Pso Well® ' patient materials informed by the model, addressed psoriasis as a long-term condition, medication management and lifestyle behaviours. OBJECTIVES: To investigate whether Pso Well® materials (i) broaden understanding of psoriasis without increasing anxiety; (ii) are acceptable; and (iii) comprise features that appear to effect change. METHODS: The Revised Illness Perceptions Questionnaire (IPQ-R modified) and the Hospital Anxiety and Depression Scale (HADS) were administered in patients before and after intervention. Numerical rating scales assessed perceptions of change in understanding and anxiety resulting from engagement with the materials. Qualitative interviews explored acceptability and perceived 'active ingredients'. RESULTS: Fifty-five patients completed pre- and postintervention questionnaires (56% female; median age 59 years). Postintervention, a large effect size was indicated in two IPQ-R domains - illness coherence [t(55) = -3·48, P = 0·001 (two-tailed), η2  = 0·19] and personal control [t(55) = -2·98, P = 0·004 (two-tailed), η2  = 0·14] - and a medium effect in one, treatment control [t(55) = -2·08, P = 0·042 (two-tailed), η2  = 0·08]. HADS scores did not change. For numerical rating scales, 80% of participants reported increased understanding of psoriasis and none reported increased anxiety. Interviews with 19 patients indicated the materials were acceptable and usable. Factors reported to broaden understanding and promote engagement with self-management included linking of related disease aspects, personally relevant content and high-quality design. CONCLUSIONS: High-quality, theory-based psoriasis materials are acceptable to patients and can improve understanding and sense of control without increasing anxiety.

Multivariate characterization of white matter heterogeneity in autism spectrum disorder.

The complexity and heterogeneity of neuroimaging findings in individuals with autism spectrum disorder has suggested that many of the underlying alterations are subtle and involve many brain regions and networks. The ability to account for multivariate brain features and identify neuroimaging measures that can be used to characterize individual variation have thus become increasingly important for interpreting and understanding the neurobiological mechanisms of autism. In the present study, we utilize the Mahalanobis distance, a multidimensional counterpart of the Euclidean distance, as an informative index to characterize individual brain variation and deviation in autism. Longitudinal diffusion tensor imaging data from 149 participants (92 diagnosed with autism spectrum disorder and 57 typically developing controls) between 3.1 and 36.83 years of age were acquired over a roughly 10-year period and used to construct the Mahalanobis distance from regional measures of white matter microstructure. Mahalanobis distances were significantly greater and more variable in the autistic individuals as compared to control participants, demonstrating increased atypicalities and variation in the group of individuals diagnosed with autism spectrum disorder. Distributions of multivariate measures were also found to provide greater discrimination and more sensitive delineation between autistic and typically developing individuals than conventional univariate measures, while also being significantly associated with observed traits of the autism group. These results help substantiate autism as a truly heterogeneous neurodevelopmental disorder, while also suggesting that collectively considering neuroimaging measures from multiple brain regions provides improved insight into the diversity of brain measures in autism that is not observed when considering the same regions separately. Distinguishing multidimensional brain relationships may thus be informative for identifying neuroimaging-based phenotypes, as well as help elucidate underlying neural mechanisms of brain variation in autism spectrum disorders.

Motivational interviewing-based training enhances clinicians' skills and knowledge in psoriasis: findings from the Pso Well® study.

BACKGROUND: Psoriasis is a common long-term, immune-mediated skin condition associated with behavioural factors (e.g. smoking, excess alcohol, obesity), which increase the risk of psoriasis onset, flares and comorbidities. Motivational interviewing (MI) is an evidence-based approach to health-related behaviour change that has been used successfully for patients with long-term conditions. This study assessed change in clinicians' MI skills and psoriasis knowledge following Psoriasis and Wellbeing (Pso Well® ) training. OBJECTIVES: To investigate whether the Pso Well training intervention improves clinicians' MI skills and knowledge about psoriasis-related comorbidities and risk factors; and to explore the acceptability and feasibility of the Pso Well training content, delivery and evaluation. METHODS: Clinicians attended the 1-day training programme focused on MI skills development in the context of psoriasis. MI skills were assessed pre- and post-training using the Behaviour Change Counselling Index. Knowledge about psoriasis-related comorbidity and risk factors was assessed with a novel 22-point measure developed for the study. Interviews with clinicians were analysed qualitatively to identify perceptions about the feasibility and acceptability of the training. RESULTS: Sixty-one clinicians completed the training (35 dermatology nurses, 23 dermatologists and three primary-care clinicians). Clinicians' MI skills (P < 0·001) and knowledge (P < 0·001) increased significantly post-training. Clinicians found the training valuable and relevant to psoriasis management. CONCLUSIONS: Attendance at the Pso Well training resulted in improvements in clinicians' knowledge and skills to manage psoriasis holistically. Clinicians deemed the training itself and the assessment procedures used both feasible and acceptable. Future research should investigate how this training may influence patient outcomes.

Primary care-based screening for cardiovascular risk factors in patients with psoriasis.

BACKGROUND: Studies assessing cardiovascular disease (CVD) risk factors in patients with psoriasis have been limited by selection bias, inappropriate controls or a reliance on data collected for clinical reasons. OBJECTIVES: To investigate whether screening for CVD risk factors in patients with psoriasis in primary care augments the known prevalence of CVD risk factors in a cross-sectional study. METHODS: Patients listed as having psoriasis in primary care were recruited, screened and risk assessed by QRISK2. RESULTS: In total, 287 patients attended (mean age 53 years, 57% women, 94% white British, 22% severe disease, 33% self-reported psoriatic arthritis). The proportion with known and screen-detected (previously unknown) risk factors was as follows: hypertension 35% known and 13% screen-detected; hypercholesterolaemia 32% and 37%; diabetes 6·6% and 3·1% and chronic kidney disease 1·1% and 4·5%. At least one screen-detected risk factor was found in 48% and two or more risk factors were found in 21% of patients. One in three patients (37%) not previously known to be at high risk were found to have a high (> 10%) 10-year CVD risk. Among the participants receiving treatment for known CVD risk factors, nearly half had suboptimal levels for blood pressure (46%) and cholesterol (46%). CONCLUSIONS: Cardiovascular risk factor screening of primary care-based adults with psoriasis identified a high proportion of patients (i) at high CVD risk, (ii) with screen-detected risk factors and (iii) with suboptimally managed known risk factors. These findings need to be considered alongside reports that detected limited responses of clinicians to identified risk factors before universal CVD screening can be recommended.

Efficacy and safety of inhaled calcium lactate PUR118 in the ozone challenge model--a clinical trial.

BACKGROUND: The ozone challenge model can be used to assess the efficacy of anti-inflammatory compounds in early phases of clinical drug development. PUR118, a calcium salt based formulation engineered in the iSPERSE(TM) dry powder delivery technology, is a novel anti-inflammatory drug for COPD. Here we evaluated the efficacy and safety of three doses of PUR118 in attenuating ozone-induced airway inflammation in healthy volunteers. METHODS: In a single-blind, phase 1B proof of concept study, 24 subjects were enrolled to sequentially receive three doses of PUR118 (5.5 mg, n = 18; 11.0 mg, n = 18; 2.8 mg, n = 16). Each dose was inhaled 3 times (1, 13, 25 h, preceded by 2 puffs salbutamol) before the ozone exposure (250 ppb, 3 h intermittent exercise). Sputum was induced 3 h after the end of exposure. RESULTS: Sputum neutrophils, sputum CD14+ cells, as well as concentrations of IL1B, IL6, IL8, MMP9, and TNFA in sputum supernatant significantly increased after ozone exposure (n = 24). The percentage of sputum neutrophils (n = 12 who completed all treatments) did not change following treatment with different doses of PUR118. The high dose treatment group (n = 16) showed a decrease in the percentage and number of sputum macrophages (p ≤ 0.05) as well as a decrease in blood neutrophils (p = 0.04), and an increase in blood CD14 + cells (p = 0.04) compared to baseline. All dosages of PUR118 were safe and well tolerated. CONCLUSION: Ozone challenge resulted in the expected and significant increase of sputum inflammatory parameters. Treatment with multiple rising doses of PUR118 was safe and three applications within 25 h prior to the ozone challenge had small effects on ozone-induced airway inflammation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01690949. Registered 12 September 2012.

Metabolizable protein supply while grazing dormant winter forage during heifer development alters pregnancy and subsequent in-herd retention rate.

Two studies were conducted to evaluate the effects of postweaning management of British crossbred heifers on growth and reproduction. In Exp. 1, 239 spring-born, crossbred heifers were stratified by weaning BW (234 ± 1 kg) and allotted randomly to 1 of 2 treatments. Treatments were fed at a rate equivalent to 1.14 kg/d while grazing dormant forage (6.5% CP and 80% NDF, DM basis) and were 1) 36% CP containing 36% RUP (36RUP) or 2) 36% CP containing 50% RUP (50RUP). Supplementation was initiated in February (1995 and 1996) or November (1997 and 1998) and terminated at the onset of breeding season (mid May). Heifers were weighed monthly up to breeding and again at time of palpation. After timed AI, heifers were exposed to breeding bulls for 42 ± 8 d. In Exp. 2, 191 spring-born, crossbred heifers were stratified by weaning BW to treatments. Heifer development treatments were 1) pasture developed and fed 0.9 kg/day of a 36% CP supplement containing 36% RUP (36RUP), 2) pasture developed and fed 0.9 kg/day of a 36% CP supplement containing 50% RUP (50RUP), and 3) corn silage-based growing diet in a drylot (DRYLOT). Heifers receiving 36RUP and 50RUP treatments were developed on dormant forage. Treatments started in February and ended at the onset of a 45-d breeding season in May. Heifer BW and hip height were taken monthly from initiation of supplementation until breeding and at pregnancy diagnosis. In Exp. 1, BW was not different (P ≥ 0.27) for among treatments at all measurement times. However, 50RUP heifers had greater (P = 0.02; 80 and 67%) pregnancy rates than 36RUP heifers. In Exp. 2, DRYLOT heifers had greater (P < 0.01) BW at breeding than 36RUP or 50RUP developed heifers. However, BW at pregnancy diagnosis was not different (P = 0.24) for between treatments. Pregnancy rates tended to be greater (P = 0.10) for 50RUP heifers than 36RUP and DRYLOT. Net return per heifer was US$99.71 and $87.18 greater for 50RUP and 36RUP heifers, respectively, compared with DRYLOT heifers due to differences in pregnancy and development costs. Retention rate after breeding yr 3 and 4 was greatest (P ≤ 0.01) for 50RUP heifers. Thus, increasing the supply of MP by increasing the proportion of RUP in supplements fed to heifers on dormant forage before breeding increased pregnancy rates, cow herd retention, and net return compared with heifers fed in drylot.

A quarter century of granzymes.

Granzymes (Grs) were discovered just over a quarter century ago. They are produced by cytotoxic T cells and natural killer cells and are released upon interaction with target cells. Intensive biochemical, genetic, and biological studies have been performed in order to study their roles in immunity and inflammation. This review summarizes research on the family of Grs.

Phase I trial and pharmacokinetic study of high-dose clofarabine and busulfan and allogeneic stem cell transplantation in adults with high-risk and refractory acute leukemia.

We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine with high-dose busulfan followed by allogeneic stem cell transplantation (SCT) in patients with high-risk and refractory acute leukemia. Patients received intravenous busulfan 0.8 mg/kg every 6 h on days -6 to -3 and clofarabine 30-60 mg/m(2) per day on days -6 to -2. Graft-versus-host disease prophylaxis included sirolimus plus tacrolimus (days -2 to +180). A total of 15 patients, median age 48 (30-58) years, with acute leukemia that was relapsed and refractory (n=8), primary refractory (n=6), or in CR2 (n=1), were treated at four clofarabine dose levels: 30 (n=3), 40 (n=3), 50 (n=3) and 60 mg/m(2) per day (n=6) with busulfan. All engrafted, and the MTD was not reached. Grades 3-4 non-hematological toxicities included vomiting (n=3), mucositis (n=9), hand-foot syndrome (n=1), acute renal failure (n=1) and reversible elevation of aspartate aminotransferase/alanine aminotransferase (n=10). The 1-year event-free survival was 53% (95% confidence interval: 33-86%), and the 1-year overall survival was 60% (95% confidence interval: 40-91%). Given the good tolerability and promising results, we recommend clofarabine 60 mg/m(2) per day × 5 days as a phase II dose in combination with busulfan (12.8 mg per kg total dose) for further study as a myeloablative regimen for allogeneic SCT for high-risk acute leukemia.

Interaction between anandamide and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery.

BACKGROUND AND PURPOSE: Anandamide and sphingosine-1-phosphate (S1P) both regulate vascular tone in a variety of vessels. This study aimed to examine the mechanisms involved in the regulation of coronary vascular tone by anandamide and S1P, and to determine whether any functional interaction occurs between these receptor systems. EXPERIMENTAL APPROACH: Mechanisms used by anandamide and S1P to regulate rat coronary artery (CA) reactivity were investigated using wire myography. Interactions between S1P and the cannabinoid (CB)(2) receptor were determined using human embryonic kidney 293 (HEK293) cells that stably over-express recombinant CB(2) receptor. KEY RESULTS: Anandamide and S1P induced relaxation of the rat CA. CB(2) receptor antagonists attenuated anandamide-induced relaxation, while S1P-mediated relaxation was dependent on the vascular endothelium and S1P(3). Anandamide treatment resulted in an increase in the phosphorylation of sphingosine kinase-1 within the CA. Conversely, anandamide-mediated relaxation was attenuated by inhibition of sphingosine kinase. Moreover, S1P(3), specifically within the vascular endothelium, was required for anandamide-mediated vasorelaxation. In addition to this, S1P-mediated relaxation was also reduced by CB(2) receptor antagonists and sphingosine kinase inhibition. Further evidence that S1P functionally interacts with the CB(2) receptor was also observed in HEK293 cells over-expressing the CB(2) receptor. CONCLUSIONS AND IMPLICATIONS: In the vascular endothelium of rat CA, anandamide induces relaxation via a mechanism requiring sphingosine kinase-1 and S1P/S1P(3). In addition, we report that S1P may exert some of its effects via a CB(2) receptor- and sphingosine kinase-dependent mechanism, where subsequently formed S1P may have privileged access to S1P(3) to induce vascular relaxation.

A comparison of two rehabilitation protocols after simultaneous bilateral total knee arthroplasty: a controlled, randomized study.

Post-operative outcomes after simultaneous bilateral total knee arthroplasty in 115 patients randomly assigned to two rehabilitation protocols were compared. The traditional-protocol group performed a series of exercises on one leg and then repeated the same sequence on the other leg. The alternate-protocol group performed the same exercises, but alternated between legs with each individual repetition. Symptoms and function were assessed pre-operatively and at 1, 3, 6 and 12 months post-operatively. The alternate-protocol group had lower visual analogue pain scale scores in the early post-operative period, as well as higher Knee Society Scores and SF-12 physical and mental health summary scores after 1 and 3 months compared with the traditional-protocol group, but there were no differences between the two groups from 6 months post-operatively. There were no significant differences between the groups in terms of range of knee motion or incidence of deep vein thrombosis. The alternate-protocol for rehabilitation resulted in an early return to function and decreased pain levels following simultaneous bilateral total knee arthroplasty and was associated with the potential to produce more positive emotional states and earlier functional independence.

Mast cells, peptides and cardioprotection - an unlikely marriage?

1 Mast cells have classically been regarded as the 'bad guys' in the setting of acute myocardial ischaemia, where their released contents are believed to contribute both to tissue injury and electrical disturbances resulting from ischaemia. Recent evidence suggests, however, that if mast cell degranulation occurs in advance of ischaemia onset, this may be cardioprotective by virtue of the depletion of mast cell contents that can no longer act as instruments of injury when the tissue becomes ischaemic. 2 Many peptides, such as ET-1, adrenomedullin, relaxin and atrial natriuretic peptide, have been demonstrated to be cardioprotective when given prior to the onset of myocardial ischaemia, although their physiological functions are varied and the mechanisms of their cardioprotective actions appear to be diverse and often ill defined. However, one common denominator that is emerging is the ability of these peptides to modulate mast cell degranulation, raising the possibility that peptide-induced mast cell degranulation or stabilization may hold the key to a common mechanism of their cardioprotection. 3 The aim of this review was to consolidate the evidence implying that mast cell degranulation could play both a detrimental and protective role in myocardial ischaemia, depending upon when it occurs, and that this may underlie the cardioprotective effects of a range of diverse peptides that exerts physiological effects within the cardiovascular system.

Mast cell degranulation--a mechanism for the anti-arrhythmic effect of endothelin-1?

BACKGROUND AND PURPOSE: The aim of this study was to investigate whether the previously reported anti-arrhythmic effect of endothelin-1 (ET-1) is mediated by degranulation of cardiac mast cells prior to myocardial ischaemia. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats received either ET-1 (1.6 nmolxkg(-1)) in the presence or absence of disodium cromoglycate (DSCG; 20 mgxkg(-1)xh(-1)) prior to coronary artery occlusion (CAO). In separate experiments rats were given compound 48/80 (50 microgxkg(-1)) to compare the effects of ET-1 with those of a known mast cell degranulator. Ischaemia-induced ventricular arrhythmias were detected through continuous monitoring of a lead I electrocardiogram. After 30 min of CAO, the hearts were removed and mast cell degranulation determined by histological analysis. A parallel series of sham groups were performed to determine the direct effects of ET-1 and compound 48/80 on mast cell degranulation in the absence of ischaemia. KEY RESULTS: ET-1 and compound 48/80 both exerted profound anti-arrhythmic effects, significantly reducing the total number of ventricular ectopic beats (P < 0.001) and the incidence of ventricular fibrillation (P < 0.05). These anti-arrhythmic effects were abolished by concomitant DSCG infusion prior to CAO. In sham animals ET-1 and compound 48/80 both induced mast cell degranulation (P < 0.001), an effect which was abolished by DSCG, confirming their ability to induce degranulation of mast cells. CONCLUSIONS AND IMPLICATIONS: These results demonstrate for the first time that when given prior to ischaemia ET-1 mediates its anti-arrhythmic effects, at least in part, via cardiac mast cell degranulation.

Adrenaline reveals the torsadogenic effect of combined blockade of potassium channels in anaesthetized guinea pigs.

BACKGROUND AND PURPOSE: Torsade de pointes (TdP) can be induced in several species by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether combined I(Kr) and I(Ks) blockade could induce TdP in anaesthetized guinea pigs and whether short-term variability (STV) or triangulation of action potentials could predict TdP. EXPERIMENTAL APPROACH: Experiments were performed in open-chest, pentobarbital-anaesthetized, adrenaline-stimulated male Dunkin Hartley guinea pigs, which received three consecutive i.v. infusions of either vehicle, the I(Kr) blocker E-4031 (3, 10 and 30 nmol kg(-1) min(-1)), the I(Ks) blocker HMR1556 (75, 250, 750 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. Phenylephrine-stimulated guinea pigs were also treated with the K(+) channel blockers in combination. Arterial blood pressure, ECGs and epicardial monophasic action potential (MAP) were recorded. KEY RESULTS: TdP was observed in 75% of adrenaline-stimulated guinea pigs given the K(+) channel blockers in combination, but was not observed in guinea pigs treated with either I(K) blocker alone, or in phenylephrine-stimulated guinea pigs. Salvos and ventricular tachycardia occurred with adrenaline but not with phenylephrine. No changes in STV or triangulation of the MAP signals were observed before TdP. CONCLUSIONS AND IMPLICATIONS: Combined blockade of both I(Kr) and I(Ks) plus the addition of adrenaline were required to induce TdP in anaesthetized guinea pigs. This suggests that there must be sufficient depletion of repolarization reserve and an appropriate trigger for TdP to occur.

Potentiation of E-4031-induced torsade de pointes by HMR1556 or ATX-II is not predicted by action potential short-term variability or triangulation.

BACKGROUND AND PURPOSE: Torsade de pointes (TdP) can be induced by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether IKs blockade or enhancement of INa could potentiate TdP induced by IKr blockade and to investigate whether short-term variability (STV) or triangulation of action potentials preceded TdP. EXPERIMENTAL APPROACH: Experiments were performed in open-chest, pentobarbital-anaesthetized, alpha 1-adrenoceptor-stimulated, male New Zealand White rabbits, which received three consecutive i.v. infusions of either the IKr blocker E-4031 (1, 3 and 10 nmol kg(-1) min(-1)), the IKs blocker HMR1556 (25, 75 and 250 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. In a second study rabbits received either the same doses of E-4031, the INa enhancer, ATX-II (0.4, 1.2 and 4.0 nmol kg(-1)) or both of these drugs. ECGs and epicardial monophasic action potentials were recorded. KEY RESULTS: HMR1556 alone did not cause TdP but increased E-4031-induced TdP from 25 to 80%. ATX-II alone caused TdP in 38% of rabbits, as did E-4031; 75% of rabbits receiving both drugs had TdP. QT intervals were prolonged by all drugs but the extent of QT prolongation was not related to the occurrence of TdP. No changes in STV were detected and triangulation was only increased after TdP occurred. CONCLUSIONS AND IMPLICATIONS: Giving modulators of ion channels in combination substantially increased TdP but, in this model, neither STV nor triangulation of action potentials could predict TdP.

Influence of short-term fasting during the luteal phase of the estrous cycle on ovarian follicular development during the ensuing proestrus of ewes.

Short-term fasting of mature ewes during diestrus results in increased serum concentrations of progesterone and a delayed pre-ovulatory surge release of LH. To determine if these changes in reproductive hormones influence subsequent follicular development, mature ewes observed in estrus were assigned randomly to control (n=10) or fasted (n=15) groups. Control ewes had ad libitum access to feed, whereas fasted ewes were not fed from day 7 through 11 of their estrous cycle. Daily blood samples were collected from control and fasted ewes throughout the fasting period. Fasting increased (P<0.001) serum concentrations of progesterone (4.4 ng/mL versus 2.7 ng/mL [+/-0.3]). On day 12, all ewes were treated with 10mg of PGF(2alpha) and fasted ewes were returned to ad libitum feed. Ovaries were collected from ewes (n=5 each group) at 0 and 72 h following PGF(2alpha) in control and 0, 72 and 96 h in fasted ewes. Ovaries were weighed and small (< or =2mm), medium (3-4mm), and large (> or =5mm) follicles were enumerated. Total numbers of follicles were less (P<0.001) in fasted than fed ewes (14.6 versus 30.2 [+/-2.2]) at 0 h, but did not differ (P=0.9) when numbers of follicles were compared at similar times before the anticipated LH surge (i.e., at 72 h versus 96 h in control and fasted ewes, respectively). Within follicular size class, numbers of small and medium follicles were decreased (P=0.04) at 0 h in fasted ewes. Numbers of large follicles did not differ (P=1.0) between groups. Although numbers of small and medium ovarian follicles in fasted ewes recovered by 96 h to values comparable to fed ewes at 72 h following PGF(2alpha), serum concentrations of estradiol 17beta (P=0.08) and FSH (P=0.06) tended to be decreased in fasted ewes before the anticipated surge release of LH. Pituitary content of LH and FSH also tended to be lower (P< or =0.09) at 96 h in fasted ewes than at 72 h in control ewes, but did not differ (P> or =0.4) at hour 0 following PGF(2alpha). Hypothalamic and stalk median eminence contents of GnRH were not influenced (P> or =0.2) by fasting at any time period. Fasting during the luteal phase perturbs gonadotropin secretion and may influence fertility by causing a delay in ovarian follicle development.