Impacts of Remote Physical Exercises on Functional Status and Mobility among Community-Dwelling Pre-Disabled Seniors during the Covid-19 Lockdown.

OBJECTIVES: To assess whether remote physical exercise interventions helped maintain function in daily life, level of physical activities, basic mobility and frailty status in pre-disabled seniors during the first Covid-19 lockdown. DESIGN: This is an interventional study conducted from May 2020 to May 2021. SETTING: Community-dwelling older adults in 2 Canadian cities. PARTICIPANTS: 84 pre-disabled seniors. INTERVENTION: 12-week physical exercise programs (1 hour/ 3 times/ week) in kinesiologist-guided groups using Zoom or phone-supervised individual booklet-based home-program (n=44) vs. Control (usual life habits; n=40). MEASUREMENTS: Functional status in daily activities (OARS scale); Daily level of aerobic (TAPA-1) and strengthening/flexibility (TAPA-2) physical activities; Basic mobility abilities (SPPB: balance, lower limbs strength, walking speed; Timed Up-and-Go) and Frailty (SOF index) were assessed at baseline and at 3, 6, 9 and 12-month follow-ups. RESULTS: The participants' mean age was 78.5 ± 7.2 and 76.5 % were women. There was a group * time effect for the OARS scale (p=0.02), the TAPA-1 (p=0.06) and the TAPA-2 (p=0.007) scores. For these outcomes, scores significantly improved during the first 3 months of follow-up and then stabilised in the intervention group whereas they remained constant in the control group over time. There was an overall time effect for the SPPB (p=0.004), the 4-m walking speed (p=0.02) and for the SOF index (p=0.004), with no between-group differences. Finally, no effect was observed for the TUG. CONCLUSION: Remote home-based physical exercise interventions and monitoring during the first Covid-19 lockdown seemed to have helped maintain seniors' level of physical activities without impacting on basic mobility abilities. Further studies are needed to identify parameters of remote exercise programs that can improve daily function and mobility in this population.

Advanced practice physiotherapy care in emergency departments for patients with musculoskeletal disorders: a pragmatic cluster randomized controlled trial and cost analysis.

BACKGROUND: Advanced practice physiotherapy (APP) models of care where physiotherapists are primary contact emergency department (ED) providers are promising models of care to improve access, alleviate physicians' burden, and offer efficient centered patient care for patients with minor musculoskeletal disorders (MSKD). OBJECTIVES: To compare the effectiveness of an advanced practice physiotherapist (APPT)-led model of care with usual ED physician care for persons presenting with a minor MSKD, in terms of patient-related outcomes, health care resources utilization, and health care costs. METHODS: This trial is a multicenter stepped-wedge cluster randomized controlled trial (RCT) with a cost analysis. Six Canadian EDs (clusters) will be randomized to a treatment sequence where patients will either be managed by an ED APPT or receive usual ED physician care. Seven hundred forty-four adults with a minor MSKD will be recruited. The main outcome measure will be the Brief Pain Inventory Questionnaire. Secondary measures will include validated self-reported disability questionnaires, the EQ-5D-5L, and other health care utilization outcomes such as prescription of imaging tests and medication. Adverse events and re-visits to the ED for the same complaint will also be monitored. Health care costs will be measured from the perspective of the public health care system using time-driven activity-based costing. Outcomes will be collected at inclusion, at ED discharge, and at 4, 12, and 26 weeks following the initial ED visit. Per-protocol and intention-to-treat analyses will be performed using linear mixed models with a random effect for cluster and fixed effect for time. DISCUSSION: MSKD have a significant impact on health care systems. By providing innovative efficient pathways to access care, APP models of care could help relieve pressure in EDs while providing efficient care for adults with MSKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05545917 . Registered on September 19, 2022.

Online physical exercise intervention in older adults during lockdown: Can we improve the recipe?

BACKGROUND: Recorded and live online physical exercise (PE) interventions are known to provide health benefits. However, the effects of prioritizing the number of live or recorded sessions remain unclear. AIMS: To explore which recorded-live sessions ratio leads to the best implementation and benefits in older adults. METHODS: Forty-six community-dwelling adults (> 60y.o.) were randomized into two groups completing a 12-week online PE intervention. Each group had a different ratio of live-recorded online sessions as follows: Live-Recorded-Live sessions (LRL; n = 22) vs. Recorded-Live-Recorded sessions (RLR; n = 24). RESULTS: Drop-out rates did not reach significance (LRL:14% vs. RLR: 29%, p = 0.20), and adherence was similar (> 85%) between groups. Both groups reported similar levels of satisfaction (> 70%), enjoyment (> 75%), and perceived exertion (> 60%). Both groups increased physical health and functional capacities, with greater improvements in muscle power (LRL: LRL: + 35 ± 16.1% vs. RLR: + 7 ± 13.9%; p = 0.010) and endurance (LRL: + 34.7 ± 15.4 vs. RLR: + 27.0 ± 26.5, p < 0.001) in the LRL group. DISCUSSION: Both online PE intervention modalities were adapted to the participants' capacities and led to a high level of enjoyment and retention. The greater physical improvements observed in the LRL group are likely due to the higher presence of the instructor compared to the RLR group. Indeed, participants received likely more feedback to appropriately adjust postures and movements, increasing the quality of the exercises. CONCLUSION: When creating online PE interventions containing both recorded and live sessions, priority should be given to maximizing the number of live sessions and not the number of recorded sessions.

From freshwaters to bivalves: Microplastic distribution along the Saint-Lawrence river-to-sea continuum.

Despite the close connection of freshwaters to human health, the occurrence and fate of microplastics in marine estuaries remain poorly documented. To study these particles in the Saint-Lawrence River (Quebec, Canada), surface water and marine bivalve samples were collected along the river-to-sea continuum. The water samples were subdivided to characterize the large microplastics (LMPs; 300-3200 µm) and the small microplastics (SMPs; 20-300 µm). Particles were identified by microscopy and infrared spectroscopy techniques. The concentration of LMPs was higher in the surface water in the downstream stations (0.0319 ± 0.0147 items.L-1) compared to the upstream stations (0.0007 ± 0.0006 items.L-1). No clear trend was observed for the SMPs. After digestion of the biological tissues, the microplastics ingested by the bivalves were recovered and characterized by microscopy coupled with infrared spectroscopy. Up to 3 items were found per bivalve suggesting that these particles are also present in the water column of the marine estuary and the gulf. The physico-chemical gradients along the continuum were monitored since they could be directly involved in the vertical and horizontal transport of microplastics. This study provides scarce field data collected along the world's largest estuary and gives new insights concerning the fate of microplastics along a river-to-sea continuum.

[Relation between grip strength of independent elders and functional decline following an emergency department visit : a pan-Canadian study]. / Capacité de prédiction de la force de préhension et de la peur de tomber des personnes âgées autonomes quant au déclin fonctionnel suite à une consultation aux urgences. Une étude pancanadienne.

OBJECTIVE: To determine whether grip strength and fear of falling are associated with functional decline at 3 or 6 months after a minor trauma assessed in the emergency department. METHOD: Prospective multicenter cohort study of patient's aged 65 years and older, independent for activities of daily living, consulting the emergency department for minor trauma. Functional status, fear of falling, and grip strength measurements were collected. Functional decline was measured at 3 and 6 months. STATISTICS: Two groups were compared : one with functional decline, the other without. A ROC curve explored the predictive power of grip strength and initial fear of falling on the occurrence of functional decline. RESULTS: Participants were 74.7 years old, 52 % men. Initial peak grip strengths were identical (p superior to 0.05). Grip strength and fear of falling were not predictive of functional decline (p = 0.55 and p = 0.53). However, fear of falling was associated with functional decline (OR: 1.141 95 % CI [1.032-1.261]; p = 0.009). CONCLUSION: In the autonomous elder with minor trauma in the emergency department, grip strength is not associated with subsequent functional decline. But fear of falling is associated with decline at 6 months.

Objectif : Déterminer si la force de préhension et la peur de tomber sont associées au déclin fonctionnel à 3 ou 6 mois d'un traumatisme mineur évalué aux urgences. Méthode : Étude prospective de cohorte multicentrique des patients de 65 ans et plus, autonomes pour les activités de la vie quotidienne, consultant aux urgences pour traumatismes mineurs. Le statut fonctionnel, la peur de tomber, et la mesure de la force de préhension ont été recueillis. Le déclin fonctionnel a été mesuré à 3 et 6 mois. Statistiques : Deux groupes sont comparés : un avec déclin fonctionnel, l'autre sans. Une courbe ROC a exploré la puissance prédictive de la force de préhension et de la peur de tomber initiale sur l'apparition du déclin fonctionnel. Résultats : Les participants avaient 74 ± 7 ans, 52 % d'hommes. Les forces de préhension maximales initiales étaient identiques (p sup�rieur a 0,05). La force de préhension et la peur de tomber ne sont pas prédictives du déclin fonctionnel (p = 0,55 et p = 0,53). Cependant, la peur de tomber est associée au déclin fonctionnel (OR: 1,141 IC95 % [1,032-1,261]; p = 0,009). Conclusion : Chez l'aîné autonome avec un traumatisme mineur aux urgences, la force de préhension n'est pas associée au déclin fonctionnel ultérieur. Mais la peur de tomber est associée à un déclin à 6 mois.

Feasibility and Acceptability of Remote Physical Exercise Programs to Prevent Mobility Loss in Pre-Disabled Older Adults during Isolation Periods Such as the COVID-19 Pandemic.

This study aimed to assess the feasibility and acceptability of remote physical exercise (PE) to prevent mobility loss among pre-disabled older adults during the COVID-19 lockdowns. Participants followed a 12-week PE remote program in Zoom© supervised groups (Web-Ex group, n=11) or phone-supervised individual booklet-based home-program (Booklet group, n=33). The total rate of adherence was 82.5% in the Web-Ex group and 85.8% in the Booklet group. The level of satisfaction was « a lot ¼ for 60% of the participants in the Web-ex group and for 37.9% of those included in the Booklet group. Respectively 10% and 31% of the participants rated the difficulty as « low ¼ in the web-ex and Booklet groups. Remote physical exercise using a web technology or booklets at home with regular and personalized follow-up during the lockdown was feasible and acceptable among pre-disabled seniors.

Feasibility, Acceptability and Effects of a Home-Based Exercise Program Using a Gerontechnology on Physical Capacities after a Minor Injury in Community-Living Older Adults: A Pilot Study.

CONTEXT: Several studies have demonstrated that physical activity can help limit decline in functional capacities of older adults. Nevertheless, many adults aged 65 and over are inactive. OBJECTIVE: To explore the feasibility, the acceptability and the effects of a home-based exercise program (HEP) using a motion capture gerontechnology in independent community-living older adults at risk of function decline. DESIGN: Interventionnal clinical trial. PARTICIPANTS: Sixteen previously independent individuals aged 65 and older recruited at the Emergency Department after being treated for a minor injury and discharged home were assigned to a home-based exercise program group (HEP=8) or to a control group (CONTR=8). Twelve participants completed the study, 6 in each group Setting: Canadian Community-dwelling in Montreal area. INTERVENTION: The HEP group engaged in a twelve-week physical activity intervention using a gerontechnology while the CONTR group continued with discharge plan from ED. MEASUREMENTS: Participants were evaluated for functional status using validated questionnaires and objective physical measures at baseline, three and six months later. Feasibility and acceptability of the HEP was assessed using data reports from the gerontechnology and from self-reported assessments. RESULTS: There was no differences between groups at baseline except for the fallrelated self-efficacy: HEP=8.33/28±1.51 vs CONTR=7/28±0 p=0.022. The HEP was found to be feasible and acceptable (adherence rate at 86% and average quality of movements at 87.5%). Significant improvement in walking speed on 4m was observed three months after baseline for HEP vs CONTR group (+0.25 vs +0.05 m/sec, p=0.025). Effects remained at follow-up. Only CONTR group resulted in a significant increase in SF-36 global score. CONCLUSION: This twelve-week HEP intervention using the Jintronix® gerontechnology is feasible, acceptable and safe for community-living older adults who sustained a minor injury. This intervention could increase walking speed, the most important predictor of adverse events in the elderly population, and that the improvement could be maintained over time.

Understanding Muslim patients: cross-cultural dental hygiene care.

BACKGROUND: Healthcare providers who understand the basic pillars of Islamic beliefs and common religious practices can apply these concepts, anticipate the needs of the Muslim patient and family, and attract Muslim patients to the practice. OBJECTIVE: Cross cultural knowledge can motivate dental hygienists to adopt culturally acceptable behaviors, strengthen patient-provider relationships and optimize therapeutic outcomes. Trends in Muslim population growth, Islamic history and beliefs, modesty practices, healthcare beliefs, contraception, childbearing, childrearing, pilgrimage, dietary practices, dental care considerations and communication are explained. MATERIALS AND METHODS: This paper reviews traditional Muslim beliefs and practices regarding lifestyle, customs, healthcare and religion as derived from the literature and study abroad experiences. RESULTS AND DISCUSSION: Recommendations are offered on how to blend western healthcare with Islamic practices when making introductions, appointments, eye contact, and selecting a practitioner. The significance of fasting and how dental hygiene care can invalidate the fast are also discussed. CONCLUSION: The ultimate goal is for practitioners to be culturally competent in providing care to Muslim patients, while keeping in mind that beliefs and practices can vary widely within a culture.

Sternal neoangiogenesis following internal mammary artery devascularization: an experimental model.

AIM: The use of bilateral internal thoracic arteries (BIMA) for coronary artery revascularization is associated with better long-term survival and longer freedom from reoperation. Concerns of deep sternal wound infections and mediastinitis have constantly emerged with the utilization of BIMA grafts on a routine basis, especially in diabetic patients. METHODS: We performed a quantitative evaluation of sternal bone healing and angiogenesis after left (LIMA) or bilateral internal mammary artery (BIMA) ligation two and four weeks after sternotomy in normal and diabetic Sprague-Dawley rats. RESULTS: The BIMA group showed a significant increase in neoangiogenesis two weeks after surgery compared to LIMA and control groups (control: 38.3 ± 5.1 vessels/mm², LIMA: 31.4 ± 3.6 vessels/mm², BIMA: 81.6 ± 7.7 vessels/mm²; P=0.047 and P=0.04, respectively). Four weeks after the procedure, bilateral devascularization was associated with lower microvessel formation when compared to LIMA or control groups (control: 50.4 ± 5.2 vessels/mm², LIMA: 64.6 ± 4.9 vessels/mm²; BIMA: 31.5 ± 4.4 vessels/mm²; P=0.006 and P=0.02, respectively). Diabetic animals showed similar results with lower four weeks microvessel formation. However, there were no significant differences when animals with induced diabetes were compared to the normal euglycemic groups for each procedure performed. CONCLUSION: BIMA ligation promotes an early increase in neoangiogenesis. Progressive sternal consolidation is associated with a significant lower level of capillaries and arterioles in the BIMA group four weeks after ligation. Diabetes did not influence the extent of neoangiogenesis between groups with similar procedures. More important clinical determinants could explain the increase incidence of sternal infection in this specific population.

Hand-held thoracic sonography for detecting post-traumatic pneumothoraces: the Extended Focused Assessment with Sonography for Trauma (EFAST).

BACKGROUND: Thoracic ultrasound (EFAST) has shown promise in inferring the presence of post-traumatic pneumothoraces (PTXs) and may have a particular value in identifying occult pneumothoraces (OPTXs) missed by the AP supine chest radiograph (CXR). However, the diagnostic utility of hand-held US has not been previously evaluated in this role. METHODS: Thoracic US examinations were performed during the initial resuscitation of injured patients at a provincial trauma referral center. A high frequency linear transducer and a 2.4 kg US attached to a video-recorder were used. Real-time EFAST examinations for PTXs were blindly compared with the subsequent results of CXRs, a composite standard (CXR, chest and abdominal CT scans, clinical course, and invasive interventions), and a CT gold standard (CT only). Charts were reviewed for in-hospital outcomes and follow-up. RESULTS: There were 225 eligible patients (207 blunt, 18 penetrating); 17 were excluded from the US examination because of battery failure or a lost probe. Sixty-five (65) PTXs were detected in 52 patients (22% of patients), 41 (63%) being occult to CXR in 33 patients (14.2% whole population, 24.6% of those with a CT). The US and CXR agreed in 186 (89.4%) of patients, EFAST was better in 16 (7.7%), and CXR better in 6 (2.9%). Compared with the composite standard, the sensitivity of EFAST was 58.9% with a likelihood ratio of a positive test (LR+) of 69.7 and a specificity of 99.1%. Comparing EFAST directly to CXR, by looking at each of 266 lung fields with the benefit of the CT gold standard, the EFAST showed higher sensitivity over CXR (48.8% versus 20.9%). Both exams had a very high specificity (99.6% and 98.7%), and very predictive LR+ (46.7 and 36.3). CONCLUSION: EFAST has comparable specificity to CXR but is more sensitive for the detection of OPTXs after trauma. Positive EFAST findings should be addressed either clinically or with CT depending on hemodynamic stability. CT should be used if detection of all PTXs is desired.

Where's the tube? Evaluation of hand-held ultrasound in confirming endotracheal tube placement.

INTRODUCTION: The diagnosis of endotracheal tube (ETT) mal-position may be delayed in extreme environments. Several methods are utilized to confirm proper ETT placement, but these methods can be unreliable or unavailable in certain settings. Thoracic sonography, previously utilized to detect pneumothoraces, has not been tested to assess ETT placement. HYPOTHESIS: Thoracic sonography could correlate with pulmonary ventilation, and thereby, help to confirm proper ETT placement. METHODS: Thirteen patients requiring elective intubation under general anesthesia, and data from two trauma patients were evaluated. Using a portable, hand-held, ultrasound (PHHU) machine, sonographic recordings of the chest wall visceral-parietal pleural interface (VPPI) were recorded bilaterally in each patient during all phases of airway management: (1) pre-oxygenation; (2) induction; (3) paralysis; (4) intubation; and (5) ventilation. RESULTS: The VPPI could be well-imaged for all of the patients. In the two trauma patients, right mainstem intubations were noted in which specific pleural signals were not seen in the left chest wall VPPI after tube placement. These signs returned after correct repositioning of the ETT tube. In all of the elective surgery patients, signs correlating with bilateral ventilation in each patient were imaged and correlated with confirmation of ETT placement by anesthesiology. CONCLUSIONS: This report raises the possibility that thoracic sonography may be another tool that could be used to confirm proper ETT placement. This technique may have merit in extreme environments, such as in remote, pre-hospital settings or during aerospace medical transports, in which auscultation is impossible due to noise, or capnography is not available, and thus, requires further scientific evaluation.

Regulation of VEGF-induced endothelial cell PAF synthesis: role of p42/44 MAPK, p38 MAPK and PI3K pathways.

1. Vascular endothelial growth factor (VEGF) is a potent angiogenic and inflammatory mediator. We have recently shown that this latter effect requires the activation of Flk-1 receptor and subsequent endothelial cell (EC) PAF synthesis. However, the intracellular events that regulate EC PAF synthesis upon Flk-1 stimulation by VEGF remain to be elucidated. 2. Using specific inhibitors and Western blot analysis, we herein report that in bovine aortic endothelial cells (BAEC), VEGF induces the synthesis of PAF through the cascade activation of Flk-1 receptor, phospholipase Cgamma (PLCgamma), protein kinase C (PKC) and p42/44 mitogen-activated protein kinases (MAPK). 3. Moreover, we demonstrate that VEGF-mediated PAF synthesis requires the activation of p38 MAPK, likely by directing the conversion of lyso-PAF to PAF. 4. Interestingly, we observed that VEGF also promoted the activation of the phosphatidyl inositol-3-phosphate kinase (PI3K) pathway, and that its blockade potentiated PAF synthesis following a VEGF treatment. Consequently, it appears that the PI3K pathway acts as a negative regulator of EC PAF synthesis. 5. Taken together, these results allow a better understanding of the intracellular events activated upon EC stimulation by VEGF, and shed a new light on the mechanisms by which VEGF induces PAF synthesis.

Vascular endothelial growth factor production by isolated rat hepatocytes after cold ischemia-warm reoxygenation.

Inflammatory disturbances in the liver microcirculation have been associated with preservation injury of hepatic grafts. Vascular endothelial growth factor (VEGF), a proinflammatory growth factor released by hepatocytes, acts on sinusoidal endothelial cells, but its implication in graft injury is still unclear. We studied VEGF production by rat hepatocytes after cold ischemia and warm reoxygenation and compared the capacity of University of Wisconsin (UW) and sodium-lactobionate-sucrose (SLS) preservation solutions to maintain this hepatocellular function. Isolated hepatocytes were kept for 0, 24, and 48 hours at 4 degrees C in either solution (cold ischemia), then incubated for 1 to 24 hours at 37 degrees C (warm reoxygenation). We assessed cell viability and production of VEGF messenger RNA (mRNA) and protein. Cell viability decreased in a linear time-dependent fashion by 10% after 48 hours of cold preservation and by an additional 40% after 24 hours of warm culture. Very little VEGF mRNA could be detected after up to 48 hours of simple cold preservation in either solution. However, subsequent warm culture led to a robust and rapid increase in VEGF mRNA expression within the first hour, which declined to close to background levels within 8 to 12 hours in culture. This effect was more important in cells preserved in SLS than UW solution. Similarly, cold preservation alone did not trigger VEGF secretion. VEGF secretion was detected after culturing hepatocytes at 37 degrees C and reached a maximal secretion rate within 12 to 15 hours. However, VEGF production by preserved cells was reduced compared with unstored cells. In conclusion, cold ischemia and warm reoxygenation triggers VEGF mRNA expression by hepatocytes, but subsequent VEGF secretion is partially impaired, suggesting posttranslational defects.

Myocardial contractile responsiveness to endothelin-1 in the post-infarction rat model of heart failure: effects of chronic quinapril.

Cardiac endothelin-1 (ET-1) levels and ET receptor expression are increased in congestive heart failure (CHF). In order to determine whether this results in increased responsiveness of ET-A or ET-B receptors to ET-1, we evaluated the contractile effects of ET-1 in isolated papillary muscles isolated from hearts of control rats and from rats 4 weeks post myocardial infarction (MI) having received no therapy or chronic quinapril therapy. The ET-1 dose-response was biphasic in normal muscles. The use of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 revealed that the initial decrease in tension was the result of ET-B receptor stimulation. Blockade of nitric oxide (NO) production with L-NAME abolished the initial decrease in tension. MI resulted in CHF that was partially reversed by quinapril. In MI, the positive inotropic effects of ET-1 were enhanced due to the loss of the initial ET-B receptor mediated decrease in tension, as well as an increase in the positive inotropic effects of ET-A receptors. This was associated with an increase in ET-A and ET-B receptor mRNA and a decrease in cardiac ecNOS protein. Four weeks of therapy with quinapril attenuated the positive inotropic effects of ET-1 and prevented the increase in ET-A receptor mRNA. Although quinapril did not restore the effects of ET-B receptor stimulation or prevent the increase in ET-B mRNA, it did restore cardiac ecNOS protein expression. Thus, the inotropic response to ET-1 is biphasic due to an overall positive inotropic effect of ET-A receptor stimulation and an ET-B receptor mediated decrease in contractility at low ET-1 concentrations which appears to be mediated by cardiac ecNOS (NO). In post-MI CHF, responsiveness to ET-A receptors increases and the ET-B mediated negative inotropic response is lost despite an increase in both receptor subtypes. Quinapril therapy attenuates these effects and normalises cardiac ecNOS protein.

Long-term effects of nonselective endothelin A and B receptor antagonism in postinfarction rat: importance of timing.

BACKGROUND: Some controversy exists as to the effects of endothelin (ET) receptor antagonism on long-term post-myocardial infarction (MI) evolution, particularly as it relates to the timing of the intervention after MI (<24 hours versus 10 days). METHODS AND RESULTS: Sham rats and rats surviving an acute MI for >20 hours (n=301) were assigned to treatment with saline or the nonselective ET(A) and ET(B) receptor antagonist LU 420627 (LU) started <24 hours (early) or 10 days (late) after MI and continued for 100 days. Long-term LU treatment led to increased mortality of rats with large MI, regardless of the timing of initiation of therapy. Early initiation of LU reduced survival from 61% to 16% (P<0.001 versus untreated), and later initiation reduced survival to 36% (P=0.012 versus untreated and P<0.001 versus early initiation). Early initiation of LU led to scar thinning, further left ventricular (LV) dilatation, LV dysfunction, and an excessive rise in right ventricular systolic pressure. Later initiation of LU did not modify scar formation but resulted in LV dilatation and dysfunction compared with the untreated group. Cardiac fibrosis tended to increase in the LU-treated MI groups. LU in the sham group reduced cardiac endothelial constitutive nitric oxide synthase but did not modify the changes that occurred with a large MI. CONCLUSIONS: The use of the nonselective ET(A) and ET(B) receptor antagonist LU results in reduced survival, ventricular dilatation, and dysfunction whether started early or late after MI. Early initiation of LU resulted in scar expansion and a particularly unfavorable outcome.

VEGF stimulation of endothelial cell PAF synthesis is mediated by group V 14 kDa secretory phospholipase A2.

1. Vascular endothelial growth factor (VEGF) is a potent inducer of inflammation, and we have shown that this latter effect is mediated through endothelial cell (EC) PAF synthesis. Since the phospholipid remodelling pathway enzymes (CoA-independent transacylase, CoA-IT; phospholipase A2, PLA2; and lyso-PAF acetyltransferase, lyso-PAF-AT) may participate in PAF synthesis, we assessed their contribution to VEGF-induced PAF synthesis in bovine aortic EC (BAEC) and human umbilical vein EC (HUVEC). 2. VEGF enhanced BAEC and HUVEC PAF synthesis by up to 28 and 4 fold above basal levels respectively. 3. A pretreatment with a CoA-IT and lyso-PAF-AT inhibitor (Sanguinarin; 500 nM) blocked VEGF-induced PAF synthesis by 95%, a specific CoA-IT inhibitor (SKF45905; 10 - 50 microM) was without effect, confirming the crucial role of the PLA2 and lyso-PAF-AT. 4. Treatment with secreted PLA2 (sPLA2) inhibitors which have been shown to inhibit both groups IIA and V sPLA2 (SB203347; 10 microM and LY311727; 100 microM) blocked EC PAF synthesis by up to 90%, whereas selective inhibition of group IIA sPLA2 (LY311727; 1 microM) had no significant effect. 5. RT - PCR and Western blot analyses demonstrated the presence of group V sPLA2 whereas group IIA sPLA2 was undetected in EC. 6. Treatment with cytosolic and calcium-independent PLA2 inhibitors (Arachidonyl trifluoromethyl ketone, Bromoenol lactone, Methyl arachydonyl fluorophosphate, up to 50 microM) did not prevent but rather potentiated the VEGF effect on EC PAF synthesis. 7. These results provide evidence that with VEGF activation of EC cells, the group V sPLA2 provides substrate for EC PAF formation.

Coronary artery endothelial dysfunction after ischemia-reperfusion and acute untreated rejection in a canine heterotopic heart transplantation model.

BACKGROUND: Acute rejection is a common problem in heart transplantation and may contribute to the development of cardiac allograft vasculopathy. This study was designed to evaluate the mechanisms of coronary endothelial dysfunction associated with ischemia-reperfusion and acute untreated rejection. METHODS: Two groups of mongrel dogs (n=7 per group) underwent heterotopic cervical heart transplantation without immunosuppression. Allografts were harvested on posttransplant day 1 (group 1) and day 5 (group 2). A third group of unoperated dogs served as control (group 3). After harvesting, epicardial coronary arteries were studied in organ chamber for endothelium-dependent and independent reactivity. RESULTS: Group 1 displayed multifocal ischemic damage without any rejection while hearts from group 2 reached grade IV rejection. Immunohistochemical studies for von Willebrand factor showed expression on coronary endothelial cells in all animals with scattered areas of denudation in transplanted groups. Endothelium-dependent responses to acetylcholine, calcium ionophore A23147, and bradykinin were unaffected in groups 1 and 2. Endothelial relaxations to sodium fluoride (Gi-protein activator) was significantly reduced in group 1 and significantly increased in group 2 compared with control. Responses to serotonin and UK14304 (receptors linked to Gi-protein) were significantly increased in group 2. Responses to thrombin were decreased in both groups. Endothelium-independent responses were unaffected. CONCLUSIONS: In the canine model of heterotopic heart transplantation, the early (24 hr) endothelial dysfunction seen after transplantation is specific to the thrombin receptor and the Gi-protein signaling pathway. Acute untreated rejection did not modify the alteration in endothelial reactivity to thrombin but enhanced the sensibility of the Gi-protein signaling pathways.

Bolus endovascular PDGFR-beta antisense treatment suppressed intimal hyperplasia in a rat carotid injury model.

BACKGROUND: Intimal thickening in accelerated arteriopathies relies on the migration of medial vascular smooth muscle cells (VSMCs) and their proliferation within the neointima. Activation of platelet-derived growth factor receptor-beta (PDGFR-beta) expressed in injured VSMCs is responsible for the migration of medial VSMCs to the intima. In the present study, we wanted to assess whether a single local endovascular delivery of antisense PDGFR-beta in injured rat carotid arteries would be sufficient to prevent intimal hyperplasia and how it might contribute to the vascular healing process. METHODS AND RESULTS: A bolus of antisense PDGFR-beta delivered into injured rat carotid arteries reduced PDGFR-beta protein overexpression by >90% from day 3 to 28 after injury. At day 28 after injury, compared with injured untreated carotids, treatment with antisense PDGFR-beta reduced intimal hyperplasia by 58% and medial VSMC migration by 49% and improved vascular reendothelialization by 100% and vascular reactivity (EC(50)) to acetylcholine by 5-fold. CONCLUSIONS: A single-bolus luminal delivery of antisense PDGFR-beta to injured rat carotids reduced intimal hyperplasia, improved the reendothelialization process, and led to the recovery of endothelium-dependent regulation of vascular tone.

Vascular endothelial growth factor effect on endothelial cell proliferation, migration, and platelet-activating factor synthesis is Flk-1-dependent.

Vascular endothelial growth factor (VEGF) is a potent inducer of endothelial cell (EC) proliferation and migration in vitro as well as inflammation in vivo. We showed recently that VEGF effect on vascular permeability was dependent on the synthesis of platelet-activating factor (PAF) by EC. Consequently, we sought to evaluate by antisense knockdown of gene expression the contribution of VEGF receptors (Flt-1 and Flk-1) on these events. VEGF (10(-11) to 10(-8) M) elicited a dose-dependent increase of bovine aortic EC proliferation, migration, and PAF synthesis by up to 2.05-, 1.31- and 35.9-fold above basal levels, respectively. A treatment with two modified antisense oligomers (1-5 x 10(-7) M) directed against Flk-1 mRNA blocked by 100, 91, and 85% the proliferation, migration, and PAF synthesis mediated by VEGF, respectively. A treatment with two antisense oligomers directed against Flt-1 mRNA failed to modulate these activities. The use of placenta growth factor (up to 10(-8) M), an Flt-1-specific agonist, induced only a slight increase (0.6-fold) of PAF synthesis. These data illustrate the crucial role of Flk-1 in EC stimulation by VEGF. The capacity to inhibit the protein synthesis of Flt-1 and Flk-1 by antisense oligonucleotides provides a new approach to block VEGF pathological effects in vivo.

Identification and characterization of a new growth hormone-releasing peptide receptor in the heart.

Hexarelin, a synthetic hexapeptide of the growth hormone-releasing peptide (GHRP) family with strong growth hormone (GH)-releasing activity, features protecting activity against postischemic ventricular dysfunction in hearts from GH-deficient and senescent rats. To document whether hexarelin action is mediated through specific cardiac receptors, perfusion of Langendorff rat hearts with hexarelin and binding studies were carried out. In the Langendorff rat heart system, hexarelin induced a dose-dependent increase in coronary perfusion pressure. Nifedipine, chelerythrine, and bisindolylmaleimide partially inhibited the vasoconstriction induced by hexarelin, suggesting that this effect was mediated at least in part by L-type Ca(2+) channels and protein kinase C. In contrast, diclofenac and 1-(7-carboxyheptyl)imidazole were without effect, suggesting that prostaglandins and thromboxanes were not involved in the coronary vasoconstriction induced by hexarelin. To characterize the hexarelin binding sites in the rat heart, [(125)I]Tyr-Bpa-Ala-hexarelin was used as photoactivatable radioligand in saturation and competitive binding studies. We specifically labeled a hexarelin receptor with an M(r) of 84 000 in rat cardiac membranes. Saturation binding curves revealed a single class of binding sites with a K(d) of 14.5 nmol/L and a density of 91 fmol/mg of protein. Competition binding studies gave an IC(50) of 2.9 micromol/L for hexarelin; MK-0677 and EP51389, both potent GH secretagogues, did not displace the binding of the photoactivatable derivative from rat cardiac membranes. Interestingly, both compounds were devoid of any vasoconstrictive activity. These results suggest the existence of a new class of hexarelin receptor in the heart, whose role in the regulation of the coronary vascular tone is yet to be determined.