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Abstract Background The impacts of multicomponent school water, sanitation, and hygiene (WaSH) interventions on children’s health are unclear. We conducted a cluster-randomized controlled trial to test the effects of a school WaSH intervention on children’s malnutrition, dehydration, health literacy (HL), and handwashing (HW) in Metro Manila, Philippines. Methods The trial lasted from June 2017 to March 2018 and included children, in grades 5, 6, 7, and 10, from 15 schools. At baseline 756 children were enrolled. Seventy-eight children in two clusters were purposively assigned to the control group (CG); 13 clusters were randomly assigned to one of three intervention groups: low-intensity health education (LIHE; two schools, n = 116 children), medium-intensity health education (MIHE; seven schools, n = 356 children), and high-intensity health education (HIHE; four schools, n = 206 children). The intervention consisted of health education (HE), WaSH policy workshops, provision of hygiene supplies, and WaSH facilities repairs. Outcomes were: height-for-age and body mass index-for-age Z scores (HAZ, BAZ); stunting, undernutrition, overnutrition, dehydration prevalence; HL and HW scores. We used anthropometry to measure children’s physical growth, urine test strips to measure dehydration, questionnaires to measure HL, and observation to measure HW practice. The same measurements were used during baseline and endline. We used multilevel mixed-effects logistic and linear regression models to assess intervention effects. Results None of the interventions reduced undernutrition prevalence or improved HAZ, BAZ, or overall HL scores. Low-intensity HE reduced stunting (adjusted odds ratio [aOR] 0.95; 95% CI 0.93 to 0.96), while low- (aOR 0.57; 95% CI 0.34 to 0.96) and high-intensity HE (aOR 0.63; 95% CI 0.42 to 0.93) reduced overnutrition. Medium- (adjusted incidence rate ratio [aIRR] 0.02; 95% CI 0.01 to 0.04) and high-intensity HE (aIRR 0.01; 95% CI 0.00 to 0.16) reduced severe dehydration. Medium- (aOR 3.18; 95% CI 1.34 to 7.55) and high-intensity HE (aOR 3.89; 95% CI 3.74 to 4.05) increased observed HW after using the toilet/urinal. Conclusion Increasing the intensity of HE reduced prevalence of stunting, overnutrition, and severe dehydration and increased prevalence of observed HW. Data may be relevant for school WaSH interventions in the Global South. Interventions may have been more effective if adherence was higher, exposure to interventions longer, parents/caregivers were more involved, or household WaSH was addressed. Trial registration number DRKS00021623.

Objectives: This study sought to determine the degree of Evolut (Medtronic) leaflet pinning, diameter expansion, leaflet overhang, and performance at different implant depths of the balloon-expandable Sapien 3 (S3, Edwards Lifesciences LLC) transcatheter heart valve (THV) within the Evolut THV., Background: Preservation of coronary access and flow is a major factor when considering the treatment of failed Evolut THVs., Methods: An in vitro study was performed with 20-, 23-, 26-, and 29-mm S3 THVs deployed within 23-, 26-, 29-, and 34-mm Evolut R THVs, respectively. The S3 outflow was positioned at various depths at node 4, 5, and 6 of the Evolut R. Neoskirt height, leaflet overhang, performance, and Evolut R valve housing diameter expansion were assessed under physiological conditions as per ISO 5840-3 standard., Results: The neoskirt height for the Evolut R was shorter when the S3 outflow was positioned at node 4 compared with node 6 (node 4 height for 23 mm = 16.3 mm, 26 mm = 17.1 mm, 29 mm = 18.3 mm, and 34 mm = 19.9 mm vs node 6 height for 23 mm = 23.9 mm, 26 mm = 23.4 mm, 29 mm = 24.7 mm, and 34 mm = 27 mm Evolut R). All configurations exhibited acceptable hydrodynamic performance irrespective of the degree of leaflet overhang, except the 29-mm S3 implanted in 34-mm Evolut R at node 4 (regurgitant fraction >20%). The valve housing radius of the index Evolut R increased when the S3 was implanted, with the increase ranging from 0 to 2.5 mm., Conclusions: Placement of the S3 at a lower implant position within an index Evolut R reduces the neoskirt height with no significant compromise to S3 valve function despite a higher degree of leaflet overhang. Low S3 implantation may facilitate future coronary access after redo transcatheter aortic valve replacement., Competing Interests: Funding Support and Author Disclosures Funding for the study was provided by Medtronic. Dr Akodad has received research funding from Medtronic, Biotronik, MUSE Explore, and Federation Française de Cardiologie. Dr Tang is a physician proctor and consultant for Medtronic; is a consultant for Abbott Structural Heart and NeoChord; and is a physician advisory board member for Abbott Structural Heart and JenValve. Dr Gada is a consultant for Abbott Vascular, Bard Medical, Boston Scientific, and Medtronic. Dr Rogers is a consultant and physician proctor to Edwards Lifesciences and Medtronic; has equity in Transmural Systems; and is a co-inventor on dedicated electrosurgery devices assigned to NIH. Dr Rutkin serves as a consultant for Medtronic. Dr Puri is a consultant to Medtronic, Boston Scientific, Philips, Bioventrix, Products & Features, Shockwave Medical, Centerline Biomedical, and VDyne. Dr Rovin is a physician proctor with Medtronic and Abbott; and is a Speakers Bureau for Medtronic and Abbott. Dr Leipsic holds institutional research core lab agreements with Medtronic, Edwards Lifesciences, Abbott, Boston Scientific, and Pi CARDIA. Dr Caskey serves as a proctor for Medtronic. Dr Sondergaard has received consultant fees and/or institutional research grants from Abbott, Boston Scientific, Edwards Lifesciences, Medtronic, and Sahajanand Medical Technology. Dr Grubb is a speaker, proctor, and principal investigator for Edwards Lifesciences; is a speaker, proctor, and principal investigator for Medtronic; and her employer receives institutional grants and educational funding from Edwards Lifesciences and Medtronic. Dr Gleason’s employer receives institutional grants and educational funding from Edwards Lifesciences and Medtronic; he has no personal financial disclosures. Ms Garde, Mr Tadros, and Mr Teodoru are all employees and shareholders of Medtronic. Dr Wood is a consultant and receives unrestricted grant support from Medtronic, Edwards Lifesciences, and Abbott Vascular. Mr Sathananthan is a consultant to Edwards Lifesciences and Medtronic; and has received speaking fees from Edwards Lifesciences and NVT. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The SMall Annuli Randomized To Evolut or SAPIEN (SMART) Trial was designed to compare the performance of the two most widely available commercial transcatheter aortic valve replacement (TAVR) devices in patients with symptomatic severe native aortic stenosis with a small aortic valve annulus undergoing transfemoral TAVR. Patients with small aortic valve annuli are typically female and are often underrepresented in clinical trials., Methods: The SMART Trial is an international, prospective, multi-center, randomized controlled, post-market trial. The trial will be conducted in approximately 700 subjects at approximately 90 sites globally. Inclusion criteria include severe aortic stenosis, aortic valve annulus area of ≤430 mm 2 based on multi-detector computed tomography, and appropriate anatomy for both the Medtronic Evolut PRO/PRO+ self-expanding and Edwards SAPIEN 3/3 Ultra balloon-expandable devices. The primary clinical outcome composite endpoint is defined as mortality, disabling stroke or heart failure rehospitalization at 12 months. The co-primary valve function composite endpoint is defined as bioprosthetic valve dysfunction at 12 months which includes hemodynamic structural valve dysfunction, defined as a mean gradient ≥20 mmHg, non-structural valve dysfunction, defined as severe prothesis-patient mismatch or ≥moderate aortic regurgitation, thrombosis, endocarditis, and aortic valve re-intervention. Powered secondary endpoints will be assessed hierarchically., Conclusions: The SMART trial will be the largest head-to-head comparative trial of transfemoral TAVR using the two most widely available contemporary TAVR devices in the setting of small aortic annuli and the largest trial to enroll primarily women., Clinical Trial Registration: URL: www.clinicaltrials.gov, Unique identifier: NCT04722250., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: The REFLECT I trial investigated the safety and effectiveness of the TriGuard™ HDH (TG) cerebral embolic deflection device in patients undergoing transcatheter aortic valve replacement (TAVR)., Methods and Results: This prospective, multicentre, single-blind, 2:1 randomized (TG vs. no TG) study aimed to enrol up to 375 patients, including up to 90 roll-in patients. The primary combined safety endpoint (VARC-2 defined early safety) at 30 days was compared with a performance goal. The primary efficacy endpoint was a hierarchical composite of (i) all-cause mortality or any stroke at 30 days, (ii) National Institutes of Health Stroke Scale (NIHSS) worsening at 2-5 days or Montreal Cognitive Assessment worsening at 30 days, and (iii) total volume of cerebral ischaemic lesions detected by diffusion-weighted magnetic resonance imaging at 2-5 days. Cumulative scores were compared between treatment groups using the Finkelstein-Schoenfeld method. A total of 258 of the planned, 375 patients (68.8%) were enrolled (54 roll-in and 204 randomized). The primary safety outcome was met compared with the performance goal (21.8% vs. 35%, P < 0.0001). The primary hierarchical efficacy endpoint was not met (mean efficacy score, higher is better: -5.3 ± 99.8 TG vs. 11.8 ± 96.4 control, P = 0.31). Covert central nervous system injury was numerically lower with TG both in-hospital (46.1% vs. 60.3%, P = 0.0698) and at 5 days (61.7 vs. 76.2%, P = 0.054) compared with controls., Conclusion: REFLECT I demonstrated that TG cerebral protection during TAVR was safe in comparison with historical TAVR data but did not meet the predefined effectiveness endpoint compared with unprotected TAVR controls., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objectives: The REFLECT II (Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Implantation) trial was designed to investigate the safety and efficacy of the TriGUARD 3 (TG3) cerebral embolic protection in patients undergoing transcatheter aortic valve replacement., Background: Cerebral embolization occurs frequently following transcatheter aortic valve replacement and procedure-related ischemic stroke occurs in 2% to 6% of patients at 30 days. Whether cerebral protection with TriGuard 3 is safe and effective in reducing procedure-related cerebral injury is not known., Methods: This prospective, multicenter, single-blind, 2:1 randomized (TG3 vs. no TG3) study was designed to enroll up to 345 patients. The primary 30-day safety endpoint (Valve Academic Research Consortium-2 defined) was compared with a performance goal (PG). The primary hierarchical composite efficacy endpoint (including death or stroke at 30 days, National Institutes of Health Stroke Scale score worsening in hospital, and cerebral ischemic lesions on diffusion-weighted magnetic resonance imaging at 2 to 5 days) was compared using the Finkelstein-Schoenfeld method., Results: REFLECT II enrolled 220 of the planned 345 patients (63.8%), including 41 roll-in and 179 randomized patients (121 TG3 and 58 control subjects) at 18 US sites. The sponsor closed the study early after the U.S. Food and Drug Administration recommended enrollment suspension for unblinded safety data review. The trial met its primary safety endpoint compared with the PG (15.9% vs. 34.4% (p < 0.0001). The primary hierarchal efficacy endpoint at 30 days was not met (mean scores [higher is better]: -8.58 TG3 vs. 8.08 control; p = 0.857). A post hoc diffusion-weighted magnetic resonance imaging analysis of per-patient total lesion volume above incremental thresholds showed numeric reductions in total lesion volume >500 mm 3 (-9.7%) and >1,000 mm 3 (-44.5%) in the TG3 group, which were more pronounced among patients with full TG3 coverage: -51.1% (>500 mm 3 ) and -82.9% (>1,000 mm 3 )., Conclusions: The REFLECT II trial demonstrated that the TG3 was safe compared with a historical PG but did not meet its pre-specified primary superiority efficacy endpoint., Competing Interests: FUNDING SUPPORT AND Author Disclosures This work was supported by an unrestricted research grant from Keystone Heart. Dr. Nazif has equity in Venus Medtech; and has received consulting fees or honoraria from Keystone Heart, Edwards Lifesciences, Medtronic, and Boston Scientific. Dr. Dhoble has received honoraria from Edwards Lifesciences, Abbott Vascular, and Keystone Heart. Dr. Forrest has received consulting fees from Edwards Lifesciences and Medtronic. Dr. Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Keystone Heart, Protembis, and Novartis for speaker and consulting fees; and has received financial support for research activities from Sanofi, Novartis, Bristol Myers Squibb, Mapi Pharma, Keystone Heart, Protembis, Boston Scientific, and V-WAVE Medical. Dr. Dwyer has received personal compensation from Novartis, EMD Serono, and Keystone Heart; and has received financial support for research activities from Bristol Myers Squibb, Novartis, Mapi Pharma, Keystone Heart, Protembis, and V-WAVE Medical. Dr. Lansky has equity in Venus Medtech; and has received consulting fees from Keystone Heart, Medtronic, Boston Scientific, and AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Transcatheter aortic-valve replacement (TAVR) is an alternative to surgery in patients with severe aortic stenosis who are at increased risk for death from surgery; less is known about TAVR in low-risk patients., Methods: We performed a randomized noninferiority trial in which TAVR with a self-expanding supraannular bioprosthesis was compared with surgical aortic-valve replacement in patients who had severe aortic stenosis and were at low surgical risk. When 850 patients had reached 12-month follow-up, we analyzed data regarding the primary end point, a composite of death or disabling stroke at 24 months, using Bayesian methods., Results: Of the 1468 patients who underwent randomization, an attempted TAVR or surgical procedure was performed in 1403. The patients' mean age was 74 years. The 24-month estimated incidence of the primary end point was 5.3% in the TAVR group and 6.7% in the surgery group (difference, -1.4 percentage points; 95% Bayesian credible interval for difference, -4.9 to 2.1; posterior probability of noninferiority >0.999). At 30 days, patients who had undergone TAVR, as compared with surgery, had a lower incidence of disabling stroke (0.5% vs. 1.7%), bleeding complications (2.4% vs. 7.5%), acute kidney injury (0.9% vs. 2.8%), and atrial fibrillation (7.7% vs. 35.4%) and a higher incidence of moderate or severe aortic regurgitation (3.5% vs. 0.5%) and pacemaker implantation (17.4% vs. 6.1%). At 12 months, patients in the TAVR group had lower aortic-valve gradients than those in the surgery group (8.6 mm Hg vs. 11.2 mm Hg) and larger effective orifice areas (2.3 cm 2 vs. 2.0 cm 2 )., Conclusions: In patients with severe aortic stenosis who were at low surgical risk, TAVR with a self-expanding supraannular bioprosthesis was noninferior to surgery with respect to the composite end point of death or disabling stroke at 24 months. (Funded by Medtronic; ClinicalTrials.gov number, NCT02701283.)., (Copyright © 2019 Massachusetts Medical Society.)

Objectives: To examine whether transcatheter aortic valve replacement (TAVR) is a safe and effective treatment option for aortic stenosis in patients with end-stage renal disease (ESRD)., Background: Patients with ESRD undergoing surgical aortic valve replacement have an operative mortality approaching 20% and a 10-year survival of approximately 12%. We investigated whether TAVR is a more reasonable option., Methods: This is a multicenter, retrospective study of all patients with ESRD who underwent TAVR in 8 institutions between 12/2011 and 02/2013. Demographic characteristics, mortality, major, and minor complications were evaluated. Outcomes were stratified by operative approach., Results: Forty-three patients with a mean age 76.2 ± 11.0 years and a mean STS predicted risk of mortality of 15.53 ± 8.70% underwent TAVR. Mean duration of dialysis was 45.2 ± 52.3 months (median 29.5 months). Transfemoral (TF) TAVR was performed in 31/43 (72.1%), transapical in 11/43 (25.6%), and transaortic in 1/43 (2.3%). Operative mortality was 14.0% (6/43) with TF mortality 6.5% (2/31) and 33.3% (4/12) in non-TF patients. Six-month mortality was 11/43 (25.6%: 16.1% TF, 50.0% non-TF). Complications included stroke in 2.3% (1/43) and life-threatening or major bleeding in 14.0% (6/43). Discharge to another healthcare facility was 27.0% (10/37). Readmission within 30 days of procedure for any cause was 18.9% (7/37)., Conclusions: Patients with ESRD who undergo TAVR are at high risk for mortality and complications. TAVR outcomes are comparable to but not substantially better than those with SAVR. Transfemoral TAVR seems to be at least as safe and effective as the current standard SAVR in patients undergoing aortic valve replacement. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objectives: To assess aortic arch morphology and aortic length in patients with dissection, traumatic injury, and aneurysm undergoing TEVAR, and to identify characteristics specific to different pathologies., Method: This was a retrospective analysis of the aortic arch morphology and aortic length of dissection, traumatic injury, and aneurysmal patients. Computed tomography imaging was evaluated of 210 patients (49 dissection, 99 traumatic injury, 62 aneurysm) enrolled in three trials that received the conformable GORE TAG thoracic endoprosthesis. The mean age of trauma patients was 43 ± 19.6 years, 57 ± 11.7 years for dissection and 72 ± 9.6 years for aneurysm patients. A standardized protocol was used to measure aortic arch diameter, length, and take-off angle and clockface orientation of branch vessels. Differences in arch anatomy and length were assessed using ANOVA and independent t tests., Results: Of the 210 arches evaluated, 22% had arch vessel common trunk configurations. The aortic diameter and the distance from the left main coronary (LMC) to the left common carotid (LCC) were greater in dissection patients than in trauma or aneurysm patients (p < .001). Aortic diameter in aneurysm patients was greater compared with trauma patients (p < .05). The distances from the branch vessels to the celiac artery (CA) were greater in dissection and aneurysm patients than in trauma patients (p < .001). The take-off angle of the innominate (I), LCCA, and left subclavian (LS) were greater, between 19% and 36%, in trauma patients than in dissection and aneurysm patients (p < .001). Clockface orientation of the arch vessels varies between pathologies., Conclusions: Arch anatomy has significant morphologic differences when comparing aortic pathologies. Describing these differences in a large sample of patients is beneficial for device designs and patient selection., (Copyright © 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Objective: As thoracic aortic aneurysms (TAAs) are more frequently being treated with endografts, the anatomic challenges of the thoracic aorta have led to design modifications of endografts. The Conformable GORE TAG (CTAG) device (W. L. Gore & Associates, Flagstaff, Ariz) was specifically designed to be more conformable in tortuous anatomy, more resistant to compression, and more accommodating to various aortic diameters compared with the original GORE TAG device. This prospective, multicenter study evaluated the safety and effectiveness of the CTAG endograft in the repair of descending TAA., Methods: This was a prospective, multicenter regulatory study with a primary end point of freedom from major device event through 1 month after treatment. Two-year outcomes included aneurysm-related morbidity (endoleaks and morphology changes), aneurysm-related mortality, and all-cause mortality., Results: Fifty-one patients were enrolled between October 2009 and October 2010, with at least one endograft implanted in 50 patients. After the regulatory study successfully completed its primary end point and expanded to a continued-access phase, 15 additional patients were enrolled in the continued-access arm of the study from February 2011 until September 2011, for a total treatment group of 66 patients for the early results and 65 patients for the long-term clinical results with imaging evaluation. There was one 30-day death (1.5%), two patients (3%) with spinal cord ischemia, and two central strokes (3%) ≤30 days. Five patients (7.6%) died ≤1 year; 1 of ascending aortic aneurysm rupture, 2 of cardiac disease, and 2 of respiratory failure. The core laboratory adjudicated 1-month imaging in 60 patients (92.3%), where nine endoleaks (15.0%) were identified (1 type Ia, 4 type II, and 4 indeterminate). Forty-five patients (69.2%) had 2-year imaging with five endoleaks (11.1%; two type II and three indeterminate), and one patient had a distal aortic dilatation that required a secondary intervention. At 2 years, 20 of 38 imaged patients (52.6%) had aneurysm shrinkage ≥5 mm, 15 (39.5%) had no change in diameter, and three patients (7.9%) had an increase in aneurysm diameter of ≥5 mm. There were no conversions, fractures, compressions, or aneurysm ruptures of the treated segment through 2 years., Conclusions: This next-generation thoracic endograft has a low rate of major device events through 2 years, with no graft compressions or device failures. The data for this new endograft demonstrate favorable outcomes and confirm low risks for treatment for patients with TAA. Follow-up will be continued for 5 years., (Published by Elsevier Inc.)

Focal adhesion kinase (FAK) has been implicated in the regulation of cell migration. In addition, FAK expression is increased in a number of highly metastatic tumor cell lines. Therefore, we investigated the role of FAK in regulating migration of prostate carcinoma cell lines with increasing metastatic potential. We show that highly tumorigenic PC3 and DU145 cells exhibit intrinsic migratory capacity, while poorly tumorigenic LNCaP cells require a stimulus to migrate. Increased metastatic potential of PC3 and DU145 cells correlates with increased FAK expression, overall tyrosine phosphorylation and activity, as measured by autophosphorylation of tyrosine 397. However, in PC3 and DU145 cells, FAK autophosphorylation is adhesion dependent whereas a second site of tyrosine phosphorylation, tyrosine 861, a Src specific site, is uncoupled from adhesion-dependent signaling events. Finally, inhibiting the FAK/Src signal transduction pathway by over expressing FRNK (Focal adhesion kinase-Related Non-Kinase), an inhibitor of FAK activation, or treatment with PP2, a Src family kinase inhibitor, significantly inhibited migration of prostate carcinoma cell lines, demonstrating that tumor cell migration continues to be dependent on signals emanating from this pathway.

Nonoperative management of splenic injuries in children is well accepted. However, the need for follow-up abdominal CT to document splenic healing has not been well studied. We retrospectively reviewed initial and follow-up abdominal CT examinations of pediatric patients admitted to our institution with documented splenic trauma who were managed nonoperatively. Eighty-four patients were admitted to our pediatric surgical service with splenic injury documented by CT from 1994 through 1998. The standard approach for splenic injury was bedrest for 5 to 21 days and limited activity for up to 90 days at the discretion of the attending surgeon. Thirty-five of the 84 had follow-up CTs during outpatient follow-up to evaluate and document splenic healing by CT criteria. The initial and follow-up studies were randomized and read blindly by pediatric radiologists using a modified American Association for the Surgery of Trauma grading system (I-V). The age range of the patients was 6 months to 17 years (mean +/- SE; 11 +/- 1 years). Nineteen (54%) were male and 16 (46%) were female. Causes of splenic trauma included motor vehicle accident (22), fall (seven), assault (four), pedestrian versus vehicle (one), and sports injury (one). Eight children (23%) had grade II injuries, 14 (40%) had grade III injuries, and 13 children (37%) had grade IV injuries on initial CT scan. Seven (88%) of the grade II splenic injuries were healed by 64 +/- 11 days. The remaining grade II injury had healed by 210 days. Thirteen (93%) of the grade III splenic injuries were healed by 76 +/- 7 days. The remaining grade III injury was healed by 140 days. Spleens in 10 (77%) of the 13 patients with grade IV injuries were healed by 81 +/- 8 days. Of the three remaining grade IV injuries two were healed by 173 +/- 14 days. The remaining patient's spleen was radiologically considered to have a grade III defect 91 days from the time of injury, and no further CTs were obtained. Of the 34 patients who underwent follow-up CT imaging until splenic healing was demonstrated the mean time to complete healing was 87 +/- 8 days postinjury (range 11-217 days). These data suggest that routine follow-up abdominal CTs may not be necessary to allow children to resume their normal activities after an appropriate time of restricted activity.

Tumor cell interactions with the local microenvironment influence a range of cellular activities. A ubiquitous and important ";signal"; for tumor cells is the surrounding protein stroma, the extracellular matrix (ECM). This protein network varies in composition and structure throughout the body and within tissues, having a profound effect on the cells interacting with it. Input from these proteins regulates normal and tumor cell functions including adhesion, motility, proliferation, apoptosis, and differentiation.

A variety of agonists including phenylephrine (PE) induce hypertrophy in neonatal ventricular cardiomyocytes. Here we report that signals provided by extracellular matrix proteins (ECM) augment the PE-induced hypertrophic response of cardiomyocytes and provide evidence that ECM-dependent signaling is mediated in part by the protein tyrosine kinase, focal adhesion kinase (FAK). Addition of PE to cultured neonatal cardiomyocytes stimulated sarcomeric organization, increased cell size, and induced atrial natriuretic factor in cardiomyocytes plated on the ECM protein laminin or fibronectin. In contrast, cardiomyocytes plated on the non-adhesive substrate gelatin exhibited a reduced capacity to undergo these PE-stimulated hypertrophic changes. In cardiomyocytes cultured on ECM, PE stimulated a rapid increase in tyrosine phosphorylation of focal adhesion proteins including FAK, paxillin, and p130 Crk-associated substrate and subsequent formation of peripheral focal complexes. Inhibition of the PE-induced hypertrophic response by genistein and herbimycin-A indicated a requirement for protein tyrosine kinases in PE signaling. To determine whether activation of FAK is required for PE-induced hypertrophy, a dominant-interfering mutant form of FAK, termed FRNK (FAK-related non-kinase), was ectopically expressed in cardiomyocytes using a replication-defective adenovirus expression system. FRNK expression attenuated PE-stimulated hypertrophy as assessed by cell size, sarcomeric organization, and induction of atrial natriuretic factor. These data indicate that the signal transduction pathways leading to cardiomyocyte hypertrophy are strongly influenced by and/or dependent upon an integrin-mediated signaling process requiring FAK.

Background/purpose: This report reviews our experience using peritoneal drainage (PD) as initial therapy for intestinal perforation in premature infants with and without necrotizing enterocolitis (NEC)., Methods: A chart review was conducted of 18 consecutive premature infants who underwent PD for intestinal perforation from 1995 to 1998. Infants were divided into two groups. Group 1 consisted of eight infants who had intestinal perforation without evidence of NEC. Group 2 consisted of 10 infants who had perforation associated with evidence of NEC. A cohort of 10 infants with intestinal perforation treated with primary laparotomy between 1990 and 1995 was identified by chart review for historical control., Results: All infants improved immediately after PD. In group 1, all survived. Seven (88%) recovered systemically after PD. Of these, five (63%) never required laparotomy. Two (25%) required delayed laparotomy. One infant (12%) failed to continue to improve 48 hours after PD and underwent urgent laparotomy and recovered. In group 2, eight (80%) infants survived. Six (60%) recovered from NEC after PD, but five required delayed laparotomy for obstruction or persistent drainage. Four infants (40%) failed to progress from their initial improvement after PD. Three underwent laparotomy; two recovered and one had total intestinal necrosis and died. The fourth infant died without exploration and total intestinal necrosis was discovered during autopsy. Thus, seven of eight survivors (88%) in group 2 required laparotomy at some point in their course., Conclusions: In premature infants with intestinal perforation, PD allows acute improvement and usually systemic recovery. In infants without evidence of NEC, PD may afford definitive treatment. In contrast, infants with evidence of NEC will likely require laparotomy, but initial PD may allow systemic stabilization and recovery of much of the involved intestine before laparotomy.

Sodium nitroprusside (SNP), a nitrosovasodilator, increases platelet cyclic GMP levels and inhibits platelet activity in vitro. The antiplatelet properties of SNP are not well established in vivo, however, and consequently are not appreciated by clinicians. In our established model of mechanically stenosed canine coronary arteries (MSCA) with intimal damage, periodic acute platelet thrombus formation (APTF) occurs, followed by embolization distally, which then causes cyclic flow reductions (CFRs) in coronary blood flow. Aspirin (ASA) abolished platelet-mediated CFRs in our model, but they recur when epinephrine (EPI) is infused (0.2 microgram/kg/min). SNP was given continuously intravenously (i.v.) to 17 dogs with MSCA; CFRs were abolished in all dogs by SNP at 4.4 +/- 2.7 micrograms/kg/min (mean +/- SD). Mean arterial blood pressure (MAP) decreased by 19 +/- 9 mm Hg (p < 0.001) from control, while heart rate (HR) increased 35 +/- 20 beats/min (p < 0.001). Platelet cyclic GMP levels were 2.9 +/- 1.1 pmol/10(8) platelets before SNP infusion, and increased to 4.3 +/- 1.6 pmol/10(8) platelets (p < 0.05) when CFRs were abolished. CFRs were not renewed during the continued SNP infusion when EPI was infused at 0.2 microgram/kg/min for 20 min in 11 dogs, but CFRs returned within 5-25 min after the SNP infusion was terminated. The return of CFRs occurred together with a decrease in platelet cyclic GMP levels to 3.3 +/- 1.4 pmol/10(8) platelets.(ABSTRACT TRUNCATED AT 250 WORDS)