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The modern practice of cardiovascular medicine involves many ethical controversies in the care of our complex patients. Accordingly, we propose a framework for a practical, clinically based "cardioethics" curriculum that might be incorporated into fellowship training to prepare cardiologists to cope with increasingly complex ethical dilemmas. This work can also be adopted into continuing medical education for cardiologists and other cardiovascular practitioners given the critical importance of collaborative care in cardiology. We discuss heart transplant allocation, futility concerns, withdrawing care, advance care planning, conflicts of interests, and distributive justice. Sound ethical decision-making in cardiology requires a combination of extensive technical knowledge, nuanced appreciation of individual patient goals and values, and thoughtful application of ethical principles and reasoning. Cardiologists have an exceptionally broad toolkit of medications and interventions to address high-stakes disease states. We should maintain a similarly broad ethical toolkit to provide the best care for our patients., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Advanced practice providers (APPs) comprise an increasing proportion of the emergency medicine (EM) workforce, particularly in rural geographies. With little known regarding potential expanding practice patterns, we sought to evaluate trends in independent emergency care services billed by APPs from 2013 to 2019., Methods: We performed a repeated cross-sectional analysis of emergency clinicians independently reimbursed for at least 50 evaluation and management (E/M) services (99281-99285, 99291) from Medicare Part B, with high-acuity services including Codes 99285 and 99291. We describe the outcome proportion of E/M services by acuity level and report at (1) the encounter level and (2) at the clinician level. We stratified analyses by clinician type and geography., Results: A total of 47,323 EM physicians, 10,555 non-EM physicians, and 26,599 APPs were included in analyses. APPs billed emergency care services independently for 5.1% (rural 7.3%, urban 4.8%) of all high-acuity encounters in 2013, increasing to 9.7% (rural 16.4%, urban 8.8%) by 2019. At the clinician level, in 2013, the average rural-practicing APP independently billed 22.8% of services as high acuity, 72.6% as moderate acuity, and 4.5% as low acuity. By 2019, the average rural-practicing APP independently billed 36.2% of services as high acuity, representing a +58.8% relative increase from 2013. Relative increases in high-acuity visits independently billed by APPs were substantially greater when compared to EM physicians across both rural and urban geographies., Conclusions: In 2019, APPs billed independent services for approximately one in six high-acuity ED encounters in rural geographies and one in 11 high-acuity ED encounters in urban geographies, and well over one-third of the average APPs' encounters were for high-acuity E/M services. Given differences in training and reimbursement between clinician types, these estimates suggest further work is needed evaluating emergency care staffing decision making., (© 2022 Society for Academic Emergency Medicine.)

Objectives: This study aimed to decrease the rate of falls in children with cognitive and physical impairments on a pediatric acute inpatient rehabilitation unit (IRU) using a novel tool, the Stoplight Mobility Alert System (SMAS)., Methods: We conducted a pilot, prospective, quality improvement study in an 8-bed (increased to 12 beds; October 1, 2019) acute inpatient pediatric IRU at a level 1 trauma center. All patients admitted between October 1, 2012, and October 1, 2020, were included as participants. Interventions used were as follows: (1) SMAS, a colored alert system placed on door slides and in-room for visual cues (red, assistance/hands on; yellow, supervision/eyes on; green, independent/hands off), and (2) handouts and one-on-one education for staff and patients/families. Main outcome measures included fall rate on the IRU., Results: Using the SMAS, the total fall rate decreased from 10.78 to 4.36 falls per 1000 patient-days. Longitudinally, the intrinsic fall rate decreased from 8.36 to 5.60 falls per 1000 patient-days, and the extrinsic fall rate decreased from 4.56 to 1.36 falls per 1000 patient-days., Conclusions: The implementation of the SMAS is effective in decreasing total, intrinsic, and extrinsic fall rates in an acute pediatric inpatient rehabilitation program both acutely and longitudinally., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Intratumoral heterogeneity can lead to uncertainty in breast carcinoma HER2 testing, both with respect to pathology reporting and clinical significance. The standard practice is to perform breast biomarker testing on a single representative section of tumor; however, concern over heterogeneity often leads to testing on additional tissue blocks. Our objective was to assess the diagnostic yield of testing multiple blocks of a single invasive breast carcinoma., Methods: We performed a retrospective review of 139 consecutive cases (between 2006 and 2012) in which clinical HER2 testing was performed in multiple blocks. Tumor characteristics and HER2 studies (both immunohistochemistry and data from in situ hybridization) were reviewed. Regional differences in morphology and HER2 immunoreactivity were recorded. In situ hybridization was performed in 25 of 139 of the cases; patterns of genetic heterogeneity were reviewed. We audited discordances in HER2 result between blocks., Results: Testing of multiple blocks yielded no additional HER2 information in 134 (96.4%) of 139 cases. Morphologic differences or heterogeneity in HER2 expression was observed in 22 (15.8%) of 139 of cases. Only 5 of these showed differences in HER2 between blocks, of which 4 were associated with equivocal HER2 immunohistochemistry, and 4 were high-grade., Conclusions: In the vast majority of cases, even those with heterogeneity, testing of a single block is sufficient for an accurate HER2 determination. High-grade tumors with equivocal HER2 status and observable heterogeneity are more likely to yield a different result on testing of additional blocks., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: We examined the effects of long-term hCG stimulation on germ cell maturation, and Sertoli and Leydig cell function in a xenotransplantation model of the human fetal testis., Materials and Methods: A total of 20 human fetal testes were ectopically xenografted on 20 castrated NCr male nude mice. Grafts were collected for analysis 24 weeks later. Mice were treated with saline as the control or with hCG beginning 4 weeks after the grafts were transplanted., Results: Of the grafts 65% survived at 24 weeks. In contrast to untreated pregrafted samples, hCG stimulated xenografts showed significantly increased density of seminiferous tubule formation with Sertoli cell migration to the basement membrane. Germ cell proliferation and differentiation from gonocytes (M2A(+)) to prespermatogonia (MAGE-4A(+)) were observed in graft samples recovered from the hCG and nonhCG treated groups at 24 weeks of treatment. Leydig cells in hCG treated grafts produced significantly more testosterone than nonhCG treated grafts. Although further studies are required to investigate the potential for further differentiation and maturation of xenografted human fetal testes, normal in utero testicular development was reproduced under long-term hCG stimulation., Conclusions: This model represents a means to study long-term effects of gonadotoxins or hormonal stimulation on the maturation of human fetal testes., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: In a significant update, the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines recommend fixed-dose statin therapy for those at risk and do not recommend nonstatin therapies or treatment to target low-density lipoprotein cholesterol (LDL-C) levels, limiting the need for repeated LDL-C testing., Objectives: The goal of this study was to examine the impact of the 2013 ACC/AHA cholesterol guidelines on current U.S. cardiovascular practice., Methods: Using the NCDR PINNACLE (National Cardiovascular Data Registry Practice Innovation and Clinical Excellence) registry data from 2008 to 2012, we assessed current practice patterns as a function of the 2013 cholesterol guidelines. Lipid-lowering therapies and LDL-C testing patterns by patient risk group (atherosclerotic cardiovascular disease [ASCVD], diabetes, LDL-C ≥190 mg/dl, or an estimated 10-year ASCVD risk ≥7.5%) were described., Results: Among a cohort of 1,174,545 patients, 1,129,205 (96.1%) were statin-eligible (91.2% ASCVD, 6.6% diabetes, 0.3% off-treatment LDL-C ≥190 mg/dl, 1.9% estimated 10-year ASCVD risk ≥7.5%). There were 377,311 patients (32.4%) not receiving statin therapy and 259,143 (22.6%) receiving nonstatin therapies. During the study period, 20.8% of patients had 2 or more LDL-C assessments, and 7.0% had more than 4., Conclusions: In U.S. cardiovascular practices, 32.4% of statin-eligible patients, as defined by the 2013 ACC/AHA cholesterol guidelines, were not currently receiving statins. In addition, 22.6% were receiving nonstatin lipid-lowering therapies and 20.8% had repeated LDL-C testing. Achieving concordance with the new cholesterol guidelines in patients treated in U.S. cardiovascular practices would result in significant increases in statin use, as well as significant reductions in nonstatin therapies and laboratory testing., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Since 2003, the Seventh Report of the Joint National Committee (JNC-7) has been the predominant guideline for blood pressure management. A 2014 expert panel recommended increasing the blood pressure targets for patients age 60 years and older, as well as those with diabetes or chronic kidney disease., Objectives: The purpose of this study was to examine the effect of the 2014 expert panel blood pressure management recommendations on patients managed in U.S. ambulatory cardiovascular practices., Methods: Using the National Cardiovascular Data Registry PINNACLE Registry, we assessed the proportion of patients who met the 2003 and 2014 panel recommendations, highlighting the populations of patients for whom the blood pressure goals changed., Results: Of 1,185,253 patients in the study cohort, 706,859 (59.6%) achieved the 2003 JNC-7 goals. Using the 2014 recommendations, 880,378 (74.3%) patients were at goal. Among the 173,519 (14.6%) for whom goal achievement changed, 40,323 (23.2%) had a prior stroke or transient ischemic attack, and 112,174 (64.6%) had coronary artery disease. In addition, the average Framingham risk score in this group was 8.5 ± 3.2%, and the 10-year ASCVD risk score was 28.0 ± 19.5%., Conclusions: Among U.S. ambulatory cardiology patients with hypertension, nearly 1 in 7 who did not meet JNC-7 recommendations would now meet the 2014 treatment goals. If the new recommendations are implemented in clinical practice, blood pressure target achievement and cardiovascular events will need careful monitoring, because many patients for whom the target blood pressure is now more permissive are at high cardiovascular risk., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine the diagnostic yield of testing multiple blocks for HER2 in cases of multifocal breast carcinoma., Methods: We identified 246 consecutive cases of multifocal invasive breast carcinoma in which HER2 was tested on more than 1 tumor focus. We performed an audit of all cases with respect to tumor size, grade, and histologic type., Results: HER2 status was concordant between multiple foci in 230 (93.5%) of 246 cases, with the largest focus having the most positive HER2 result in 242 (98.4%) of 246 cases. We did not find a single case in which a smaller focus demonstrated a more positive HER2 status unless this focus was either higher grade or different histologically., Conclusions: Our findings support the evaluation of HER2 on the largest focus, with additional testing on smaller foci having a different histologic type or higher grade.

Testicular spermatozoa are utilized to achieve pregnancy in couples with severe male factor infertility. Several studies suggest that aneuploidy rates in spermatozoa are elevated at the testicular level in infertile patients compared to ejaculates of normal controls. However, essential data regarding aneuploidy rates between ejaculated and testicular spermatozoa in the same individuals is lacking. The purpose of our study was to compare aneuploidy rates at the testicular and post-testicular level from the same patients with persistently high sperm DNA damage. Ejaculates and testicular biopsies were obtained from eight patients with persistently high DNA damage (>30%). Both ejaculated and testicular samples were analyzed for sperm DNA damage and sperm aneuploidy for chromosomes 13, 18, 21, X, and Y. In addition, semen samples from ten normozoospermic men presenting for fertility evaluation served as a control group. A strong correlation between the alteration of spermatogenesis and chromatin deterioration was observed in our study. In the same individuals, testicular samples showed a significantly lower DNA damage compared to ejaculated spermatozoa (14.9% ± 5.0 vs. 40.6% ± 14.8, P<0.05), but significantly higher aneuploidy rates for the five analyzed chromosomes (12.41% ± 3.7 vs. 5.77% ± 1.2, P<0.05). While testicular spermatozoa appear favourable for ICSI in terms of lower DNA damage, this potential advantage could be offset by the higher aneuploidy rates in testicular spermatozoa.

Genitourinary sarcoidosis is uncommon, with only rare documented cases of testicular involvement reported. We detail the case of a 37-year-old male who initially presented for azoospermia and secondary infertility. A testicular biopsy revealed nonnecrotizing granulomas and a chest x-ray identified perihilar lymphadenopathy and granulomatous lung nodules. A corticosteroid regimen was administered, and routine semen analyses were conducted. Significant improvements were noted after prednisone treatments. A successful in vivo fertilization was obtained. This is the first known case of testicular sarcoidosis diagnosed during investigations into azoospermia and secondary infertility which, after treatment with corticosteroids, resulted in natural fertilization.

Telomeres play a fundamental role in the organization of the sperm nucleus resulting in the looped chromosome configuration and non-random positioning of chromosomes. Telomeres localize in the nuclear periphery and interact dynamically by forming dimers and tetramers. The purpose of this study was to evaluate the relationship of telomere interactions to DNA damage, a factor known to adversely influence male fertility. Telomeres were localized by fluorescence in situ hybridization (FISH) using human chromosome pan-telomeric probe in ten samples with low and ten samples with high sperm DNA damage. The samples with a low DNA fragmentation index (DFI) had a mean number of telomere signals of 21.7±1.9 compared to a mean of 26.5±3.4 signals in the samples with a high DFI (p<.005). The percentage of cells with a typical telomere distribution of ≤23 telomere-telomere dimers was observed in 70.8%±15.6 samples with a low DFI compared to 44.2%±22.4 in samples with a high DFI (p<.05). These results suggest that sperm DNA damage is associated with disruption of the normal telomere-telomere interactions leading to possible loss of the looped chromosome configuration. Improperly packed and organized sperm chromatin might have a high probability of disrupting the extremely structured sequence of sperm chromosome deposition, activation, and processing by the oocyte at the time of fertilization. These results might provide additional information on the nature of sperm DNA damage and the role of such damage on fertilization and development of the zygote.

Men with high sperm DNA damage have a reduced fertility potential. Correlation of specific clinical factors to the degree of sperm DNA damage remains unclear. This retrospective study evaluated the frequency and severity of sperm DNA damage in men with different aetiologies of male factor infertility. Patients with male factor infertility (n=288) underwent flow cytometry-based sperm DNA damage assessment and results were correlated with the major aetiologies of male infertility: varicocele, bacteriospermia and idiopathic infertility. Sperm DNA damage was significantly correlated to the patient's age, sperm motility, normal morphology and vitality (P < 0.001). High sperm DNA damage (30%) was most frequently found in the group with bacteriospermia (48%), compared with 30% of the men with varicoceles and 22% of the men with idiopathic infertility (P < 0.02). While some tendency was observed for a correlation of increasing sperm DNA damage in patients with grade III and bilateral varicoceles, this difference did not reach statistical significance. The data support the importance of proper physical and laboratory investigations of the fertility status in men to correctly diagnose and treat male infertility., (2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: To compare DNA damage in ejaculated and testicular spermatozoa in patients with previously unsuccessful oral antioxidant treatment., Design: Prospective clinical study., Setting: University-affiliated teaching hospital., Patient(s): Twelve men with persistently high sperm DNA damage., Intervention(s): Evaluation of DNA damage of ejaculated and testicular spermatozoa by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay., Main Outcome Measure(s): The DNA damage of ejaculated spermatozoa compared with that of testicular spermatozoa, both samples collected on the day of intracytoplasmic sperm injection., Result(s): Ejaculated spermatozoa showed a threefold higher DNA damage when compared with testicular samples (39.7% +/- 14.8 vs. 13.3% +/- 7.3)., Conclusion(s): Our results indicated that in patients with previously unsuccessful oral antioxidant treatment the retrieved testicular spermatozoa had a lower degree of DNA damage compared with ejaculated sperm collected on the same day., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: To analyze the relationship between DNA damage and standard semen parameters (SSP) in patients who present for fertility evaluation. Evaluation of male fertility includes assessment of the SSP and increasingly sperm DNA damage. However, the relationship between DNA damage and SSP remains controversial., Methods: Following Institutional Research Ethics Board approval, semen samples from 2586 unselected nonazoospermic patients were subjected to computer-assisted semen analysis and flow cytometry-based sperm DNA damage assessment expressed as the DNA fragmentation index., Results: Sperm DNA damage was significantly negatively correlated to sperm SSP (concentration, motility, and normal morphology) and positively correlated to patient's age. DNA damage increased in association with the number of abnormalities in SSP. Patients with oligoasthenoteratozoospermia had significantly higher DNA damage and more frequent DNA damage over 30% compared with normozoospermic patients and patients with abnormalities in 1 or 2 SSP., Conclusions: Our results indicate that DNA damage is significantly correlated to SSP as well as age. In addition, the degree of DNA damage increases with the number of abnormal parameters in a sample and is most severe in patients with oligoasthenoteratozoospermia. Complex and possibly age-related mechanisms of DNA damage in human spermatozoa may be responsible for the strong relationship between SSP and DNA fragmentation index.

Assessment of sperm DNA damage has been suggested as a negative predictor of fertility potential. Multiple pathological factors acting at both the intra-testicular and post-testicular levels may contribute to sperm DNA damage. The relative contribution of each of these factors in an individual with high DNA damage (>30%) is unclear. The management of patients with elevated DNA damage is also challenging. The purpose of our retrospective study was to evaluate the clinical course of patients with sperm DNA damage over 30% and to assess the effect of non-specific (oral antioxidant) and cause-specific treatments on the quality of their sperm DNA. Results of our retrospective study suggest that the evaluated group with high DNA damage was diagnostically heterogeneous and comprised patients with varicoceles, bacteriospermia and idiopathic infertility. A three month course of antioxidant therapy reduced sperm DNA damage in only 30/61 (49%) patients with significant improvement between the initial and post-treatment DNA Fragmentation Index (DFI) results (46.8%+/-14.1 vs. 36.7%+/-16.6, p < .001). The positive effect of antioxidants could be age-dependent, as patients older that 40 years of age showed no improvement after such treatment. The cause-specific treatments showed superior results compared to antioxidants alone. Improvement was observed in 7/9 (78%) of patients after surgical varicocele repair between the initial and post-treatment DFI results (44.7%+/-12.8 vs. 28.4%+/-9.5, p < .03). The majority of the patients 13/14 (93%) with bacteriospermia had improvement in sperm DFI results after antibiotic treatment (50.4%+/-19.1 vs. 38.6%+/-18.7, p < .001).

Purpose: We examined the relationship between L-PGDS (lipocalin-type prostaglandin D synthase) levels in seminal plasma and the presence or absence of obstruction in the male seminal tract., Materials and Methods: Semen samples were collected and analyzed from 1) 10 patients with normal semen parameters, 2) 9 with obstructive azoospermia, 3) 20 after vasectomy and 4) 14 with nonobstructive azoospermia. Seminal L-PGDS was measured using an enzyme-linked immunosorbent assay technique., Results: We found that seminal plasma L-PGDS in the groups with obstruction was significantly lower than in any of the other groups (p <0.001). Using a cutoff of 100 microg/l all men with obstructive azoospermia had L-PGDS less than 100 microg/l, while none with normal sperm parameters did. Men with nonobstructive azoospermia had less homogeneity of L-PGDS levels, including 29.6% with L-PGDS more than 100 microg/l., Conclusions: Our results suggest that seminal L-PGDS level can potentially be a biomarker for assessing patency in the seminal tract in men with azoospermia. In men with azoospermia and high seminal L-PGDS (more than 100 microg/l) the diagnosis of nonobstructive azoospermia can be potentially made without biopsy. Our study shows that using semen L-PGDS levels provides a diagnosis of nonobstructive azoospermia in almost 30% of these men.

Our study aimed to compare the frequency of epididymal protein P34H deficiency in a population of men undergoing routine infertility evaluation with that in men with proven fertility. Our results suggest that a significant proportion of men investigated for male infertility may be epididymal protein P34H deficient.

The purpose of our study was to analyze the relationship of leukocytospermia to sperm DNA damage as assessed by the DNA integrity assay. Results indicate that leukocytospermia has a significant negative effect on the standard semen parameters of concentration, motility, and morphology but at most a very weak effect on DNA integrity as measured by the DNA fragmentation assay.

The purpose of our study was to evaluate the effect of age and sperm DNA integrity on sperm survival. Semen samples from fifty six unselected patients undergoing infertility evaluation were assessed in terms of standard semen parameters, DNA integrity, and sperm survival after 6-24 h of incubation. Prolonged incubation of density gradient selected sperm adversely effects sperm survival in older patients and patients with extensive sperm DNA damage. Immediate preparation of such samples prior to use for assisted reproductive technology (ART) may overcome the negative effect of extended incubation.

The purpose of this study was to analyze the relationship of male age and DNA integrity in men presenting for investigation of infertility. We found that men 45 years and older had significantly greater DNA fragmentation than younger men.

The objective of this study was to examine the relationship between DNA integrity and protamines in human sperm. One hundred forty-nine male infertility patients were included in an Institutional Review Board-approved study. Sperm were evaluated for DNA fragmentation using the DNA Integrity Assay, a test equivalent to the sperm chromatin structure assay (SCSA). Additionally, nuclear proteins were extracted and the protamine-1/protamine-2 ratio (P1/P2), protamine-1 (P1), protamine-2 (P2), and total protamine concentrations were evaluated. We identified 37 patients with abnormally low P1/P2 ratios, 99 patients with normal P1/P2 ratios, and 13 patients with abnormally high P1/P2 ratios. DNA fragmentation was significantly elevated in patients with low P1/P2 ratios (37.1 +/- 6.02) vs those with normal and high P1/P2 ratios (26.7 +/- 1.9 and 23.8 +/- 3.2, respectively; P < .05) and was inversely correlated with the P1/P2 ratio (R(s) -0.18, P < .05), P1 concentration (R(s) -0.29, P < .001), P2 concentration (R(s) - 0.24, P < .005), and total protamine concentration (R(s) -0.28, P < .001). Furthermore, chi2 analysis revealed a significant increase in the incidence of marked DNA fragmentation in patients with diminished levels of either P1 or P2. The present study is the first to report that human sperm protamine content is significantly related to DNA fragmentation. In particular, sperm P1 and P2 concentrations inversely correlate with DNA fragmentation, indicating a protective role of the protamines against sperm DNA damage. In light of recent studies highlighting the negative effect of sperm DNA damage on ART outcomes, these findings indicate a possible clinical significance for human sperm protamine levels.

Background: Acute intramedullary stabilization of femoral shaft fractures in multiply injured patients is controversial. Intravasation of medullary fat during canal pressurization has been suspected to trigger adult respiratory distress syndrome. The goal of the present study was to evaluate the effect, on the lungs, of a filter placed into the ipsilateral common iliac vein during medullary canal pressurization in a canine model., Methods: With use of an established model of fat embolization, twelve mongrel dogs were randomized into two groups. In six dogs, a special filter was inserted percutaneously into the left common iliac vein while the dogs were under general anesthesia. In all dogs, the left femur and tibia were then pressurized by injection of bone cement and insertion of intramedullary rods. Hemodynamic measurements and echocardiographic images were recorded throughout the experiment. After one hour, the animals were killed and the lungs were harvested for histomorphometric analysis., Results: Without the filter, the mean pulmonary artery pressure increased by 11.8 +/- 2.1 mm Hg (p < 0.001). With the filter, the mean pulmonary artery pressure increased by only 2.2 +/- 0.8 mm Hg (p < 0.02). Without the filter, there was a significant increase in the index of pulmonary vascular resistance as compared with the baseline value (p < 0.05). With the filter, there was no such increase. Histomorphometric analysis demonstrated that the presence of the filter reduced the absolute area of embolization and the volume percentages of lung and pulmonary vasculature embolized., Conclusions: In this canine experiment, temporary placement of a venous filter prior to medullary canal pressurization reduced the embolic load and minimized its hemodynamic effects.

Purpose: Hypocapnia, a recognized complication of high frequency oscillation ventilation, has multiple adverse effects on lung and brain physiology in vivo, including potentiation of free radical injury. We hypothesized that hypocapnia would potentiate the effects of mesenteric ischemia-reperfusion on bowel, liver and lung injury., Methods: Anesthetized male Sprague-Dawley rats were ventilated with high frequency oscillation and were randomized to one of four groups, exposed to either mesenteric ischemia-reperfusion or sham surgery, and to either hypocapnia or normocapnia., Results: All animals survived the protocol. Ischemia-reperfusion caused significant histologic bowel injury. Bowel 8-isoprostane generation was greater in ischemia-reperfusion vs sham, but was attenuated by hypocapnia. Laser-Doppler flow studies of bowel perfusion confirmed that hypocapnia attenuated reperfusion following ischemia. Plasma alanine transaminase, reflecting overall hepatocellular injury, was not increased by ischemia-reperfusion but was increased by hypocapnia; however, hepatic isoprostane generation was increased by ischemia-reperfusion, and not by hypocapnia. Oxygenation was comparable in all groups, and compliance was impaired by ischemia-reperfusion but not by hypocapnia., Conclusion: Hypocapnia, although directly injurious to the liver, attenuates ischemia-reperfusion induced lipid peroxidation in the bowel, possibly through attenuation of blood flow during reperfusion.

Previous independent studies have indicated that abnormally low parameters of sperm DNA integrity and sperm membrane integrity correlate to reduced fertility due in part to implantation disorders. The purpose of our study was to evaluate the relationship between sperm plasma membrane functional integrity assessed by the hypo-osmotic swelling test (HOST) and sperm DNA integriy test assesed by DNA fragmentation index (DFI). Semen samples from 102 random patients were evaluated in terms of standard semen parameters and assessed by DFI and HOST. Both tests showed a significant correlation to standard semen parameters (p < .05). In addition, patients with abnormal HOST results had a higher likehood of a subnormal or abnormal DFI result (p < .001). Our results suggest that a common sublethal insult may manifest as abnormalities in both the nucleus and the plasma membrane that act at the implantation and/or subsequent levels of development rather than at the fertilization stage.

Unlabelled: Cerebral lipid microemboli (LME) may cause postoperative cognitive dysfunction after orthopedic and cardiovascular surgery. In 13 anesthetized rats, we created a cranial window to study LME using orthogonal polarization spectral imaging videomicroscopy. All rats received 0.2 mL of human marrow fat, obtained from surgical waste during arthroplasty, injected into the superior vena cava. Five rats died within seconds of this injection, despite resuscitation efforts. Seven minutes later, we injected an additional 0.1 mL in 6 of the 8 surviving rats. We observed the videomicroscopy for 1 h in all 8 rats. Arterial blood pressure (BP) was continuously measured. No LME were observed in the first 7 min (n = 8); however, within seconds of the additional 0.1 mL injection, mean BP decreased from 79 +/- 31 mm Hg to 28 +/- 12 mm Hg (n = 6; P < 0.02). Epinephrine and crystalloid infusion increased BP to 161 +/- 9 mm Hg and 20-100 LME were seen within 5 min. LME changed shape and fragmentation, erosion, and streaming patterns were noted, with transient arteriolar occlusion (10-220 s). Increasing BP resulted in reperfusion of occluded arterioles. No venous LME were noted. Postmortem, brain and lung LME were found with no patent foramen ovale. This model may be useful in studying cerebral LME., Implications: Marrow lipid may pass through the lung during orthopedic surgery, creating cerebral lipid microemboli (LME). We created a cranial window in rats to study LME flowing through pial-cortical vessels. Cerebral LME appeared after resuscitation from hypotension and vessel occlusion was transient. This model may be useful in studying cerebral LME.

Hypercapnic acidosis protects against direct lung injury in in vivo and ex vivo models, however, lung injury/acute respiratory distress syndrome commonly occurs after a nonpulmonary etiology. We investigated whether therapeutic hypercapnia (TH)-deliberate elevation of carbon dioxide (CO2) tension-would protect against lung injury after splanchnic ischemia-reperfusion injury in an in vivo model. TH was associated with preservation of lung mechanics, attenuation of protein leakage, and improved oxygenation compared with control conditions. Lung protection was therapeutic as well as prophylactic. Protection was dose-dependent, but inspired CO2 concentrations above 5.0% were associated with little additional lung protection. Before lung injury, increasing FICO2 resulted in a dose-dependent increase in PaO2. Lung protection with hypercapnia occurred despite pulmonary artery pressures that were greater than observed with normocapnia. Reperfusion increased lipid peroxidation (tissue 8-isoprostane concentration) in the bowel, liver, and lung, and caused histologically apparent bowel injury; however, none of these effects was altered by TH. Therefore, TH-induced by adding CO2 to inspired gas-provides consistent protection against lung injury in terms of lung permeability, oxygenation, and lung mechanics after mesenteric ischemia-reperfusion. These data further support the emerging evidence for ongoing physiologic study of TH at the bedside.

Objective: Although mechanical ventilation can potentially worsen preexisting lung injury, its importance in the setting of lung transplantation has not been explored. This study was undertaken to examine the effect of 2 ventilatory strategies on the development of ischemia-reperfusion injury after lung transplantation., Methods: In a rat lung transplant model animals were randomized into 2 groups defined by the ventilatory strategy during the early reperfusion period. In conventional mechanical ventilation the transplanted lung was ventilated with a tidal volume equal to 50% of the inspiratory capacity of the left lung and a low positive end-expiratory pressure. In minimal mechanical stress ventilation the transplanted lung was ventilated with a tidal volume equal to 20% of the inspiratory capacity of the left lung, and positive end-expiratory pressure was adjusted according to the shape of the pressure-time curve to minimize pulmonary stress., Results: After 3 hours of reperfusion, oxygenation from the transplanted lung was significantly higher with minimal mechanical stress ventilation than with conventional ventilation. In addition, elastance, cytokine levels, and morphologic signs of injury were significantly lower in the group with minimal mechanical stress ventilation., Conclusions: This study demonstrates that the mode of mechanical ventilation used in the early phase of reperfusion of the transplanted lung can influence ischemia-reperfusion injury, and a protective ventilatory strategy on the basis of minimizing pulmonary mechanical stress can lead to improved lung function after lung transplantation.

Objectives: This study was designed to document the association of endocardial fibroelastosis (EFE) and maternal autoantibodies., Background: Neonatal lupus erythematosus is associated with the transplacental passage of maternal anti-Ro and anti-La antibodies, leading to complete atrioventricular block (CAVB). In some cases, CAVB is associated with EFE. Isolated EFE may be independently related to maternal anti-Ro and anti-La antibodies., Methods: We identified three cases (one fetus and two infants, all female) of isolated EFE in infants born to autoantibody-positive mothers in the absence of CAVB. Demographics, echocardiograms, and pathology were reviewed. Immunohistochemical analyses for immunoglobulin (Ig)G, IgM, IgA, T-cell, B-cell, and terminal deoxynucleoleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) (test for cell apoptosis) staining were performed on multiple sections of the heart in each case and compared with negative controls., Results: Two cases died and one received a cardiac transplant. All three cases had histologically confirmed EFE. All cases demonstrated significant diffuse IgG infiltration. To a lesser extent, myocardial tissue was also positive for IgM, CD43, and Granzyme B. None of the specimens were TUNEL positive., Conclusions: These are the first reported cases of isolated EFE associated with maternal anti-Ro and anti-La antibodies in the absence of CAVB. The diffuse deposition of IgG and the presence of a T-cell infiltrate throughout the myocardium suggest that the transplacental passage of maternal autoantibodies induces an immune reaction within the myocardium, leading to isolated EFE. Autoantibody-mediated EFE may be an etiologic factor in cases of fetal and neonatal "idiopathic" dilated cardiomyopathy.

Background: Maternal anti-Ro and anti-La antibodies are associated with congenital heart block (CHB). Although endocardial fibroelastosis (EFE) has been described in isolated cases of autoantibody-mediated CHB, the natural history and pathogenesis of this disease are poorly understood., Methods and Results: We retrospectively reviewed the clinical history, echocardiography, and pathology of fetuses and children with EFE associated with CHB born to mothers positive for anti-Ro or anti-La antibodies at 5 centers. Thirteen patients were identified, 6 with a prenatal and 7 with a postnatal diagnosis. Six mothers were positive for anti-Ro and anti-La antibodies, and 7 were positive for anti-Ro antibodies only. Only 1 mother had autoimmune disease. Severe ventricular dysfunction was seen in all fetal and postnatal cases. Four fetal and 3 postnatal cases had EFE at initial presentation. However, 2 fetal and 4 postnatal cases developed EFE 6 to 12 weeks and 7 months to 5 years from CHB diagnosis, respectively, even despite ventricular pacing in 6 postnatal cases. Eleven (85%) either died (n=9) or underwent cardiac transplantation (n=2) secondary to the EFE. Pathologic assessment of the explanted heart, available in 10 cases, revealed moderate to severe EFE in 7 and mild EFE in 3 cases, predominantly involving the left ventricle. Immunohistochemistry in 4 cases (including 3 fetuses) demonstrated deposition of IgG in 4 and IgM in 3 and T-cell infiltrates in 3 cases, suggesting an immune response by the affected fetus or child., Conclusions: EFE occurs in the presence of autoantibody-mediated CHB despite adequate ventricular pacing. Autoantibody-associated EFE has a very high mortality rate, whether developing in fetal or postnatal life.

Background: We developed an orthotopic model of human lung cancer that exhibits highly predictable regional and systemic metastases. This study examines the response of the model when treated with conventional and experimental chemotherapy., Methods: NCI-H460 tumor fragments were implanted into the right caudal lung lobe of a nude rat. Treatment commenced 2 weeks later. We assessed response by comparing primary tumor and mediastinal lymph node weights, total body weight, and length of survival with untreated, tumor-bearing control animals. We also calculated the incidence of metastasis to kidney, bone, brain, and contralateral lung in treated versus untreated animals., Results: Mitomycin and cisplatin showed broad activity against primary and metastatic disease. The matrix metalloproteinase inhibitor batimastat, low-dose cisplatin, and mitomycin significantly prolonged survival. High-dose cisplatin caused renal toxicity that shortened survival. Brain metastases did not respond to mitomycin, consistent with its poor blood-brain barrier penetration., Conclusions: Responses were similar to NCI-H460 in vitro data and consistent with clinical experience for these drugs. Drug-related toxicities similar to those seen in clinical practice were detected.

Bilateral congenital diaphragmatic hernia is a rare, life-threatening malformation. We describe a case of bilateral Bochdalek hernia diagnosed prenatally. The sonographic clues to the diagnosis were anterior displacement of the heart with relatively minimal lateral shift. The definitive diagnosis was made by demonstrating the liver in the right thorax and bowel loop and stomach in the left thorax. Color and power Doppler demonstrated the hepatic vessels embracing both sides of the heart from behind.

Background: We tested the hypothesis that the pressure-time (P-t) curve during constant flow ventilation can be used to set a noninjurious ventilatory strategy., Methods: In an isolated, nonperfused, lavaged model of acute lung injury, tidal volume and positive end-expiratory pressure were set to obtain: (1) a straight P-t curve (constant compliance, minimal stress); (2) a downward concavity in the P-t curve (increasing compliance, low volume stress); and (3) an upward concavity in the P-t curve (decreasing compliance, high volume stress). The P-t curve was fitted to: P = a. tb +c, where b describes the shape of the curve, b = 1 describes a straight P-t curve, b < 1 describes a downward concavity, and b > 1 describes an upward concavity. After 3 h, lungs were analyzed for histologic evidence of pulmonary damage and lavage concentration of inflammatory mediators. Ventilator-induced lung injury occurred when injury score and cytokine concentrations in the ventilated lungs were higher than those in 10 isolated lavaged rats kept statically inflated for 3 h with an airway pressure of 4 cm H2O., Results: The threshold value for coefficient b that discriminated best between lungs with and without histologic and inflammatory evidence of ventilator-induced lung injury (receiver-operating characteristic curve) ranged between 0.90-1.10. For such threshold values, the sensitivity of coefficient b to identify noninjurious ventilatory strategy was 1.00. A significant relation (P < 0.001) between values of coefficient b and injury score, interleukin-6, and macrophage inflammatory protein-2 was found., Conclusions: The predictive power of coefficient b to predict noninjurious ventilatory strategy in a model of acute lung injury is high.

Background: Gene therapy provides the potential to modify donor organs to better withstand transplantation, but this has yet to be realized. In vivo gene transfer using adenoviral vectors has had limited success because of host immune response that induces inflammation and limits the amount and duration of transgene expression. We hypothesize that transplantation immunosuppression can attenuate the post-transfection host-immune response to allow for improved gene transfer following adenoviral-mediated transfection., Methods: We intratracheally transfected with adenovirus containing the beta-galactosidase gene and randomized the rats to either the immunosuppression group, receiving daily cyclosporine, azathioprine, and methylprednisolone, or the control group, receiving no immunosuppression. We evaluated transgene expression and post-transfection inflammation at time points ranging from 1 day to 5 weeks., Results: Following transfection, control rats showed relatively low levels of transgene expression, which rapidly decreased to non-detectable levels. In contrast, immunosuppressed rats demonstrated significantly higher levels of transgene expression overall (p < 0.00005), peaking at almost 3 times that of the control group (p < 0.02), and showing prolonged and elevated transgene expression at 5 weeks (p < 0.02). On histologic sections of the lungs, immunosuppressed rats exhibited overall lesser grades of post-transfection inflammation., Conclusions: Transplant immunosuppression provides the means to attenuate the severe immune response to adenoviral-mediated gene transfection and thereby increase and prolong transgene expression.

Purpose: The purpose of this study was to investigate the relationship between smoking and p53 tumor suppressor gene alterations, and their association with clinicopathologic features and prognosis in non-small cell lung cancer (NSCLC)., Methods: For 111 of 119 stage I-III NSCLC patients that had been followed prospectively, tumor p53 protein accumulation was measured immunohistochemically (IHC). Staining was evaluated as a score (p53IHCS) combining intensity and percent distribution., Results: Forty-eight of 111 (43%) tumors had p53IHCS > 1. p53 IHC was associated with increasing tumor size (T) (p = 0.035), nodal status (N) (p = 0.091), stage (p = 0.054), and histology: squamous cell carcinoma (70%) and adenocarcinoma (27%) (p = 0.0002). In logistic regression analysis, p53 IHC was associated with squamous cell histology versus other histotypes [adjusted odds ratio (OR)5.90, 95% confidence interval (CI) 2.34-14.90]. p53 IHC was not associated with smoking variables. In multivariate proportional hazards analysis, p53IHCS and pack-years smoked (PY), both as continuous variables, were negative prognostic factors. The adjusted hazard ratios (HR) for the survival outcome recurrence for p53IHCS and PY were 1.20 (95% CI 1.02-1.40) and 1.03 (95% CI 1.01-1.04), and for death due to recurrent disease (DRD) were 1.35 (95% CI 1.11-1.64) and 1.03 (95% CI 1.01-1.04), respectively. Comparing the 75th percentile to the baseline 0, the adjusted HR for p53IHCS (5 vs. 0) was 4.5 and for PY (55 vs. 0) was 5.1 for the outcome DRD. Both variables demonstrated a dose-response relationship with survival., Conclusions: PY and p53IHCS are significant, independent and important predictors of recurrence and DRD in stage I-III NSCLC.

Purpose: We examined the effect of inhaled nitric oxide (NO) on the acute pulmonary hypertension and right ventricular (RV) dilation after fat embolism., Methods: A bilateral cemented arthroplasty (BCA), created fat embolism in 20 dogs. In Part A, 12 dogs were randomized to an NO group (n=6, inhaled NO 40 ppm before BCA and throughout the study) or a control group (n=6). In Part B, a third group of dogs (n=8) were given NO 20-40 ppm 2-3 min after BCA when pulmonary artery pressure (PAP) increased. Transesophageal echocardiography (TEE) and invasive hemodynamic monitoring evaluated the hemodynamic response to BCA. Postmortem, quantitative morphometry was used to estimate the number of fat emboli and diameter of lung vessel occluded by fat., Results: Part A: The increase in PAP in the NO group (16 +/- 1 to 34 +/- 9 mmHg) within three minutes of BCA was not different from that in the control group (14 +/- 4 to 35 +/- 9 mmHg). Within three minutes of BCA, TEE demonstrated RV dilation in all groups (P < 0.05) but there was no difference in the change in RV area in the NO and control groups. When NO was given after BCA, no difference in PAP or RV dilation was noted from that in the control group. There were no differences, at post mortem, between the groups in the diameter of lung vessel occluded by fat, Conclusion: Whether given before the embolic insult or two to three minutes after the onset of pulmonary hypertension, inhaled NO did not attenuate the acute pulmonary hypertension or RV dilation after cemented arthroplasty.