Echocardiographic assessment of pressure volume relations in heart failure and valvular heart disease: using imaging to understand physiology.

Pressure volume (PV) based analysis, using classic hemodynamic principles, has served as a basis for our understanding of cardiac physiology and disease states for decades. However, PV analysis has been restricted to primarily the basic research setting and for preclinical testing and has not be widely applied in part because of the invasive nature of the procedure and the expertise required to obtain adequate data using the conductance catheter. Development of single beat methodologies that rely on echocardiographic measurements of ventricular volume and Doppler and peripheral estimates of ventricular pressure and timing of the cardiac cycle has enabled broader application of PV analysis. This review explores the physiologic background, basic methodology, and recent and potential future applications of noninvasive PV analysis.

A novel 4-cM minimally deleted region on chromosome 11p15.1 associated with high grade nonmucinous epithelial ovarian carcinomas.

Prior cytogenetic and restriction fragment length polymorphism studies have demonstrated that allelic deletion of chromosome 11p is common in human invasive epithelial ovarian tumors. To construct a highly detailed deletion map of chromosome 11p, we used 13 polymorphic microsatellite CA repeat primers to identify regions harboring potential tumor suppressor genes. Twenty-three of 48 samples (48%) of invasive epithelial ovarian cancer showed LOH involving at least one locus, consistent with prior studies. None of the five mucinous tumors showed allelic deletion at any of the 13 primers, suggesting that loss of heterozygosity at chromosome 11p may not be involved in the pathogenesis of mucinous ovarian cancer. Two separate minimally deleted regions were identified in nonmucinous ovarian cancer. The first is an 11-cM region on chromosome 11pl5.5-15.3 that extends from D11S2071 to D11S988 and includes the HRAS locus. The second is a novel 4-cM region on 11p15.1, defined by marker D11S1310. Deletion of both regions at 11p15.5-15.3 and 11p15.1 is strongly associated with high grade nonmucinous epithelial ovarian cancer.

Direct interaction of a vancomycin derivative with bacterial enzymes involved in cell wall biosynthesis.

BACKGROUND: The glycopeptide antibiotic vancomycin complexes DAla-DAla termini of bacterial cell walls and peptidoglycan precursors and interferes with enzymes involved in murein biosynthesis. Semisynthetic vancomycins incorporating hydrophobic sugar substituents exhibit efficacy against DAla-DLac-containing vancomycin-resistant enterococci, albeit by an undetermined mechanism. Contrasting models that invoke either cooperative dimerization and membrane anchoring or direct inhibition of bacterial transglycosylases have been proposed to explain the bioactivity of these glycopeptides. RESULTS: Affinity chromatography has revealed direct interactions between a semisynthetic hydrophobic vancomycin (DCB-PV), and select Escherichia coli membrane proteins, including at least six enzymes involved in peptidoglycan assembly. The N(4)-vancosamine substituent is critical for protein binding. DCB-PV inhibits transglycosylation in permeabilized E. coli, consistent with the observed binding of the PBP-1B transglycosylase-transpeptidase. CONCLUSIONS: Hydrophobic vancomycins interact directly with a select subset of bacterial membrane proteins, suggesting the existence of discrete protein targets. Transglycosylase inhibition may play a role in the enhanced bioactivity of semisynthetic glycopeptides.

Scoring transitions to REM sleep in rats based on the EEG phenomena of pre-REM sleep: an improved analysis of sleep structure.

Algorithms for scoring sleep/waking states and transitions to REM sleep (NRTs) in rats are presented and validated. Both algorithms are based on electroencephalographic (EEG) power in delta (0.5-4.0 Hz), theta (6-9 Hz) and sigma (10-14 Hz) frequency bands, and electromyogram (EMG) intensity. Waking is scored when EMG intensity is high or (sigma power).(theta power) is low. Nonrapid eye movement (NREM) sleep is scored in nonwaking epochs having high (delta power)/(theta power). Rapid eye movement (REM) sleep is scored in nonwaking epochs having low (delta power)/(theta power). NRTs are identified by the EEG phenomena of the pre-REM sleep phase of NREM sleep. Algorithms are validated by comparison with records scored independently by two investigators based on visual examination of EEGs and EMGs. The sleep/waking-state scoring algorithm produces greater than 90% agreement with visual scoring. The NRT-scoring algorithm produces 88-92% agreement with visual scoring. Scoring NRTs based on the phenomena of the pre-REM sleep phase of NREM sleep, instead of relying solely on REM sleep expression for identification of REM sleep onset, reveals a significant population of brief REM sleep episodes that are ignored by most sleep cycle analyses and allows independent quantification of REM sleep timing and maintenance.

Protecting the brachial plexus during median sternotomy.

Injury to the brachial plexus was prospectively assessed in 335 patients undergoing median sternotomy for cardiac operation. All patients were placed in the hand-up position (elbows elevated, arms abducted 90 degrees, and elbows flexed) after right internal jugular vein cannulation (23 cannulation attempts were bilateral). Twenty-eight patients had new upper extremity complaints after the operation, of whom 16 (4.8%) had symptoms considered related to injury of the brachial plexus: one with generalized weakness of the left arm, six with localized weakness, pain, or paresthesia plus objective hypesthesia or weakness, and nine with paresthesias but no objective signs. Four injuries were right sided, four left sided, and eight bilateral. At the time of discharge, 15 of 16 were symptom free and the patient with generalized weakness was rapidly improving. Postoperative plexopathy was not related to degree of sternal retraction, dissection of the internal mammary artery, or cannulation of the internal jugular vein. We believe the low incidence and benign course of brachial plexus problems in these patients resulted from careful sternal retraction and use of the hands-up position. Finally, our data do not support internal jugular cannulation as a major cause of plexus injuries after median sternotomy.

Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation.

N6-Cyclopentyladenosine (CPA), an A1 adenosine receptor agonist, increased EEG slow-wave activity in nonREM sleep when administered either systemically (0.1-3 mg/kg) or intracerebroventricularly (3.5-10 micrograms) in the rat. The power spectrum of EEG changes (as calculated by Fourier analysis) matched that produced by total sleep deprivation in the rat. The effects of CPA on the nonREM-sleep EEG were dose-dependent. These findings suggest that adenosine is an endogenous mediator of sleep-deprivation induced increases in EEG slow-wave activity, and therefore that increased adenosine release is a concomitant of accumulation of sleep need and may be involved in homeostatic feedback control of sleep expression.

Thermal effects of laser stapedectomy in an animal model: CO2 versus KTP.

Although use of the laser for stapedectomy has become common in recent years, controversy remains regarding whether the CO2 or visible-spectrum lasers (argon and KTP) are best suited for this operation. The main concern has been the potential for thermal injury to the inner ear with the visible-spectrum lasers attributable to their absorption characteristics. To further investigate this issue, the author performed 20 laser stapedectomies on adult chinchillas. Following placement of a 0.127-mm-diameter copper/constantan thermocouple (sampling at 12 Hz) beneath the footplate on the medial wall of the vestibule via a distant fenestration site, thermal changes with a micromanipulator-based CO2 and fiberoptic KTP system were compared. This was the first live animal model comparison of these two lasers. There was no statistical difference in the mean temperature elevation between the two systems (P = 0.395).

Changes in deglutition following tonsillectomy in neurologically impaired children.

Tonsillectomy for improvement of dysphagia in children is well recognized, but its effects upon deglutition in the neurologically impaired child have not been described. A review was performed of pre- and post-operative oral-pharyngeal motility (OPM) studies obtained on 15 children (aged 1-10 years; mean 4.6 years) with neurologically-based dysphagia who underwent tonsillectomy for upper airway obstruction (13) or recurrent tonsillitis (2). Each OPM study was rated independently by two trained observers for the presence or absence of 13 features of deglutition. Subjects served as their own control in comparative analysis. There was a mean improvement of 4.33 features of deglutition (mode: 4, range: -1(-)+7) following tonsillectomy. Of 10 children with pre-existing laryngeal penetration or aspiration, two had partial resolution and five had complete resolution following surgery. Post-operatively, two children developed new laryngeal penetration with one also having aspiration. The inter-observer reliability for the OPM study interpretation was 0.90. We conclude that tonsillectomy has a role in the neurologically impaired child with dysphagia, but a pre-operative OPM study is indicated to identify silent aspiration and to aid in necessary counseling for the possibility of a deterioration of deglutition following surgery.

Evolution of definitions and understanding of vascular complications related to transcatheter aortic valve replacement.

Vascular complications have emerged as a major clinical challenge during transcatheter aortic valve replacement (TAVR). Recent reports demonstrate that major vascular complications not only predict major bleeding, transfusions, and renal failure, but are also associated with increased mortality. During the early development of TAVR, heterogeneous definitions of vascular complications were used in the literature. However, the Valve Academic Research Consortium has made significant progress in standardizing outcomes definitions in the study of this emerging technology. This has resulted in a rapidly expanding body of high-quality clinical research exploring important outcomes of TAVR, including vascular complications. This review seeks to summarize the literature and to explore the current state of knowledge with respect to the incidence, predictors, clinical impact, and management of vascular complications associated with TAVR.

Paravalvular leak after transcatheter aortic valve replacement.

Paravalvular leak (PVL) is a frequent complication of transcatheter aortic valve replacement (TAVR) that occurs at a much higher rate after TAVR than after conventional surgical aortic valve replacement. Recent reports indicating that PVL may be associated with increased late mortality have raised significant concern. However, the heterogeneity of methods for assessing and quantifying PVL, in addition to lack of consistency in the timing of this assessment, complicate the understanding of its true prevalence, severity, and clinical implications. The following review is an effort to consolidate current knowledge in this area in order to better understand the incidence, progression, and clinical impact of post-TAVR PVL, as well as to focus future research efforts on the assessment, prevention, and treatment of this important complication.

Intercellular calcium waves in neurons.

Spontaneous intercellular Ca2+ waves were observed in groups of neurons in two different culture preparations: primary mouse cortical neurons and GT1-1 immortalized neurons. Waves of increased intracellular Ca2+ concentration propagated at rates of 100-200 microns/s over as many as 200 cells and were abolished by the removal of extracellular calcium, by nimodipine, by tetrodotoxin, and by the gap junction inhibitor octanol. A sister clone of the GT1 line, GT1-7 neurons, showed no intercellular Ca2+ waves and were found to have a significantly lower level of connexin26 mRNA than the GT1-1 line. Although we cannot definitively rule out a role for synaptic communication, we propose that intercellular Ca2+ waves in cultured neurons are generated by Ca2+ influx caused primarily by the propagation of depolarization via gap junctions. Intercellular Ca2+ signaling via gap junctions may represent an important mechanism for nonsynaptic neuronal signaling.

Heart block after coronary artery bypass--effect of chronic administration of calcium-entry blockers and beta-blockers.

We evaluated risk of heart block after cardiopulmonary by-pass (CPB) in patients with normal conduction undergoing coronary artery bypass grafting who chronically received calcium-entry blockers, beta-blockers, or combined therapy. Before CPB, calcium-entry blockers alone produced an increase in P-R intervals but no change in heart rate; calcium-entry blocker effects were undetectable after CPB, beta-Blockers alone or with calcium-entry blockers produced lower heart rates and longer P-R intervals throughout the entire perioperative period when compared to no therapy (control) or calcium-entry blockers alone. Complete heart block did not occur; one control patient had transient second degree block after CPB. First degree block appeared transiently in 5% of the patients after anesthetic induction and in 15% on emergence from CPB, but was unrelated to drug therapy. We conclude that chronic calcium-entry blocker therapy has minimal effects on conduction perioperatively; beta-blocker effects persist for up to 10 hr after CPB; and the risk of heart block with either drug or combination is low and should not be a factor in their continued administration preoperatively.

Taxol and cisplatin inhibit proliferation of T47D human breast cancer cells.

We have examined the influence of taxol and cisplatin on the rate and extent of proliferation of T47D cells grown in the presence of 5% fetal bovine serum (FBS). An 8-day exposure of the cells to taxol inhibited the growth completely maintaining the number of cells to the level seen at initial plating. The taxol effect was evident at 10 nM-1 microM concentration and the half maximum inhibition was calculated to be 20 nM taxol. While the cells in the control group taxol-treated group remained at the initial number. Similar observations were made regarding the influence of cisplatin, which caused 80-90% inhibition in the number of the cells. When combined, taxol and cisplatin caused a further inhibition in the proliferation of T47D cells. The results of our studies demonstrate that both taxol and cisplatin, the known antineoplastic agents, block the proliferation of T47D human breast cancer cells effectively and are potentially useful chemotherapeutic agents for the management of breast cancer.

Interaction of newly synthesized antiprogesterone ZK98299 with progesterone receptor from human myometrium.

We have undertaken characterization of binding of the newly synthesized progesterone receptor (PR) antagonist ZK98299 in the cellular fractions of human myometrium. Specific [3H]progesterone and [3H]ZK98299 binding was observed in the cytosol and the nuclear fractions, and could be competitively replaced by either of the steroids in their radioinert form. Although PR occupied by both steroids exhibited nuclear uptake, the extent of nuclear binding was lower with [3H]ZK98299-receptor complexes. The binding of both ligands to PR was a function of the duration of incubation and the protein concentration: it was saturable at 3-6 nM steroids with a dissociation constant of approximately 2 nM. However, the number of ZK98299 binding sites (72 fmoles/mg protein) was lower compared to that of progesterone (322 fmoles/mg protein). The relative binding affinity (RBA) of ZK98299 for the nuclear PR was about 33% that of progesterone. The results of our study suggest that ZK98299 binds to PR in the cytosol and the nuclear fractions. The antiprogestin effects of ZK98299 reported in the literature are PR-mediated and may result from suboptimal nuclear binding/retention of antiprogestin-receptor complexes. Since this study did not involve isolation and study of individual PR isoforms, PR-A and PR-B, the present data should be viewed as representing an average of contributions by the two receptor forms.

Traumatic rupture of the thoracic aorta. A 20-year review: 1969-1989.

Acute traumatic injury of the thoracic aorta is a relatively common injury of deceleration accidents, usually high-speed motor vehicle accidents. The limiting factor to successful hospital management of these victims is early diagnosis and prompt treatment. Between the years 1969 and 1989, 116 patients (87 men and 29 women) were diagnosed with acute traumatic injury of the aorta. The mean age was 38.8 years, and the range was from 11 to 82 years. All patients who presented to the hospital emergency departments were included in the evaluation. The diagnosis of aortic rupture was firmly established by either aortography, surgery, or autopsy. The site of injury in 105 (90.5%) was the aortic isthmus, that is, distal to the origin of the left subclavian artery. In nine patients (7.7%) the injury was in the distal thoracic aorta. Two patients had injuries of the aortic arch. Associated injuries were present in 110 patients (95%); 16 patients (14%) had no external evidence of chest injury. Only 50 patients (43%) had the opportunity for definitive surgical management. The nonsurgical group comprised 66 patients (57%), and all of these died; the cause of death was unsuspected, suspected, or diagnosed after hospital admission from the emergency department. Of the surgical group, 36 patients (72%) survived, whereas 14 patients (28%) died. The surgical management comprised partial cardiopulmonary bypass in 31 patients that included seven deaths, simple aortic cross-clamping in 14 that included six deaths, and nonheparinized bypass in four that included one death. The incidence of paraplegia was 3.2% (one patient) with cardiopulmonary bypass, 28.5% (four patients) with simple aortic cross-clamping and none with nonheparinized bypass.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-like growth factor-1 receptor and its ligand regulate the reentry of adult ventricular myocytes into the cell cycle.

To determine whether insulin-like growth factor-1 (IGF-1) stimulation in vitro of ventricular myocytes isolated from infarcted hearts is characterized by the reentry of cells into the cell cycle, the expression and kinase activity of cyclins E, A, and B and DNA synthesis were evaluated 5 days after coronary artery occlusion and 24 and 48 h following the addition of IGF-1. Myocytes surviving an acute myocardial infarction were employed because of their increase in surface insulin-like growth factor-1 receptors (IGF-1R). Western blot analysis documented that IGF-1 resulted in an upregulation of cyclins D1, E, A, and B in viable postinfarcted myocytes. Cyclin E- and A-associated histone H1 kinase activity and cyclin D1-associated retinoblastoma protein-associated kinase activity also increased, but cyclin B kinase activity was not enhanced by IGF-1. These changes in cyclins and kinase activities were characterized by a significant increase in the number of cells labeled by bromodeoxyuridine, from approximately 630/10(6) to nearly 9, 000/10(6) myocytes. This latter value was reduced by more than 50% by antisense oligodeoxynucleotide to IGF-1R mRNA. However, IGF-1 stimulation did not induce nuclear mitotic division and cytokinesis. In conclusion, the growth-promoting effect of IGF-1 on adult myocytes is regulated by the density of IGF-1R, which conditions the activation of the replicatory machinery of the cells. The failure of IGF-1 to enhance cyclin B kinase activity may be responsible for a block in the cell cycle and the inability of myocytes to progress through the M phase and subsequently divide.

Effects of antiprogestins on the rate of proliferation of breast cancer cells.

We have examined the influence of progestins (progesterone, R5020) and antiprogestins (RU486, ZK98299, Org 31710 and Org 31806) on the rate of proliferation of wild type T47D cells cultured in whole fetal bovine serum (FBS) or in single charcoal stripped fetal bovine serum (SSFBS). All of the progesterone antagonists RU486, ZK98299 and two novel antiprogestins Org 31710 and Org 31806 inhibited cell proliferation when cells were cultured in FBS. In contrast, all of the antiprogestins with the exception of ZK98299 enhanced cell growth when cells were cultured in SSFBS. This stimulatory effect of RU486 was observed only at a high concentration of the ligand (1 microM). The effect of R5020, however, was concentration independent. The number of cells in the presence of RU486 was approximately 600% followed by R5020 approximately 400% above control values after a 28 day culturing period. In contrast, when the cells were grown in the presence of medium containing non-stripped whole serum, RU486 inhibited the extent of cell proliferation by 45%. Estradiol (E2) stimulated the rate of proliferation in cells cultured in SSFBS. Similar to when cells were cultured in whole serum, the antiprogestins inhibited cell growth in E2-supplemented SSFBS. Detection of the growth enhancement effects of progesterone receptor (PR) ligands such as RU486 and R5020 on the cells grown in charcoal-stripped medium appear to require the removal of E2 by charcoal stripping of the serum.