PubMed Health⌕ Search

Biomedical subjects

S M Hollenberg

Publications and source records attributed to S M Hollenberg.

At least 19 recordsLinked to original sources
PubMed2001

Coronary endothelial dysfunction after heart transplantation predicts allograft vasculopathy and cardiac death.

BACKGROUND: Coronary endothelial dysfunction may be an early marker for cardiac allograft vasculopathy (CAV) in orthotopic heart transplant recipients. Using serial studies with intravascular ultrasound and Doppler flow-wire measurements, we have previously demonstrated that annual decrements in coronary endothelial function are associated with progressive intimal thickening. The present study tested whether endothelial dysfunction predicts subsequent clinical events, including cardiac death and CAV development. METHODS AND RESULTS: Seventy-three patients were studied yearly beginning at transplantation until a prespecified end point was reached. End points were angiographic evidence of CAV (>50% stenosis) or cardiac death (graft failure or sudden death). At each study, coronary endothelial function was measured with intracoronary infusions of adenosine (32-microgram bolus), acetylcholine (54 microgram over 2 minutes), and nitroglycerin (200 microgram) into the left anterior descending coronary artery; intravascular ultrasound images and Doppler velocities were recorded simultaneously. Of the 73 patients studied, 14 reached an end point during the study (6 CAV and 8 deaths, including 4 with known CAV, 1 graft failure, and 3 sudden). On the last study performed, the group with an end point had decreased epicardial (constriction of 11.1+/-2.9% versus dilation of 1.7+/-2.2%, P=0.01) and microvascular (flow increase of 75+/-20% versus 149+/-16%, P=0.03) endothelium-dependent responses to acetylcholine compared with the patients who did not reach an end point. Responses to adenosine and nitroglycerin did not differ significantly. CONCLUSIONS: Endothelial dysfunction, as detected by abnormal responses to acetylcholine, preceded the development of clinical end points. These data implicate endothelial dysfunction in the development of clinically significant vasculopathy and suggest that serial studies of endothelial function have clinical utility.

Acetylcholine↗
PubMed2001

Characterization of a hyperdynamic murine model of resuscitated sepsis using echocardiography.

A small animal model of sepsis that reproduces the vasodilation, hypotension, increased cardiac output, and response to treatment seen in patients with septic shock would be useful for studies of pathophysiology and treatment, but no current models replicate all of these features. Mice were made septic by cecal ligation and puncture and resuscitated with fluids and antibiotics every 6 h. Blood pressure was measured in anesthetized mice with manometric catheters, and echocardiography was performed in these animals every 6 h. Survival in treated septic mice was improved compared with untreated mice (44% versus 0%, p < 0.01). In control mice, heart rate (HR, 420 +/- 31 beats/min), mean arterial pressure (Pa, 100 +/- 8 mm Hg), stroke volume (SV, 26 +/- 4 microl), and cardiac output (12.5 +/- 6.6 ml/min) were unchanged over 48 h. In septic mice Pa was significantly decreased (102 +/- 14 to 65 +/- 19 mm Hg, p < 0.02), starting at 12 h. HR and cardiac output increased significantly (HR, 407 +/- 70 to 524 +/- 76 beats/min, cardiac output, 11.6 +/- 2.0 to 17.1 +/- 1.5 ml/min, p < 0.01). SV (24 +/- 5 microl) remained constant. This fluid-resuscitated, antibiotic-treated model replicates the mortality, hypotension, and hyperdynamic state seen in clinical sepsis. Precise determination of serial hemodynamics in this model may be useful to elucidate pathophysiologic mechanisms and to evaluate new therapies for septic shock.

Animals↗
PubMed2001

Assessing coronary blood flow dynamics with the TIMI frame count method: comparison with simultaneous intracoronary Doppler and ultrasound.

This study compared the TIMI frame count (TFC), which has been proposed as a method for quantifying coronary blood flow, with coronary flow and microvascular function measured with intracoronary Doppler and intracoronary ultrasound. Coronary blood flow volume was calculated from coronary blood velocity (by intracoronary Doppler) and lumen area (by intracoronary ultrasound) in the LAD in 46 post-heart transplant patients at baseline and after intracoronary adenosine. TFC correlated significantly with average peak coronary blood velocity (r = -0.42; P = 0.004) and coronary lumen area (r = 0.39; P = 0.008), but not with coronary blood flow volume (r = -0.01; P = 0.96) or the coronary flow reserve response to adenosine (r = 0.09; P = 0.58). In conclusion, TFC is a simple method of assessing coronary blood velocity but not volumetric flow. While TFC does not predict coronary flow reserve, as a measure of velocity it does provide an assessment of basal microvascular tone, information that is complementary to that afforded by flow reserve measurements.

Adult↗
PubMed2001

Evidence of transcellular permeability pathway in microvessels.

We used video fluorescence microscopy of the vascular bed in the cremaster muscle of rat and mouse to study the transfer of plasmalemma vesicles (caveolae) across the microvessel barrier in situ. The water-soluble styryl pyridinium dye RH414, which adsorbs to and fluoresces at the membrane-water interface, was used as a marker for vesicular traffic through endothelial cells. Fluorescein isothiocyanate (FITC), similar in molecular size to the styryl pyridinium probe, was used to mark for dye transfer by the paracellular pathway. Transcellular dye flux was determined by comparing the fluorescence intensities of RH414 and FITC on either side of the vessel wall (i.e., in microvessel lumen and in muscle tissue at various distances from the microvessel wall). We observed that RH414 accumulated in the interstitium more rapidly than FITC. We next studied the role of the 60-kDa albumin-binding glycoprotein gp60, hypothesized to activate transcellular permeability, in stimulating the transcellular vesicle traffic. Introduction of anti-gp60 antibody into the microvessel to cross-link and activate gp60 markedly increased the transvascular flux of RH414. Control isotype-matched antibody had no effect on the RH414 flux. The sterol-binding agent filipin, which disassembles caveolae, inhibited the RH414 flux induced by gp60 cross-linking. The transfer of styryl pyridinium dyes in intact microvessels suggests that plasmalemmal membrane traffic across the skeletal muscle microvessel barrier is a constitutively active process. The results indicate that the gp60-dependent pathway is important in regulating endothelial permeability in situ via a transcellular mechanism.

Animals↗
PubMed2001

Cardiogenic shock.

Mortality rates in patients with cardiogenic shock remain frustratingly high. Its pathophysiology involves a downward spiral in which ischemia causes myocardial dysfunction, which in turn worsens ischemia. Areas of viable but nonfunctional myocardium can contribute to the development of cardiogenic shock. Rapid diagnosis and prompt initiation of supportive therapy to maintain blood pressure and cardiac output, followed by expeditious coronary revascularization, are crucial. The SHOCK multicenter randomized trial has provided important new data that support a strategy of emergent cardiac catheterization and revascularization with angioplasty or coronary surgery when feasible. This strategy can improve survival and represents standard therapy at this time. In hospitals without direct angioplasty capability, stabilization with IABP and thrombolysis followed by transfer to a tertiary care facility may be the best option.

Angioplasty, Balloon, Coronary↗
PubMed2001

Assessment of sequential same arm agreement of blood pressure measurements by a CVProfilor DO-2020 versus a Baumanometer mercury sphygmomanometer.

OBJECTIVE: The aim of this study was to assess the accuracy of sequential same arm blood pressure measurement by the mercury sphygmomanometer with the oscillometric blood pressure measurements from a device that also determines arterial elasticity. METHODS: A prospective, multicentre, clinical study evaluated sequential same arm blood pressure measurements, using a mercury sphygmomanometer (Baumanometer, W. A. Baum Co., Inc., Copiague, New York, USA) and an oscillometric non-invasive device that calculates arterial elasticity (CVProfilor DO-2020 Cardiovascular Profiling System, Hypertension Diagnostics, Inc., Eagan, Minnesota, USA). Blood pressure was measured supine in triplicate, 3 min apart in a randomized sequence after a period of rest. RESULTS: The study population of 230 normotensive and hypertensive subjects included 57% females, 51% Caucasians, and 33% African Americans. The mean difference between test methods of systolic blood pressure, diastolic blood pressure, and heart rate was -3.2 +/- 6.9 mmHg, +0.8 +/- 5.9 mmHg, and +1.0 +/- 5.7 beats/minute. For systolic and diastolic blood pressure, 60.9 and 70.4% of sequential measurements by each method were within +/- 5 mmHg. Few or no points fell beyond the mean +/- 2 standard deviations lines for each cuff bladder size. CONCLUSION: Sequential same arm measurements of the CVProfilor DO-2020 Cardiovascular Profiling System measures blood pressure by an oscillometric method (dynamic linear deflation) with reasonable agreement with a mercury sphygmomanometer.

Adolescent↗
PubMed2001

Arterial elasticity among normotensive subjects and treated and untreated hypertensive subjects.

OBJECTIVE: The aim of this study was to determine arterial elasticity in normotensive and hypertensive individuals. BACKGROUND: In addition to blood pressure, other parameters serve as markers for vascular disease. Arterial elasticity is one parameter that can be determined by a modified Windkessel model of the circulation. This model estimates, from a computerized pulse contour analysis, the proximal (capacitive) elasticity of the large arteries and the distal (reflective) elasticity of the small arteries. METHODS: A prospective, multi-center, controlled clinical study evaluated large-artery and small-artery elasticity indices in four groups: (1) normotensives without a family history of hypertension; (2) normotensives with a family history of hypertension; (3) treated and controlled hypertensives; and (4) untreated and uncontrolled hypertensives. Blood pressure, using a mercury manometer, and arterial elasticity, using a CVProfilor DO-2020 CardioVascular Profiling System (Hypertension Diagnostics, Inc., Eagan, MN, USA), were measured supine in triplicate 3 min apart in a randomized sequence. RESULTS: There were 212 evaluable subjects of mean age 46 years; 57% were women, 51% Caucasian and 33% African-American. Comparing normotensives without a family history and untreated hypertensives, both large-artery and small-artery elasticity indices were significantly different (P < 0.0001). After controlling for age and body surface area, a significant linear trend (P = 0.0001) across the four groups was detected for both large- and small-artery elasticity indices. CONCLUSION: As the hypertension status worsened, large- and small-artery elasticity indices decreased, suggesting a potential for the diagnostic use of arterial elasticity determinations.

Arteries↗
PubMed2001

CHMP1 is a novel nuclear matrix protein affecting chromatin structure and cell-cycle progression.

The Polycomb-group (PcG) is a diverse set of proteins required for maintenance of gene silencing during development. In a screen for conserved partners of the PcG protein Polycomblike (Pcl), we have identified a new protein, human CHMP1 (CHromatin Modifying Protein; CHarged Multivesicular body Protein), which is encoded by an alternative open reading frame in the PRSM1 gene and is conserved in both complex and simple eukaryotes. CHMP1 contains a predicted bipartite nuclear localization signal and distributes as distinct forms to the cytoplasm and the nuclear matrix in all cell lines tested. We have constructed a stable HEK293 cell line that inducibly overexpresses CHMP1 under ecdysone control. Overexpressed CHMP1 localizes to a punctate subnuclear pattern, encapsulating regions of nuclease-resistant, condensed chromatin. These novel structures are also frequently surrounded by increased histone H3 phosphorylation and acetylation. CHMP1 can recruit a PcG protein, BMI1, to these regions of condensed chromatin and can cooperate with co-expressed vertebrate Pcl in a Xenopus embryo PcG assay; this is consistent with a role in PcG function. In combination, these observations suggest that CHMP1 plays a role in stable gene silencing within the nucleus.

Amino Acid Sequence↗
PubMed2001

CHMP1 functions as a member of a newly defined family of vesicle trafficking proteins.

A multivesicular body is a vesicle-filled endosome that targets proteins to the interior of lysosomes. We have identified a conserved eukaryotic protein, human CHMP1, which is strongly implicated in multivesicular body formation. Immunocytochemistry and biochemical fractionation localize CHMP1 to early endosomes and CHMP1 physically interacts with SKD1/VPS4, a highly conserved protein directly linked to multivesicular body sorting in yeast. Similar to the action of a mutant SKD1 protein, overexpression of a fusion derivative of human CHMP1 dilates endosomal compartments and disrupts the normal distribution of several endosomal markers. Genetic studies in Saccharomyces cerevisiae further support a conserved role of CHMP1 in vesicle trafficking. Deletion of CHM1, the budding yeast homolog of CHMP1, results in defective sorting of carboxypeptidases S and Y and produces abnormal, multi-lamellar prevacuolar compartments. This phenotype classifies CHM1 as a member of the class E vacuolar protein sorting genes. Yeast Chm1p belongs to a structurally-related, but rather divergent family of proteins, including Vps24p and Snf7p and three novel proteins, Chm2p, Chm5p and Chm6p, which are all essential for multivesicular body sorting. These observations identify the conserved CHMP/Chmp family as a set of proteins fundamental to understanding multivesicular body sorting in eukaryotic organisms.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2000

Increased microvascular reactivity and improved mortality in septic mice lacking inducible nitric oxide synthase.

Persistent vasodilation characteristic of septic shock may result from overproduction of nitric oxide and can lead to pressor-refractory hypotension and death. To evaluate the significance of cytokine-inducible nitric oxide synthase (iNOS) in the pathogenesis of sepsis, we used a clinically relevant mouse model of sepsis and compared mortality and microvascular reactivity in wild-type (WT) mice and transgenic mice deficient in iNOS. WT C57BL/6 and iNOS-deficient mice were made septic by cecal ligation and puncture. Treated mice were given fluids and antibiotics every 6 hours. Microvascular vasoconstriction in response to topical norepinephrine was measured in cremasteric arterioles (15 to 30 microm) by videomicroscopy. Mortality at 48 hours was significantly lower in treated septic iNOS-deficient mice (45%) than in treated septic WT mice (76%), untreated septic iNOS-deficient mice (87%), or untreated WT mice (100%) (P<0.01). Norepinephrine-induced vasoconstriction was decreased in WT septic mice (EC(50) 200+/-56 nmol/L) compared with WT and iNOS-deficient shams (16+/-4 and 13+/-6 nmol/L), and vasoconstriction was significantly improved in septic iNOS-deficient mice (35+/-13 nmol/L, P<0.01). Microvascular catecholamine responsiveness and survival were improved in iNOS-deficient mice in a clinically relevant model of sepsis, suggesting that iNOS plays an important, but not exclusive, role in refractory vasodilation in patients with septic shock.

Animals↗
PubMed2000

Pharmacologic issues in the management of septic shock.

Despite our increased understanding of the biochemistry and physiology of sepsis, the treatment of septic shock remains a challenge. Initial management of septic shock entails urgent and emergent stabilization of the patient followed by broad-spectrum, empiric antibiotic therapy. After volume resuscitation, vasopressors or inotropic therapy or both may be necessary to restore perfusion. Adjunctive therapies and monitoring strategies may be helpful in preventing complications in the intensive care setting. Additional research and clinical trials are needed to identify supportive interventions that may affect the outcome of the septic patient.

Adrenal Cortex Hormones↗
PubMed2000

Nitric oxide synthase inhibition increases venular leukocyte rolling and adhesion in septic rats.

OBJECTIVE: Excess production of nitric oxide (NO) has been implicated in hypotension and blood flow abnormalities in sepsis, but NO is also an important inhibitor of leukocyte rolling and adhesion. Leukocyte adhesion is increased in sepsis despite elevated NO production. We hypothesized that inhibition of NO synthase (NOS) could increase leukocyte adhesion in sepsis. DESIGN: Prospective animal study. SETTING: Experimental animal laboratory. SUBJECTS: Twenty-five male rats, anesthetized with ketamine and acepromazine. INTERVENTIONS: Topical superfusion of the nonselective NOS inhibitor N(G)-monomethyl-L-arginine (NMA) on skeletal muscle postcapillary venules. MEASUREMENTS AND MAIN RESULTS: Rats made septic by cecal ligation and puncture were compared with controls that underwent sham ligation. Leukocyte rolling and adhesion were measured in cremasteric postcapillary venules of septic and control rats using in vivo videomicroscopy. The effects of NOS inhibition on leukocyte rolling and adhesion were also measured. After a stable baseline was reached, 1 microM of the nonselective NOS inhibitor NMA was suffused topically followed by physiologic buffer. The effects of L-arginine on leukocyte rolling and adhesion were also measured, both before and after suffusion of NMA. Leukocyte rolling and adhesion was increased in septic rats as compared with controls (control 5.5+/-0.9 rolling cells/min, 1.0+/-0.3 adherent cells/min; septic 13.7+/-2.0 rolling cells/min, 3.1+/-0.6 adherent cells/min; p < .001), and NOS inhibition further increased leukocyte rolling and adhesion in both septic and control rats (control 14.0+/-1.7 rolling cells/min, 2.8+/-0.5 adherent cells/min; septic 25+/-2.1 rolling cells/min, 5.4+/-0.5 adherent cells/min; both p < .001 vs. baseline). Prior suffusion of excess L-arginine prevented the increase in leukocyte adhesion with NMA in septic rats (2.6+/-0.4 adherent cells/min vs. 3.0+/-0.6 adherent cells/min; n = 3; p > .05). When administered after NMA, excess L-arginine partially reversed leukocyte adhesion in septic rats (5.4+/-0.7 adherent cells/min, with NMA vs. 4.3+/-0.7 adherent cells/min, after L-arginine; n = 5; p < .05). Venular shear did not differ between septic and control rats (600+/-109 (sec(-1)) vs. 620+/-37 (sec(-1)); p > .05). CONCLUSIONS: Although NOS inhibition may ameliorate hypotension in sepsis, such therapy may be deleterious by increasing leukocyte adhesion.

Animals↗
PubMed2000

Noncardiac surgery: postoperative arrhythmias.

Postoperative arrhythmias are common and represent a major source of morbidity after both cardiac and noncardiac surgical procedures. Postoperative dysrhythmias are most likely to occur in patients with structural heart disease. The initiating factor for an arrhythmia in a given patient after surgery is usually a transient insult, such as hypoxemia, cardiac ischemia, catecholamine excess, or electrolyte abnormality. Management includes correction of these imbalances and medical therapy directed at the arrhythmia itself. The physiologic impact of arrhythmias depends on arrhythmia duration, ventricular response rate, and underlying cardiac function. Similarly, urgency and type of treatment is determined by the physiologic impact of the arrhythmia, as well as by underlying clinical status. The purpose of this review is to provide current concepts of diagnosis and acute management of arrhythmias after noncardiac surgery. A systematic approach to arrhythmia diagnosis and evaluation of predisposing factors is presented, followed by consideration of specific bradyarrhythmias and tachyarrhythmias in the postoperative setting.

Anti-Arrhythmia Agents↗
PubMed1999

Misexpression of Polycomb-group proteins in Xenopus alters anterior neural development and represses neural target genes.

In Drosophila, the Polycomb-group constitutes a set of structurally diverse proteins that act together to silence target genes. Many mammalian Polycomb-group proteins have also been identified and show functional similarities with their invertebrate counterparts. To begin to analyze the function of Polycomb-group proteins in Xenopus development, we have cloned a Xenopus homolog of Drosophila Polycomblike, XPcl1. XPcl1 mRNA is present both maternally and zygotically, with prominent zygotic expression in the anterior central nervous system. Misexpression of Pcl1 by RNA injection into embryos produces defects in the anterior central nervous system. The forebrain and midbrain contain excess neural tissue at the expense of the ventricle and include greatly thickened floor and roof plates. The eye fields are present but Rx2A, an eye-specific marker, is completely repressed. Overexpression of Pcl1 in Xenopus embryos alters two hindbrain markers, repressing En-2 and shifting it and Krox-20 in a posterior direction. Similar neural phenotypes and effects on the En-2 expression pattern were produced by overexpression of three other structurally unrelated Polycomb-group proteins: M33, XBmi-1, and mPh2. These observations indicate an important role for the Polycomb-group in regulating gene expression in the developing anterior central nervous system.

Animals↗
PubMed1999

Cardiogenic shock.

PURPOSE: To review the cause, epidemiology, pathophysiology, and treatment of cardiogenic shock. DATA SOURCES: A MEDLINE search of the English-language reports published between 1976 and 1998 and a manual search of bibliographies of relevant papers. STUDY SELECTION: Experimental, clinical, and basic research studies related to cardiogenic shock. DATA EXTRACTION: Data in selected articles were reviewed, and relevant clinical information was extracted. DATA SYNTHESIS: Cardiogenic shock is a state of inadequate tissue perfusion due to cardiac dysfunction, most commonly caused by acute myocardial infarction. Mortality rates for patients with cardiogenic shock remain frustratingly high, ranging from 50% to 80%. The pathophysiology of cardiogenic shock involves a downward spiral: Ischemia causes myocardial dysfunction, which, in turn, worsens ischemia. Areas of nonfunctional but viable (stunned or hibernating) myocardium can also contribute to the development of cardiogenic shock. The key to achieving a good outcome is an organized approach that includes rapid diagnosis and prompt initiation of therapy to maintain blood pressure and cardiac output. Expeditious coronary revascularization is crucial. When available, emergency cardiac catheterization and angioplasty seem to improve survival. More recent developments, such as placement of coronary stents and use of glycoprotein IIb/IIIa antagonists, are promising but have not yet been well studied in patients with cardiogenic shock. In hospitals without direct angioplasty capability, stabilization with intra-aortic balloon counterpulsation and thrombolysis followed by transfer to a tertiary care facility may be the best option. CONCLUSIONS: Improved understanding of the pathophysiology of shock and myocardial infarction has led to improved treatment. If cardiogenic shock is managed with rapid evaluation and prompt initiation of supportive measures and definitive therapy, outcomes can be improved.

Angioplasty, Balloon, Coronary↗
PubMed1999

Simultaneous intracoronary ultrasound and Doppler flow studies distinguish flow-mediated from receptor-mediated endothelial responses.

Abnormalities in vascular endothelial function, which occur early in atherosclerosis, may play an etiologic role in the development of the disease or represent a marker for the extent of atherosclerosis. Endothelial dysfunction, usually characterized by demonstration of decreased endothelium-dependent vasorelaxation, may be a sensitive and specific method to detect vascular disease in its earliest stages. In this context, separation of abnormalities in receptor-mediated and flow-mediated endothelium-dependent vasodilatory responses may allow for the most accurate characterization of endothelial dysfunction. In 35 patients undergoing routine annual cardiac catheterization after heart transplantation, changes in epicardial lumen area and coronary blood flow in response to intracoronary administration of adenosine, acetylcholine, and nitroglycerin were measured simultaneously using an intravascular ultrasound (IVUS) catheter positioned over a Doppler flow wire in the left anterior descending coronary artery. The combination of these techniques allowed for distinction between receptor-mediated and flow-mediated endothelium-dependent vascular responses. Peak flow with the endothelium-independent resistance vessel dilator adenosine occurred at 18+/-2 sec; the maximal lumen area response occurred later, at 43+/-11 sec (P < 0.001). Acetylcholine, an endothelium-dependent small- and large-vessel vasodilator, caused an immediate increase in both flow and lumen area, but a second peak of dilation was observed, and maximal area occurred 46 sec after maximal flow (54+/-14 vs. 100+/-26 sec, P < 0.001). Simultaneous IVUS and Doppler flow measurements after infusion of vasoactive agents allows for distinction between and evaluation of the relative contribution of agonist-mediated and flow-mediated responses, which may offer important and unique insights into coronary endothelial function.

Acetylcholine↗