Intelligent aids for parallel experiment planning and macromolecular crystallization.

This paper presents a framework called Parallel Experiment Planning (PEP) that is based on an abstraction of how experiments are performed in the domain of macromolecular crystallization. The goal in this domain is to obtain a good quality crystal of a protein or other macromolecule that can be X-ray diffracted to determine three-dimensional structure. This domain presents problems encountered in real-world situations, such as a parallel and dynamic environment, insufficient resources and expensive tasks. The PEP framework comprises of two types of components: (1) an information management system for keeping track of sets of experiments, resources and costs; and (2) knowledge-based methods for providing intelligent assistance to decision-making. The significance of the developed PEP framework is three-fold--(a) the framework can be used for PEP even without one of its major intelligent aids that simulates experiments, simply by collecting real experimental data; (b) the framework with a simulator can provide intelligent assistance for experiment design by utilizing existing domain theories; and (c) the framework can help provide strategic assessment of different types of parallel experimentation plans that involve different tradeoffs.

Statistical methods for the objective design of screening procedures for macromolecular crystallization.

The crystallization of a new macromolecule is still very much a trial-and-error process. As is well known, it requires the search of a large parameter space of experimental settings to find the relatively few idiosyncratic conditions that lead to diffraction-quality crystals. Crystallographers have developed a variety of screens to help identify initial crystallization conditions, including those based on systematic grids, incomplete factorial and sparse-matrix approaches. These are somewhat subjectively formulated based on accumulated data from past crystallization experiments. Ideally, one would prefer as objective a procedure as possible; however, that requires objective methods that incorporate a broad source of crystallization data. The Biological Macromolecular Crystallization Database (BMCD), a repository of all published crystallization conditions, is an obvious source of this data. This database has been augmented with a hierarchical classification of the macromolecules contained in the BMCD as well as extensive data on the additives used with them. A statistical analysis of the augmented BMCD shows the existence of significant correlations between families of macromolecules and the experimental conditions under which they crystallize. This in turn leads to a Bayesian technique for determining the probability of success of a set of experimental conditions based on the data in the BMCD as well as facts about a macromolecule known prior to crystallization. This has been incorporated into software that enables users to rank experimental conditions for new macromolecules generated by a dense partial factorial design. Finally, an additional advantage of the software described here is that it also facilitates the accumulation of the data required for improving the accuracy of estimation of the probabilities of success - knowledge of the conditions which lead to failure of crystallization.

Computerized tomographic localization of clinically-guided sacroiliac joint injections.

OBJECTIVE: The goal of this study was to use computed tomographic (CT) scanning to localize clinically guided sacroiliac (SI) joint injections and identify other structures affected by this procedure. DESIGN: A prospective, double-blind, correlational outcome study design was used. Injection of 39 SI joints with a mixture of bupivacaine (0.25%), methylprednisolone (40 mg), and iohexol (Omnipaque; 180 mg/dl) using a clinically guided technique, (i.e., no image guidance) was performed. Patients had CT scans obtained both immediately after needle placement and after contrast injection. Neither the patients nor their clinicians were aware of the CT findings at the time of injection. SETTING: Academic multidisciplinary pain center. PATIENTS: Patients with SI disease by clinical criteria. RESULTS: Intra-articular injection was accomplished in 8 of 37 (22%) patients. Injected material was identified within 1 cm of the joint 68% of the time. Epidural (spinal canal) injected material was seen 24% of the time. CONCLUSIONS: The low rate of intra-articular injection seen with this clinically-guided technique suggests restraint in its use for injection therapy. Some image guidance (e.g., fluoroscopy, CT) is probably necessary to reliably inject the SI joint. Perhaps in clinical settings, where image guidance is not readily available, a clinically-guided technique could initially be tried in patients at low risk for complications from such injections. This study also provides an anatomic explanation for the occasional weakness observed after SI joint injection.

Developmental expression of urine concentration-associated genes and their altered expression in murine infantile-type polycystic kidney disease.

Currently, there is little understanding of what factors regulate the development of urine concentrating capability in normal or polycystic kidney. The present study examined the developmental expression of genes associated with urine concentration in developing mice, including C57BL/6J-cpk/cpk mice with autosomal recessive-infantile (AR) polycystic kidney disease (PKD). Concentration of urine requires: 1) medullary collecting ducts (CD) located within a hypertonic interstitium, 2) CD cell expression of functional arginine vasopressin V2 receptors (AVP-V2R), and 3) the presence of appropriate CD water channels (aquaporins, AQP 2 and 3). An increase in urine osmolarity, normally seen between 1 and 3 weeks of age, was absent in cpk cystic mice. Aldose reductase mRNA expression (a gene upregulated by medullary hyperosmolarity) increased in normal mice, but remained low in the cystic kidney, suggesting the absence of a hypertonic medullary interstitium. AVP-V2R, AQP2, and AQP3 mRNA expression normally increase between 7 and 14 days. However, all were dramatically overexpressed even at 7 days of age in the cpk kidney in vivo, but decreased in vitro. Activation of the AVP-V2 receptor stimulates the production of cAMP, a substance known to promote cyst enlargement. To determine if CD cAMP, generated from increased AVP-V2Rs, was accelerating the PKD, cystic mice and their normal littermates were treated with OPC31260, a relatively specific AVP-V2R antagonist. OPC31260 treatment of cystic mice led to an amelioration of the cystic enlargement and azotemia. Treatment also decreased renal AQP2 mRNA but increased AVP-V2R and AQP3 mRNA expression in vivo. AVP upregulates the expression of AVP-V2R, AQP2, and AQP3 mRNAs in vitro. Renal EGF, known to inhibit AVP-V2R activity, downregulates AVP-V2R mRNA in vitro. Brief in vivo EGF treatment, known to decrease PKD in cpk mice, led to increased expression of AVP-V2R, AQP2, and AQP3 mRNAs at 2 weeks in both normal and cystic mice but no change was evident at 3 weeks of age. In conclusion, the development of urinary concentration ability correlates with the development of an increased medullary osmotic gradient which is diminished in murine ARPKD. However, CD genes associated with this process are overexpressed in vivo but underexpressed in vitro in the cystic kidney. The overexpression and/or overactivity of the AVP-V2R appears to contribute to the progression of PKD since an AVP-V2R antagonist inhibits cystic renal enlargement in the cpk mouse.

Radial artery pressure monitoring underestimates central arterial pressure during vasopressor therapy in critically ill surgical patients.

OBJECTIVES: Radial artery pressure is known to differ from central arterial pressure in normal patients (distal pulse amplification) and in the early postcardiopulmonary bypass period. The adequacy of the radial artery as a site for blood pressure monitoring in critically ill patients receiving high-dose vasopressors has not been carefully examined. DESIGN: Prospective observational study comparing simultaneous intra-arterial measurements of radial (peripheral) and femoral artery (central) pressures. SETTING: Clinical investigation in a university-based surgical intensive care unit. PATIENTS: Fourteen critically ill patients with presumed sepsis who received norepinephrine infusions at a rate of > or =5 microg/min. INTERVENTIONS: All patients were managed in accordance with our standard practice for presumed sepsis, which consisted of intravascular volume repletion followed by vasopressor administration titrated to a mean arterial pressure of > or =60 mm Hg. MEASUREMENTS AND MAIN RESULTS: Systolic and mean arterial pressures were significantly higher when measured from the femoral vs. radial site (p < .005). The higher mean arterial pressures enabled an immediate reduction in norepinephrine infusions in 11 of the 14 patients. No change in cardiac output or pulmonary artery occlusion pressure was noted after dose reduction. In the two patients in whom simultaneous recordings were made after discontinuation of norepinephrine infusions, equalization of mean arterial pressures was observed. CONCLUSIONS: Radial artery pressure underestimates central pressure in hypotensive septic patients receiving high-dose vasopressor therapy. Clinical management, based on radial pressures, may lead to excessive vasopressor administration. Awareness of this phenomena may help minimize adverse effects of these potent agents by enabling dosage reduction.

Impaired neuroendocrine response mediates refractoriness to cardiopulmonary resuscitation in spinal anesthesia.

OBJECTIVE: To determine the extent of neurogenic control on adrenal secretion in a canine model of high spinal anesthesia and cardiac arrest. DESIGN: Randomized, controlled, acute intensive study. SETTING: University intensive care laboratory. SUBJECTS: Nineteen healthy, anesthetized, mongrel dogs. INTERVENTIONS: Cardiac arrest was induced in 11 spinally anesthetized dogs and 8 sham-control animals; cardiopulmonary resuscitation (CPR) was started 60 secs later. Epinephrine was injected at 4 mins and every 2 mins thereafter. Arterial blood samples were obtained before anesthesia, before arrest, and after 1, 3, 5, 7, 9, and 11 mins of CPR. MEASUREMENTS AND MAIN RESULTS: At 1 and 3 mins after cardiac arrest, the control group exhibited significant increases of epinephrine and norepinephrine concentrations (p < .05) that were absent in the spinal anesthesia group. Plasma renin increased in both groups whereas aldosterone and cortisol remained unchanged. CONCLUSIONS: Spinal anesthesia abolishes the catecholamine release that follows cardiac arrest, while a previously postulated direct adrenal effect of hypoxia stimulating catecholamine release was not confirmed in these experiments. Since epinephrine treatment restores coronary perfusion pressure (CPP) during CPR, we conclude that catecholamine deficiency is the most likely mechanism for inadequate CPP during CPR conducted in the presence of spinal anesthesia.

Hepatocyte growth factor (HGF/SF) in Alzheimer's disease.

Hepatocyte growth factor (HGF/SF), is a heparin-binding polypeptide which stimulates DNA synthesis in a variety of cell types and also promotes cell migration and morphogenesis. HGF/SF mRNA has been found in a variety of tissues, including brain. In a previous study, we showed that basic fibroblast growth factor (bFGF), another heparin-binding protein is increased in Alzheimer's disease (AD), and appears to be associated with the heparan-sulfate proteoglycans bound to B/A4 amyloid (Biochem. Biophys. Res. Commun. 171 (1990) 690-696). In the present study, we examined the distribution of HGF/SF in 4% paraformaldehyde fixed samples of prefrontal cortex from control and Alzheimer patients, in order to assess the possibility that HGF/SF may be found in association with the pathologic changes which occur in Alzheimer's disease. A specific polyclonal antibody directed against HGF/SF revealed widespread HGF/SF-like immunoreactivity in both the cerebral cortex and white matter. Confocal microscopy confirmed that HGF/SF could be found in both GFAP positive astrocytes and LN3 positive microglia cells, as well as rare scattered cortical neurons. In the AD cases studied, the immunoreactivity was increased within both the astrocytes and microglial cells surrounding individual senile plaques. No staining was seen within the neurofibrillary tangles. Western blot analysis confirmed the normal molecular form of HGF/SF in Alzheimer's disease. Quantitative ELISA assay demonstrated a significant increase in HGF/SF in AD relative to age matched controls. These studies confirm the presence of HGF/SF immunoreactivity within neurons, astrocytes and microglial cells. They also indicate that HGF/SF may be increased within senile plaques as a function of the gliosis and microglial proliferation which occurs in association with these structures in Alzheimer's disease.

Molecular dynamics simulation study of DNA dodecamer d(CGCGAATTCGCG) in solution: conformation and hydration.

A molecular dynamics simulation of the dodecamer duplex d(CGCGAATTCGCG) using the particle mesh Ewald sum assumed a B-conformation remarkably close to the observed X-ray structure. The Ewald summation method effectively eliminates the usual "cut-off" of long-range interactions and allowed us to evaluate the full effect of the electrostatic forces. This simulation showed remarkable agreement with the Dickerson X-ray structure in both average structure and B-factors; within the EcoRI site itself, the rms deviation between the average theoretical and observed structures was 1.1 A. The width of the minor groove fluctuated between a wide and narrow configuration with the latter corresponding closely to the X-ray structure. The simulation also suggested a strong sequence-dependent signature on the minor groove width in both wide and narrow conformers. Hydration shells in both the major and minor grooves were observed. The "spine of hydration" in the minor groove was clear. In the major groove the first hydration shell appears to be a ribbon-like structure that reproduces the principal features of observed X-ray structures; subtle variations of this hydration pattern suggest sequence dependencies. Sequence-dependent features were also examined for helical and other geometric parameters. The successful reproduction of many experimentally observed fine structural features shows that the Ewald summation significantly improves the fidelity of the calculations.

The effect of gabapentin on neuropathic pain.

OBJECTIVE: To evaluate the effects of gabapentin on pain scores and opiate use. DESIGN: Retrospective review of patients charts who received gabapentin for at least 30 days. Data were collected concerning patients' diagnosis, current drug use, concurrent drug use, gabapentin dose, pain scores, and patient-reported side effects. Patients were divided into three groups based on their pain diagnosis; low back, neuropathic, and myofascial pain. The neuropathic group was subdivided into postherpetic neuralgia, diabetic neuropathy, sympathetically maintained pain, and phantom pain. SETTING: Two tertiary referral teaching hospitals in southeastern Michigan. RESULTS: A total of 122 charts were reviewed and included in this study. A significant decrease in pain scores with gabapentin was seen in the neuropathic pain group (paired t-test, p < .0001) but not in the low back pain group. Of the neuropathic pain group, patients with postherpetic neuralgia had the greatest decrease in pain scores. Ten patients showed a > 75% decrease in pain scores, of these: nine had a direct nerve injury, and one had postherpetic neuralgia. Opiate use was unchanged in all groups. Patients who were taking opiates had significantly less benefit with gabapentin use in terms of pain score. Patient-reported side effects were similar to those reported in a nonchronic pain population. CONCLUSION: Gabapentin may be a useful adjunct for treating neuropathic pain with a minimum of side effects. Particular advantage may be gained with the use of this drug for postherpetic neuralgia and direct peripheral nerve injuries.

Heparin binding and oligomerization of hepatocyte growth factor/scatter factor isoforms. Heparan sulfate glycosaminoglycan requirement for Met binding and signaling.

Hepatocyte growth factor/scatter factor (HGF/SF) is a heparin-binding polypeptide that stimulates cell proliferation, motility, and morphogenesis by activation of its receptor, the c-Met tyrosine kinase. HGF/SF consists of a series of structural units, including an amino-terminal segment with a hairpin loop, four kringle domains, and a serine protease-like region. In this study, we demonstrate that the amino-terminal (N) domain retains the heparin-binding properties of full-length HGF/SF. In contrast to a previous hypothesis, selected basic amino acid residues in the hairpin loop are not critical for heparin binding, although alanine substitution at a subset of these sites markedly reduced the biological activity of the HGF/SF isoform, HGF/NK1. Covalent cross-linking experiments performed with wild-type and heparan sulfate glycosaminoglycan (HSGAG)-deficient Chinese hamster ovary (CHO) cells revealed that Met-HGF/NK1 binding was strongly dependent on HSGAG. Addition of heparin to HSGAG-deficient CHO cells not only restored ligand binding, but also increased ligand-dependent Met tyrosine phosphorylation and c-fos expression. Moreover, our results showed that heparin stimulated ligand oligomerization through an interaction with the N domain. These findings establish the importance of the N domain for heparin-ligand and ligand-ligand interactions, and demonstrate a crucial role for HSGAG in receptor binding and signal transduction.

Dynamic contributions to the DNA binding entropy of the EcoRI and EcoRV restriction endonucleases.

Molecular Dynamics simulations on DNA-EcoRI and DNA-EcoRV complexes suggest that the DNA within these complexes is significantly more ordered than free DNA. Similarly, both the protein and the DNA are more ordered in the specific (cognate) DNA-EcoRV complex than they are in the non-cognate DNA-protein complex, consistent with recently proposed analogies between protein folding and sequence-specific DNA-protein recognition. Analysis of the trajectories shows that the net entropy gain upon specific binding to be the result of opposing contributions. Solvent release, which increases entropy versus configurational terms (as measured by the magnitude of the atomic fluctuations), and collective terms from tight coupling between the motions of the protein and the DNA.

Differences in the inhibition of translation by cisplatin, transplatin, and certain related compounds.

The non-therapeutic cisplatin congeners transplatin and chloroethylenetriamine platinum (dien) inhibited translation to a similar extent as cisplatin did. The IC50 values were: cisplatin 23 microM, transplatin 54 microM, and dien 117 microM. Unlike certain heavy metal inhibitors of translation, the effect of neither cisplatin nor the congeners was reversed by 3':5'-cyclic adenosine monophosphate (cAMP). This suggests that the effect of these platinum compounds does not occur by the heavy metal mechanism. Polyribosomes and ribosomal subunits formed in transplatin-inhibited reactions differed from those in reactions inhibited by cisplatin. Specifically, large polyribosomes and complete 80S ribosomal subunits accumulated in the presence of transplatin. This indicates that while cisplatin slowed initiation of peptide synthesis, the trans-isomer slowed elongation. Substantive differences were not found between cisplatin and the monofunctional compound dien. This congener increased the non-peptidyl disintegrations per minute in the acid precipitates of assays containing [35S]methionine. The high background indicated that an interaction between the label and a precipitable component of the system was induced by dien. However, consumption of methionine by this interaction did not appear to be the cause of the inhibition. Although there may be differences in the mechanisms of the effects, the finding that the non-therapeutic congeners inhibit translation at similar concentrations as cisplatin suggests that this inhibition is not responsible for the anticancer effect. On the other hand, the possibility that decreased translation could play an important role in the toxicity of these compounds in certain quiescent cells cannot be ruled out.

Spin-labeled nucleotide mobility in the boundary of the EcoRI endonuclease binding site.

A complex consisting of the EcoRI endonuclease site-specifically bound to spin-labeled DNA 26mers was prepared to provide a model system for studying possible conformational changes resulting from protein binding. EPR was used to monitor the mobility of the spin labels that were strategically placed in position 6, 9, or 11 with respect to the dyad axis of the 26mer. These positions are located within the flanking region on either side of the EcoRI hexamer binding site. This allows the monitoring of potential distal structural changes in the DNA helix caused by protein binding. The spectral line shapes indicate that the spin label closest to the EcoRI endonuclease binding site, i.e., in position 6, is most influenced by the binding event. The EPR data are analyzed according to a model that distinguishes between spectral effects due to a change in the hydrodynamic shape of the complex and those resulting from local variations in the spin-label mobility as characterized by a local order parameter S. S reflecting the motional restriction of the spin-labeled base is 0.20 +/- 0.01 for all three oligomers as well as for the two complexes with the label in position 9 or 11, while the position 6 labeled complex yields S = 0.25. To further evaluate the origin of the slightly larger EPR effect observed with position 6 labeled material, molecular dynamics (MD) simulations were used to explore the space accessible to the probes in positions 6, 9, and 11. MD results gave similar nitroxide trajectories for all three labeled 26mers in the absence or presence of EcoRI. Thus, the small position 6 effect is attributed to a structural distortion in the major groove of the DNA at this location possibly corresponding to a bend induced by protein binding. The observation that the spectral changes are small indicates the absence of any significant structural disruption being propagated along the helix as a result of protein binding. Also, the fact that the line shape of the 26mers did not change as expected from hydrodynamic theory in view of the significant increase in molecular volume upon protein binding suggests that there are additional relaxation processes involving the protein and nucleic acid.

Coronary perfusion pressure during cardiopulmonary resuscitation after spinal anesthesia in dogs.

Cardiac arrest during spinal anesthesia is a rare event, but when it does happen cardiopulmonary resuscitation (CPR) is often ineffectual. This study examines the effect of spinal anesthesia on coronary perfusion pressure (CPP) during CPR and the subsequent response of CPP to epinephrine administration. Twenty mongrel dogs were anesthetized, and randomly assigned to a spinal injection with either 0.5 mg/kg bupivacaine or with an equivalent volume of normal saline. Twenty minutes later, ventricular fibrillation was electrically induced and after 1 min CPR was started. CPP was measured every minute. After 4 min of CPR, epinephrine 0.01 mg/kg was given followed by 0.1, 0.2, and 0.4 mg/kg epinephrine intravenously (IV) at 6, 8, 10 min of CPR, respectively. The bupivacaine (n = 11) group had significantly less CPP than the sham spinal (n = 8) group, 12-13 mm Hg as compared to 27-34 mm Hg. Only 4/11 dogs (36%) in the bupivacaine group had CPP > or = 15 mm Hg during the first 4 min after arrest as compared to 8/8 (100%) in the sham spinal group. This increased to 7/11 dogs (64%) after 0.01 mg/kg epinephrine and to 9/11 after 0.1 mg/kg epinephrine. Total spinal anesthesia decreases CPP and thus the efficacy of CPR in dogs below the threshold previously established for predicting successful resuscitation. Epinephrine is effective in increasing CPP during CPR above the critical threshold. These data suggest that if cardiac arrest occurs during spinal anesthesia, epinephrine should be given in doses of 0.01-0.02 mg/kg IV initially and then increasing to 0.1 mg/kg IV. When this does not work, and ineffective CPR is suspected, alternative resuscitative measures should be considered.

Complexes between chaperonin GroEL and the capsid protein of bacteriophage HK97.

The 42 kDa capsid protein of bacteriophage HK97 requires the GroEL and GroES chaperonin proteins of its Escherichia coli host to facilitate correct folding, both in vivo and in vitro. In the absence of GroES and ATP, denatured gp5 forms a stable complex with the 14 subunit GroEL molecule. We characterized the electrophoretic and biochemical properties of this complex. In electrophoresis on a native (nondenaturing) gel, the band of the gp5-GroEL complex shifts to a slower migrating position relative to uncomplexed GroEL. The results show that there is only one subunit of gp5 bound to each GroEL 14-mer and that the shift in band position is due primarily to a change in the overall charge of the complex relative to uncomplexed GroEL, and not to a change in size or shape. GroEL forms similar complexes with proteolytic fragments of gp5, with a series of sequence duplication derivatives of gp5, and with other proteins. Electrophoretic examination of these complexes shows that a band shift occurs with proteins larger than 31-33 kDa but not with smaller proteins. For those proteins that cause a band shift upon complex formation, the magnitude of the shift is correlated with the predicted if the charge of the complex were simply the sum of the charge of GroEL and the charge of the substrate protein. We suggest that binding of a substrate protein to GroEL is accompanied by a net binding of solution cations to the complex, but only in the case of proteins above a minimum size of 31-33 kDa. The gp5-GroEL complex is in an association/dissociation equilibrium, with a binding constant measured in the range of 11-17 microM-1.

Preliminary characterization of EcoRI-DNA co-crystals: incomplete factorial design of oligonucleotide sequences.

A full understanding of the sequence specificity of EcoRI endonuclease requires structural information on complexes where the DNA contains one 'incorrect' base pair; historically, these sites are referred to as EcoRI* sites. They are inherently asymmetric, unlike the canonical EcoRI site, GAATTC, which possesses a twofold axis of rotational symmetry. All previously determined DNA-EcoRI complexes incorporated this symmetry axis into the space group, requiring the design of 'new' oligonucleotides to produce an asymmetric unit appropriate to an EcoRI* complex. The incomplete factorial approach of Carter & Carter [Carter & Carter (1979). J. Biol. Chem. 254, 12219-12223.] was used to design the DNA sequence. Factors included the location and type of EcoRI* substitution and the length and AT richness of the sequences on both sides of the RI site. Co-crystals were obtained with several sequences, including one with TCGTGGACTTCGTG. Diffraction data were collected from one crystal of this complex to 3.2 A resolution; the unit-cell parameters are a = b = 123.8 and c = 148.9 A and the space group is P3(2)21. Unit-cell and space-group information was also obtained for the EcoRI* sites AAATTC, GGATTC and GAGTTC. These experiments demonstrated the need for a rapid, economical method that would distinguish DNA-protein co-crystals from crystals of protein only. This can be readily achieved with a single small crystal and a staining method based on methylene blue and methyl violet, which stain DNA and protein, respectively.

Pharmacist-operated drug information centers in the United States.

Pharmacist-operated drug information centers (DICs) in the United States were surveyed to obtain current information on the availability and scope of their services. Questionnaires were mailed in late 1991 to 179 institutions believed to have organized DICs. Topics covered in the questionnaire included staffing, resources, funding, and services provided. The results were compared with previous survey results to identify trends. Through 1992, 120 usable responses were received. Compared with findings from earlier surveys, DICs' affiliations with medical centers and hospitals have declined and affiliations with pharmacy schools have increased. More personnel work in DICs than ever. Computers are now used by nearly every DIC, there is an increased emphasis on quality-assurance programs for services rendered, and many DICs have increased revenue with new and expanded services. Although DICs are no longer increasing in number, their services are becoming more sophisticated.

Effect of vancomycin infusion on cardiac function in patients scheduled for cardiac operation.

Patients scheduled for cardiac operation often receive vancomycin before the operation to decrease postoperative staphylococcal wound infections. In animal studies, vancomycin depressed cardiac function approximately 15%. Because of the potentially serious consequences of myocardial depression in patients undergoing cardiac operation, we examined the effect of vancomycin infusion on cardiac hemodynamics in patients scheduled for cardiac operation. Patients who were scheduled for cardiac operation and vancomycin prophylaxis were enrolled in our study. After baseline cardiac output, mean arterial pressure, central venous pressure, and pulmonary capillary wedge pressure were measured, 1 gm of vancomycin HCl was infused over 1 hour. Cardiac output, mean arterial pressure, central venous pressure, and pulmonary capillary wedge pressure were measured at 15, 30, 60, 90, and 120 minutes after the start of the infusion. In the 46 patients that completed the study, no significant change was observed in cardiac output or systemic vascular resistance at any time when compared with baseline. Mean arterial pressure increased significantly (p = 0.03) between baseline (90.8 +/- 2.4 standard error of mean) and 90 minutes (94.1 +/- 2.4 standard error of mean). One patient had a transient 30% fall in mean arterial pressure and systemic vascular resistance with facial flushing during the infusion. In conclusion, we found that vancomycin infusion over 1 hour in patients before cardiac operation is safe and not associated with cardiac depression.