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Biomedical subjects

M L White

Publications and source records attributed to M L White.

At least 19 recordsLinked to original sources

Impact of the European Working Time Directive on the training of paediatric anaesthetists.

The European Working Time Directive and the New Deal have decreased the number of hours worked by anaesthetic trainees. We implemented the Working Time Directive in May 2004 and evaluated the effect of its implementation on training. During two 6-month periods, one before and one after the change, we determined the number of operating lists undertaken by each Specialist Registrar in Anaesthesia. After implementation of the Working Time Directive, the mean number of lists performed by Specialist Registrars decreased from 24 to 21 lists per registrar per month, a 13% decrease. Exposure to subspecialty lists was the same in both periods, but this was at the expense of general lists and those in remote locations. We conclude that the Working Time Directive has had a measurable impact on the training of paediatric anaesthetists, but that the significance of this change for clinical practice has not yet been measured.

Anesthesiology↗

Preoperative and intraoperative predictors of postoperative morbidity, poor graft function, and early rejection in 190 patients undergoing liver transplantation.

HYPOTHESIS: Preoperative and intraoperative variables predict in part adverse outcome after liver transplantation. DESIGN: Prospective, blinded, cohort study. SETTING: Tertiary care hospital. SUBJECTS: A total of 190 adult patients undergoing primary liver transplantation. MAIN OUTCOME MEASURE: Adverse outcome was prospectively defined as either in-hospital death or prolonged postoperative hospitalization (>14 days) associated with morbidity. Potential preoperative and intraoperative risk factors were collected. Associations were tested by univariate analysis followed by multivariate analysis in which preoperative factors were entered before intraoperative factors. RESULTS: Adverse outcome occurred in 44.7% of patients. Incidences of other complications were as follows: in-hospital mortality (8.4%), primary graft nonfunction (4.2%), poor early graft function (1.1%), and early rejection (31.2%). Univariate predictors of adverse outcome were United Network for Organ Sharing status (P =.003), Child-Turcotte-Pugh score (P =.02), POSSUM physiological score (P =.002), recipient age (P =.01), preoperative serum high-density lipoprotein cholesterol level (P =.03), preoperative serum creatinine level (P =.002), preoperative serum total IgG level (P =.004), duration in hospital preoperatively (P =.03), operative duration (P<.001), allogeneic erythrocyte transfusions (P<.001), total intraoperative fluids (P =.002), and use of inotropic agents (P =.01). In the final multivariate model, predictors of adverse outcome were United Network for Organ Sharing status (P =.03), recipient age (P =.002), and total intraoperative fluids (P =.04). Most patients who died or had a prolonged hospitalization exhibited dysfunction of more than 1 organ system, including pulmonary, renal, and infectious complications. CONCLUSIONS: Adverse outcome occurs frequently after liver transplantation, usually involves multiple organ systems, and is predicted in part by several preoperative and intraoperative factors.

Cholesterol, HDL↗

Sulcal hyperintensity on fluid-attenuated inversion recovery mr images in patients without apparent cerebrospinal fluid abnormality.

OBJECTIVE: Failure to suppress cerebrospinal fluid (CSF) signal intensity (sulcal hyperintensity) on fluid-attenuated inversion recovery (FLAIR) images has been reported in patients with abnormal CSF, such as those with meningitis and subarachnoid hemorrhage. Our study investigates the clinical history and MR findings associated with sulcal hyperintensity on FLAIR images in patients without apparent CSF abnormality. SUBJECTS AND METHODS: Three hundred consecutive MR imaging examinations were prospectively screened for patients with sulcal hyperintensity on FLAIR images. Nine patients with clinical, CT, or laboratory evidence suggesting abnormal CSF were excluded. The distribution of sulcal hyperintensity on FLAIR images and associated abnormal enhancement were evaluated. The presence of the "dirty CSF" sign (mild increase in CSF signal on unenhanced T1-weighted images or mild decrease on T2-weighted images) in the corresponding hyperintense sulcus was also assessed. RESULTS: Twenty-six (8.9%) of the 291 patients had sulcal hyperintensity (16 focal, 10 diffuse) associated with 18 masses (6.1%) and eight vascular abnormalities (2.7%). Sulcal hyperintensity was frequently associated with the dirty CSF sign (69.2%) and abnormal contrast enhancement (overall, 96.2%; 88.5%, leptomeningeal; 53.8%, vascular enhancement). CONCLUSION: Our study shows that sulcal hyperintensity on FLAIR imaging can occur in patients without apparent CSF abnormality. Its frequent association with mass effect, vascular disease, abnormal vascular enhancement, and dirty CSF sign suggests that an increase in blood pool, a small amount of protein leakage, and the "flow-entering" phenomenon of the congested blood may contribute to sulcal hyperintensity on FLAIR images.

Adolescent↗

Geographic clustering of Pneumocystis carinii pneumonia in patients with HIV infection.

To detect whether there was geographic clustering of Pneumocystis carinii pneumonia cases among patients with human immunodeficiency virus (HIV) infection, we performed a retrospective analysis of a clinical database. The rates of pneumocystosis were analyzed by zip code zones for evidence of geographical clustering. During the study period, 118 patients at our AIDS Treatment Center had a first episode of P. carinii pneumonia. An analysis of the 24 zip code zones for which a P. carinii pneumonia rate was calculated (requiring a denominator of at least 10 known HIV- infected individuals residing in that zone) showed a trend toward geographic clustering (p = 0.07); when all 45 Cincinnati zip code zones were included in the analysis, clustering of cases was observed (p = 0. 02). By contrast, no clustering was observed for 52 HIV-infected control subjects with respiratory disease or for 960 HIV-infected patients treated at our center during the same time period. These data raise intriguing questions about exposure to exogenous sources of P. carinii and suggest the need for prospective studies.

AIDS-Related Opportunistic Infections↗

Preoperative and postoperative endotoxemia in children with congenital heart disease.

STUDY OBJECTIVES: Recent data indicate that increases in inflammatory cytokines are seen in patients with diverse cardiac diseases. However, the primary stimulus for cytokine secretion during cardiac illness remains unknown. Since bacterial endotoxin is a potent inducer of cytokines, we determined the incidence, magnitude, and clinical relevance of endotoxemia in children with congenital heart disease before and after surgical repair. DESIGN: A prospective, observational study. SETTING: A large, urban, university-affiliated, tertiary-care children's hospital. PATIENTS: Thirty children with a variety of congenital heart defects (median age, 59 days; median weight, 4.0 kg) were sequentially enrolled. INTERVENTIONS: Blood was sampled prior to surgery, and at 1, 8, 24, 48, and 72 h following cardiopulmonary bypass. Assays included plasma endotoxin, lipopolysaccharide-binding protein (LBP), and interleukin-6 (IL-6). MEASUREMENTS AND RESULTS: Twenty-nine of 30 patients (96%) had evidence of endotoxemia during the study period. Twelve of the 30 patients (40%) were significantly endotoxemic prior to surgery. LBP, a plasma marker that responds to bacteria and endotoxin, rose significantly following cardiopulmonary bypass, as did the plasma levels of IL-6. Fifteen of 30 patients met prospectively defined criteria for experiencing a severe hemodynamic disturbance in their postoperative course. These patients had significantly higher preoperative plasma LBP (p < 0.02) and plasma endotoxin levels (p < 0.05), compared to patients with less-severely disturbed hemodynamics. Mortality was 25% in patients with preoperative endotoxemia, compared with no mortality in patients who were not endotoxemic before surgery (p = 0.05). CONCLUSIONS: These data demonstrate that endotoxemia in children with congenital heart disease is more common than previously suspected, and is associated with clinical outcomes. We conclude that clinical trials targeting endotoxin will be necessary to determine if endotoxin is a causal, etiologic agent in the disease process.

Acute-Phase Proteins↗

Dissociation between the time course of ethanol and extracellular dopamine concentrations in the nucleus accumbens after a single intraperitoneal injection.

BACKGROUND: Dopamine release in the nucleus accumbens has been linked to the reinforcing effects of ethanol, but the time course or relationship of this response to ethanol concentrations in the brain has not been studied. METHODS: Various doses of ethanol (0-2.0 g/kg) were administered intraperitoneally to male Sprague Dawley rats, and dopamine and ethanol were simultaneously analyzed in dialysate samples from the nucleus accumbens. A separate study to compare the ethanol-induced dopamine response in male and female rats was carried out by using a 1 g/kg intraperitoneal dose of ethanol. RESULTS: In male rats, 1 and 2 g/kg ethanol significantly increased dialysate dopamine by 40% over basal, whereas 0.25 and 0.5 g/kg ethanol produced a nonsignificant 20% increase. Dialysate ethanol concentrations exhibited a curvilinear decline after reaching peak levels for the lower doses but showed a linear decrease after 1 and 2 g/kg. There was a dissociation between the time courses of extracellular dopamine and ethanol after 1 and 2 g/kg ethanol treatment. The dopamine response returned to basal within 90 min, whereas the ethanol concentrations remained elevated. In a separate study that compared male and female rats, the ratio of the dopamine response over basal to the dialysate ethanol concentrations was significantly decreased at 60 min after an injection of 1 g/kg. However, there were no differences between males and females. CONCLUSIONS: The dissociation between dopamine and ethanol levels may reflect the development of acute tolerance to ethanol-induced dopamine release in the nucleus accumbens within the time course of a single acute injection. Given the strong links between dopamine and ethanol reinforcement, our findings may be relevant for understanding the time course of ethanol's reinforcing effects in vivo.

Animals↗

Cervical spine: MR imaging techniques and anatomy.

MR imaging techniques of the cervical spine are reviewed. Cervical spine anatomy is described, with special attention given to the intervertebral disks, the arterial system, and the peripheral and central nervous systems. Anatomic structures are detailed on sagittal, axial, and coronal MR images.

Cervical Vertebrae↗

Population pharmacokinetics and pharmacodynamics of the anti-CD11a antibody hu1124 in human subjects with psoriasis.

The pharmacokinetics of hu1124, a human anti-CD11a antibody, were investigated in human subjects with psoriasis. CD11a is a subunit of LFA-1, a cell surface molecule involved in T cell mediated immune responses. Subjects received a single dose of 0.03, 0.1, 0.3, 0.6, 1, 2, 3, or 10 mg/kg of hu1124 intravenously over 1-3 hr. Blood samples were collected at selected times from 60 min to 72 days after administration. Plasma samples were assayed for hu1124 by ELISA, and pharmacokinetic analyses were performed on the drug plasma concentrations. As the dose of hu1124 was increased, the clearance decreased from 322 ml/day per kg at 0.1 mg/kg to 6.6 ml/day per kg at 10 mg/kg of hu1124. The plasma hu1124 concentration-time profile suggested that the clearance of hu1124 was saturable above 10 micrograms/ml. In addition, treatment with hu1124 caused a rapid reduction in the level of CD11a expression on CD3-positive lymphocytes (T cells) to about 25% of pretreatment levels. Regardless of the hu1124 dose administered, cell surface CD11a remained at this reduced level as long as hu1124 was detectable (> 0.025 microgram/ml) in the plasma. When hu1124 levels fell below 3 micrograms/ml, the drug was rapidly cleared from the circulation and expression of CD11a returned to normal within 7-10 days thereafter. In vitro, half-maximal binding of hu1124 to lymphocytes was achieved at about 0.1 microgram/ml and saturation required more than 10 micrograms/ml. One of the receptor-mediated pharmacokinetic/pharmacodynamic models which was developed describes the dynamic interaction of hu1124 binding to CD11a, resulting in the removal of hu1124 from the circulation and reduction of cell surface CD11a. The model accounts for the continually changing number of CD11a molecules available for removing hu1124 from the circulation based on prior exposure of cells expressing CD11a to hu1124. In addition, the model also accounts for saturation of CD11a molecules by hu1124 at drug concentrations of approximately 10 micrograms/ml, thereby reducing the clearance rate of hu1124 with increasing dose.

Animals↗

Current and future imaging of acute cerebral ischemia: assessment of tissue viability by perfusion imaging.

With the advances and availability of new imaging modalities, the role of imaging of acute stroke has been broadened from making diagnosis to providing valuable information for patient management. We need to have rapid diagnostic modalities that distinguish reversible ischemic tissue from irreversibly damaged tissue for successful thrombolytic therapy. Although diffusion imaging has been reported to have both high sensitivity and specificity for acute ischemia in clinical studies, previous reports do not conclude whether the diffusion abnormality is indicative of reversibly or irreversibly injured tissue. Perfusion imaging such as perfusion magnetic resonance imaging and single-photon emission computed tomography may have the potential for providing useful information that determines tissue viability and/or reversibility. Cerebral blood flow thresholds evaluated by pretreatment single-photon emission computed tomography provide important information that is potentially useful in the management of acute stroke patients with intra-arterial thrombolysis. Perfusion imaging, when combined with diffusion imaging, may thus be potentially useful in improving patient selection for thrombolytic therapy.

Acute Disease↗

Gender differences in blood levels, but not brain levels, of ethanol in rats.

Female rodents tend to drink more alcohol than males, a difference that emerges at puberty and appears to vary over the female estrous cycle. In addition, male and female rodents display different responses to alcohol; for example, female rats are reported to have faster elimination rates than males. We were interested in whether circulating ovarian hormones influence alcohol distribution to or elimination from the brain of rats, which might explain observed differences in drinking behavior. We administered 0.8 g/kg of ethanol via intraperitoneal injection to age-matched male and female Sprague-Dawley rats. Extracellular brain ethanol was sampled using microdialysis, and vascular ethanol concentrations were determined via tail blood collection, in two separate experiments. Ethanol pharmacokinetic parameters were calculated for both compartments. There were no differences in pharmacokinetic parameters due to gender or estrous cycle stage in brain ethanol concentration profiles. There were, however, differences in blood ethanol profiles: females showed faster elimination rates and a smaller area under the ethanol concentration versus time curve than males. In addition, the maximum concentration varied significantly across the estrous cycle. These results suggest that (1) circulating ovarian hormones do not influence alcohol distribution to the brain, but do influence distribution to more peripheral tissues such as the tail; and (2) apparent differences in tail blood alcohol levels may not reflect differences in brain levels.

Animals↗

Pharmacokinetics of a recombinant amino terminal fragment of bactericidal/permeability increasing protein (rBPI21) after liver surgery in rats and humans.

Major liver resections are associated with considerable morbidity and mortality. Gut-derived bacteria and bacterial endotoxin (LPS) are considered to play a central role in the pathophysiology of these complications. Like human BPI, rBPI21 binds to LPS from Gram-negative bacteria. By binding and clearing of LPS, rBPI21 can inhibit a number of endotoxin-induced humoral and cellular responses. Because of this capacity, rBPI21 could partially compensate for the loss of hepatic mononuclear phagocytic system function after liver resection. However, the liver is also thought to be an important organ for the clearance of BPI, and reduction of liver mass could result in a decreased clearance and exceedingly high plasma levels of rBPI21. In this study we therefore investigated the pharmacokinetics of rBPI21 in rats and in patients undergoing a major liver resection. Rats were administered an intravenous (i.v.) bolus of rBPI21 after undergoing a 60% or 80% hepatectomy (with sham-operated controls). Patients undergoing a hemihepatectomy and healthy volunteers received rBPI21 or placebo by continuous i.v. infusion for 48 h. Plasma concentrations were measured by sandwich ELISA. In rats, 60% hepatectomy did not consistently change the clearance of rBPI21, whereas 80% hepatectomy decreased the clearance of rBPI21 severalfold. In hemihepatectomized patients, the clearance of rBPI21 after major hepatectomy was also slower, when compared with healthy volunteers, but this difference had disappeared within 24 h. Our data indicate that the administration of rBPI21 in patients undergoing liver resection is well tolerated and does not result in exceedingly high plasma levels. Additional studies on the efficacy of rBPI21 in the prevention of complications after hepatectomy are needed.

Animals↗

A phase I safety and pharmacokinetic study of a recombinant amino terminal fragment of bactericidal/permeability-increasing protein in healthy male volunteers.

A phase I pharmacokinetic and safety clinical trial of rBPI23, a recombinant amino terminal fragment of bactericidal/permeability-increasing protein, was conducted in healthy male volunteers. rBPI23 was administered as a 5 or 30 min infusion at doses of .1 to 1 mg/kg. The pharmacokinetics of rBPI23 in human subjects were described by a bi-exponential disposition function with evidence of concentration-dependent kinetics. The alpha half-life increased significantly with increasing dose, from 4-5 min at .1 mg/kg to 7-8 min at 1 mg/kg. The beta half-life varied between 18 and 29 min regardless of dose and the clearance varied from 5 to 10 mL/min/kg. Very little, if any, of the administered rBPI23 was excreted intact in the urine. Electrocardiograms, ionized calcium concentration, prothrombin and partial prothrombin times, hematologic parameters, and blood chemistries remained normal. Furthermore, no antibody response to rBPI23 was observed in any of the subjects.

Adolescent↗

Effect of a recombinant N-terminal fragment of bactericidal/permeability-increasing protein (rBPI23) on cerebrospinal fluid inflammation induced by endotoxin.

Endotoxin triggers the subarachnoid inflammation of gram-negative meningitis. This study examined the ability of a recombinant N-terminal fragment of bactericidal/permeability-increasing protein (rBPI23) to block endotoxin-induced meningitis in rabbits. Intracisternal (ic) injection of 10-20 ng of meningococcal endotoxin induced high cerebrospinal fluid (CSF) concentrations of tumor necrosis factor (TNF) and CSF pleocytosis and increased CSF lactate concentrations. ic administration of rBPI23 significantly reduced meningococcal endotoxin-induced TNF release into CSF (P < .005), lactate concentrations (P < .001), and CSF white blood cell counts (P < .01). No such effect was observed in animals receiving intravenous rBPI23. Concentrations of rBPI23 in CSF were high after ic administration but low or undetectable after systemic administration. Thus, high concentrations of rBPI23 can effectively neutralize meningococcal endotoxin in CSF, but low CSF concentrations after systemic administration currently limit its potential usefulness as adjunctive drug treatment in gram-negative meningitis.

Animals↗

Inhibition of endotoxin-induced cytokine release and neutrophil activation in humans by use of recombinant bactericidal/permeability-increasing protein.

To investigate the effects of a recombinant endotoxin-binding protein, bactericidal/permeability-increasing protein (rBPI23), on cytokine release and neutrophil activation in endotoxemia in humans, 8 volunteers were challenged twice with endotoxin and concurrently received either rBPI23 or placebo in a randomized, placebo controlled, double-blind crossover study, rBPI23 treatment significantly lowered circulating endotoxin levels (P = .02) and resulted in a significant reduction in the release of tumor necrosis factor (TNF), soluble TNF receptors p55 and p75, interleukin (IL)-6, IL-8 (P < .01 for each), and IL-10 levels (P = .02) but did not prevent the endotoxin-induced rise in body temperature. The early endotoxin-induced leukopenia was blunted (P = .08), and neutrophil degranulation, as measured by circulating levels of elastase/alpha 1-antitrypsin complexes (P = .03) and lactoferrin (P < .01), was largely prevented by rBPI23. The results of this study indicate that rBPI23 is capable of neutralizing many of the biologic effects of endotoxin in humans.

Antimicrobial Cationic Peptides↗

Measurement of bactericidal/permeability-increasing protein in human body fluids by sandwich ELISA.

A sensitive sandwich ELISA has been developed to measure levels of native bactericidal/permeability-increasing protein (BPI) as well as two recombinant forms of BPI (rBPI and rBPI23) in human body fluids. The linear range for the rBPI and rBPI23 standard curves were 100-6000 pg/ml and 25-800 pg/ml respectively. Recovery of different concentrations of rBPI spiked into pooled human plasma samples averaged 83% and ranged from 65% at 300 ng/ml to 97% at 3 ng/ml. Recovery of rBPI23 averaged 56% and ranged from 30% at 0.5 ng/ml to 90% at 50,000 ng/ml. Because LBP is present in normal human plasma and shares sequence homology with BPI, the effects of rLBP on the BPI ELISA were also evaluated. Under standard assay conditions, rLBP caused minimal interference with BPI detection. At 100 micrograms/ml, rLBP generated a signal equivalent to 3 ng/ml of rBPI and 0.6 ng/ml of rBPI23. Matched serum and plasma samples were collected from 20 healthy adults to measure endogenous levels of BPI. The range of BPI concentrations was < 0.2-2.1 ng/ml in plasma and 4.9-72.1 ng/ml in serum. Western blot analysis indicated that the BPI ELISA immunoreactivity in plasma and serum correlated with the presence of a protein doublet (M(r) approximately 60,000), which comigrated with native BPI extracted from human neutrophils. These data demonstrate that low levels of holo-BPI are present in plasma, and suggest that additional quantities of BPI were released from neutrophils during the process of coagulation.

Acute-Phase Proteins↗

Cytosine arabinoside and mitoxantrone treatment of relapsed or refractory childhood leukemia: initial response and relationship to multidrug resistance gene 1.

The objective of this study was to determine the response rate and toxicity of high-dose cytosine arabinoside (AC) and mitoxantrone (M) in relapsed or refractory childhood acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) and to correlate response with the expression of the multidrug resistance gene 1 (mdr1). Twenty-nine patients were treated with AC 1.0 g/m2 infused over 2 h every 12 h for eight doses (days 1-4) and M 12 mg/m2 infused over 1 h (days 3-6). Mdr1 expression was determined by a polymerase chain reaction (pcr) assay. Ten of 15 patients (67%) with AML obtained a complete remission (CR) of 3 to 30+ months duration. Eight of 14 (57%) ALL patients obtained a CR of 1 to 23+ months duration. The major toxicities were hematopoietic and infectious. Seventy-nine per cent of patients developed a documented infection during induction. Mdr1 did not correlate with a lower induction rate. This AC/M regimen is active in childhood AML and ALL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Analysis of Pneumocystis carinii organism burden, viability and antigens in bronchoalveolar lavage fluid in AIDS patients with pneumocystosis: correlation with disease severity.

OBJECTIVES: We examined 96 bronchoalveolar lavage fluid (BALF) specimens from AIDS patients with proven Pneumocystis carinii pneumonia (PCP) in order to compare the relationship of organism burden, viability and antigen expression with disease severity at the time of clinical presentation. METHODS: Tinctorial analysis of BALF specimens with proven PCP using Diff-Quik, cresyl echt violet and erythrosin B stains to evaluate organism burden and viability. P. carinii antigen examination was performed by Western blot analysis. RESULTS: P. carinii cluster ratios were more sensitive than cyst counts as an indicator of organism burden, and correlated well with the alveolar-arterial oxygen gradient as a measure of disease severity. Erythrosin B, the vital stain used to measure P. carinii viability, displayed a wide range of values and provided little useful information. Antigens of 35-45 and 95kD, which were specific for P. carinii, were found by immunoblot analysis in BALF cellular fraction of most patients with pneumocystosis. By contrast, antigens of 52 and 66 kD, which were found in both BALF supernatant and cellular fractions of P. carinii patients and controls, most likely represented albumin and immunoglobulin G heavy chain, respectively, of host origin. The 35-45 kD antigen was found in 88% of the BALF specimens and appeared to represent an important marker of P. carinii infection. The 95 kD antigen was detected in 49% of the specimens. CONCLUSIONS: We conclude that analysis of P. carinii characteristics in BALF specimens of patients with pneumocystis may provide additional information. These data will also be helpful in developing more sensitive assays and in targeting specific P. carinii factors for future investigation.

AIDS-Related Opportunistic Infections↗

Prediction of change in mitral valve area after mitral balloon commissurotomy using cine computed tomography.

RATIONALE AND OBJECTIVES: Mitral balloon commissurotomy (MBC) can successfully increase the mitral valve area (MVA) in mitral stenosis, but the outcome is variable. In multicenter studies, qualitative echocardiographic scores obtained before MBC are only weakly predictive of the increase in MVA after MBC. METHODS: To evaluate whether the change in MVA after MBC can be predicted by evaluating mitral valve morphology using cine computed tomography (CT), we studied 12 women with mitral stenosis and 11 female control subjects. RESULTS: In the patients with mitral stenosis, MVA increased from 1.13 +/- 0.24 to 1.93 +/- 0.56 cm2 (P < .0001) after MBC. A standard echocardiographic score assessment of mitral valve morphology before MBC was not associated with the change in MVA after MBC in these patients (P > .20). However, the total mitral valve morphology score evaluated by cine computed tomography was strongly associated with the change in MVA after MBC (r = -.87; P < .0005). In addition, the individual morphologic characteristics of mitral valve mobility (P < .0025), leaflet thickness (P < .05), and subvalvular disease (P < .05) were significant predictors of the change in MVA after MBC. CONCLUSION: Cine computed tomography may be useful for predicting immediate increases in MVA in patients after MBC and may be helpful for preoperative assessment of these patients.

Catheterization↗