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Biomedical subjects

L Mark

Publications and source records attributed to L Mark.

At least 19 recordsLinked to original sources
PubMed2006

Dissecting the regions of virion-associated Kaposi's sarcoma-associated herpesvirus complement control protein required for complement regulation and cell binding.

Complement, which bridges innate and adaptive immune responses as well as humoral and cell-mediated immunity, is antiviral. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a lytic cycle protein called KSHV complement control protein (KCP) that inhibits activation of the complement cascade. It does so by regulating C3 convertases, accelerating their decay, and acting as a cofactor for factor I degradation of C4b and C3b, two components of the C3 and C5 convertases. These complement regulatory activities require the short consensus repeat (SCR) motifs, of which KCP has four (SCRs 1 to 4). We found that in addition to KCP being expressed on the surfaces of experimentally infected endothelial cells, it is associated with the envelope of purified KSHV virions, potentially protecting them from complement-mediated immunity. Furthermore, recombinant KCP binds heparin, an analogue of the known KSHV cell attachment receptor heparan sulfate, facilitating infection. Treating virus with an anti-KCP monoclonal antibody (MAb), BSF8, inhibited KSHV infection of cells by 35%. Epitope mapping of MAb BSF8 revealed that it binds within SCR domains 1 and 2, also the region of the protein involved in heparin binding. This MAb strongly inhibited classical C3 convertase decay acceleration by KCP and cofactor activity for C4b cleavage but not C3b cleavage. Our data suggest similar topological requirements for cell binding by KSHV, heparin binding, and regulation of C4b-containing C3 convertases but not for factor I-mediated cleavage of C3b. Importantly, they suggest KCP confers at least two functions on the virion: cell binding with concomitant infection and immune evasion.

Animals↗
PubMed2001

Dynamic behavior of lung surfactant.

We have previously developed an adsorption-limited model to describe the exchange of lung surfactant and its fractions to and from an air-liquid interface in oscillatory surfactometers. Here we extend this model to allow for diffusion in the liquid phase. Use of the model in conjunction with experimental data in the literature shows that diffusion-limited transport i.s important for characterizing the transient period from the start of oscillations to the achievement of steady-state conditions. Matching previous data shows that upon high levels of film compression, large changes occur in adsorption rate, desorption rate, and diffusion constant, consistent with what one might expect if the subsurface region was greatly enriched in DPPC. Collapse of the surfactant film that occurs during compression leads to a .significant elevation of surfactant concentration immediately heneath the interface, consistent with the subsurface depot of surfactant that has heen postulated by other investigators. Modeling studies also uncovered a phenomenon of surfactant behavior in which the interfacial tension remains constant at its minimum equilibrium value while the film is compressed, hut without collapse of the film. The phenomenon was due to desorption of surfactant from the interface and termed "pseudo-film collapse.'' The new model also gave improved agreement with steady-state oscillatory cycling in a pulsating bubble surfactometer.

Adsorption↗
PubMed2001

Decreased surfactant protein-B expression and surfactant dysfunction in a murine model of acute lung injury.

This study examines the relationships between inflammation, surfactant protein (SP) expression, surfactant function, and lung physiology in a murine model of acute lung injury (ALI). 129/J mice received aerosolized endotoxin lipopolysaccharide [LPS] daily for up to 96 h to simulate the cytokine release and acute inflammation of ALI. Lung elastance (E(L)) and resistance, lavage fluid cell counts, cytokine levels, phospholipid and protein content, and surfactant function were measured. Lavage and lung tissue SP content were determined by Western blot and immunohistochemistry, and tissue messenger RNA (mRNA) levels were assessed by Northern blot and in situ hybridization. Tumor necrosis factor-alpha and neutrophil counts in bronchoalveolar lavage fluid increased within 2 h of LPS exposure, followed by increases in total protein, interleukin (IL)-1beta, IL-6, and interferon-gamma. E(L) increased within 24 h of LPS exposure and remained abnormal up to 96 h. SP-B protein and mRNA levels were decreased at 24, 48, and 96 h. By contrast, SP-A protein and mRNA levels and SP-C mRNA levels were not reduced. Surfactant dysfunction occurred coincident with changes in SP-B levels. This study demonstrates that lung dysfunction in mice with LPS-ALI corresponds closely with abnormal surfactant function and reduced SP-B expression.

Animals↗
PubMed2000

Pivotal role of anionic phospholipids in determining dynamic behavior of lung surfactant.

Phosphatidylglycerol (PG) and phosphatidylinositol (PI) are anionic phospholipids (APLs) present in lung surfactant of virtually all species studied, although their specific contribution to function is unknown. This study examines how APLs influence surfactant monolayer stability and adsorption under static and dynamic conditions. Interfacial properties of surfactants reconstituted with native phospholipids (PL), and phospholipids devoid of anionic species (DAPL), were characterized by pulsating bubble surfactometry. Measurements were made for PL and DAPL alone; with 3% surfactant proteins B and C (SP-B/C); with SP-B/C and 5% surfactant protein A (SP-A); and with SP-B/C, SP-A, and 8% neutral lipids (NL). Equilibrium and dynamic properties of PL and DAPL were similar. However, whereas (DAPL + SP-B/C) and (DAPL + SP-B/C + SP-A) mixtures were similar to corresponding PL mixtures with respect to gamma(equil), they displayed markedly different dynamic behavior. In particular, the degree of film compression required to reach gamma(min) was significantly increased in DAPL mixtures (80 to 90% area reduction) compared with PL, although both samples reached gamma(min) < 3.0 dynes/cm. The addition of NL to (DAPL + SP-B/C + SP-A) produced an increase in gamma(min) to 15 to 20 dynes/cm during dynamic compression, whereas NL had no significant impact on the behavior of (PL + SP-B/C + SP-A). Purified PG (5% wt/wt) restored nearly normal dynamic properties to (DAPL + SP-B/C + SP-A + NL), whereas phosphatidylcholine (PC) (5% wt/wt) had no beneficial effect. These results suggest that APLs play a critical role in promoting surface film stability during dynamic compression through interactions with nonlipid surfactant components, and prevent destabilization of the surface film by cholesterol and other NL.

Animals↗
PubMed2000

Discrimination between neoplastic and nonneoplastic brain lesions by use of proton MR spectroscopy: the limits of accuracy with a logistic regression model.

BACKGROUND AND PURPOSE: The most accurate method of clinical MR spectroscopy (MRS) interpretation remains an open question. We sought to construct a logistic regression (LR) pattern recognition model for the discrimination of neoplastic from nonneoplastic brain lesions with MR imaging-guided single-voxel proton MRS data. We compared the LR sensitivity, specificity, and receiver operator characteristic (ROC) curve area (Az) with the sensitivity and specificity of blinded and unblinded qualitative MRS interpretations and a choline (Cho)/N-acetylaspartate (NAA) amplitude ratio criterion. METHODS: Consecutive patients with suspected brain neoplasms or recurrent neoplasia referred for MRS were enrolled once final diagnoses were established by histopathologic examination or serial neurologic examinations, laboratory data, and imaging studies. Control spectra from healthy adult volunteers were included. An LR model was constructed with 10 input variables, including seven metabolite resonance amplitudes, unsuppressed brain water content, water line width, and the final diagnosis (neoplasm versus nonneoplasm). The LR model output was the probability of tumor, for which a cutoff value was chosen to obtain comparable sensitivity and specificity. The LR sensitivity and specificity were compared with those of qualitative blinded interpretations from two readers (designated A and B), qualitative unblinded interpretations (in aggregate) from a group of five staff neuroradiologists and a spectroscopist, and a quantitative Cho/NAA amplitude ratio > 1 threshold for tumor. Sensitivities and specificities for each method were compared with McNemar's chi square analysis for binary tests and matched data with a significance level of 5%. ROC analyses were performed where possible, and Az values were compared with Metz's method (CORROC2) with a 5% significance level. RESULTS: Of the 99 cases enrolled, 86 had neoplasms and 13 had nonneoplastic diagnoses. The discrimination of neoplastic from control spectra was trivial with the LR, reflecting high homogeneity among the control spectra. An LR cutoff probability for tumor of 0.8 yielded a specificity of 87%, a comparable sensitivity of 85%, and an area under the ROC curve of 0.96. Sensitivities, specificities, and ROC areas (where available) for the other methods were, on average, 82%, 74%, and 0.82, respectively, for readers A and B, 89% (sensitivity) and 92% (specificity) for the group of unblinded readers, and 79% (sensitivity), 77% (specificity), and 0.84 (Az) for the Cho/NAA > 1 criterion. McNemar's analysis yielded significant differences in sensitivity (n approximately 86 neoplasms) between the LR and reader A, and between the LR and the Cho/NAA > 1 criterion. The differences in specificity between the LR and all other methods were not significant (n approximately 13 nonneoplasms). Metz's analysis revealed a significant difference in Az between the LR and the Cho/NAA ratio criterion.

Adolescent↗
PubMed1999

Disseminating information using an anesthesiology consultant report: impact on patient perceptions of quality of care.

STUDY OBJECTIVE: To determine if providing an Anesthesiology Consultant Report (ACR) to patients would result in enhanced patients' perceptions of their knowledge about their care and improve their perception of the quality of their care. DESIGN: Randomized, unblinded study. SETTING: Outpatient center associated with tertiary care center. PATIENTS: 371 outpatients without adverse anesthetic events. INTERVENTIONS: Patients were randomized to receive either routine discharge instructions or routine instructions and an anesthesia discharge summary (ACR). MEASUREMENTS AND MAIN RESULTS: Short questionnaire with discharge packet regarding knowledge of anesthetic and questions regarding satisfaction and perceptions of quality of care was distributed. The patients in the group that received an ACR were more satisfied with the management of their pain and other symptoms (p < 0.05, by Wilcoxon rank sums) and were more satisfied overall with the quality of the anesthesia care (p < 0.01, by Wilcoxon rank sums). Taken another way, significantly more patients deemed the quality of their anesthetic care as excellent in the ACR group compared to control (83% vs. 67%, p < 0.01). CONCLUSIONS: Providing patients, with uneventful anesthetic courses, with information regarding their anesthetic care, in the form of the ACR, results in improved perceptions of the quality of care.

Anesthesia↗
PubMed1999

Surfactant function and composition after free radical exposure generated by transition metals.

Surfactant dysfunction in acute lung injury has been postulated as a result of free radical damage to lipid and protein components. This study examines whether transition metals with different redox potentials and different binding affinities for lipids and proteins affect interfacial properties differently. Purified whole calf lung surfactant (CLS) was incubated with 0.125 mM Fe2+, Fe3+, Fe3+-EDTA complex, or Cu2+ either alone or with 0.25 mM H2O2 or H2O2 plus 0.25 mM ascorbate for 4 and 24 h. Lipid peroxidation was assessed by measurement of thiobarbituric acid-reactive substances (TBARS), and free radical-mediated alterations in protein structure were assessed by fluorescamine assay and Western blot analysis. Function was assayed by pulsating bubble surfactometry. Lipid peroxidation was detected in samples incubated with Fe2+, Fe3+, and Fe3+-EDTA but not with Cu2+. All transition metal-based free radical systems affected surfactant protein composition by fluorescamine assay, indicating free radical-mediated modification of protein side chains. Western blot analysis demonstrated surfactant protein A modification, with the generation of higher- and lower-molecular-mass immunoreactive products. Despite biochemical evidence of lipid and protein modification, surfactant dysfunction was minimal and was manifest as an increase in the compression ratio required to achieve surface tension < 1 dyn/cm. This dysfunction was readily reversed by the addition of 5 mM Ca2+ either before or after oxidation. These data indicate that copper- and iron-based free radical-generating systems modify the lipid and protein components of surfactant differently but suggest that these changes have little effect on surfactant function.

Animals↗
PubMed1999

Biophysical characterization and modeling of lung surfactant components.

The present study characterizes the dynamic interfacial properties of calf lung surfactant (CLS) and samples reconstituted in a stepwise fashion from phospholipid (PL), hydrophobic apoprotein (HA), surfactant apoprotein A (SP-A), and neutral lipid fractions. Dipalmitoylphosphatidylcholine (DPPC), the major PL component of surfactant, was examined for comparison. Surface tension was measured over a range of oscillation frequencies (1-100 cycles/min) and bulk phase concentrations (0.01-1 mg/ml) by using a pulsating bubble surfactometer. Distinct differences in behavior were seen between samples. These differences were interpreted by using a previously validated model of surfactant adsorption kinetics that describes function in terms of 1) adsorption rate coefficient (k1), 2) desorption rate coefficient (k2), 3) minimum equilibrium surface tension (gamma*), 4) minimum surface tension at film collapse (gammamin), and 5) change in surface tension with interfacial area for gamma < gamma* (m2). Results show that DPPC and PL have k1 and k2 values several orders of magnitude lower than CLS. PL had a gammamin of 19-20 dyn/cm, significantly greater than CLS (nearly zero). Addition of the HA to PL restored dynamic interfacial behavior to nearly that of CLS. However, m2 remained at a reduced level. Addition of the SP-A to PL + HA restored m2 to a level similar to that of CLS. No further improvement in function occurred with the addition of the neutral lipid. These results support prior studies that show addition of HA to the PL markedly increases adsorption and film stability. However, SP-A is required to completely normalize dynamic behavior.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1997

Detection of glutamate/glutamine resonances by 1H magnetic resonance spectroscopy at 0.5 tesla.

Midfield proton magnetic resonance spectroscopy (MRS) provides a noninvasive method to monitor glutamate and glutamine (Glx) levels in vivo. Experiments to detect the gamma and beta resonances of Glx have been performed by using commercial 0.5 T and 1.5 T MR scanners on seven patients with elevated blood ammonia and eight normal volunteers. Compared with the spectral sensitivity obtained on an otherwise identical system operating at 1.5 T, the singlet resonance of N-acetyl aspartate (NAA) was decreased by a factor of 1.48, which is significantly less than expected using the ratio of Boltzman populations at the two field strengths. However, the resonances of Glx at 0.5 T increased in signal-to-noise ratio (SNR) by a factor of 2. The increased SNR of Glx is principally due to improved B0 main-field homogeneity and collapse of the strongly J-coupled Glx resonances. Our preliminary results suggest that midfield proton MRS will provide significant clinical utility in the detection of Glx levels in human brain.

Adult↗
PubMed1997

Accuracy of single-voxel proton MR spectroscopy in distinguishing neoplastic from nonneoplastic brain lesions.

PURPOSE: To measure the accuracy of single-voxel, image-guided proton MR spectroscopy in distinguishing normal from abnormal brain tissue and neoplastic from nonneoplastic brain disease. METHODS: MR spectroscopy was performed at 0.5 T with the point-resolved spectroscopic pulse sequence and conventional postprocessing techniques. Subjects consisted of a consecutive series of patients with suspected brain neoplasms or recurrent neoplasia and 10 healthy adult volunteers. Fifty-five lesions in 53 patients with subsequently verified final diagnoses were included. Spectra were interpreted qualitatively by visual inspection by nonblinded readers (prospectively) with the benefit of prior clinical data and imaging studies, and by blinded readers (retrospectively). The nonblinded readers interpreted the spectra as diagnostic or not, and, if diagnostic, as neoplastic or nonneoplastic. The blinded readers classified the spectra as diagnostic or not, and, if diagnostic, as normal or abnormal and as neoplastic or nonneoplastic (when abnormal). The sensitivity, specificity, positive and negative predictive values, and accuracy were calculated from blinded and nonblinded MR spectroscopy interpretations. A receiver operator characteristic (ROC) curve analysis was performed on blinded MR spectroscopy interpretations. RESULTS: The diagnostic accuracy averaged across four blinded readers in differentiating patients from control subjects was .96, while the area under the aggregate (pooled interpretations) ROC curve approached unity. Accuracy in the nonblinded and blinded discrimination of neoplastic from nonneoplastic disease was .96 and .83, respectively. The area under the aggregate ROC curve in the blinded discrimination of neoplasm from nonneoplasm was .89. CONCLUSIONS: Image-guided proton spectra obtained at 0.5 T from patients with suspected neoplasia can be distinguished from spectra in healthy control subjects, and neoplastic spectra can be distinguished from nonneoplastic spectra with a high degree of diagnostic accuracy.

Adult↗
PubMed1996

Comparison of sevoflurane/fentanyl and isoflurane/fentanyl during elective coronary artery bypass surgery. Sevoflurane Venture Group.

PURPOSE: Due to the progressive aging of the surgical population, the proportion of patients with coronary artery disease (CAD) is likely to increase. The effects of the new inhalational anaesthetic sevoflurane must be determined in patients with known CAD. METHODS: This multicentre, randomized, open-label study compared the haemodynamic and cardiovascular effects of sevoflurane and isoflurane with fentanyl in 284 ASA physical status II-IV patients undergoing elective coronary artery bypass graft (CABG). RESULTS: Satisfactory records were available in 272 patients, 139 sevoflurane (Group S) and 133 isoflurane (Group I). There were no differences between groups for demographic data except that more patients in Group S were taking preoperative beta-blockers (P = 0.03). The mean end-tidal MAC and MAC.hr requirements between groups were not different (Group S received 0.63 +/- 0.02 MAC and 1.00 +/- 0.05 MAC. hr while Group I received 0.58 +/- 0.02 MAC and 0.92 +/- 0.05 MAC. hr P = NS). The preCPB use of intravenous fentanyl was not different between groups. There was a similar decrease in haemodynamic variables in both groups after induction that persisted throughout the preCPB period. The incidence of preCPB myocardial ischaemia, adverse haemodynamic events and use of vasoactive drugs did not differ between groups. The incidence of postoperative myocardial infarction was 2.2% for Group S and Group I was 4.5% (P = NS). There were five postoperative deaths, one of which was attributed to a cardiac cause (Group I). CONCLUSION: In patients undergoing elective CABG with low risk factors, either sevoflurane or isoflurane, combined with fentanyl, provided an acceptable preCPB haemodynamic profile and cardiac outcomes.

Aged↗
PubMed1996

Magnetic resonance imaging of cerebrospinal fluid volume and the influence of body habitus and abdominal pressure.

BACKGROUND: Although the cerebrospinal fluid (CSF) is the pathway of anesthetic delivery and the diluent for neuraxially administered drugs, little is known about its volume, including variability among individuals, longitudinal distribution, or influence of body habitus. Models made to investigate subarachnoid anesthetic distribution lack valid dimensions. CSF volume was measured in volunteers, and the effect of obesity and abdominal compression on CSF volume was evaluated using magnetic resonance imaging. METHODS: Low thoracic and lumbosacral axial magnetic resonance images of 25 healthy volunteers were obtained at 8-mm intervals by fast spin-echo sequence, which highlights CSF. A repeat image series was performed in 15 subjects during external abdominal compression. In two subjects, images were obtained without compression for the entire vertebral column. Dural sac and spinal cord areas were determined in a blinded fashion for each image using video/digital analysis. Area of the sac minus area of the cord constituted area of CSF and roots ("CSF/root"); this area multiplied by 8 mm resulted in CSF/root volume per section. RESULTS: There is great interindividual variability in CSF/root volume. From the T11-T12 disc to the sacral terminus of the dural sac, the mean volume for all subjects is 49.9 +/- 12.1 ml (mean +/- SD; range 28.0-81.1 ml). This volume was significantly less in relatively obese subjects (42.9 +/- 9.5 ml) than in nonobese subjects (53.5 +/- 12.9 ml). Abdominal compression decreased CSF/root volume by 3.6 +/- 3.2 ml. Sections through intervertebral foramina showed the biggest decrease with abdominal compression, with a lesser change in sections with veins and no change in the absence of these anatomic features. Total vertebral CSF/root volume in two subjects was 94.84 and 120.01 ml, respectively. CONCLUSIONS: CSF volume is widely variable between individuals. The decreased CSF volume that results from increased abdominal pressure, such as with obesity or pregnancy, may produce more extensive neuraxial blockade through diminished dilution of anesthetic. The mechanism by which increased abdominal pressure decreases CSF volume is probably inward movement of soft tissue in the intervertebral foramen, which displaces CSF.

Abdomen↗
PubMed1995

Autonomic regulation of tissue resistance in the guinea pig lung.

Although the autonomic nervous system is known to influence airway tone and resistance in both the normal and inflamed lung, its effects on tissue resistance (Rti) have not been defined. To characterize autonomic neural control of Rti in the lung, we measured airway resistance (Raw) and Rti, lung elastance, and lung hysteresivity after adrenergic, cholinergic, and nonadrenergic noncholinergic (NANC) blockade in anesthetized mechanically ventilated guinea pigs by using the alveolar capsule technique. Five animals received 1 mg/kg i.v. phentolamine (alpha-blocker), eight received 1 mg/kg i.v. propranolol (beta-blocker), six received 0.1 mg/kg i.v. atropine (parasympatholytic), six had surgical bilateral vagotomy, and five were treated 14 days before study with 50 mg/kg sc capsaicin (peptidergic neurotransmitter depleter). Measurements were recorded at 5- to 10-min intervals for 120 min after pharmacological induction of autonomic blockade. Capsaicin treatment resulted in decreases in lung resistance (RL), Raw, and dynamic elastance (Edyn) compared with controls but Rti was not significantly affected. beta-Blockade resulted in significant increases in RL, Raw, and Edyn but did not affect Rti. alpha-Blockade and vagolytic maneuvers had no effect on RL, Raw, Rti, or Edyn. Furthermore, there was no effect of cholinergic, adrenergic, or NANC blockade on the relationship between Rti or elastance and breathing frequency or mean lung volume during tidal breathing. Our results suggest that, in the normal guinea pig lung, baseline Raw is modulated by both the beta-adrenergic and NANC nervous systems but Rti tone is largely independent of nervous system regulation.

Airway Resistance↗
PubMed1994

Effects of acute lung injury on dynamic tissue properties.

The dynamic properties of lung tissue after acute injury (ALI) were characterized by studying parenchymal strips prepared from guinea pigs endobronchially treated with hydrochloric acid. Forty-eight-hour samples (10 x 4 x 4 mm) from control (C), acid-damaged (D), and uninvolved (U) lungs of treated animals had elastance and resistance measured in a perfused organ bath system during uniaxial length oscillation at a mean force of 750 mg over a 1.5 (0.1-3 Hz)-fold decade frequency range and 5-fold (1-5%) strain amplitude range. Results were interpreted using a quasi-linear viscoelastic model with tissue stress expressed as an exponential function of strain. Among C strips, elastance increased linearly with the logarithm of frequency, whereas resistance decreased hyperbolically with frequency; both were strain amplitude independent. In contrast, elastance among D strips was uniformly greater (P < 0.0001) and was inversely strain amplitude dependent (P < 0.01); resistance was markedly elevated (P < 0.0001) but decreased hyperbolically with frequency similar to C strips. Resistance and elastance changes among U strips were intermediate between those for D and C strips. Histological grading of cellular infiltration, alveolar septal thickening, and hemorrhage correlated with functional changes. The frequency and amplitude dependencies and magnitude changes for resistance and elastance were similar to those previously observed in intact dog lungs after ALI. These findings suggest that ALI can affect the rheological properties of lung parenchyma independently of surfactant and that changes in lung mechanics after ALI may, in part, be determined at the parenchymal level.

Acute Disease↗