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Angiotensin I-converting enzyme (ACE, CD143) has two homologous domains, each having a functional active site. Fine epitope mapping of 8 mAbs to the C-terminal domain of human ACE was carried out using plate precipitation assays, mAbs' cross-reactivity with ACE from different species, site-directed mutagenesis, and antigen- and cell-based ELISAs. Almost all epitopes contained potential glycosylation sites. Therefore, these mAbs could be used to distinguish different glycoforms of ACE expressed in different tissues or cell lines. mAbs 1B8 and 3F10 were especially sensitive to the composition of the N-glycan attached to Asn 731; mAbs 2H9 and 3F11 detected the glycosylation status of the glycan attached to Asn 685 and perhaps Asn1162; and mAb 1E10 and 4E3 recognized the glycan on Asn 666. The epitope of mAb 1E10 is located at the N-terminal end of the C domain, close to the unique 36 amino acid residues of testicular ACE (tACE). Moreover, it binds preferentially to tACE on the surface of human spermatozoa and thus may find application as an immunocontraceptive drug. mAb 4E3 was the best mAb for quantification of ACE-expressing somatic cells by flow cytometry. In contrast to the other mAbs, binding of mAb 2B11 was not markedly influenced by ACE glycosylation or by the cell culture conditions or cell types, making this mAb a suitable reference antibody. Epitope mapping of these C-domain mAbs, particularly those that compete with N-domain mAbs, enabled us to propose a model of the two-domain somatic ACE that might explain the interdomain cooperativity. Our findings demonstrated that mAbs directed to conformational epitopes on the C-terminal domain of human ACE are very useful for the detection of testicular and somatic ACE, quantification using flow cytometry and ELISA assays, and for the study of different aspects of ACE biology.

We investigated the role of caveolae in the mechanism of increased pulmonary vascular permeability and edema formation induced by the activation of polymorphonuclear neutrophils (PMNs). We observed that the increase in lung vascular permeability induced by the activation of PMNs required caveolin-1, the caveolae scaffold protein. The permeability increase induced by PMN activation was blocked in caveolin-1 knockout mice and by suppressing caveolin-1 expression in rats. The response was also dependent on Src phosphorylation of caveolin-1 known to activate caveolae-mediated endocytosis in endothelial cells. To address the role of PMN interaction with endothelial cells, we used an intercellular adhesion molecule (ICAM)-1 blocking monoclonal antibody. Preventing the ICAM-1–mediated PMN binding to endothelial cells abrogated Src phosphorylation of caveolin-1, as well as the increase in endothelial permeability. Direct ICAM-1 activation by crosslinking recapitulated these responses, suggesting that ICAM-1 activates caveolin-1 signaling responsible for caveolae-mediated endothelial hyperpermeability. Our results provide support for the novel concept that a large component of pulmonary vascular hyperpermeability induced by activation of PMNs adherent to the vessel wall is dependent on signaling via caveolin-1 and increased caveolae-mediated transcytosis. Thus, it is important to consider the role of the transendothelial vesicular permeability pathway that contributes to edema formation in developing therapeutic interventions against PMN-mediated inflammatory diseases such as acute lung injury.

Cellulose ester membranes (CEM) were enriched with the following purified matrix proteins: collagen I, II, IV, proteoglycan and laminin. Fifteen milligrams of each were placed on CEM which were then folded into open-ended tubes implanted i.p. and s.c. CEM were removed after 3, 6 and 12 months and examined histologically. There was no evidence of hematopoiesis or new bone formation on the implanted, enriched CEM at any of the intervals examined. Collagen I and proteoglycan-enriched CEM showed evidence of increased sinusoid-like vascular structures.

Caveolae mediated transendothelial transport of albumin has recently been shown to be the primary mechanism regulating microvascular endothelial albumin permeability. The authors investigated the effects of isoflurane and sevoflurane on pulmonary endothelial albumin permeability and assessed the potential role of the caveolae scaffold protein, caveolin-1, in these effects.Isolated rat lungs and cultured rat lung microvessel endothelial cells (RLMVECs) were exposed to 1.0 or 2.0 minimum alveolar concentration (MAC) isoflurane or sevoflurane for 30 min. I-albumin permeability-surface area product and capillary filtration coefficient were determined in the isolated lungs. In RLMVECs, uptake and transendothelial transport of I-albumin were measured in the absence and presence of pretreatment with 2 mm methyl-beta-cyclodextrin, a caveolae-disrupting agent. Uptake of fluorescent-labeled albumin, as well as phosphorylation of Src kinase and caveolin-1, was also determined. In Y14F-caveolin-1 mutant (nonphosphorylatable) expressing RLMVECs, uptake of I-albumin and phosphorylation of caveolin-1 were evaluated.In the isolated lungs, 2.0 MAC isoflurane increased I-albumin permeability-surface area product by 48% without affecting capillary filtration coefficient. In RLMVECs, isoflurane more than doubled the uptake of I-albumin and caused a 54% increase in the transendothelial transport of I-albumin. These effects were blocked by pretreatment with methyl-beta-cyclodextrin. The isoflurane-induced increase in uptake of I-albumin in wild-type RLMVECs was abolished in the Y14F-caveolin-1 mutant expressing cells. Isoflurane also caused a twofold increase in Src and caveolin-1 phosphorylation. Neither 1.0 MAC isoflurane nor 1.0 or 2.0 MAC sevoflurane affected any index of albumin transport or phosphorylation of caveolin-1.Isoflurane, but not sevoflurane, increased lung transendothelial albumin permeability through enhancement of caveolae-mediated albumin uptake and transport in the isolated lung. This effect may involve an enhanced phosphorylation of caveolin-1.

In hepatitis C virus (HCV)-infected patients receiving pegylated interferon (PEG-IFN)/ribavirin (RBV) combination therapy, anemia is a well-known side effect. The purpose of this study was to describe the time course and extent of hemoglobin (Hb) changes and the erythropoietic response to PEG-IFN/RBV-induced anemia.In this multicenter, observational, 8-wk study, laboratory parameters were measured weekly for 8 wk or until early withdrawal. Primary endpoints included changes in Hb and serum erythropoietin (sEPO) from baseline to week 8; other measures were changes in reticulocytes and RBV dose. The predictive value of baseline factors for maximum Hb decline was assessed.In the 97 evaluable patients, mean Hb decreased from 14.4 +/- 1.4 g/dl (baseline) to 11.9 +/- 1.3 g/dl (week 8). Twenty-one percent of patients withdrew before week 8. The estimated erythropoietic response was lower than that seen in two historic control populations of iron deficiency anemia patients. Mean RBV dose decreased from 986 +/- 190 mg/day (baseline) to 913 +/- 228 mg/day (week 8). Fifty-seven out of 77 (74%) patients who completed the study maintained their initial prescribed RBV dose. Patients maintained on the initial dose of RBV who had a higher baseline Hb and viral load showed a trend toward larger Hb declines. Platelets and white blood cells (WBCs) also declined during the study.HCV-infected patients receiving PEG-IFN/RBV therapy have reductions in Hb, platelets, and WBCs, possibly due to bone marrow suppression. They also have diminished endogenous sEPO production for their degree of anemia.

In humans, the sole endogenous source of carbon monoxide is heme degradation. We report the development of prolonged carboxyhemoglobinemia in a critically ill mechanically ventilated patient who required massive transfusion because of retroperitoneal hemorrhage secondary to pheochromocytoma. After the transfusion of 27 U of packed red blood cells, the maximum carboxyhemoglobin level was 6.4%. Although ventilation was controlled with a fraction of inspired oxygen of 0.35- 0.5 and external drainage of blood occurred, the concentration of carboxyhemoglobin remained at 1.7%-5.6% for days. Red blood cells for transfusion may be contaminated with carbon monoxide and may have carboxyhemoglobin levels of up to 12%; this may also have contributed to carboxyhemoglobinemia in our patient. If significantly increased concentrations of carboxyhemoglobin develop, therapy to decrease the concentration of carboxyhemoglobin (such as fraction of inspired oxygen of 1.0 and/or minute ventilation or hyperbaric oxygen) or removal of the source should be considered.

IMPLICATIONS The elimination of potassium in patients with end-stage kidney failure is limited. An increase in potassium concentrations can lead to lethal arrhythmias. In the described case, a large potassium concentration was treated during a liver transplantation using a new technical approach.

To describe the difficulties that can be encountered during mechanical ventilation of severe status asthmaticus and to discuss the safety of permissive hypercapnia as a ventilatory strategy and the role and limitations of inhalation anesthesia in the treatment of refractory cases.Case series and review of literature.Intensive care unit of a tertiary care hospital.Two patients with severe status asthmaticus.Administration of inhalational anesthetics.Both patients had respiratory failure secondary to status asthmaticus requiring mechanical ventilation and permissive hypercapnia. They also received inhalational anesthetics because of refractory bronchoconstriction. Levels of PaCO(2) in each case were among the highest and most prolonged elevations (150 mm Hg for several hours) reported to date. In one case, life-threatening difficulties with ventilation were encountered related to the use of an anesthesia ventilator. Although they had complications related to the severity of their illnesses, both were treated to recovery.Mechanical ventilation in severe status asthmaticus can be challenging. Permissive hypercapnia is a relatively safe strategy in the ventilatory management of asthma. High levels of hypercapnia and associated severe acidosis are well tolerated in the absence of contraindications (i.e., preexisting intracranial hypertension). Inhalation anesthesia may be useful in the treatment of refractory cases of asthma but should be used carefully because it may be hazardous owing to poor flow capabilities of most anesthesia ventilators.

Nonsteroidal antiinflammatory drugs(NSAIDs) are known as clinically effective agents for treatment of inflammatory diseases. Inhibition of cyclooxygenase has been thought to be a major facet of the pharmacological mechanism of NSAIDs. However, it is difficult to ascribe the antiinflammatory effects of NSAIDs solely to the inhibition of prostaglandin synthesis. Human neutrophil elastase (HNElastase; HNE, EC 3.4.21.37) has been known as a causative factor in inflammatory diseases. To investigate the specific relationship between HNElastase inhibition and specificity of molecular structure of several NSAIDs, HNElastase was purified by Ultrogel AcA54 gel filtration, CM-Sephadex ion exchange, and HPLC (with TSK 250 column) chromatography. HNElastase was inhibited by aspirin and salicylate in a competitive manner and by naproxen, ketoprofen, phenylbutazone, and oxyphenbutazone in a partial competative manner, but not by ibuprofen and tolmetin. HNElastase-phenylbutazone-complex showed strong Raman shifts at 200, 440, 1124, 1194, 1384, 1506, and 1768 cm(-1). The Raman bands 1194, 1384, and 1768 cm(-1) may represent evidences of the conformational change at -N=N-phi radical, pyrazol ring, and -C=O radical of the elastase-drug complex, respectively. Phenylbutazone might be bound to HNElastase by ionic and hydrophobic interaction, and masked the active site. Inhibition of HNElastase could be another mechanism of action of NSAIDs besides cyclooxygenase inhibition in the treatment of inflammatory diseases. Different inhibition characteristics of HNE-lastase by NSAIDs such as aspirin, phenylbutazone-like drugs and ineffective drugs could be important points for drawing the criteria for appropriate drugs in clinical application.

Cerebral venous sinus thrombosis (CVST) can present with a headache similar to that after a dural puncture. We report on a patient who developed postural headache after epidural anesthesia for delivery. The headache became more intense during the following 6 days, and the patient had a tonic clonic seizure. A magnetic resonance angiogram demonstrated CSVT, and anticoagulation therapy was started, with resolution of the symptoms over 2 wk. Any postdural-puncture headache that loses its positional character, becomes persistent, or does not improve with a properly performed blood patch should raise the suspicion of CVST.

Volatile anesthetics are known to have immunomodulatory effects in conditions of organ injury. A recent study in an experimental sepsis model has shown remarkably improved survival when mice were exposed to volatile anesthetics. In the present study, we show that hexafluoroisopropanol – a water-soluble primary sevoflurane metabolite – has beneficial effects on the overall survival in a murine model of cecal ligation and puncture. Seven-day survival as well as tissue damage markers including transaminases and high mobility group box protein-1 were assessed as measures of end organ damage. In animals undergoing cecal ligation and puncture procedure hexafluoroisopropanol conditioning - but not late postconditioning 24 hours after sepsis induction - significantly increased survival rate (17% vs. 77%, p = 0.037) and attenuated secretion of organ damage markers. This study shows survival benefits by administration of the metabolite of a volatile anesthetic. If successfully translated, hexafluoroisopropanol might offer interesting therapeutic opportunities in the future treatment of abdominal sepsis.

Background Inhalational anesthetics have been shown to influence T cell functions both in vitro and in vivo, in many cases inducing T cell death, suggesting that exposure to these drugs could modify the course of an autoimmune disease. We tested the hypothesis that in mice immunized to develop experimental autoimmune encephalomyelitis (EAE), a well established model of multiple sclerosis (MS), treatment with the commonly used inhalational anesthetic sevoflurane would attenuate disease symptoms. Methods C57Bl6 female mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide residues 35 to 55 to induce a chronic demyelinating disease. At day 10 after immunization, the mice were subjected to 2 h of 2.5% sevoflurane in 100% oxygen, or 100% oxygen, alone. Following treatment, clinical scores were monitored up to 4 weeks, after which brain histology was performed to measure the effects on astrocyte activation and lymphocyte infiltration. Effects of sevoflurane on T cell activation were studied using splenic T cells isolated from MOG peptide-immunized mice, restimulated ex vivo with MOG peptide or with antibodies to CD3 and CD28, and in the presence of different concentrations of sevoflurane. T cell responses were assessed 1 day later by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for proliferation, lactate dehydrogenase (LDH) release for cell death, and inflammatory activation by production of interleukin (IL)-17 and interferon (IFN)γ. Results Clinical scores in the oxygen-treated group increased until day 28 at which time they showed moderate to severe disease (average clinical score of 2.9). In contrast, disease progression in the sevoflurane-treated group increased to 2.1 at day 25, after which it remained unchanged until the end of the study. Immunohistochemical analysis revealed reduced numbers of infiltrating leukocytes and CD4+ cells in the CNS of the sevoflurane-treated mice, as well as reduced glial cell activation. In splenic T cells, low doses of sevoflurane reduced IFNγ production, cell proliferation, and increased LDH release. Conclusions These results are the first to show attenuation of EAE disease by an inhaled anesthetic and are consistent with previous reports that inhaled anesthetics, including sevoflurane, can suppress T cell activation that, in the context of autoimmune diseases such as MS, could lead to reduced clinical progression.

We report a case of pancreatitis, which occurred while the patient was on a propofol drip and then recurred after resolution following an inadvertent rechallenge with propofol. The initial episode was associated with hypertriglyceridemia, whereas the latter was not. The association between propofol and pancreatitis is definite and may occur independently of significant hypertriglyceridemia.

In this review some of the major mechanistic pathways by which tumor cells are thought to invade host tissues are discussed. Tumor invasion has been conceived to be the result of pathological, close-range interactions between malignant cells and host stroma. The sequence of events that characterize invasion can be summarized as follows: (a) Tumor cell clusters break from the confinement of the primary tumor. Loss of intercellular junctions (desmosomes), alterations in the chemical composition and physical properties of the cell surface coat (loss of fibronectin and heparan sulfate; excessive amounts of hyaluronate), and loosening of cell-substrate interactions (loss of hemidesmosomes, fibronectin, and heparan sulfate), are among the most frequently listed causes of tumor cell shedding. (b) Increased proteolytic activities at the invasion front cause focal alterations in the surrounding extracellular matrix, thereby changing its physical properties. Collagenases and cathepsins, as well as elastase and other neutral proteinases are the enzymes most frequently associated with matrix destruction and invasion. In some tissues this process is effectively regulated by inhibitors of matrix-degrading, proteolytic enzymes. (c) Tumor cells migrate into the altered matrix, possibly moving as aggregates along guidance tracks provided by host structures (blood vessels, lymphatics, nerves) or matrix macromolecules (collagen and fibronectin tracks). Migration seems to be preceded by increased swelling of glycosaminoglycan (i.e., hyaluronate) in the matrix, ahead of the migrating cell population. Various host cell types (mast cells, fibroblasts, endothelial cells, macrophages, etc.) may participate in these events.

The cause of exercise intolerance in congestive heart failure is unclear. Hemodynamic and ventilatory responses were measured during symptomatic maximal upright bicycle exercise in 28 patients with chronic severe left ventricular failure who achieved a maximal oxygen uptake of only 12 +/- 4 ml/min/kg (+/- standard deviation). All patients reached anaerobic metabolism as the respiratory exchange ratio rose and arterial pH fell significantly. Pulmonary capillary wedge pressure increased from 20 +/- 10 mm Hg at rest to 38 +/- 9 mm Hg at peak exercise and cardiac index increased from 2.51 +/- 0.73 to 4.54 +/- 1.65 liters/min/m2 (both p less than 0.001). Systemic vascular resistance decreased, but pulmonary vascular resistance did not change during exercise. Despite the marked pulmonary venous hypertension at peak exercise, blood gases were unchanged (PaO2, 96 +/- 15 mm Hg; PaCO2, 35 +/- 7 mm Hg). Systemic arterial oxygen content increased from 16 +/- 2 to 17 +/- 2 vol% (p less than 0.01). Changes in pulmonary capillary wedge pressure did not correlate with changes in arterial oxygen content. Results were similar whether patients were limited by dyspnea or fatigue. Thus, exercise intolerance in patients with severe left ventricular failure is associated with marked elevation of pulmonary capillary wedge pressure and anaerobic metabolism without hypoxemia or altered carbon dioxide tension. These findings suggest that exercise ability in congestive heart failure is more dependent on cardiac output than on ventilatory consequences of pulmonary congestion.

The pathophysiologic role of high levels of circulating catecholamines in patients with congestive heart failure remains unclear. To assess the hemodynamic contribution of circulating catecholamines, metyrosine (alpha-methyl-p-tyrosine), an inhibitor of catecholamine synthesis, was administered to nine patients with acutely decompensated chronic congestive heart failure. Baseline left ventricular ejection fraction averaged 23.3 +/- 9.9%, whereas cardiac output averaged 3.69 +/- 1.03 liters/min, with a pulmonary wedge pressure of 27.4 +/- 8.5 mm Hg. After 48 h of metyrosine administration, plasma norepinephrine concentration decreased from 919.4 +/- 810.6 to 335.4 +/- 143.1 pg/ml (p less than 0.05). Plasma epinephrine concentration averaged 176.4 +/- 166.0 pg/ml at baseline, and was unchanged during metyrosine administration. Despite the significant decrease in circulating norepinephrine, no significant hemodynamic changes were observed during metyrosine administration. These results suggest that high levels of circulating norepinephrine may be more a marker of severe congestive heart failure than an important contributor to the underlying pathophysiology at this advanced stage of the disease process.

Fibroblasts from normal adult forearm skin and neonatal foreskin were cultured and examined for their ability to synthesize and secrete elastase and neutral cathepsin. All of the cultures examined produced detectable amounts of elastase using insoluble elastin as substrate. An enzyme was also found that hydrolyzed the synthetic elastin substrate, N-succinyl-(Ala)3-p-nitroanilide, but did not degrade insoluble elastin. In addition, activity against the synthetic cathepsin substrate N-benzoyl-DL-phenylalanine-naphthyl ester was found. Inhibitor profiles indicate that the elastin and N-succinyl-(Ala)3-p-nitroanilide degrading activities are due to metalloproteinases. Degradation of N-benzoyl-DL-phenylalanine-naphthyl ester can be inhibited by phenylmethylsulfonyl fluoride. These proteinases were usually found associated with the cell layer. Although activities of the measured proteinases were detected in all cultures, increased or decreased enzyme activities were not predictably related to passage number or length of serum starvation. Degree of confluence also affected proteinase activities. Separation of the dermal-epidermal junction can be produced by the injection of these proteinases into intact mouse skin.

High-density (HD) lipoprotein cholesterol levels have been inversely associated with the incidence of coronary heart disease. The clinical features were reviewed and the prevalence of clin...

We consecutively and prospectively studied 219 critically ill patients to evaluate the accuracy of the physical examination in assessing ETT position and the appropriateness of taking routine chest x-ray films after intubation in the ICU. As a result of x-ray findings, 14 percent of the patients required ETT repositioning, and 5 percent had main-stem intubations. Endobronchial intubation was more common in females than in males, and frequently occurred after emergency intubations. Sixty percent of the main-stem intubations occurred despite the presence of equal breath sounds on examination. Techniques to minimize the risk of tube malposition, such as cuff ballottement in the suprasternal notch and referencing the ETT centimeter markings, were not completely reliable. This study confirms the unreliability of the physical examination to assess ETT position. Chest x-ray films after intubation are indicated to verify tube position, particularly after emergency intubations. Other techniques such as use of a lighted stylet require evaluation to determine whether they are more cost-effective in verifying ETT placement in patients who have no other indication for postintubation x-ray films.

Most therapeutic modalities are associated with risks. Recent research has stressed the importance of quantitative risk assessments which permit comparisons with other risk factors, such as background radiation, hazards of other modes of therapy, and various life-style risks. Although more data are available on the theoretical and clinical aspects of radiation side effects than about the risks of any other mode of therapy, there is a large gap between the opinions of experts and the view of the public.

Modifications and adaptations of chemical techniques have been used to quantitate hydroxyproline (collagen), total protein and DNA in fixed, paraffin-embedded and sectioned tissue. The assays are rapid and sensitive to between 0.1 and 1.0 micrograms of each of the three components. Values for the ratio of collagen to total protein or collagen per DNA obtained from sectioned material are the same as values derived from fresh or fixed starting material. Depending on the tissue and the sample size, as little as three to five 5 micron thick sections can be analysed for these three components. The ratios of collagen per total protein or collagen per DNA are given for several murine tissues. The assay of these components in tissue sections will allow a more precise correlation between histological appearance and the quantitative biochemical changes that may accompany many pathological disorders. The techniques are particularly useful in retrospective studies where the experimental material may be en bloc.

We conducted a randomized prospective trial in 19 disease-free soft tissue sarcoma patients with doxorubicin-induced cardiomyopathy identified by ECG radionuclide angiography at rest and during exercise to determine the efficacy of the free radical scavenger, N-Acetyl Cysteine (NAC), in reversing the drug's cardiotoxic effect. Of the 19 patients, 11 received oral NAC (5.5 gm/m2 daily for 30 days) and eight patients served as controls. Patients were stratified for age less than greater than 45 years, time from final dose of doxorubicin to randomization less than greater than 8 months, and history of treatment with mediastinal irradiation. The two groups were well-matched for all parameters. Cumulative mean doxorubicin dose (523 mg/m2 and 532 mg/m2) and range 500-600 mg/m2 was comparable. Left ventricular (LV) ejection fraction before randomization was not significantly different between the two groups either at rest (39 +/- 10% control, 38 +/- 13% NAC) or during exercise (38 +/- 12% control, 35 +/- 11% NAC). Neither rest nor exercise ejection fraction values changed significantly in either group between prerandomization and 1-month postrandomization studies. Late studies performed in seven NAC patients 3-5 months after randomization revealed no difference in LV ejection fraction compared to 1-month postrandomization values. Clinical course in patients with overt congestive heart failure was similar in both groups. LV function did not return to normal in any patient in either group. We conclude that N-Acetyl Cysteine has no effect in reversing long standing doxorubicin-induced cardiomyopathy.

The amount of cross-sectional area (XSA) narrowing in each 5 mm long segment of each of the four major epicardial coronary arteries was determined in each of five patients with type III hyperlipoproteinemia (HLP) and symptomatic, fatal atherosclerotic coronary disease (CAD). Four had angina pectoris; two had acute myocardial infarcts which healed, and two died suddenly. Of the four major epicardial coronary arteries, all four were narrowed 76% to 100% in XSA by atherosclerotic plaques in two patients, three were narrowed to this degree in two patients, and two were so narrowed in one patient. Three patients had severe narrowing of the left main coronary artery. The percent of 5 mm long segments of coronary artery narrowed to various degrees was as follows: 96% to 100%, 0 to 37 (mean 14); 76% to 95%, 14 to 61 (mean 35); 51% to 75%, 9 to 41 (mean 24); 26% to 50%, 0 to 42 (mean 16), and 0% to 25%, 0 to 27 (mean 11). Utilizing a scoring system of 1 to 4 for the four categories of narrowing (1 = 0% to 25%, 2 = 26% to 50%, 3 = 51% to 75% and 4 = 76% to 100% XSA narrowing), scores per 5 mm segment for each patient ranged from 2.5 to 3.9 (mean 3.1). Thus these five type III HLP patients had severe diffuse coronary narrowing by atherosclerotic plaques.

Radionuclide cineangiography was used to evaluate 32 patients who sustained long-term remission of soft tissue sarcoma after adjuvant therapy with a cumulative doxorubicin dose from 480 to 550 mg/m body surface area. Left ventricular ejection fraction at rest was below normal (less than 45%) in eight of 32 patients. The abnormal response of ejection fraction to exercise identified an additional 12 patients with diminished left ventricular functional reserve. Ejection fraction determined at rest or during exercise did not differ 1 to 9 months) and those studied 30 months (range, 21 to 43 months) after completing doxorubicin treatment. Sequential studies in 13 patients, done 6 to 15 months after initial post-doxorubicin evaluation also showed persistent depression of average ejection fraction at rest and with exercise, with the continued deterioration of left ventricular function in six patients. Left ventricular dysfunction, evident in over half of asymptomatic patients even long after "acceptable" cumulative doses of doxorubicin, may persist for years.

Acute lung injury (ALI) is associated with high mortality due to the lack of effective therapeutic strategies. Mechanical ventilation itself can cause ventilator-induced lung injury. Pulmonary vascular barrier function, regulated in part by Src kinase-dependent phosphorylation of caveolin-1 and intercellular adhesion molecule-1 (ICAM-1), plays a crucial role in the development of protein-/neutrophil-rich pulmonary edema, the hallmark of ALI. Amide-linked local anesthetics, such as ropivacaine, have anti-inflammatory properties in experimental ALI. We hypothesized ropivacaine may attenuate inflammation in a “double-hit” model of ALI triggered by bacterial endotoxin plus hyperinflation via inhibition of Src-dependent signaling. C57BL/6 (WT) and ICAM-1 −/− mice were exposed to either nebulized normal saline (NS) or lipopolysaccharide (LPS, 10 mg) for 1 hour. An intravenous bolus of 0.33 mg/kg ropivacaine or vehicle was followed by mechanical ventilation with normal (7 ml/kg, NTV) or high tidal volume (28 ml/kg, HTV) for 2 hours. Measures of ALI (excess lung water (ELW), extravascular plasma equivalents, permeability index, myeloperoxidase activity) were assessed and lungs were homogenized for Western blot analysis of phosphorylated and total Src, ICAM-1 and caveolin-1. Additional experiments evaluated effects of ropivacaine on LPS-induced phosphorylation/expression of Src, ICAM-1 and caveolin-1 in human lung microvascular endothelial cells (HLMVEC). WT mice treated with LPS alone showed a 49% increase in ELW compared to control animals (p = 0.001), which was attenuated by ropivacaine (p = 0.001). HTV ventilation alone increased measures of ALI even more than LPS, an effect which was not altered by ropivacaine. LPS plus hyperinflation (“double-hit”) increased all ALI parameters (ELW, EVPE, permeability index, MPO activity) by 3–4 fold compared to control, which were again decreased by ropivacaine. Western blot analyses of lung homogenates as well as HLMVEC treated in culture with LPS alone showed a reduction in Src activation/expression, as well as ICAM-1 expression and caveolin-1 phosphorylation. In ICAM-1 −/− mice, neither addition of LPS to HTV ventilation alone nor ropivacaine had an effect on the development of ALI. Ropivacaine may be a promising therapeutic agent for treating the cause of pulmonary edema by blocking inflammatory Src signaling, ICAM-1 expression, leukocyte infiltration, and vascular hyperpermeability.

• Medical personnel who perform dermabrasions are exposed to airborne blood and tissue fragments. The safety or hazards of exposure to such aerosols have not been adequately studied. Using scanning electron microscopy, the air density and size distribution of particles produced during dermabrasion were analyzed. Such particles are of sufficient size to allow for access to and retention by mucosal and pulmonary surfaces. Transmission electron microscopy reveals amorphous particles without discernible cell membranes. Commonly used personnel protection standards do not prevent respiration of these particulates. Mathematical estimation of particle size production allows extrapolation of these data to other rotary instrument applications. ( Arch Dermatol. 1989;125:1637-1643)

Groups of 10 CF1 female mice, irradiated to the thorax with a dual-head /sup 137/Cs gamma-RAY source, received single doses of 0, 5, 10, 15, or 25 Gy. One to forty-eight weeks later collagen synthesis was measured in minced skin specimens incubated in medium containing (/sup 3/H)proline and then assayed for radioactive hydroxyproline. A progressive, generally dose-dependent increase in collagen biosynthesis, up to 50% above control sites, was found 1, 4, and 12 weeks after radiation exposure. These changes showed further small fluctuations at 12-36 weeks, increasing again at the 48-week interval. At the same times throughout the study fibroblasts were cultured from skin explants. Following the second subculture, these cells were also incubated in medium containing (/sup 3/H)proline, and collagen synthesis was again determined by (/sup 3/H)hydroxyproline assay. At all radiation dose levels studied, collagen production increased threefold by 12 weeks postradiation and remained elevated for the 48-week duration of the study. In vitro radiation dose response differences were not observed.

Type III hyperlipoproteinemia is characterized by increased plasma levels of triglycerides and cholesterol, palmar-tuberoeruptive xanthoma, and premature cardiovascular disease. Three major classes of molecular defects will predispose patients to develop type III hyperlipoproteinemia: a deficiency in apolipoprotein E, a structural defect in the E apolipoprotein, and a functional defect in the liver receptor system. Most patients with type III hyperlipoproteinemia have a structural defect in apolipoprotein E associated with increased synthesis and decreased catabolism of apolipoprotein E, delayed catabolism of chylomicron remnants, and development of plasma lipoprotein abnormalities characteristic of type III hyperlipoproteinemia. Analysis of cardiovascular disease in patients with type III hyperlipoproteinemia showed extensive coronary and peripheral vascular atherosclerosis indistinguishable from the atherosclerosis of non-hyperlipidemic and other dyslipoproteinemic patients. The xanthoma and elevated plasma cholesterol and triglyceride levels in patients with type III hyperlipoproteinemia respond to dietary and drug therapy.

Introduction The aim of this randomized controlled trial was to investigate whether volatile anesthetics used for postoperative sedation have any beneficial effects on myocardial injury in cardiac surgery patients after on-pump valve replacement. Methods Anesthesia was performed with propofol. After arrival in the intensive care unit (ICU), 117 patients were randomized to be sedated for at least 4 hours with either propofol or sevoflurane. Sevoflurane was administered by using the anesthetic-conserving device. Troponin T, creatine kinase, creatine kinase from heart muscle tissue, myoglobin, and oxygenation index were determined on arrival at the ICU, 4 hours after sedation, and in the morning of the first postoperative day (POD1). Primary end points were cardiac injury markers on POD1. As secondary end points oxygenation, postoperative pulmonary complications, and ICU and hospital stay were documented. Results Fifty-six patients were analyzed in the propofol arm, and 46 patients in the sevoflurane arm. Treatment groups were comparable with regard to patient demographics and intraoperative characteristics. Concentration of troponin T as the most sensitive marker for myocardial injury at POD1 was significantly lower in the sevoflurane group compared with the propofol group (unadjusted difference, -0.4; 95% CI, -0.7 to -0.1; P < 0.01; adjusted difference, -0.2; 95% CI, -0.4 to -0.02; P = 0.03, respectively). Conclusions The data presented in this investigation indicate that late postconditioning with the volatile anesthetic sevoflurane might mediate cardiac protection, even with a late, brief, and low-dose application. Trial registration ClinicalTrials.gov: NCT00924222.

IntroductionSevere sepsis is associated with approximately 50% mortality and accounts for tremendous healthcare costs. Most patients require ventilatory support and propofol is commonly used to sedate mechanically ventilated patients. Volatile anesthetics have been shown to attenuate inflammation in a variety of different settings. We therefore hypothesized that volatile anesthetic agents may offer beneficial immunomodulatory effects during the course of long-term intra-abdominal sepsis in rats under continuous sedation and ventilation for up to 24 hours.MethodsSham operation or cecal ligation and puncture (CLP) was performed in adult male Wistar rats followed by mechanical ventilation. Animals were sedated for 24 hours with propofol (7 to 20 mg/kg/h), sevoflurane, desflurane or isoflurane (0.7 minimal alveolar concentration each).ResultsSeptic animals sedated with propofol showed a mean survival time of 12 hours, whereas >56% of all animals in the volatile groups survived 24 hours (PPPPConclusionsThis is the first study to assess prolonged effects of sepsis and long-term application of volatile sedatives compared to propofol on survival, cardiovascular, inflammatory and end organ parameters. Results indicate that volatile anesthetics dramatically improved survival and attenuate systemic inflammation as compared to propofol. The main mechanism responsible for adverse propofol effects could be an enhanced plasma endotoxin concentration, leading to profound hypotension, which was unresponsive to fluid resuscitation.