Activation of complement by hydroxyl radical in thermal injury

Complement activation resulting from local burn injury of skin and other soft tissues can be linked to systemic complications, such as intravascular hemolysis, neutrophil activation, and acute lung injury. This study was designed to clarify the relationship between cutaneous thermal injury, oxygen radical formation, and complement activation in vivo. A model for "selective" venous sampling from the area of a partial-thickness cutaneous burn over 25% to 30% of the total body surface in the rat was developed. Interventions involving oxygen radical scavengers, antioxidant enzymes, xanthine oxidase inhibitors, an iron chelator, complement depletion, and neutrophil depletion were used to probe the nature of the oxygen products involved in complement activation. Plasma from the area of burn was examined for total hemolytic complement activity, content of C5a-related chemotactic peptide, and relationship of oxygen products to appearance of this peptide. Xanthine oxidase inhibitors, hydroxyl radical scavengers, and complement depletion diminished the generation of C5a activity at the burn site, whereas neutrophil depletion was without effect. These data suggest that C5a activity may be related to oxygen products from xanthine oxidase. The catalase sensitivity and iron dependency of C5a generation suggest that hydroxyl radical may be related to complement activation and C5a appearance. This is the first report to directly link oxygen radical generation and complement activation in vivo.     

Profound pulmonary shunting without edema following stereotaxic biopsy of hypothalamic germinoma. Case report

Hypoxemia is a nearly constant accompaniment of head injury. Diverse theories have been proposed to explain this relationship. The authors report the case of a patient who suffered an episode of severe, transient, arterial oxygen desaturation during "controlled" brain trauma: an otherwise uneventful stereotaxic biopsy of a small germinoma of the hypothalamus. Evidence is provided that pure ventilation-perfusion mismatching, without pulmonary edema, underlay the hypoxemia. The hypothalamus is intimately involved in matching pulmonary ventilation to perfusion; the hypoxemia of various brain injuries may be mediated by perturbation of this structure.     

Effects of metastatic cascades on metastatic patterns: studies on colon-26 carcinomas in mice

The present studies are based on autopsy data showing that in upper esophageal and lower rectal carcinomas, hematogenous metastasis occurs mainly first to the lungs, and cancer cells from pulmonary metastases generate arterial metastases. In lower esophageal and upper rectal carcinomas, hematogenous metastases occur first in the liver, then in the lungs, and are further disseminated by the arterial route. The arterial metastatic patterns are different in the 2 groups. One possible explanation for these differences in pattern is that liver "residence" is associated with different metastatic behavior; this has been tested in a model system. Experiments with the transplantable colon-26 carcinoma in mice reveal that, when cancer cells from common s.c. transplant sites are grown in the liver, lungs or liver-and-lungs, and then injected into the bloodstream of fresh recipients via the left ventricle, the portal vein or the tail vein, different patterns and degrees of colonization of 11 different target sites are observed. These results are consistent with the hypothesis that growth of cancers in different anatomic sites may modify the subsequent arterial metastatic patterns, due to site-induced changes occurring in cancer cell populations, which influence metastasis from metastases or so-called "cascade" processes.     

Simultaneous visualization of seven different DNA probes by in situ hybridization using combinatorial fluorescence and digital imaging microscopy.

Combinatorial labeling of probes (i.e., with two or more different reporters) increases the number of target sequences that can be detected simultaneously by fluorescence in situ hybridization. We have used an epifluorescence microscope equipped with a digital imaging camera and computer software for pseudocoloring and merging images to distinguish up to seven different probes using only three fluorochromes. Chromosome-specific centromere repeat clones and chromosome-specific "composite" probe sets were generated by PCR in which different mixtures of modified nucleotides, including fluorescein-conjugated dUTP, were incorporated. Cosmid clones were labeled similarly by nick-translation. The technique has been used to delineate the centromeres of seven different human chromosomes, on both 4',6-diamidino-2-phenylindole-stained metaphase spreads and interphase nuclei, to map six cosmid clones in a single hybridization experiment and to detect chromosome translocations by chromosome painting. Multiparameter hybridization analysis should facilitate molecular cytogenetics, probe-based pathogen diagnosis, and gene mapping studies.     

P300 and conceptual loosening in normals: an event-related potential correlate of "thought disorder?".

Reduced amplitude of the P300 component of the event-related potential (ERP) has frequently been reported in schizophrenic patients and their first-degree relatives. The present study examined the relationship between this ERP measure of attentional processing and loosening of associations in normal university students (termed "allusive thinking"). Among male subjects, scores reflecting increased conceptual loosening, measured using the Lovibond scoring method for the Goldstein-Scheerer Object Sorting Test (OST), were significantly correlated with smaller P300 amplitude recorded during an auditory target detection task. There was no association between OST score and either performance of the target detection task or self-reported psychopathology. It is suggested that reduced P300 amplitude could reflect altered attentional processing in individuals with a constitutional trait factor of thought disorder.     

The introductory placebo washout: a retrospective evaluation

We examined the effects of the "introductory placebo washout" technique by reanalyzing the results of a recent trial of an experimental antidepressant. At the beginning, all patients were placed on placebo in a single-blind design. Patients who were rated as placebo responders with the physician-administered Hamilton Rating Scale for Depression (HRSD) were excluded from the trial. In spite of this technique, an alternative measure of depression indicated that many patients with a positive response to placebo had been entered in the trial. In the reanalysis, elimination of these "hidden placebo responders" did not lower the final placebo response rate and actually diminished the differences observed at the end of the study between the active treatment and placebo groups. These data suggest that the introductory placebo washout may have unpredictable, possibly confounding effects on patient samples in trials of antidepressant agents.     

Cerebral blood flow and metabolism in severely head-injured children. Part 1: Relationship with GCS score, outcome, ICP, and PVI

The literature suggests that in children with severe head injury, cerebral hyperemia is common and related to high intracranial pressure (ICP). However, there are very few data on cerebral blood flow (CBF) after severe head injury in children. This paper presents 72 measurements of cerebral blood flow ("CBF15"), using the 133Xe inhalation method, with multiple detectors over both hemispheres in 32 children aged 3 to 18 years (mean 13.6 years) with severe closed head injury (average Glasgow Coma Scale (GCS) score 5.4). In 25 of the children, these were combined with measurements of arteriojugular venous oxygen difference (AVDO2) and of cerebral metabolic rate of oxygen (CMRO2). In 30 patients, the first measurement was taken approximately 12 hours postinjury. In 18 patients, an indication of brain stiffness was obtained by withdrawal and injection of ventricular cerebrospinal fluid and calculation of the pressure-volume index (PVI) of Marmarou. The CBF and CMRO2 data were correlated with the GCS score, outcome, ICP, and PVI. Early after injury, CBF tended to be lower with lower GCS scores, but this was not statistically significant. This trend was reversed 24 hours postinjury, as significantly more hyperemic values were recorded the lower the GCS score, with the exception of the most severely injured patients (GCS score 3). In contrast, mean CMRO2 correlated positively with the GCS score and outcome throughout the course, but large standard deviations preclude making predictions based on CMRO2 measurements in individual patients. Early after injury, there was mild uncoupling between CBF and CMRO2 (CBF above metabolic demands, low AVDO2) and, after 24 hours, flow and metabolism were completely uncoupled with an extremely low AVDO2. Consistently reduced flow as found in only four patients; 28 patients (88%) showed hyperemia at some point in their course. This very high percentage of patients with hyperemia, combined with the lowest values of AVDO2 found in the literature, indicates that hyperemia or luxury perfusion is more prevalent in this group of patients. The three patients with consistently the highest CBF had consistently the lowest PVI: thus, the patients with the most severe hyperemia also had the stiffest brains. Nevertheless, and in contrast to previous reports, no correlation could be established between the course of ICP or PVI and the occurrence of hyperemia, nor was there a correlation between the levels of CBF and ICP at the time of the measurements. The authors argue that this lack of correlation is due to: 1) a definition of hyperemia that is too generous, and 2) the lack of a systematic relationship between CBF and cerebral blood volume     

Assessing the need for multicompetent allied health care professionals in the HMO setting

In the past decade, changes in health care reimbursement and emphasis on cost containment have changed patterns of health care delivery. Among these changes are the rapid decline of the hospital as the center of care, and an emphasis on managed systems of health care delivery. Health maintenance organizations (HMOs) have grown rapidly, and now control a significant portion of the health care marketplace. As such, HMOs provide nontraditional employment settings for allied health professionals. To date, little is known regarding the status of allied health professionals in the HMO setting. The purpose of this study was to describe the perceived need for nontraditional multicompetent allied health professionals in the HMO setting. Results indicate that group and staff model HMOs have a high number of traditionally prepared allied health professionals. In addition, a large number of these sites employ multicompetent professionals, most of whom receive "in-house" training. Further research regarding the role expectations for such professionals is indicated.     

The scopolamine model of dementia: chronic transdermal administration

The transient impairments of memory produced by the muscarinic antagonist scopolamine have been adopted as a pharmacological model of Alzheimer-type dementia in normal volunteers. In this study we examined the effects of chronic (72 h) transdermal administration of scopolamine on memory, attention, sedation and visual function. The transdermal patches provided constant plasma levels of scopolamine for the duration of the study. Indices of the peripheral effects of scopolamine (visual near-point and pupil size) showed impairments that were sustained for 3 days. However, measures of sedation and memory revealed impairments that were maximal the day after patch application and which were no longer present 3 days after application. This pattern of results is discussed in relation to pharmacological modelling of Alzheimer's disease.     

Hypoxia,energy state and pulmonary vasomotor tone

Vasomotor responses to hypoxia constitute a fundamental adaptation to a commonly encountered stress. It has long been suspected that changes in cellular energetics may modulate both hypoxic systemic artery vasodilatation (HSV) and hypoxic pulmonary artery vasoconstriction (HPV). Although limitation of energy has been shown to underlie hypoxic relaxation in some smooth muscles, the response to hypoxia in vascular smooth muscle does not appear to be a simple function of energy stores, but instead may involve perturbations of ATP or energy delivery to mechanisms controlling muscle force, and/or changes associated with anaerobic metabolism. Recent work in pulmonary vascular smooth muscle has demonstrated that energy stores are maintained during hypoxic pulmonary vasoconstriction, and that this is dependent on glucose availability and up-regulation of glycolysis. There is increasing evidence that glycolysis is preferentially coupled to a variety of membrane associated ATP dependent processes, including the Na(+) pump, Ca(2+)-ATPase, and possibly some protein kinases. These and other mechanisms may influence excitation-contraction coupling in both systemic and pulmonary arteries by effects on intracellular Ca(2+) and/or Ca(2+) sensitivity. Hypoxia has also been postulated to have major effects on other cytosolic second messenger systems including phosphatidylinositol pathways, cell redox state and mitochondrial reactive oxygen species production. This review examines the relationship between energy state, anaerobic respiration and hypoxic vasomotor tone, with a particular emphasis on hypoxic pulmonary vasoconstriction.