Thomas A. Raffin

Effects of anti-C5a antibodies on the adult respiratory distress syndrome in septic primates.

In vitro and in vivo studies have suggested that human complement component C5a plays a key role in neutrophil injury in the adult respiratory distress syndrome (ARDS). First, using leukocyte aggregometry, we demonstrated that the addition of a recently developed rabbit anti-human polyclonal antibody to C5a des arg to endotoxin-activated plasma prevented leukocyte aggregation in vitro. We then administered the anti-C5a des arg antibody to septic primates (Macaca fascicularis). Three groups of primates, control, septic, and anti-C5a antibody treated septic, were studied (n = 4 in each group). A 30-min infusion of Escherichia coli (1 X 10(10)/kg) resulted in severe sepsis and ARDS. Primates were killed 4 h after completion of the E. coli infusion. Septic animals not treated with anti-C5a antibody had 75% mortality (3/4), decreased oxygenation, severe pulmonary edema, and profound hypotension. Septic primates treated with anti-C5a antibodies did not die and did not develop decreased oxygenation (P less than 0.05) or increased extravascular lung water (P less than 0.05). They also had a marked recovery in their mean arterial blood pressure (P less than 0.05). This study demonstrates that treatment with rabbit anti-human C5a des arg antibodies attenuates ARDS and some of the systemic manifestations of sepsis in nonhuman primates.

Ethical consideration of incidental findings on adult brain MRI in research

Objective: To characterize the frequency and severity of incidental findings in brain MRIs of young and older adult research volunteers, and to provide an evaluation of the ethical challenges posed by the detection of such findings. Methods: The authors reviewed 151 research MRI scans obtained retrospectively from subjects recruited to studies as healthy volunteers. Incidental findings were classified into four categories: no referral, routine, urgent, or immediate referral. p Values for significance were computed from χ2 tests of contingency. Results: Of 151 studies, the authors found an overall occurrence of incidental findings having required referral of 6.6%. By age, there were more findings in the older cohort (aged >60 years) than in the younger cohort (p < 0.05) and in more men than women in the older cohort (p < 0.001). Three of four (75%) findings in the younger cohort were classified in the urgent referral category; 100% of the findings in the older cohort were classified as routine (p < 0.05). Conclusion: The significant presence but different characteristics of incidental findings in young and older subjects presumed to be neurologically healthy suggest that standards of practice are needed to guide investigators in managing and communicating their discovery.

Discovery and Disclosure of Incidental Findings in Neuroimaging Research

To examine different protocols for handling incidental findings on brain research MRIs, and provide a platform for establishing formal discussions of related ethical and policy issues.

Diagnostic Decision: Indications for Arterial Blood Gas Analysis

: Arterial blood gas analysis is used to evaluate oxygen and carbon dioxide gas exchange and acid-base status. Few studies identify indications for arterial blood gas analysis, especially with regard to optimizing the quality of patient care. General indications in severely ill adults usually include pathophysiologic abnormalities that can alter gas exchange or acid-base disturbances. Most commonly identified general indications have not been prospectively studied to determine if this analysis is necessary for diagnosis or management. Clinical settings where analysis is indicated involve patients with acute asthma in the emergency room, postoperative treatment of patients who have had coronary artery bypass graft surgery, stable patients in the intensive care unit, and patients receiving prophylactic supplemental low-flow oxygen by nasal cannula. Advances in noninvasive monitoring have suggested other possible clinical settings. However, further prospective, controlled clinical studies are needed to establish indications for arterial blood gas analysis and the role of noninvasive monitoring.

PG490-88, a Derivative of Triptolide, Blocks Bleomycin-Induced Lung Fibrosis

In this study we evaluate the antifibrotic properties of PG-490-88, a water-soluble derivative of triptolide. Triptolide is an oxygenated diterpene that is derived from a traditional Chinese herb that has potent immunosuppressive and antitumor activity. We used the intratracheal bleomycin mouse model and found that PG490-88 inhibits fibrosis in the bleomycin group when given the same day or 5 days after bleomycin. PG490-88 also markedly reduced the number of myofibroblasts in the bleomycin treatment group. An enzyme-linked immunosorbent assay of transforming growth factor (TGF)-beta in the bronchoalveolar lavage fluid showed a significant decrease in TGF-beta in the PG490-88-treated groups compared to the bleomycin-treated group. Additionally, triptolide blocked bleomycin-induced increase in TGF-beta mRNA in cultured normal human lung fibroblasts. The efficacy of PG490-88 when administered late after bleomycin installation suggests a potential role in the treatment of idiopathic pulmonary fibrosis.

Ethical and practical considerations in managing incidental findings in functional magnetic resonance imaging.

Functional magnetic resonance imaging has emerged as a powerful tool for mapping the neurologic underpinnings of sensory, motor and cognitive function. Much of this evolution carries assumptions about the subject population under study and, in particular, the neurologic status of subjects entered into studies either as healthy controls or as belonging to a specific disease group. Recent reports of incidental MRI abnormalities in normal volunteers for fMRI studies have brought to attention a variety of practical challenges and ethical dilemmas for researchers, many of whom are not physicians and most of whom have no formal radiological training. We propose a minimum standard for consenting subjects in fMRI protocols, and consider strategies over the longer term that call for expert physician participation, archiving of incidental findings including false positives, and the adoption of guidelines for handling variation in neural activations or performance that appear outside expected norms.

Minimal long-term cardiopulmonary dysfunction following treatment for Hodgkin's disease

UNLABELLED We studied the long term cardiopulmonary function, at rest and during exercise, of 57 patients who were at least 1 year (mean 5 years) post-treatment for Hodgkins disease. To establish the maximum degree of dysfunction we studied 40 patients who had extensive intrathoracic disease treated with radiotherapy alone (Exten-X; n = 20) or combined modality therapy (Exten-XC; n = 20). Patients without intrathoracic disease given either prophylactic mantle therapy (Proph-X, n = 10) or no chest irradiation ( CONTROL n = 7) were used as controls. An abnormal electrocardiogram, by virtue of a conduction defect, was observed in seven patients, six in the Exten-X or Exten-XC groups. Borderline abnormalities including ST-T changes, prolonged QT interval, or axis deviation occurred in 14 patients distributed evenly throughout the groups. Resting mean pulmonary function test values were normal in all treatment groups. Exercise tolerance, as indicated by peak oxygen consumption (VO2), was significantly lower for the Exten-XC group compared to Proph-X (p less than 0.01). However, the mean value of VO2 for group Exten-XC was only 15% below that predicted. Of the 12 patients with abnormally low VO2 (greater than 20% below their predicted value), 11 were in the Exten-X or Exten-XC group with no difference between the two groups. Patients who received radiotherapy to at least one lung field, using either the thin lung block technique or open field irradiation, had significantly lower exercise tolerance than those treated with full thickness blocks (p less than 0.05). Despite these abnormalities only a single patient complained of marked dyspnea. We conclude that extensive treatment to the mantle field, especially when followed by chemotherapy in patients with extensive intrathoracic Hodgkins disease, can result in minimal cardiopulmonary dysfunction in approximately one-third of patients.

Complement levels in septic primates treated with anti-C5a antibodies

During gram-negative sepsis it is known that endotoxin activates complement by the alternate pathway. The complement anaphylatoxin C5a, a result of this activation, is thought to play a key role in attracting and activating neutrophils in the lungs, leading to the adult respiratory distress syndrome. Complement levels were measured in primates made septic by Escherichia coli infusions. Anti-human C5a antibodies were administered to study their effect on neutrophil-mediated lung injury. Control (I), septic (II) and septic + anti-C5a antibody (III) groups (n = 4) were studied. The antibody-treated group (III) demonstrated a significant attenuation of septic shock and pulmonary edema as has been previously reported. All complement profiles were corrected for varying hemoglobin concentrations. C3, C4, and C5 levels were measured by radial immunodiffusion and were depleted in both septic groups. Once the levels were depleted from the plasma, they did not recover. The depletion of C4 indicates that classical pathway activation also occurred. C3a, C4a, and C5a levels were measured by radioimmunoassay. Significantly increased peak levels were reached in the septic groups 15 min after initiation of the E. coli infusion. There were no significant differences in early peak C3a and C4a levels between groups II and III. However, the mean peak C5a level in group III (anti-C5a antibodies) was 42% lower than that in group II, and after this early peak, C5a levels were not elevated above control levels in group III. The antibody to human C5a was thus shown to be cross-reactive with primate C5a and was specific since C3a and C4a levels were not decreased in group III.(ABSTRACT TRUNCATED AT 250 WORDS)

Nicotine addiction through a neurogenomic prism: ethics, public health, and smoking.

Studies are under way to examine the neurogenetic factors contributing to smoking behaviors. The combined approaches of genomics, molecular biology, neuroscience, and pharmacology are expected to fuel developments in pharmacogenetics, to create new genetic tests, and ultimately to provide the basis for innovative strategies for smoking cessation and prevention. The emergence of a neurogenomic understanding of nicotine addiction is likely to induce fundamental changes in popular, clinical, and public health views of smoking, which could significantly shape existing practices and policies to reduce tobacco use. Still a nascent area of research, nicotine addiction provides an excellent case study through which to anticipate key ethical and policy issues in both behavioral genetics and the neurogenomics of addictive behaviors.

Effect of NADPH oxidase inhibition on endothelial cell ELAM-1 mRNA expression

Neutrophil adherence to endothelium is partially mediated by the expression of endothelial leukocyte adhesion molecule-1 (ELAM-1) on endothelial cells activated by agents such as lipopolysaccharide (LPS) and phorbol myristate acetate (PMA). To elucidate molecular mechanisms involved in the induction of ELAM-1 on endothelial cells, we investigated the effect of the NADPH oxidase inhibitor, apocynin (4-hydroxy-3-methoxyacetophenone), on ELAM-1 mRNA expression in human umbilical vein endothelial cells (HUVEC) by Northern blot analysis. Apocynin downregulated both LPS- and PMA-induced ELAM-1 mRNA expression in a dose-dependent manner. Our results suggest NADPH oxidase might play a key role in ELAM-1 mRNA expression in HUVEC.