Dale E. Hammerschmidt

Managing Incidental Findings in Human Subjects Research: Analysis and Recommendations

No consensus yet exists on how to handle incidental findings (IFs) in human subjects research. Yet empirical studies document IFs in a wide range of research studies, where IFs are findings beyond the aims of the study that are of potential health or reproductive importance to the individual research participant. This paper reports recommendations of a two-year project group funded by NIH to study how to manage IFs in genetic and genomic research, as well as imaging research. We conclude that researchers have an obligation to address the possibility of discovering IFs in their protocol and communications with the IRB, and in their consent forms and communications with research participants. Researchers should establish a pathway for handling IFs and communicate that to the IRB and research participants. We recommend a pathway and categorize IFs into those that must be disclosed to research participants, those that may be disclosed, and those that should not be disclosed.

Complement-induced granulocyte aggregation: an unsuspected mechanism of disease.

The capacity of blood cells to aggregate, best exemplified by the response of platelets to vascular injury, is generally thought to be beneficial. However, if aggregation occurs inappropriately—tha...

Association of complement activation and elevated plasma-C5a with adult respiratory distress syndrome. Pathophysiological relevance and possible prognostic value.

Clinical and experimental observations suggest that aggregation of polymorphonuclear granulocytes (PMN) in response to activated complement (C) might contribute to the genesis of the adult respiratory distress syndrome (ARDS), aggregating PMN causing pulmonary dysfunction by becoming lodged in the lung as leucoemboli. PMN-aggregating activity can be detected in C-activated plasma and reflects C5a levels. In 61 patients at risk for ARDS a strong and highly significant correlation was found between the presence of PMN-aggregating activity in the plasma and the development of ARDS; this correlation was also significant when patients with sepsis were excluded from analysis. In patients followed prospectively detection of elevated C5a seemed to be a useful predictor of ARDS. Since corticosteroids have been shown to inhibit PMN aggregation both in vitro and in vivo, the evidence for a role for PMN aggregation in the genesis of ARDS supports the use of corticosteroids in this disorder.

Fat Embolism Prophylaxis with Corticosteroids: A Prospective Study in High-Risk Patients

The efficacy of corticosteroid treatment in the prophylaxis of the fat embolism syndrome was evaluated in a prospective, randomized, double-blind study of high-risk patients with long-bone fractures. Using a set of objective diagnostic criteria, we saw a significant difference in the incidence of the syndrome between corticosteroid- (0 of 21) and placebo-treated patients (9 of 41) (p less than 0.05). There were no complications related to corticosteroid treatment. No routine laboratory or physical findings reliably predicted the development of the fat embolism syndrome except petechial rash, which occurred only in 5 placebo-treated patients who developed the syndrome. Complement activation was present in all patients studied who had the syndrome (5 of 27) but also in many patients who did not meet our diagnostic criteria, suggesting a multifactorial cause. These data support the prophylactic value of corticosteroid treatment in patients at high risk for the fat embolism syndrome, particularly if several unfavorable predictors are present.

The limitations of "vulnerability" as a protection for human research participants.

Vulnerability is one of the least examined concepts in research ethics. Vulnerability was linked in the Belmont Report to questions of justice in the selection of subjects. Regulations and policy documents regarding the ethical conduct of research have focused on vulnerability in terms of limitations of the capacity to provide informed consent. Other interpretations of vulnerability have emphasized unequal power relationships between politically and economically disadvantaged groups and investigators or sponsors. So many groups are now considered to be vulnerable in the context of research, particularly international research, that the concept has lost force. In addition, classifying groups as vulnerable not only stereotypes them, but also may not reliably protect many individuals from harm. Certain individuals require ongoing protections of the kind already established in law and regulation, but attention must also be focused on characteristics of the research protocol and environment that present ethical challenges.

Ibuprofen inhibits granulocyte responses to inflammatory mediators. A proposed mechanism for reduction of experimental myocardial infarct size

The use of nonsteroidal antiinflammatory agents to reduce myocardial infarct size has demonstrated a dichotomy between ibuprofen, which reduces myocardial infarct size, and aspirin, which does not. A feline model of coronary ischemia using ligation of the anterior descending artery demonstrated that intravenous ibuprofen (2.5–20 mg/kg) given immediately and 2 h after ligation significantly decreased (by about 40%) myocardial infarct size. In contrast, aspirin did not diminish infarct size at any achieved dose; in fact, at some doses it tended to increase infarct size. In vitro studies with purified granulocytes demonstrated a similar dichotomy between ibuprofen and aspirin. Ibuprofen inhibits granulocyte aggregation, superoxide production, lysosomal enzyme release, and granulocytemediated endothelial cytotoxicity, while aspirin is without effect on these modalities. We propose that ibuprofens beneficial effect in experimental myocardial ischemia is related to its ability to inhibit activated granulocytes and thus to diminish myocardial cell death in experimental myocardial infarction.

Aggregation, chemotaxis, and chemiluminescence of canine granulocytes. Studies utilizing improved cell preparation techniques.

Wishing to extrapolate in vitro observations of granulocyte function and pharmacology made with human cells to animal models of diseases in which we believe granulocyte stimulation to play a major role, we examined techniques for preparation of canine granulocytes and conducted a survey of the function and pharmacology of those cells. Isotonic density gradients of PercollTMproved a simple and highly satisfactory method of preparation. Canine granulocytes in most respects paralleled human cells in function and pharmacology, except that canine cells lacked receptors for formylated oligopeptides and resisted them as stimuli; canine plasma contained a heat-labile inhibitor of canine PMN aggregation, oxidative metabolism, and myeloperoxidase release; canine PMNs were not inhibited in aggregation by protease inhibitors such as aprotinin; canine response to ibuprofen and steroids was more variable than that of human cells, and synergy between those agents was less readily demonstrated; heterologous stimulation (canine cells by human C5a or vice versa) led to a different time course and maximum response from those observed in the homologous systems. Canine granulocytes were readily marked with indium-111, and functioned normally in vitro and survived well in vivo after marking. We conclude that the dog is a suitable animal for studying the role of stimulated PMNs in disease, as long as the observed differences are taken into account in experimental design and data interpretation.

Hemodynamic profile of adverse clinical reactions to Fluosol-DA 20%.

Hemodynamic changes of 2 patients to a 0.5-ml test-dose infusion of Fluosol-DA 20% are presented. The first patient had the following symptoms and signs approximately 2 min after receiving the test dose: normotensive bradycardia of 30 beat/min, a 35% drop in cardiac output, a 50% increase in systemic vascular resistance, and a 100% increase in pulmonary artery systolic and diastolic pressures. The patient complained of shortness of breath and diffuse pressure pain of the chest. All the signs and symptoms gradually resolved without treatment over the following 3 min. The second patient complained of mild, vague chest and abdominal pressure 2 min after the test dose. The only associated hemodynamic change was a slight increase in pulmonary artery systolic pressure. A 74% drop in the neutrophil count returned to the pretest value in 10 min. In contrast to anaphylactic or anaphylactoid-type reactions, these patients did not have urticaria and had an increase in systemic vascular resistance. Their reactions were reminiscent of those occurring during systemic complement activation. The possible mechanisms and prevention of these reactions are discussed.

Historical perspective and clinical implications of the Pelger-Huet cell

The unique historical aspects of Pelger and Huets discovery of the Pelger‐Huet cell highlight the diagnostic challenge that this morphologic finding presents to the physician. Making the diagnosis of the benign autosomal dominant anomaly is complicated by the morphologically similar pseudo‐Pelger‐Huet cell, which can signify underlying myeloid dsyplasia. This article relates the history of the Pelger‐Huet anomaly as well as describes the clinical significance and diagnostic workup for the finding of a Pelger‐Huet cell on peripheral smear. Am. J. Hematol., 2009.

Steroids decrease granulocyte membrane fluidity, while phorbol ester increases membrane fluidity. Studies using electron paramagnetic resonance.

High concentrations of corticosteroids inhibit granulocyte responses and disrupt agonist receptor function. Dose-response and time-course considerations make it unlikely that these effects are mediated via the glucocorticoid receptor, a concept further supported by the ability of sex steroids to work similar effects. We postulated that steroids nonspecifically altered granulocyte membrane fluidity, which we measured directly by electron paramagnetic resonance. As predicted, methylprednisolone caused a dose-dependent increase in order parameter (decrease in fluidity) calculated on the basis of EPR spectra, using 5-doxylstearic acid (5-DS) as a probe of resting PMN membranes. This trend was highly significant (P < 0.001; P at 0.5 mg/ml < 0.01). Qualitatively similar results (but with different dose-response features) were obtained with conjugated estrogen. Granulocyte agonists (such as PMA) showed an opposite effect, which was not oxidatively mediated and which was steroid-inhibitable. 16-DS showed less prominent effects, suggesting that the membrane leaflets were more strongly affected than was the deep region of the membrane. Ibuprofen, which has similar effects to those of methylprednisolone on PMN aggregation and receptor function, caused a fluidizing rather than a stiffening of the membrane; this surprising result may indicate that there is a critical range of membrane fluidity for normal function, outside of which-in either direction-agonist receptor dysfunction occurs. We conclude that the immediate effects of very high doses of steroids are probably not mediated by corticoid receptors; instead, they may be due to changes in membrane fluidity.