Papers by Dale Hammerschmidt
The Journal of Laboratory and Clinical Medicine, 2003
Inflammation, 1990
High concentrations of corticosteroids inhibit granulocyte responses and disrupt agonist receptor... more 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 mem-b~ne. 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.
Http Dx Doi Org 10 1080 15265160490497083, Aug 17, 2010
Vulnerability is one of the least examined concepts in research ethics. Vulnerability was linked ... more 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.
Minnesota medicine, 2008
Leprosy is uncommon in North America. Because it has a prolonged incubation period and can masque... more Leprosy is uncommon in North America. Because it has a prolonged incubation period and can masquerade with a variety of manifestations, many patients with leprosy experience a significant delay in diagnosis and treatment. Lepra reactions are of 2 types: reversal (type 1) and erythema nodosum leprosum (ENL) (type 2). Type 1 or reversal reactions represent an increase in cell-mediated immunity, whereas type 2 or ENL is caused by antigen-antibody complex formation and deposition after antigen release from dying lepra bacilli. This article describes the diagnostic challenges presented by a Minnesota patient eventually found to have lepromatous leprosy. That challenge was compounded by the fact that the clinical scenario closely mimicked connective tissue/immune complex disease and by the fact that the patient presented in a location where the incidence and prevalence of leprosy is extremely low.
The Journal of laboratory and clinical medicine, 1984
A prospective study of 10 patients undergoing hemodialysis showed that less neutropenia and compl... more A prospective study of 10 patients undergoing hemodialysis showed that less neutropenia and complement activation occurred with dialyzer reuse. Neutrophil counts fell 95% +/- 5% (SEM) with first use and 66% +/- 8% and 48% +/- 10% with second and third uses, respectively (p less than 0.05). The production of complement component C5a-desarg, as measured by the bioassay granulocyte aggregation, was decreased by 96% +/- 1% and 93% +/- 2% with second and third uses, respectively (p less than 0.05). We investigated the role of the dialyzer disinfectant formaldehyde in decreased neutropenia. In vitro, formaldehyde inhibited granulocyte aggregation and chemotaxis and the dialyzer membrane's ability to generate granulocyte aggregating activity; however, this occurred only at concentrations higher than those likely to obtain in patients. The ability of dialysis membranes to generate granulocyte aggregating activity in plasma was decreased 55% +/- 5% by their prior sequential preincubation...
Blood, 1988
The effects of adenosine, adenosine deaminase (ADA), and an irreversible ADA inhibitor 2'-deo... more The effects of adenosine, adenosine deaminase (ADA), and an irreversible ADA inhibitor 2'-deoxycoformycin (DCF) on granulocyte aggregation in response to four different stimuli: the synthetic chemotaxin N-formyl-met-leu-phe (FMLP), zymosan-activated plasma (ZAP), the calcium ionophore A23187, and phorbol myristate acetate (PMA) were studied. Adenosine inhibited granulocyte aggregation in response to 10(-7) mol/L FMLP in a dose-dependent fashion; inhibition in the presence of 1 mumol/L adenosine was 25% +/- 3% (SD) and was 50% (the maximal inhibition observed) with 1 mmol/L adenosine. Quantitatively similar results were obtained when ZAP or A23187 was used as the aggregant but the response to PMA was not affected. ADA not only reversed the inhibition due to adenosine but actually augmented the aggregation to FMLP by 118% +/- 9%. Similar results were obtained with ZAP and A23187 but not with PMA. These effects of ADA depended on its enzymatic activity as they could be blocked by p...
Journal of Laboratory and Clinical Medicine, 2004
In the early 1900s, the laboratory of Dr William Howell at Johns Hopkins University was actively ... more In the early 1900s, the laboratory of Dr William Howell at Johns Hopkins University was actively involved in trying to parse the contributors to the plasma-coagulation system. Fibrinogen was known, and it was clear that a multistep process led to the creation of a "fibrin ferment" capable of making fibrinogen into a clot, but the details were just being worked out. Jay McLean, a student in Howell's laboratory, found in 1916 that the injection of a liver extract into experimental animals led to excessive bleeding. There followed a series of experiments over the next several years-some involving McLean, some not-in which both fat-and water-soluble liver extracts with anticoagulant properties were produced. The name heparin was introduced in a 1918 paper by Howell and Holt in the American Journal of Physiology. The original extracts were not terribly pure, and controversy arose as to just who had discovered what. However, several groups of researchers became interested in the possibility that liver-derived compounds might include clinically useful anticoagulants; work by Charles Best, Gordon Murray, and their co-workers at the Connaught Laboratories of the University of Toronto eventually led to a product pure enough for clinical trials. This month's cover shows Dr McLean some years after his seminal observation. In the last decade, the use of unfractionated heparins from animal tissues has begun to give way to the use of low-molecular-weight heparins, heparin-like defined glycosaminoglycan mixtures ("heparinoids"), and alternative thrombin inhibitors such as hirudin. A paper in this month's issue of the JOURNAL addresses an indirect action of heparin on coagulation: the mobilization of an endogenous inhibitor of the tissue-factor pathway. Dr Ellen Brodin and her colleagues at the
Journal of Laboratory and Clinical Medicine, 1998
Journal of Laboratory and Clinical Medicine, 1998
Journal of Laboratory and Clinical Medicine, 2004
As this issue of the Journal of Laboratory and Clinical Medicine was being prepared, a remarkable... more As this issue of the Journal of Laboratory and Clinical Medicine was being prepared, a remarkable anniversary passed. Two hundred and fifty years earlier, in 1753, the Scottish naval physician Dr James Lind (inset) published his groundbreaking "A Treatise of the Scurvy." 1 Lind's remarkably modern book is widely considered to be the first formal publication of a prospective, controlled clinical trial; it describes a 1747 experiment showing the efficacy of fruits in the treatment of scurvy. Anticipating modern evidence-based medicine, Lind began his volume with a critical review of the existing literature. He stratified such work according to its reliability: learned opinion was distinguished from instructive anecdote and in turn from detailed reports of significant numbers of patients. The current theories of the origin of scurvy were then analyzed against the information available, and the idea was put forth that a dietary deficiency would most satisfactorily explain the clinical course and epidemiology. He then went on to describe his key experiment. While serving as ship's surgeon on the HMNS Salisbury in 1747, Lind had the occasion to deal with an outbreak of scurvy among the crew. He selected twelve afflicted seamen, taking care that "Their cases were as similar as I could have them." They were divided into six pairs, and each pair was given a different treatment. Two sailors received oranges and lemons as a supplement to their diet; another pair had apple cider added to theirs. The remaining four pairs had four of the then-current treatments used in His Majesty's Navy: a selection of tonics, purgatives, and "acidulatives." As now is well known, the sailors receiving citrus fruits recovered quickly and were actually able to return to duty. Those receiving cider
Resuscitation, 1989
In order to shed light on the controversy surrounding the choice of resuscitative fluids in shock... more In order to shed light on the controversy surrounding the choice of resuscitative fluids in shock, we used a canine model which we feel to be a superior mimic of human traumatic shock, combining hemorrhage (to a mean arterial pressure of 50 mmHg1, fracture of both femora, and soft tissue crush. After 90 min, animals were resuscitated by reinfusion of shed blood, supplemented by 5W albumin (n = 81 or lactated Ringer's solution (n = 81. Plasma colloid osmotic pressure (COP), transcapillary escape rate for albumin (TERl, total lung water and extravascular lung water (EVLW) were measured. COP fell in both groups, but remained above 9 mmHg in the albumin recipients, while falling below 7 in those receiving crystalloid (P < 0.051. Overall, the increase in EVLW averaged 20%; albumin recipients fared better (9.7%) than Ringer's recipients (31.1%). but wide inter-animal variation precluded statistical significance (P = 0.0951. TER rose 30% per hour, without difference between groups. Quality of resuscitation (achieved blood pressure and cardiac output1 was somewhat better in the albumin group. We conclude that this model allows study of the early microvascular leakage seen in shock; within the time-frame studied (maximum 4.5 h following shock), colloid and crystalloid resuscitation were approximately equivalent.
JAMA: The Journal of the American Medical Association, 1983
A case of fatal radiographic contrast medium (RCM)-induced pulmonary granulocyte aggregation (leu... more A case of fatal radiographic contrast medium (RCM)-induced pulmonary granulocyte aggregation (leukostasis) showed massive elevation of the postmortem histamine level. Suspicion of this phenomenon in diverse clinical settings permits clinical and pathological documentation via increased plasma levels of C3a and other means. The existence of effective prophylaxis stimulates a search for predictive tests.
JAMA: The Journal of the American Medical Association, 1982
Anisodamine hydrochloride is a vasoactive drug produced in the People&amp;amp;#39;s Republic ... more Anisodamine hydrochloride is a vasoactive drug produced in the People&amp;amp;#39;s Republic of China that appears efficacious in clinical and experimental bacteremic shock, and about whose mode of action little is known. Suspecting that the drug might work by inhibition of platelet or granulocyte aggregation, or both, we tested it in these systems. Anisodamine proved a modest inhibitor of granulocyte aggregation and a powerful inhibitor of platelet aggregation; thromboxane synthesis was inhibited in anisodamine-treated platelets, further suggesting that the biochemical mode of action might be inhibition of cyclo-oxygenase or thromboxane synthetase.
JAMA: The Journal of the American Medical Association, 1980
In a kindred with a mild, recessively inherited variant of the Ehlers-Danlos syndrome (EDS), a pl... more In a kindred with a mild, recessively inherited variant of the Ehlers-Danlos syndrome (EDS), a platelet aggregation defect segregated concordantly with skin and joint abnormalities. This defect was partially corrected in vitro by addition of normal plasma or cryoprecipitate. The plasma of the patients with EDS failed to support the aggregation of normal gel-filtered platelets in response to collagen; this defect was completely corrected by the addition of normal human fibronectin. Since fibronectin is an important adhesive glycoprotein in connective tissue and is required for normal platelet interactions with collagen, we propose that both platelet malfunction and joint hypermobility in this kindred are likely explained by a defective fibronectin.
JAMA: The Journal of the American Medical Association, 1981
Previous studies from our laboratories have demonstrated that granulocytes (PMNs), when exposed t... more Previous studies from our laboratories have demonstrated that granulocytes (PMNs), when exposed to activated complement (C) (specifically C5a), will aggregate and be provoked to damage cultured endothelial cells in vitro; it was postulated that these phenomena might also occur in vivo, constituting a previously unsuspected mechanism of immune tissue damage. The studies here presented confirm by intravital microscopy that PMN aggregation and leukoembolization in fact occur in live animals when C is activated or C5a is infused, and that these are accompanied by extravasation of plasma proteins in a pattern suggesting endothelial damage. It is concluded that altered microvascular behavior of PMNs is a possible pathogenetic mechanism in disease states associated with C activation.
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Papers by Dale Hammerschmidt