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Biomedical subjects

T G Buchman

Publications and source records attributed to T G Buchman.

At least 19 recordsLinked to original sources
PubMed2001

Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans.

Patients with sepsis have impaired host defenses that contribute to the lethality of the disorder. Recent work implicates lymphocyte apoptosis as a potential factor in the immunosuppression of sepsis. If lymphocyte apoptosis is an important mechanism, specific subsets of lymphocytes may be more vulnerable. A prospective study of lymphocyte cell typing and apoptosis was conducted in spleens from 27 patients with sepsis and 25 patients with trauma. Spleens from 16 critically ill nonseptic (3 prospective and 13 retrospective) patients were also evaluated. Immunohistochemical staining showed a caspase-9-mediated profound progressive loss of B and CD4 T helper cells in sepsis. Interestingly, sepsis did not decrease CD8 T or NK cells. Although there was no overall effect on lymphocytes from critically ill nonseptic patients (considered as a group), certain individual patients did exhibit significant loss of B and CD4 T cells. The loss of B and CD4 T cells in sepsis is especially significant because it occurs during life-threatening infection, a state in which massive lymphocyte clonal expansion should exist. Mitochondria-dependent lymphocyte apoptosis may contribute to the immunosuppression in sepsis by decreasing the number of immune effector cells. Similar loss of lymphocytes may be occurring in critically ill patients with other disorders.

Adolescent↗
PubMed2001

Extreme warfarin sensitivity in siblings associated with multiple cytochrome P450 polymorphisms.

Warfarin use is complicated by an erratic dose response. Warfarin is metabolized by two distinct subfamilies of the cytochrome P450 (CYP) complex. We describe two siblings with extreme sensitivity to warfarin who share an unusual CYP genotype. These individuals illustrate both the importance of genetics in influencing the metabolism of warfarin as well as the potential utility of genetic testing as a guide to prescribing this medication.

Aged↗
PubMed2001

The heat shock paradox: does NF-kappaB determine cell fate?

Cellular injury induces an adaptive response whether the insult is physical (e.g., heat, radiation), chemical (e.g., reactive oxygen species), infectious (e.g., bacteria), or inflammatory (e.g., lipopolysaccharide). Recent data indicate that the interactions of these responses are not predictable and that sequence permutations can have opposite effects on outcome after injury. Our overarching hypothesis is that interactions among stress responses contribute to the fate of cells, tissues, and organisms and that modulation of these interactions can have important affects on both function and survival. For example, whereas it is well known that a prior heat shock stress can protect cells against inflammatory stress both in vitro and in vivo, we and others have shown that induction of a subsequent heat stress in cells 'primed' by inflammation can precipitate cell death by apoptosis. We call this seemingly paradoxical ability of heat shock to induce cytoprotection and cytotoxicity the heat shock paradox. The molecular mechanisms by which cells integrate responses to these and other stresses are poorly understood. We present data linking the heat shock paradox to the activity of the acute-phase transcription factor nuclear factor kappa B (identifying an 'NF-kappaB paradox') and hypothesize that the mechanism is linked to the downstream effects of induction of NF-kappaB's endogenous inhibitor, IkappaBalpha, a putative heat shock protein.

Acute-Phase Reaction↗
PubMed2001

A prospective, randomized study comparing percutaneous with surgical tracheostomy in critically ill patients.

OBJECTIVE: To determine the relative cost-effectiveness of percutaneous dilational tracheostomy (PDT) and surgical tracheostomy (ST) in critically ill patients. DESIGN: Prospective randomized study. SETTING: Medical, surgical, and coronary intensive care units at Barnes-Jewish Hospital, a tertiary care medical center. PATIENTS: Eighty critically ill mechanically ventilated patients requiring elective tracheostomy. INTERVENTIONS: Randomization to either PDT performed in the intensive care unit or ST performed in the operating room. MEASUREMENTS AND MAIN RESULTS: Treatment groups were well matched with respect to age (PDT, 65.44 +/- 2.82 [mean +/- se] years; ST, 61.4 +/- 2.89 years, p = Ns), gender (PDT, 45% males; ST, 47.5% males, p = NS), severity of illness (Acute Physiology and Chronic Health Evaluation II score: PDT, 16.87 +/- 0.84; ST, 17.88 +/- 0.92, p = NS), and principle diagnosis. PDT was performed more quickly (PDT, 20.1 +/- 2.0 mins; ST, 41.7 +/- 3.9 mins, p < .0001) and was associated with lower patient charges than ST (total patient charges: PDT, 1,569 dollars +/- 157 dollars vs. ST, 3,172 dollars +/- 114 dollars; equipment/supply charges: PDT, 688 dollars +/- 103 dollars vs. ST, 1,526 dollars +/- 87 dollars; professional charges: PDT, 880 dollars +/- 54 dollars vs. ST, 1,647 dollars +/- 50 dollars; p < .0001 for all). There were no differences in days intubated before tracheostomy (PDT, 12.7 +/- 1.1 days; ST, 15.6 +/- 1.9, p = .20), intensive care unit length of stay (PDT, 24.5 +/- 2.5 days; ST, 28.5 +/- 3.1 days, p = .33), or hospital length of stay (PDT 49.7 +/- 4.2 days; ST, 43.7 +/- 3.5 days, p = .28) when we compared these two techniques. CONCLUSIONS: PDT is a cost-effective alternative to ST. The reduction in patient charges associated with PDT in this study resulted from the procedure being performed in the intensive care unit, thus eliminating the need for operating room facilities and personnel. PDT may become the procedure of choice for electively establishing tracheostomy in the appropriately selected patient who requires long-term mechanical ventilation.

Cost-Benefit Analysis↗
PubMed2001

Association between heart rate variability recorded on postoperative day 1 and length of stay in abdominal aortic surgery patients.

OBJECTIVE: To determine whether heart rate variability (HRV) measured in the surgical intensive care unit (ICU) on the first postoperative day predicts clinical outcome in patients undergoing abdominal aortic surgery. DESIGN: Prospective study. SETTING: Eighteen-bed surgical ICU of a 1,442-bed university hospital. PATIENTS: One hundred and six patients admitted to the ICU after abdominal aortic surgery. MEASUREMENTS AND MAIN RESULTS: Twenty-four-hour Holter recordings were analyzed for standard time and frequency domain indices and one nonlinear index (slope) of HRV. Clinical and demographic data were collected from medical records. Patients were dichotomized into short (< or = 7 days) and long (> 7 days) length of stay (LOS) by median split. Patients with long LOS had increased heart rates and decreased short- and intermediate-term HRV but no difference in overall HRV, which primarily reflects circadian rhythm. Independent predictors of LOS were increased age, insulin-dependent diabetes, and decreased HRV. CONCLUSIONS: Increased heart rates and decreased intermediate-term HRV indices measured on postoperative day 1 were independent predictors of complicated recovery. The strongest HRV predictors of outcome were natural logarithm very-low-frequency power measured over 24 hrs and during the daytime. Results support the potential use of HRV for the prediction of postsurgical resource utilization.

Aged↗
PubMed2001

Injury in the era of genomics.

The traditional approach to the study of biology employs small-scale experimentation that results in the description of a molecular sequence of known function or relevance. In the era of the genome the reverse is true, as large-scale cloning and gene sequencing come first, followed by the use of computational methods to systematically determine gene function and regulation. The overarching goal of this new approach is to translate the knowledge learned from a systematic, global analysis of genomic data into a complete understanding of biology. For investigators who study shock, the specific goal is to increase understanding of the adaptive response to injury at the level of the entire genome. This review describes our initial experience using DNA microarrays to profile stress-induced changes in gene expression. We conclude that efforts to apply genomics to the study of injury are best coordinated by multi-disciplinary groups, because of the extensive expertise required.

Forecasting↗
PubMed2001

Complex systems analysis: a tool for shock research.

For the past century, students of shock have focused research efforts to illuminate specific mechanisms that cause, or fail as a consequence of, circulatory collapse. Although clinical strategies aimed at supporting or restoring individual organ systems have proven effective, many patients succumb to more generalized multiple organ system failure. We suggest that general biological systems failure cannot be interpreted through reliance on reductionist science. We propose that complex systems analysis is an essential tool for shock research and we evaluate its application to genomic technologies.

Animals↗
PubMed2001

Shock at the millennium II. Walter B. Cannon and Lawrence J. Henderson.

Walter B. Cannon and Lawrence J. Henderson, students of shock in the early twentieth century, were contemporaries for four decades in the Harvard Department of Physiology. While their discoveries continue to have important clinical applications, both men established complementary methods of scientific investigation and description. Both men were inspired by Claude Bernard, hewing to his principle of the stability of the milieu intérieur. Cannon, the traditional experimentalist, employed a reductionist approach by holding constant the confounding variables of his experiments; in contrast, Henderson, the strategist of theoretical analysis, deduced patterns and relationships from less constrained models, focusing on complexity using mathematics and graphs. In delineation, Cannon described mechanisms; Henderson described the organization of systems. Cannon's emphasis on homeostasis with the identification of feedback arcs dominated shock research for the balance of the twentieth century. Henderson's perspective designating the importance of organization to those restorative mechanisms could well reemerge to dominate the twenty-first.

History, 20th Century↗
PubMed2001

Interleukin-1 receptor antagonist as therapy for inflammatory disorders.

IL-1 is a pivotal mediator of the immune response and has been implicated in inflammatory and infectious diseases. As a consequence, the administration of IL-1 receptor antagonist (IL-1ra), a recombinantly synthesised endogenous inhibitor of IL-1, has appeal as a therapeutic strategy in these conditions. To date, the largest clinical experiences with IL-1ra have been in the setting of sepsis and rheumatoid arthritis (RA). Like other anti-inflammatory agents that target a specific mediator, IL-1ra was found to lack efficacy when given in conjunction with standard therapy in patients with sepsis and septic shock. In contrast, recent studies enrolling patients with RA suggest that IL-1ra significantly ameliorates disease activity and retards joint destruction. Whether the respective lack of efficacy and success of IL-1ra in these two diseases is a result of differences in the pathologic processes involved, or reflects the nature in which the clinical studies were conducted, is unclear. Further, the effectiveness of IL-1ra compared to other anticytokine and conventional treatments in RA remains to be clarified. Nonetheless, the recent finding that IL-1ra has the ability to favourably influence a chronic inflammatory disease supports the hypothesis that inhibition of a single mediator of the immune response may have clinical impact.

Arthritis, Rheumatoid↗
PubMed2000

p53-dependent and -independent pathways of apoptotic cell death in sepsis.

Sepsis induces extensive apoptosis of lymphocytes, which may be responsible for the profound immune suppression of the disorder. Two potential pathways of sepsis-induced lymphocyte apoptosis, Fas and p53, were investigated. Lymphocyte apoptosis was evaluated 20-22 h after sepsis by annexin V or DNA nick-end labeling. Fas receptor-deficient mice had no protection against sepsis-induced apoptosis in thymocytes or splenocytes. p53 knockout mice (p53-/-) had complete protection against thymocyte apoptosis but, surprisingly, had no protection in splenocytes. p53-/- mice had no improvement in sepsis survival compared with appropriately matched control mice with sepsis. We conclude that both p53-dependent and p53-independent pathways of cell death exist in sepsis. This differential apoptotic response of thymocytes vs splenocytes in p53-/- mice suggests that either the cellular response or the death-inducing signal is cell-type specific in sepsis. The fact that p53-/- lymphocytes of an identical subtype (CD8-CD4+) were protected in thymi but not in spleens indicates that cell susceptibility to apoptosis differs depending upon other unidentified factors.

Animals↗
PubMed2000

Myocardial infarction as a complication of injury.

BACKGROUND: MI is a rare complication of trauma. We anticipate that the aging of the population and the concomitant rise in geriatric trauma will result in an increase in acute illnesses of the elderly (such as MI) complicating recovery from injury. The purpose of this article is to define the presentation of MI in the immediate postinjury period. STUDY DESIGN: Medical records of all trauma patients in whom MI developed during their hospitalizations at a single Level I trauma center, the Barnes Hospital/Washington University Medical Center, between 1990 and 1999 were screened through the trauma registry. Nineteen patients with possible postinjury MI were identified. Of these, five had bona fide cases of postinjury MI, five had ambiguity about whether MI preceded or followed trauma, one had an MI resulting in trauma, and eight were excluded because they did not meet strict diagnostic criteria for MI. RESULTS: The five patients with posttraumatic MI were older than the general trauma population with ages ranging from 51 to 81 years (mean +/- SD = 72 +/- 14 years). Each had preexisting medical illnesses, some of which are recognized to predispose to coronary artery disease. There were no identifiable precipitants other than the recent injury. Importantly, only one of the five patients had chest pain as a presenting symptom and each of the five cases was complicated by acute congestive heart failure. CONCLUSIONS: MI remains a rare but important complication of injury and may increase owing to the changing demographics of trauma victims. Methods for thorough history-gathering to identify preexisting conditions, for early hemodynamic monitoring and anticoagulation for MI in the setting of trauma, and for identifying preexisting conditions should be defined. The presentation of MI in the setting of injury is atypical and complications are frequent.

Age Factors↗
PubMed2000

Cytochrome P450 polymorphisms are associated with reduced warfarin dose.

BACKGROUND: Warfarin use is complicated by an erratic dose response. Interpatient variability associated with warfarin therapy may be partly attributable to polymorphisms of the cytochrome P450 (CYP) complex. The purpose of this study was to ascertain the frequency and influence of CYP polymorphisms on warfarin dosing in our patient population. METHODS: Patients receiving warfarin therapy were recruited from the inpatient divisions of our hospital. Genotyping for known polymorphic alleles of the CYP subfamilies CYP2C9 (CYP2C9*1, CYP2C9*2, and CYP2C9*3) and CYP2A6 (CYP2A6*1, CYP2A6*2) with the use of standard methods of polymerase chain reaction amplification was performed. An unpaired t test was used to statistically compare genotypes. RESULTS: Genotype frequency in 38 patients is as follows: CYP2C9*1/CYP2C9*1, 71%; CYP2C9*1/CYP2C9*2, 21%; CYP2C9*2/CYP2C9*2, 3%; CYP2C9*1/CYP2C9*3, 5%; CYP2A6*1/CYP2A6*1, 95%; CYP2A6*1/CYP2A6*2, 5%. Compared to a wild-type genotype, the presence of the CYP2C9*2, CYP2C9*3, or CYP2A6*2 allele was associated with a significant reduction in weekly warfarin dose (mean weekly warfarin dose [+/- SE] for wild-type genotype was 0.397 +/- 0.024 mg/kg/wk vs 0.307 +/- 0.03 mg/kg/wk for carriers of CYP2C9*2, CYP2C9*3, or CYP2A6*2 polymorphism; P =.03). CONCLUSIONS: Polymorphisms that impair warfarin metabolism are common, occurring in 34% of patients, and are associated with increased warfarin sensitivity. The use of genotypic information to prescribe more accurate doses of warfarin may increase the safety and efficacy of this medication.

Anticoagulants↗