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Biomedical subjects

Craig M Coopersmith

Publications and source records attributed to Craig M Coopersmith.

At least 19 recordsLinked to original sources
PubMed2007

Impact of a methicillin-resistant Staphylococcus aureus active surveillance program on contact precaution utilization in a surgical intensive care unit.

OBJECTIVE: To determine the impact of an active surveillance for methicillin-resistant Staphylococcus aureus (MRSA) on contact precaution utilization, as measured by additional number of contact precaution days attributable to the active surveillance program. DESIGN: Prospective cohort study. SETTING: Twenty-four-bed surgical intensive care unit (ICU). PATIENTS: All patients admitted to the surgical ICU. INTERVENTIONS: Nasal cultures for MRSA were performed at admission to a surgical ICU for 19 months. Patients admitted>48 hrs also received weekly and discharge nasal cultures. MEASUREMENTS AND MAIN RESULTS: Clinical data, including start date and initial indication for contact precautions, were prospectively collected. Of 1,893 admissions, 253 (13%) were found to be MRSA-positive during their ICU stay. One hundred forty-six (58%) were identified by nasal culture alone. Compared with the first 10 months of study, the prevalence of MRSA on admission to the ICU during the last 9 months of the study period significantly increased (7.2% vs. 11.4%, p<.001). Acquisition of MRSA by noncolonized patients remained constant between the first 10 months and last 9 months of study (7.0 vs. 5.5 cases per 1000 patient days, p=.29). Two hundred fourteen (6%) of 3461 total contact precaution days in the ICU were attributable to MRSA active surveillance. In sensitivity analyses, the implementation of rapid, same-day results for MRSA active surveillance would increase contact precaution days by 15% compared with no surveillance. If the total number of vancomycin-resistant enterococci patients in the ICU were reduced by 50%, the contact precaution days attributable to active surveillance would increase to 9%. CONCLUSIONS: MRSA active surveillance increased total contact precaution days in this ICU by 6% yet detected 58% of MRSA cases that would have been otherwise missed. Despite an increasing prevalence of MRSA on admission to the ICU, the acquisition rate has remained constant.

Humans↗
PubMed2006

Adoptive transfer of dying cells causes bystander-induced apoptosis.

The anti-apoptotic Bcl-2 protein has the remarkable ability to prevent cell death from several noxious stimuli. Intriguingly, Bcl-2 overexpression in one cell type has been reported to protect against cell death in neighboring non-Bcl-2 overexpressing cell types. The mechanism of this "trans" protection has been speculated to be secondary to the release of a cytoprotective factor by Bcl-2 overexpressing cells. We employed a series of adoptive transfer experiments in which lymphocytes that overexpress Bcl-2 were administered to either wild type mice or mice lacking mature T and B cells (Rag-1-/-) to detect the presence or absence of the putative protective factor. We were unable to demonstrate "trans" protection. However, adoptive transfer of apoptotic or necrotic cells exacerbated the degree of apoptotic death in neighboring non-Bcl-2 overexpressing cells (p < or= 0.05). Therefore, this data suggests that dying cells emit signals triggering cell death in neighboring non-Bcl-2 overexpressing cells, i.e., a "trans" destructive effect.

Adoptive Transfer↗
PubMed2006

Epidemiology of methicillin-resistant Staphylococcus aureus colonization in a surgical intensive care unit.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a cause of healthcare-associated infections among surgical intensive care unit (ICU) patients, though transmission dynamics are unclear. OBJECTIVE: To determine the prevalence of MRSA nasal colonization at ICU admission, to identify associated independent risk factors, to determine the value of these factors in active surveillance, and to determine the incidence of and risk factors associated with MRSA acquisition. DESIGN: Prospective cohort study. SETTING: Surgical ICU at a teaching hospital. PATIENTS: All patients admitted to the surgical ICU. RESULTS: Active surveillance for MRSA by nasal culture was performed at ICU admission during a 15-month period. Patients who stayed in the ICU for more than 48 hours had nasal cultures performed weekly and at discharge from the ICU, and clinical data were collected prospectively. Of 1,469 patients, 122 (8%) were colonized with MRSA at admission; 75 (61%) were identified by surveillance alone. Among 775 patients who stayed in the ICU for more than 48 hours, risk factors for MRSA colonization at admission included the following: hospital admission in the past year (1-2 admissions: adjusted odds ratio [aOR], 2.60 [95% confidence interval {CI}, 1.47-4.60]; more than 2 admissions: aOR, 3.56 [95% CI, 1.72-7.40]), a hospital stay of 5 days or more prior to ICU admission (aOR, 2.54 [95% CI, 1.49-4.32]), chronic obstructive pulmonary disease (aOR, 2.16 [95% CI, 1.17-3.96]), diabetes mellitus (aOR, 1.87 [95% CI, 1.10-3.19]), and isolation of MRSA in the past 6 months (aOR, 8.18 [95% CI, 3.38-19.79]). Sixty-nine (10%) of 670 initially MRSA-negative patients acquired MRSA in the ICU (corresponding to 10.7 cases per 1,000 ICU-days at risk). Risk factors for MRSA acquisition included tracheostomy in the ICU (aOR, 2.18 [95% CI, 1.13-4.20]); decubitus ulcer (aOR, 1.72 [95% CI, 0.97-3.06]), and receipt of enteral nutrition via nasoenteric tube (aOR, 3.73 [95% CI, 1.86-7.51]), percutaneous tube (aOR, 2.35 [95% CI, 0.74-7.49]), or both (aOR, 3.33 [95% CI, 1.13-9.77]). CONCLUSIONS: Active surveillance detected a sizable proportion of MRSA-colonized patients not identified by clinical culture. MRSA colonization on admission was associated with recent healthcare contact and underlying disease. Acquisition was associated with potentially modifiable processes of care.

Adolescent↗
PubMed2006

TAT-BH4 and TAT-Bcl-xL peptides protect against sepsis-induced lymphocyte apoptosis in vivo.

Apoptosis is a key pathogenic mechanism in sepsis that induces extensive death of lymphocytes and dendritic cells, thereby contributing to the immunosuppression that characterizes the septic disorder. Numerous animal studies indicate that prevention of apoptosis in sepsis improves survival and may represent a potential therapy for this highly lethal disorder. Recently, novel cell-penetrating peptide constructs such as HIV-1 TAT basic domain and related peptides have been developed to deliver bioactive cargoes and peptides into cells. In the present study, we investigated the effects of sepsis-induced apoptosis in Bcl-x(L) transgenic mice and in wild-type mice treated with an antiapoptotic TAT-Bcl-x(L) fusion protein and TAT-BH4 peptide. Lymphocytes from Bcl-x(L) transgenic mice were resistant to sepsis-induced apoptosis, and these mice had a approximately 3-fold improvement in survival. TAT-Bcl-x(L) and TAT-BH4 prevented Escherichia coli-induced human lymphocyte apoptosis ex vivo and markedly decreased lymphocyte apoptosis in an in vivo mouse model of sepsis. In conclusion, TAT-conjugated antiapoptotic Bcl-2-like peptides may offer a novel therapy to prevent apoptosis in sepsis and improve survival.

Animals↗
PubMed2006

The systemic inflammatory response syndrome.

The systemic inflammatory response syndrome (SIRS) is the body's response to an infectious or noninfectious insult. Although the definition of SIRS refers to it as an "inflammatory" response, it actually has pro- and anti-inflammatory components. This review outlines the pathophysiology of SIRS and highlights potential targets for future therapeutic intervention in patients with this complex entity.

Biomarkers↗
PubMed2006

A new safety event reporting system improves physician reporting in the surgical intensive care unit.

BACKGROUND: Medical errors are common, and physicians have notably been poor medical error reporters. In the SICU, reporting was generally poor and reporting by physicians was virtually nonexistent. This study was designed to observe changes in error reporting in an SICU when a new card-based system (SAFE) was introduced. STUDY DESIGN: Before implementation of the SAFE reporting system, education was given to all SICU healthcare providers. The SAFE system was introduced into the SICU for a 9-month period from March 2003 through November 2003, to replace an underused online system. Data were collected from the SAFE card reports and the online reporting systems during introduction, removal, and reimplementation of these cards. Reporting rates were calculated as number of reported events per 1,000 patient days. RESULTS: Reporting rates increased from 19 to 51 reports per 1,000 patient days after the SAFE cards were introduced into the ICU (p</= 0.001). Physician reporting increased most, rising from 0.3 to 5.8 reports per 1,000 patient days; nursing reporting also increased from 18 to 39 reports per 1,000 patient days (both p</=0.001). When the SAFE cards were removed, physician reporting declined to 0 reports per 1,000 patient days (p=0.01) and rose to 8.1 (p=0.001) when the cards were returned, similar to nursing results. A higher proportion of physician reports were events that caused harm compared with no effect (p < 0.05). CONCLUSIONS: A card reporting system, combined with appropriate education, improved overall reporting in the SICU, especially among physician providers. Nurses were more likely to use reporting systems than were physicians. Physician reports were more likely to be of events that caused harm.

Adult↗
PubMed2006

Genetic research and testing in critical care: surrogates' perspective.

OBJECTIVE: Genetic testing is increasingly a component of clinical research in critical illness and has potential for integration into routine care. This study explored the perspectives of surrogate decision-makers (SDMs) for acutely ill patients with respect to social, legal, and ethical aspects of genetic testing. SETTING: Medical and surgical intensive care units in an urban tertiary care hospital. INTERVENTION: Questionnaires administered to SDMs for critically ill patients over a 12-month period. MEASUREMENTS AND MAIN RESULTS: A majority of eligible SDMs participated (117/146; 80.8%). SDMs were more likely to permit genetic testing for purposes of diagnosing a treatable life-threatening disease (114/117; 97.4%) or chronic disease (111/117; 94.9%) than for an untreatable life-threatening illness (95/117; 81.2%) (p < .001). SDMs were receptive to testing to explain familial traits (112/117; 95.7%) or ethnic traits (105/117; 89.7%) (p = .131). SDMs were concerned about potential for economic discrimination, with a majority expressing reluctance to permit testing if employers (93/117; 79.5%), health insurers (90/117; 76.9%), or life insurers (92/117; 78.6%) could access results. There was a greater willingness to allow participation in studies in which data were collected anonymously (90/117; 76.9%) vs. nonanonymously (75/117; 64.1%) (p = .04). Finally, SDMs placed greater trust in universities and nonprofit organizations (107/117; 91.4%) than either the federal government (75/117; 64.1%) or pharmaceutical companies (46/117; 39.3%) to perform genetic research (p < .01). CONCLUSIONS: SDMs expressed concerns regarding economic discrimination, confidentiality of data, and trust in entities conducting clinical investigation that may represent barriers both to performing studies in which genetic information is collected and to implementation of gene-based technologies in the critical care environment.

Biomedical Research↗
PubMed2006

Vasoactive drugs and the gut: is there anything new?

PURPOSE OF REVIEW: Systemic changes in blood pressure and cardiac output induced by pressors and inotropes do not always correlate to improvements in regional perfusion. Since the gut is often referred to as the 'motor' of the systemic inflammatory response syndrome, the impact of vasoactive agents on splanchnic perfusion has theoretical importance. This review will highlight recent studies examining secondary effects of vasoactive agents on intestinal perfusion, metabolism, and barrier function. RECENT FINDINGS: Norepinephrine has minimal impact on mesenteric blood flow although the combination of norepinephrine and dobutamine increases splanchnic blood flow in sepsis. Dopamine also increases mesenteric blood flow although this may be associated with negative hepatic energy balance at high does. Vasopressin and epinephrine both have negative effects on splanchnic blood flow. Newer inodilators levosimendan and olprinone preferentially improve mesenteric perfusion in animal models. SUMMARY: Secondary effects of norepinephrine and dopamine on splanchnic perfusion are minor compared with their systemic effects. While vasopressin usage is increasing in the intensive care unit, caution should be used because of its adverse effects on gut perfusion. Experimental agents for the treatment of heart failure have beneficial gut-specific effects although the clinical significance of this is currently limited by their availability.

Adrenergic beta-Agonists↗
PubMed2005

Efficacy and safety of an insulin infusion protocol in a surgical ICU.

BACKGROUND: Hyperglycemia is associated with complications in the surgical intensive care unit. The purpose of this study was to determine the efficacy and safety of nurse-driven insulin infusion protocols in lowering blood glucose (BG) in critical illness. STUDY DESIGN: All patients in a 24-bed surgical intensive care unit who required i.v. insulin infusions during 3 noncontiguous 6-month periods from 2002 to 2004 were evaluated. In the preintervention phase, 71 patients received a physician-initiated insulin infusion without a developed protocol. They were compared with 95 patients who received a nurse-driven insulin infusion protocol with a target BG of 120 to 150 mg/dL and to 119 patients who received a more stringent protocol with a target BG of 80 to 110 mg/dL. RESULTS: There was a stepwise decrease in average daily BG levels, from 190 to 163 to 132 mg/dL (p < 0.001). The less stringent protocol decreased the time to achieve a BG level < 150 mg/dL from 14.1 to 7.4 hours compared with physician-driven management (p < 0.05) resulting in similar time on an insulin infusion (53 versus 48 hours). The more intensive protocol brought BG levels < 150 mg/dL in 7.2 hours and < 111 mg/dL in 13.6 hours, but increased the length of time a patient was on an insulin infusion to 77 hours. The incidence of severe hypoglycemia (BG < 40 mg/dL) was statistically similar between the groups, ranging between 1.1% and 3.4%. CONCLUSIONS: Implementation of a nurse-driven protocol led to more rapid and more effective BG control in critically ill surgical patients compared with physician management. Tighter BG control can be obtained without a significant increase in hypoglycemia, although this is associated with increased time on an insulin infusion.

Adult↗
PubMed2005

Prevention of lymphocyte apoptosis--a potential treatment of sepsis?

Sepsis is the leading cause of death in surgical intensive care units and is a major cause of morbidity and mortality in neonatal and medical intensive care units. The Centers for Disease Control and Prevention estimates that, in the United States alone, approximately 500,000 people develop sepsis and 175,000 people die each year. Sepsis is a growing problem; its incidence has tripled from 1972 to 1992. Recently, apoptosis has been identified as an important mechanism of cell death in animal models of sepsis and endotoxemia. During sepsis, there is extensive apoptotic death of lymphocytes and gastrointestinal epithelial cells. The extensive apoptotic death of lymphocytes is likely an important cause of the profound immunosuppression that is a hallmark of patients with sepsis. The apoptosis of gastrointestinal epithelial cells may compromise the integrity of the bowel wall, resulting in translocation of bacteria or endotoxins into the systemic circulation. The potential importance of apoptosis in the pathophysiology of sepsis is illustrated by results from animal models that demonstrate that blocking lymphocyte apoptosis improves survival in sepsis. A variety of strategies to inhibit apoptosis may ultimately provide an effective therapy for this highly lethal disorder.

Animals↗
PubMed2005

Early antibiotic administration but not antibody therapy directed against IL-6 improves survival in septic mice predicted to die on basis of high IL-6 levels.

Elevated interleukin (IL)-6 levels correlate with increased mortality following sepsis. IL-6 levels >14,000 pg/ml drawn 6 h after cecal ligation and puncture (CLP) are associated with 100% mortality in ND4 mice, even if antibiotic therapy is initiated 12 h after septic insult. Our first aim was to see whether earlier institution of antibiotic therapy could improve overall survival in septic mice and rescue the subset of animals predicted to die on the basis of high IL-6 levels. Mice (n = 184) were subjected to CLP, had IL-6 levels drawn 6 h later, and then were randomized to receive imipenem, a broad spectrum antimicrobial agent, beginning 6 or 12 h postoperatively. Overall 1-wk survival improved from 25.5 to 35.9% with earlier administration of antibiotics (P < 0.05). In mice with IL-6 levels >14,000 pg/ml, 25% survived if imipenem was started at 6 h, whereas none survived if antibiotics were started later (P < 0.05). On the basis of these results, we examined whether targeted antibody therapy could improve survival in mice with elevated IL-6 levels. A different cohort of mice (n = 54) had blood drawn 6 h after CLP, and then they were randomized to receive either monoclonal anti-IL-6 IgG or irrelevant rat IgG. Anti-IL-6 antibody failed to improve either overall survival or outcome in mice with IL-6 levels >14,000 pg/ml. These results demonstrate that earlier systemic therapy can improve outcome in a subset of mice predicted to die in sepsis, but we are unable to demonstrate any benefit in similar animals using targeted therapy directed at IL-6.

Animals↗
PubMed2005

Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways.

Patients with sepsis are immune compromised, as evidenced by their failure to clear their primary infection and their propensity to develop secondary infections with pathogens that are often not particularly virulent in normal healthy individuals. A potential mechanism for immunosuppression in sepsis is lymphocyte apoptosis, which may occur by either a death receptor or a mitochondrial-mediated pathway. A prospective study of blood samples from 71 patients with sepsis, 55 nonseptic patients, and 6 healthy volunteers was undertaken to quantitate lymphocyte apoptosis and determine cell death pathways and mechanisms of apoptosis. Apoptosis was evaluated by flow cytometry and Western blotting. Lymphocyte apoptosis was increased in CD4 and CD8 T cells, B cells (CD20), and NK cells (CD56) in septic vs nonseptic patients. Samples taken sequentially from 10 patients with sepsis showed that the degree of CD3 T cell apoptosis correlated with the activity of his/her sepsis. In septic patients, apoptotic lymphocytes were positive for active caspases 8 and 9, consistent with death occurring by both mitochondrial-mediated and receptor-mediated pathways. In support of the concept that both death pathways were operative, lymphocyte apoptosis occurred in cells with markedly decreased Bcl-2 (an inhibitor of mitochondrial-mediated apoptosis) as well as cells with normal concentrations of Bcl-2. In conclusion, apoptosis occurs in a broad range of lymphocyte subsets in patients with sepsis and correlates with the activity of the disease. Lymphocyte loss occurs by both death receptor and mitochondrial-mediated apoptosis, suggesting that there may be multiple triggers for lymphocyte apoptosis.

Adult↗
PubMed2005

Iron dysregulation combined with aging prevents sepsis-induced apoptosis.

BACKGROUND: Sepsis, iron loading, and aging cause independent increases in gut epithelial and splenic apoptosis. It is unknown how their combination will affect apoptosis and systemic cytokine levels. MATERIALS AND METHODS: Hfe-/- mice (a murine homologue of hemochromatosis) abnormally accumulate iron in their tissues. Aged (24-26 months) or mature (16-18 months) Hfe-/- mice and wild type (WT) littermates were subjected to cecal ligation and puncture (CLP) or sham laparotomy. Intestine, spleen, and blood were harvested 24 h later and assessed for apoptosis and cytokine levels. RESULTS: Gut epithelial and splenic apoptosis were low in both aged septic and sham Hfe-/- mice, regardless of the amount of iron in their diet. Mature septic WT mice had increased apoptosis compared to age-matched sham WT mice. Mature septic Hfe-/- mice had similar levels of intestinal cell death to age-matched septic WT mice but higher levels of splenic apoptosis. Apoptosis was significantly lower in septic aged Hfe-/- mice than septic mature Hfe-/- animals. Interleukin-6 was elevated in septic aged Hfe-/- mice compared to sham mice. CONCLUSIONS: Although sepsis, chronic iron dysregulation, and aging each increase gut and splenic apoptosis, their combination yields cell death levels similar to sham animals despite the fact that aged Hfe-/- mice are able to mount an inflammatory response following CLP and mature Hfe-/- mice have elevated sepsis-induced apoptosis. Combining sepsis with two risk factors that ordinarily increase cell death and increase mortality in CLP yields an apoptotic response that could not have been predicted based upon each element in isolation.

Aging↗
PubMed2005

Mechanisms of decreased intestinal epithelial proliferation and increased apoptosis in murine acute lung injury.

OBJECTIVES: The aim of this study was to determine the effects of acute lung injury on the gut epithelium and examine mechanisms underlying changes in crypt proliferation and apoptosis. The relationship between severity and timing of lung injury to intestinal pathology was also examined. DESIGN: Randomized, controlled study. SETTING: University research laboratory. SUBJECTS: Genetically inbred mice. INTERVENTIONS: Following induction of acute lung injury, gut epithelial proliferation and apoptosis were assessed in a) C3H/HeN wild-type and C3H/HeJ mice, which lack functional Toll-like receptor 4 (n = 17); b) C57Bl/6 mice that received monoclonal anti-tumor necrosis factor-alpha or control antibody (n = 22); and c) C57Bl/6 wild-type and transgenic mice that overexpress Bcl-2 in their gut epithelium (n = 21). Intestinal epithelial proliferation and death were also examined in animals with differing degrees of lung inflammation (n = 24) as well as in a time course analysis following a fixed injury (n = 18). MEASUREMENTS AND MAIN RESULTS: Acute lung injury caused decreased proliferation and increased apoptosis in crypt epithelial cells in all animals studied. C3H/HeJ mice had higher levels of proliferation than C3H/HeN animals without additional changes in apoptosis. Anti-tumor necrosis factor-alpha antibody had no effect on gut epithelial proliferation or death. Overexpression of Bcl-2 did not change proliferation despite decreasing gut apoptosis. Proliferation and apoptosis were not correlated to severity of lung injury, as gut alterations were lost in mice with more severe acute lung injury. Changes in both gut epithelial proliferation and death were apparent within 12 hrs, but proliferation was decreased 36 hrs following acute lung injury while apoptosis returned to normal. CONCLUSIONS: Acute lung injury causes disparate effects on crypt proliferation and apoptosis, which occur, at least in part, through differing mechanisms involving Toll-like receptor 4 and Bcl-2. Severity of lung injury does not correlate with perturbations in proliferation or death in the gut epithelium, and acute lung injury-induced changes in intestinal epithelial proliferation persist longer than those in apoptosis.

Animals↗
PubMed2005

Relationship between tracheostomy timing and duration of mechanical ventilation in critically ill patients.

OBJECTIVE: Tracheostomy practice in the setting of critical illness is controversial because evidence demonstrating unequivocal benefit is lacking. We undertook this study to determine the relationship between tracheostomy timing and duration of mechanical ventilation, intensive care unit length of stay, and hospital length of stay and to evaluate the relative influence of clinical and nonclinical factors on tracheostomy practice. DESIGN: Analysis of Project Impact, a multi-institutional critical care administrative database. SETTING: Medical school. PATIENTS: Data from 43,916 patients were reviewed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Tracheostomy was performed in 2,473 (5.6%) of 43,916 patients analyzed. Tracheostomy patients had a higher survival rate than nontracheostomy patients (78.1 vs. 71.7%, p < .001) and underwent this procedure following a median (25th-75th percentile) of 9.0 (5.0-14.0) days of ventilatory support. Tracheostomy frequency and timing varied significantly comparing patient, intensive care unit, and hospital characteristics (p < .05 for all). Tracheostomy timing correlated significantly with duration of mechanical ventilation (r = .690), intensive care unit (r = .610), and hospital length of stay (r = .341, p < .001 for all). At most, 22% of patients were supported via tracheostomy at any given time. Although a minority, tracheostomy patients accounted for 26.2%, 21.0%, and 13.5% of all ventilator, intensive care unit, and hospital days, respectively. CONCLUSIONS: Although practice varies substantially, tracheostomy timing appears significantly associated with duration of mechanical ventilation, intensive care unit length of stay, and hospital length of stay. These findings emphasize the need for an adequately supported multiple-center trial to better define patient selection for tracheostomy and to test the hypothesis that timing of this procedure influences clinically important outcomes.

Critical Care↗
PubMed2005

Intestinal dysplasia induced by simian virus 40 T antigen is independent of p53.

Transgenic mice expressing simian virus 40 large T antigen in enterocytes develop intestinal hyperplasia that progresses to dysplasia with age. Hyperplasia is dependent on T antigen binding to the retinoblastoma (pRb) family of tumor suppressor proteins. Mice expressing a truncated T antigen that inactivates the pRb-family, but is defective for binding p53, exhibit hyperplasia but do not progress to dysplasia. We hypothesized that the inhibition of the pRb family leads to entry of enterocytes into the cell cycle, resulting in hyperplasia, while inactivation of p53 is required for progression to dysplasia. Therefore, we examined T antigen/p53 complexes from the intestines of transgenic mice. We found that T antigen did not induce p53 stabilization, and we could not detect T antigen/p53 complexes in villus enterocytes. In contrast, T antigen expression led to a large increase in the levels of the cyclin-dependent kinase inhibitor p21. Furthermore, mice in which pRb was inactivated by a truncated T antigen in a p53 null background exhibited intestinal hyperplasia but no progression to dysplasia. These data indicate that loss of p53 function does not play a role in T antigen-induced dysplasia in the intestine. Rather, some unknown function of T antigen is essential for progression beyond hyperplasia.

Animals↗