Calcium channel blockers and the incidence of breast and prostate cancer: A meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Breast cancer (BCa) and prostate cancer (PCa), both hormone-dependent cancers, are the second leading cause of death in both women and men, respectively. Calcium channel blockers (CCBs) have been thought to increase the risk of cancer by inhibiting calcium signal-mediated apoptosis, but the evidence for this association remains inconclusive. We have reviewed pertinent literature and pooled data to establish a consensus on the relationship of CCB use and the incidence of these two cancers. METHODS: PubMed was used to conduct a search for English articles from inception to April 2016. Relevant data including study design, number of total participants and CCB users, total cases of BCa and PCa, age (mean and/or range), follow-up period and statistical outcomes were retrieved. Quality assessment was carried out using Newcastle Ottawa system, with the selection of high-quality studies. Summary effects were obtained using random- and mixed-effects models, followed by sensitivity analysis, and testing for publication bias. RESULTS AND DISCUSSION: This meta-analysis includes 11 relevant studies for BCa and 6 for PCa. The odds ratio (OR) association between BCa and CCB use was 1.14 (95%CI: 1.02, 1.27, P = .02). The OR association between PCa and CCB use was 1.12 (95%CI .94-1.35, P = .21). WHAT IS NEW AND CONCLUSION: Although a statistically significant association between CCB use and incidence of BCa does exist, the limitations of the individual studies restrict the clinical application of this relationship. Our meta-regression model does newly identify a 9-year latency period of CCB use and a significantly increased risk of BCa. No significant association exists between CCB use and the incidence of PCa. Our meta-regression shows CCB may have a protective effect upon PCa incidence among older populations.

Effects of continuous tube feeding of dietary fat emulsions on eicosanoid production and on fatty acid composition during an acute septic shock in rats.

The effects of a short-term (5 days) continuous intragastric tube feeding of diets containing n - 6 polyunsaturated fatty acids (PUFA) from safflower oil (SO) or n - 3 PUFA from menhaden oil (MO) on the production of proinflammatory mediators, and on the number of animals surviving after an intravenous injection of lipopolysaccharide (LPS) were investigated in rats. The phospholipid fatty acid composition of cell membranes from several organs and of plasma were also analyzed. No marked differences in the number of animals surviving or in the production of tumor necrosis factor-alpha were observed between the 2 groups of animals. However, 90 min after LPS exposure the plasma levels of prostaglandin (PG) E2 and 6-keto-PGF1 alpha decreased significantly (40% and 60%, respectively) for the group of rats fed MO diet compared to those fed SO diet (P < 0.05). Following continuous infusion of liquid MO diet, the amount of arachidonic acid (AA) detected was significantly lower in plasma (23%), spleen (43%), lungs (41%), and liver (38%), but was unchanged in the heart tissues. The percent of eicosapentaenoic acid (EPA) incorporated into phospholipids of plasma, spleen, lungs, liver, and heart were 7.6, 4.4, 2.1, 7.2, and 1.1%, respectively. These data indicate that after continuous MO feeding, a significant decrease in the production of proinflammatory eicosanoids was associated with a marked reduction in AA content. Further, these data suggest that nutritional intervention may have a therapeutic potential to ameliorate clinical symptoms due to excessive productions of eicosanoids during acute septic complications.

Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes.

Total GLUT4 content in skeletal muscle from individuals with type 2 diabetes is normal; however, recent studies have demonstrated that translocation of GLUT4 to the plasma membrane is decreased in response to insulin stimulation. It is not known whether physical exercise stimulates GLUT4 translocation in skeletal muscle of individuals with type 2 diabetes. Five subjects (two men, three women) with type 2 diabetes and five normal control subjects (5 men), as determined by a standard 75-g oral glucose tolerance test, were recruited to determine whether an acute bout of cycle exercise activates the translocation of GLUT4 to the plasma membrane in skeletal muscle. Each subject had two open biopsies of vastus lateralis muscle; one at rest and one 3-6 weeks later from the opposite leg after 45-60 min of cycle exercise at 60-70% of VO2max. Skeletal muscle plasma membranes were prepared by subcellular fractionation, and GLUT4 content was determined by Western blotting. Plasma membrane GLUT4 increased in each subject in response to exercise. The mean increase in plasma membrane GLUT4 for the subjects with type 2 diabetes was 74 +/-20% above resting values, and for the normal subjects the increase was 71+/-18% above resting values. Although plasma membrane GLUT4 content was approximately 32% lower at rest and after exercise in the muscle of the subjects with type 2 diabetes, the differences were not statistically significant. We conclude that in contrast to the previously reported defect in insulin-stimulated GLUT4 translocation in skeletal muscle of individuals with type 2 diabetes, a single bout of exercise results in the translocation of GLUT4 to the plasma membrane in skeletal muscle of individuals with type 2 diabetes. These data provide the first direct evidence that GLUT4 translocation is an important cellular mechanism through which exercise enhances skeletal muscle glucose uptake in individuals with type 2 diabetes.

Effects of sesamin-supplemented dietary fat emulsions on the ex vivo production of lipopolysaccharide-induced prostanoids and tumor necrosis factor alpha in rats.

BACKGROUND: Sesamin, a nonfat constituent of sesame oil, inhibits Delta(5)-desaturase activity, resulting in accumulation of dihomo-gamma-linolenic acid (DGLA), which displaces arachidonic acid (AA) and consequently decreases the formation of proinflammatory 2-series prostaglandins. OBJECTIVE: We sought to determine whether dietary supplementation with sesamin augments the antiinflammatory effects of dietary linseed oil in rats. DESIGN: We investigated the effects of continuous tube feedings of emulsions containing safflower oil or linseed oil with sesamin (SO+ and LO+) or without sesamin (SO and LO) on liver fatty acid composition and on endotoxin-induced production of prostaglandin E(2), 6-keto-prostaglandin F(1alpha), and tumor necrosis factor alpha (TNF-alpha) by whole blood from rats (n = 6 per diet group). RESULTS: We found a significant accumulation of DGLA only in the liver phospholipids of animals fed SO+ and LO+ (1.8 +/- 0.2 and 1.4 +/- 0.3 mol%, respectively), which suggests that sesamin inhibited Delta(5)-desaturation of n-6 fatty acids. These changes were associated with significant reductions in plasma prostaglandin E(2) concentrations in animals fed SO+ compared with those fed SO (P: < 0. 05). Despite a significant reduction in tissue AA content in the LO group, the prostaglandin E(2) concentrations did not differ significantly from those of the SO group. Plasma concentrations of TNF-alpha were significantly lower (P: < 0.05) in the animals fed LO+ than in those fed SO (199 +/- 48 and 488 +/- 121 ng/L, respectively). CONCLUSION: These data indicate that in rats, tube feedings of diets containing sesamin exerted antiinflammatory effects that were augmented by concurrent consumption of linseed oil.

Rapid incorporation of fish or olive oil fatty acids into rat hepatic sinusoidal cell phospholipids after continuous enteral feeding during endotoxemia.

Therapeutic modalities that downregulate macrophage and endothelial production of eicosanoid mediators by displacing membrane arachidonic acid (20:4 omega 6) may benefit patients at increased risk of septic complications. The objective of this study in rats was to assess the incorporation of fish or olive oil fatty acids into hepatic Kupffer and endothelial (K&E) cell phospholipids after 4 d of continuous enteral feeding during endotoxemia. Either endotoxin (ETX) (0.5-1 mg-1.day-1) or vehicle was infused intravenously during the last 72 h. Dietary fish and olive oil fatty acids were rapidly incorporated into both K&E and plasma phospholipids irrespective of ETX cotreatment. Rats infused with the fish oil-enriched diet had a significantly lower relative percent of both K&E linoleic acid (18:2 omega 6) and 20:4 omega 6, whereas rats infused with the olive oil-enriched diet only had a lower relative percent of 18:2 omega 6 compared with control rats receiving corn oil. Provision of specific dietary lipids by continuous enteral infusion may prove efficacious for the rapid modulation of hepatic sinusoidal cell membrane fatty acids under either normal or endotoxemic conditions.

Heart disease and hypertension in severe obesity: the benefits of weight reduction.

Severe obesity is associated with abnormalities of cardiac structure and function. These include an increased cardiac workload and ventricular hypertrophy. Hypertension in combination with severe obesity seriously burdens the heart because the increased preload and afterload compound cardiac work. Weight reduction induced by gastric operations for severe obesity is associated with resolution of hypertension, reduction in ventricular wall thickness and cardiac chamber size, as well as improved systolic function. Additional data are needed to predict when in the course of development of obese cardiomyopathy the changes in contractile function become irreversible. Additionally, the impact of coronary artery disease on the progression of obese cardiomyopathy and the effects of surgical weight reduction on cardiac structure and function need to be further clarified. Studies of the association between obesity, its treatment, and modification of cardiovascular risk are a major focus of preventive cardiology today.

Plasma lipid changes after supplementation with beta-glucan fiber from yeast.

BACKGROUND: Dietary fiber has been shown to improve blood lipids. OBJECTIVE: The purpose of this study was to evaluate the effect on serum lipids of a yeast-derived beta-glucan fiber in 15 free-living, obese, hypercholesterolemic men. DESIGN: After a 3-wk period in which subjects ate their usual diet, 15 g fiber/d was added to the diet for 8 wk and then stopped for 4 wk. Plasma lipids were measured weekly during baseline and at week 7 and 8 of fiber consumption, and again at week 12. RESULTS: Compared with baseline, fiber consumption significantly reduced plasma total cholesterol (by 8% at week 7 and 6% at week 8; P < 0.05 using Bonferroni correction); week 12 values did not differ from baseline. No significant differences were noted between baseline LDL cholesterol and values at weeks 7, 8, or 12 when comparing individual groups by using Bonferroni correction, even though the overall one-way analysis of variance with repeated measures was highly significant (P < 0.001). LDL-cholesterol concentrations did decline by 8% at week 8 compared with baseline. There was a significant effect of diet on plasma HDL-cholesterol concentrations (P < 0.005 by one-way ANOVA with repeated measures). However, a group difference was observed only between baseline and week 12 (16% increase; P < 0.05 by Bonferroni correction). Triacylglycerol concentrations did not change. CONCLUSIONS: The yeast-derived beta-glucan fiber significantly lowered total cholesterol concentrations and was well tolerated; HDL-cholesterol concentrations rose, but only 4 wk after the fiber was stopped.

Hepatic utilization of exogenous nucleotide precursors for restoration of ATP after cold ischemia in rats.

The study objective was to assess hepatic utilization of exogenous adenosine or adenine to enhance ATP recovery in rat liver after cold ischemia. ATP was measured noninvasively by 31P nuclear magnetic resonance (NMR) in perfused livers before and after 18 h of cold ischemia. The hepatocellular concentration of ATP during the initial postischemic reperfusion without adenosine or adenine coinfusion was 60% of that in fresh liver. The ATP increased significantly (P < 0.001) to 139% and 82% of baseline in postischemic livers coinfused for 90 min with adenosine or adenine (final concentration, 1 mmol/L), respectively. Less than 0.5% of the excess adenosine was catabolized to uric acid. In conclusion, adenosine and, to a lesser extent, adenine are salvaged by liver after extended cold ischemia to enhance ATP restoration. Provision of these ATP precursors, as components of an enteral formulation may facilitate the repletion of liver ATP and foster early resumption of liver function after an ischemic insult.

Rapid modulation of lung and liver macrophage phospholipid fatty acids in endotoxemic rats by continuous enteral feeding with n-3 and gamma-linolenic fatty acids.

Dienoic eicosanoids derived from phospholipid arachidonic acid (AA) in lung and liver macrophages promote leukosequestration, thrombosis, and tissue injury. Current enteral diets (diet A) are enriched with linoleic acid (LA), a precursor of AA. Novel diets low in LA and containing eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) foster formation of less inflammatory eicosanoids. The study objective was to assess the rapidity and extent of LA and AA displacement in vivo from alveolar macrophage (AM phi), lung, and liver Kupffer and endothelial (KE) cell phospholipids in rats fed enterally with diets enriched with 5.3% (by wt) EPA and either 1.2% or 4.6% GLA (diets B and C, respectively). After surgical placement of catheters, the rats were fed enterally and co-infused intravenously with either endotoxin or vehicle continuously for 3 or 6 d. Rats given either diet B or C had significantly lower (P < 0.01) relative percentages of AA and LA within the AM phi, lung, and KE cell phospholipids, and concomitantly higher percentages of EPA compared with rats infused with diet A after 3 d of enteral feeding irrespective of endotoxin co-infusion. Incorporation of dihomo-gamma-linolenic acid (DHGLA), the metabolite of GLA, into lung and KE phospholipids was significant in rats given diet C. Most of the changes in fatty acid composition occurred by day 3. The polyunsaturated fatty acid composition of AM phi, lung, and KE cell phospholipids can be rapidly modified by continuous short-term enteral feeding with EPA- and GLA-enriched diets irrespective of concurrent endotoxemia.

The effect of dietary polyunsaturated fatty acids (PUFA) on acute rejection and cardiac allograft blood flow in rats.

For six weeks, recipient (Lewis RT11) and donor rats (LBNF11/n) were fed three diets that varied only in their lipid content. Diet A (MO) contained 19.5% menhaden oil and 0.5% safflower oil and was rich in omega 3 PUFA; diet B (SO) was 20% safflower oil rich in omega 6 PUFA; and diet C (BT) was 20% beef tallow rich in omega 9 monounsaturated fatty acids and saturated fat. In the first set of graft survival studies a group fed laboratory chow was included (CHOW). Heterotopic cardiac transplantation from donor to recipient animals was performed after the six-week feeding period. The effect of these diets on cardiac allograft survival, mixed lymphocyte response, and blood flow in the rejecting grafts was investigated. The median graft survival in days was significantly prolonged in the rats maintained on either MO (12 days) or SO (14.5 days) compared with the BT (8 days)-or lab chow (7.5 days)-fed animals (P < 0.05). Cyclosporine (CsA) administered at subtherapeutic levels further increased the differences between the PUFA-fed animals and the BT-fed group. The myocardial blood flow of the rejecting allografts was measured using an 85Sr-labeled microsphere technique on the fifth posttransplant day. Flow was greatest in the MO-fed group, and both MO and SO groups had significantly higher myocardial blood flow than BT-fed rats (P < 0.05) or those bearing isografts. The allogenic mixed lymphocyte responses of peripheral blood mononuclear cells (PBMC) and splenic lymphocytes were suppressed in MO- and SO-fed groups compared with BT-fed animals. The immunosuppressive effect of dietary PUFA warrants further investigation, and their use as a possible adjunctive treatment in organ transplantation should be considered.

Effect of membrane free fatty acid alterations on the adhesion of human colorectal carcinoma cells to liver macrophages and extracellular matrix proteins.

Epidemiologic studies have linked diets high in animal fat with colon carcinogenesis. A number of animal tumor models have shown that diets rich in omega-3 fatty acids inhibit colon carcinogenesis while diets rich in omega-6 fatty acids promote tumor growth. This study examines whether modification of the membrane fatty acid composition of both moderately (CX-1) and poorly differentiated (MIP-101 and Clone A) human colorectal carcinoma cells alters their interaction with Kupffer cells and extracellular matrix proteins (collagen type IV, fibronectin and laminin). The cells were treated with 15-16 micrograms/ml of docosahexanoic acid (22:6, omega 3) or linoleic acid (18:2,omega 6). Gas chromatography showed significant alterations in the membrane fatty acid composition of the human colorectal cancer cell lines. Binding assays were performed by measuring adherence of 51Cr-labelled tumor cells to Kupffer cell monolayers or to immobilized proteins. Omega-3 treatment significantly decreased the Kupffer cell binding of only the CX-1 line while omega-6 treatment decreased binding of all three cell lines. In contrast both omega-3 and omega-6 treatment of MIP-101 cells decreased binding to the extracellular matrix proteins with the omega-6 effect being more pronounced. These results indicate that the binding characteristics of the colon cancer cells to both Kupffer cells and extracellular matrix proteins may be determined in part by the membrane fatty acid composition. Decreased adherence to extracellular matrix proteins may lead to increased cell motility and invasiveness. Since Kupffer cell binding precedes tumor cell phagocytosis and killing, decreased binding may improve tumor cell survival.

On genetic screening of donors for artificial insemination.

Reliable information on the frequency of birth defects in children conceived by artificial insemination is lacking and should be collected. Genetic screening of donors for artificial insemination is recommended, and guidelines are proposed. These consider the kinds of disorder in the presumptive donor, or his relatives, that would preclude his use as a donor, and the steps to be taken with relatives, that would preclude his use as a donor, and the steps to be taken with respect to genetic counseling if a defective baby is born following the procedure.

Endotoxin-exposed atria exhibit G protein-based deficits in inotropic regulation.

BACKGROUND: Diminished response at the myocardial beta 1-adrenoceptor is established in endotoxemia. The myocardial muscarinic-2 acetylcholine receptor (M2ACHR) has not been investigated in endotoxemia, although it shares a G protein-mediated link to adenyl cyclase (AC). This study aimed to assess the contractile responses elicited at the M2ACH and beta 1 receptors, their respective G proteins, and the AC unit in endotoxemia. METHODS: Isometric force and rate of contraction were measured in atria from Sprague-Dawley rats after exposure to 24-hour continuous intravenous infusion of 0.2 mg/kg endotoxin or vehicle. The responses to isoproterenol, acetylcholine, sodium fluoride (NaF), and forskolin were studied. RESULTS: In a comparison of endotoxic versus control atria, diminished force response at the beta 1-adrenoceptor was confirmed (4.98 +/- 1.343 vs 7.26 +/- 1.568 gx10 [gx10 is unit of measure used for force], p = 0.0006, n = 10), and an analogous defect at the M2ACHR was identified (6.66 +/- 0.906 vs 8.16 +/- 1.307 gx10, p = 0.009, n = 10). NaF was able to directly activate Gs and G(i) in a dose-dependent differential manner. Both Gs (5.40 +/- 0.795 vs 7.81 +/- 1.057 gx10, p = 0.0015, n = 6) and G(i) (2.73 +/- 0.528 vs 3.76 +/- 0.332 gx10, p = 0.003) force responses were diminished in endotoxic atria. Stimulus of AC by forskolin yielded similar force increases (3.15 +/- 0.731 vs 3.21 +/- 0.667 gx10, p = 0.89, n = 9). CONCLUSIONS: In this model only contractile responses were altered by endotoxemia. The use of NaF revealed dysfunction distal to agonist receptor interaction and with the data from M2ACHR activation confirmed that this defect is not adrenergic specific. The preserved response at AC localized the site of this myocardial receptor dysfunction to the G proteins.

The effect of interleukin-1 and interleukin-2 on the adrenergic control of hormone-sensitive lipase in the human adipocyte.

The effect of interleukin-1 and interleukin-2 on lipolysis and the adrenergic control of lipolysis was studied. Biopsy specimens of human adipose tissue were incubated in media containing 3H-palmitate and 14C-glucose, and the ratio of these isotopes was used to determine adipocyte lipolysis. Isoproterenol, clonidine, and theophylline were used in the media to stimulate the beta 1- and alpha 2-receptors and the subreceptor mechanism, respectively. Interleukin-1 had no effect on basal lipolysis, and at maximal receptor stimulation, it had no effect on the adrenergic receptor control of lipolysis. Interleukin-2 had no effect on basal lipolysis or on the beta-adrenergic receptor. Interleukin-2 significantly (p less than 0.02) decreased the alpha 2-inhibition of lipolysis by 68%. The effect of interleukin-2 on the alpha-receptor was demonstrated to be a significant 45% decrease (p less than 0.03) in the receptor responsiveness (a measure of the postreceptor mechanism) with no alteration in receptor sensitivity (a measure of receptor number). This data suggest that interleukin-2 stimulates lipolysis by decreasing the alpha 2-adrenergic inhibition of hormone-sensitive lipase.

A gastroplasty that avoids stapling in continuity.

BACKGROUND: Staple line perforations have been the principal cause of failure after vertical-banded gastroplasty in patients followed at least 4 years at our institution. In the present study an operation was devised that created a vertical-banded gastroplasty not dependent on staple lines to avoid this complication. METHODS: One hundred two patients with a body mass index (BMI) greater than 35 kg/m2 underwent vertical-banded gastroplasty from Jan. 1 to Dec. 30, 1986, with an orifice size of 45 to 47 mm external circumference and division between the vertical staple lines to prevent gastric pouch to gastric fundus fistula. RESULTS: Ninety-eight of the patients have been followed up for a minimum of 4 years. Sixty-two percent of patients obtained an excellent or good final result after 4.5 +/- 0.1 years. This was a BMI of less than 35 kg/m2 or less than 50% excess weight. This acceptable long-term result was achieved 90% of the time if the patient was obese (BMI, 35 to 40 kg/m2) before surgery and in 75% of patients who were morbidly obese (BMI, 40 to 50 kg/m2) but in only 30% of patients who were superobese (BMI > 50 kg/m2) before surgery. Staple line disruption was markedly reduced; however, stenosis or failure to lose weight or late weight gain required reoperation in 36% of the patients. CONCLUSIONS: Gastric bypass was superior to reversal or revision of the gastroplasty as a remedial operation. This study again questions the value of vertical-banded gastroplasty in the treatment of obesity even when staple line disruption is markedly diminished.

Late results of vertical banded gastroplasty for morbid and super obesity.

Two hundred one patients who underwent vertical banded gastroplasty have been followed up for a minimum of 2 years to more than 5 years. Staple line perforations occurred in 48% of patients, and 36% underwent reoperation. The instability of the operation becomes apparent only with careful follow-up. More than 50% of patients who maintained a small orifice of less than or equal to 11 mm in diameter and an intact staple line over 3 to 5 years achieved an excellent result (0% to 25% excess weight), which equals the best results in the literature for any gastric-limiting operation, whether bypass or gastroplasty. The results of this operation for super obesity (a body mass index greater than or equal to 50 kg/m2) are disappointing. Only 8% of these patients achieve an excellent result. Failure of vertical banded gastroplasty in the morbidly obese (body mass index of 40 to 50 kg/m2) is frequently technical, and a method that eliminates dependence on integrity of staples should be evaluated. Results should be reported so that unsatisfactory results are apparent. Mean weight loss and mean percent excess weight loss are both highly satisfactory in this study, whereas unsatisfactory results ranged from 10% to 21% for each of the 5 years of follow-up.

Antibiotic prophylaxis for surgery in morbidly obese patients.

The rate of wound infections in morbidly obese patients who underwent gastroplasty surgery at our institution was 16.5% compared with a rate of 2.5% in normal-weight patients who underwent clean-contaminated surgery. Both groups received 1 gm of cefazolin intramuscularly before surgery was performed. We hypothesized that this regimen of prophylaxis did not provide adequate tissue levels in the morbidly obese. Morbidly obese patients who were undergoing gastroplasty were randomly selected to receive 1 gm cefazolin in the buttock fat, buttock muscle, or by intravenous injection. A fourth group of morbidly obese patients received 2 gm of cefazolin intravenously. Normal-weight patients who were undergoing upper abdominal surgery received 1 gm of cefazolin intravenously. At incision and closure, both blood and tissue levels of cefazolin were significantly (p less than 0.001) lower for all morbidly obese patients who received 1 gm cefazolin when compared with the blood and tissue levels of the drug found in normal-weight patients. The cefazolin levels obtained were below the minimal inhibitory concentrations of greater than 2 micrograms/ml for gram-positive cocci and of greater than 4 micrograms/ml for gram-negative rods. Only when the morbidly obese patient received 2 gm cefazolin were both the serum and adipose tissue levels adequate. For a 4-month period, all morbidly obese patients received 2 gm cefazolin prophylaxis, and the wound infection rate dropped to 5.6% compared with the previous rate of 16.5% (p less than 0.03). We conclude that antibiotic prophylaxis must be specially tailored to the needs of these obese patients.

Rapid modulation of liver-specific transcription factors after injury.

BACKGROUND: The reaction to injury is a well-orchestrated physiologic response involving the coordinated actions of multiple integrated systems. It initially occurs at the molecular level and involves changes in gene transcription. We hypothesized that the molecular mechanisms regulating the generation of an inflammatory response are similar to those orchestrating developmental and tissue-specific expression of proteins and, in the case of the acute phase response, occur through manipulation of liver-specific transcription factors and their binding activity. METHODS: Female BALB/c mice, 7 to 8 weeks old, were subjected to a 15% body surface area burn. Total and polyadenylated liver RNA was isolated, and Northern blot analysis was performed to determine the kinetics of the acute phase proteins albumin and fibrinogen and the liver-specific transcriptional factors CCAAT-enhancer binding protein (C/EBP) alpha, hepatocyte nuclear factor (HNF)-1 alpha, and HNF-4. RESULTS: Induction of the injury response was shown by an increase in fibrinogen messenger RNA levels and a decrease in albumin mRNA levels. The liver-specific transcription factor C/EBP alpha decreased after injury and remained significantly lower than control at 3 hours. HNF-4 mRNA levels fell more slowly, reaching significantly lower levels at 6 hours and remaining suppressed at 34 hours. HNF-1 alpha showed the most rapid fall in mRNA levels at 30 minutes after injury and remained significantly below control levels at 34 hours. CONCLUSIONS: The minimal burn injury model leads to the molecular induction of the acute phase response and induces significant and rapid changes in the liver-specific transcription factors C/EBP alpha, HNF-1 alpha, and HNF-4. These changes may represent a mechanism through which the organ-specific response to injury is mediated.

An educational intervention in the surgical intensive care unit to improve ethical decisions.

BACKGROUND: The objective of this study was to determine whether an educational intervention on medical ethics offered during a surgical intensive care unit (SICU) rotation could effect meaningful change in a tertiary SICU. METHODS: A case-based education program was presented weekly to the surgical residents during their SICU rotation. Cases for study were designed to deal with specific ethical issues common to the SICU. Cases were studied with the residents in a group facilitated by a SICU attending physician and a nursing director. The effect of the course was monitored by case review and by the length of stay (LOS) assessment for patients who died in the SICU during 1990, the base year, through 1993. RESULTS: Discussions of an ethical nature occurred more regularly and earlier during these 4 years as determined by case reviews. For patients who died after being in the SICU a minimum of more than 30 days, a marked decrease occurred in the SICU LOS from 27.8 +/- 3.7 days in 1990 to 15.7 +/- 2.4 days in 1993 (p < 0.05). The number of deaths per year and the average acuity measured by the diagnosis related group score were similar during the 4 years. The LOS in the hospital for dying patients from non-SICU services remained similar during the same time frame. These changes resulted in the dying patients using 1003 SICU days in 1993, down from the 2028 days used in 1990 (p < 0.05). CONCLUSIONS: We conclude that through offering a clinical ethics program during the SICU portion of the residency training, residents increased knowledge and skill in addressing and integrating practical ethical issues into their surgical resident practice. In addition, patient care directly improved with an associated reduced SICU LOS and reduced cost.

Injury induces rapid changes in hepatocyte nuclear factor-1: DNA binding.

BACKGROUND: Transcriptional regulation in the liver plays a critical role in mediating the acute phase response to injury. The molecular mechanisms driving these transcriptional events, however, are poorly defined in vivo. The liver-specific transcription factor hepatocyte nuclear factor (HNF)-1 binds to the 5' upstream region of many acute phase genes. To explore the connection between injury and transcriptional regulatory mechanisms, we investigated the effect of injury on HNF-1 binding activity. METHODS: Liver nuclear extracts were prepared from animals after burn or anesthetized sham burn injury. HNF-1 binding activity, affinity, and off rate were assessed by electrophoretic mobility shift analysis. RESULTS: HNF-1 binding activity decreased by 28% 1 1/2 hours after injury. The dissociation constant for HNF-1 increased from 0.6 nm to 11.8 nm at 1 1/2 hours after burn injury partly because of an increase in off rate for the HNF-1: DNA complex. CONCLUSIONS: Burn injury leads to a significant decrease in HNF-1 binding activity as a result of decreased affinity of HNF-1 for DNA. These injury-induced alterations in binding of a liver-specific transcription factor for its DNA binding site represent a mechanism for rapidly modulating acute phase gene transcription in vivo.