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Biomedical subjects

Steven A Conrad

Publications and source records attributed to Steven A Conrad.

At least 19 recordsLinked to original sources

Circadian oscillation of gene expression in murine calvarial bone.

UNLABELLED: The genes encoding the core circadian transcription factors display an oscillating expression profile in murine calvarial bone. More than 26% of the calvarial bone transcriptome exhibits a circadian rhythm, comparable with that observed in brown and white adipose tissues and liver. Thus, circadian mechanisms may directly modulate oxidative phosphorylation and multiple metabolic pathways in bone homeostasis. INTRODUCTION: Although circadian rhythms have been associated historically with central regulatory mechanisms, there is emerging evidence that the circadian transcriptional apparatus exists in peripheral tissues. The aim of this study was to determine the presence and extent of circadian oscillation in the transcriptome of murine calvarial bone. MATERIALS AND METHODS: Cohorts of 8-week-old male AKR/J mice were maintained in a controlled 12-h light:12-h dark cycle on an ad libitum diet for 2 weeks. Groups of three mice were killed every 4 h over a 48-h period. The level of gene expression at successive times-points was determined by quantitative RT-PCR and Affymetrix microarray. Data were analyzed using multiple statistical time series algorithms, including Cosinor, Fisher g-test, and the permutation time test. RESULTS: Both the positive (Bmal1, Npas2) and negative (Cry1, Cry2, Per1, Per2, Per3) elements of the circadian transcriptional apparatus and their immediate downstream targets and mediators (Dbp, Rev-erbalpha, Rev-erbbeta) exhibited oscillatory expression profiles. Consistent with findings in other tissues, the positive and negative elements were in antiphase relative to each other. More than 26% of the genes present on the microarray displayed an oscillatory profile in calvarial bone, comparable with the levels observed in brown and white adipose tissues and liver; however, only a subset of 174 oscillating genes were shared among all four tissues. CONCLUSIONS: Our findings show that the components of the circadian transcriptional apparatus are represented in calvarial bone and display coordinated oscillatory behavior. However, these are not the only genes to display an oscillatory expression profile, which is seen in multiple pathways involving oxidative phosphorylation and lipid, protein, and carbohydrate metabolism.

Adipose Tissue, Brown↗

Circadian clocks are resounding in peripheral tissues.

Circadian rhythms are prevalent in most organisms. Even the smallest disturbances in the orchestration of circadian gene expression patterns among different tissues can result in functional asynchrony, at the organism level, and may to contribute to a wide range of physiologic disorders. It has been reported that as many as 5%-10% of transcribed genes in peripheral tissues follow a circadian expression pattern. We have conducted a comprehensive study of circadian gene expression on a large dataset representing three different peripheral tissues. The data have been produced in a large-scale microarray experiment covering replicate daily cycles in murine white and brown adipose tissues as well as in liver. We have applied three alternative algorithmic approaches to identify circadian oscillation in time series expression profiles. Analyses of our own data indicate that the expression of at least 7% to 21% of active genes in mouse liver, and in white and brown adipose tissues follow a daily oscillatory pattern. Indeed, analysis of data from other laboratories suggests that the percentage of genes with an oscillatory pattern may approach 50% in the liver. For the rest of the genes, oscillation appears to be obscured by stochastic noise. Our phase classification and computer simulation studies based on multiple datasets indicate no detectable boundary between oscillating and non-oscillating fractions of genes. We conclude that greater attention should be given to the potential influence of circadian mechanisms on any biological pathway related to metabolism and obesity.

Adipose Tissue↗

Heparin-induced thrombocytopenia in a pediatric patient receiving extracorporeal support and treated with argatroban.

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is rare in the pediatric population, with a majority occurring in the pediatric intensive care unit setting. All reported cases have been associated with the use of unfractionated heparin. Because unfractionated heparin is the anticoagulant of choice for extracorporeal life support, the development of HIT in these patients can be devastating. We report a case of HIT with evidence of small-vessel arterial thromboembolism in a 17-month-old child receiving extracorporeal membrane oxygenation and continuous renal replacement therapy successfully treated with argatroban. CASE: The patient was a 17-month-old boy with severe respiratory failure secondary to asthma and mucus plugging that failed conventional and unconventional ventilation. Venovenous extracorporeal membrane oxygenation was initiated, and within 24 hrs, there was a precipitous decrease in the platelet count, with the development of cutaneous ischemia involving his lower limbs. Heparin-associated antibodies were positive. Argatroban was started, and the child maintained on extracorporeal membrane oxygenation and continuous renal replacement therapy, with resolution of the cutaneous ischemia and rebound of the thrombocytopenia. DISCUSSION: HIT is rare in the pediatric population. Recognition of HIT is vital because withdrawal of heparin is the first and most important therapy. For patients on extracorporeal membrane oxygenation or continuous renal replacement therapy who develop HIT, synthetic thrombin inhibitors (hirulogs) have been reported as an alternative. However, little information on their use in extracorporeal life support has been published, particularly in the pediatric population. CONCLUSION: This report documents a pediatric case of HIT successfully treated with argatroban, allowing continuation of the venovenous extracorporeal membrane oxygenation and continuous renal replacement therapy, with resolution of the thromboembolic ischemia and thrombocytopenia.

Anticoagulants↗

Heparin-induced thrombocytopenia in a pediatric patient receiving extracorporeal membrane oxygenation managed with argatroban.

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is rare in the pediatric population, with a majority occurring in the pediatric intensive care unit setting. All cases reported to date have been associated with the use of unfractionated heparin. Because unfractionated heparin is the anticoagulant of choice for extracorporeal membrane oxygenation (ECMO) and other extracorporeal therapies, the development of HIT in these patients can be devastating, making management problematic. We report a case of HIT type II with evidence of small-vessel arterial thrombosis in a 17-month-old boy receiving ECMO and continuous renal replacement therapy successfully treated with argatroban. CASE: The patient was a 17-month-old boy with severe hypercapnic and hypoxemic respiratory failure secondary to asthma and mucus plugging that failed conventional and unconventional ventilation. Venovenous ECMO was initiated, and within 24 hrs, there was a precipitous decrease in the platelet count, with the development of cutaneous ischemia involving his lower limbs. Argatroban was started and the child maintained on ECMO and continuous renal replacement therapy, with resolution of the cutaneous ischemia and recovery of the platelet count. Heparin-associated antibodies were positive. DISCUSSION: HIT is rare in the pediatric population. Recognition of HIT is vital because withdrawal of heparin is the first and most important therapy. For patients receiving ECMO or continuous renal replacement therapy who develop HIT, synthetic thrombin inhibitors have been reported as an alternative. However, little information on their use in extracorporeal life support has been published, particularly in the pediatric population. CONCLUSION: This report documents a pediatric case of HIT type II successfully treated with argatroban, allowing continuation of the ECMO and continuous renal replacement therapy therapy, with resolution of the cutaneous ischemia and thrombocytopenia.

Journal Article↗

Characterization of peripheral circadian clocks in adipose tissues.

First described in the suprachiasmatic nucleus, circadian clocks have since been found in several peripheral tissues. Although obesity has been associated with dysregulated circadian expression profiles of leptin, adiponectin, and other fat-derived cytokines, there have been no comprehensive analyses of the circadian clock machinery in adipose depots. In this study, we show robust and coordinated expression of circadian oscillator genes (Npas2, Bmal1, Per1-3, and Cry1-2) and clock-controlled downstream genes (Rev-erb alpha, Rev-erb beta, Dbp, E4bp4, Stra13, and Id2) in murine brown, inguinal, and epididymal (BAT, iWAT, and eWAT) adipose tissues. These results correlated with respective gene expression in liver and the serum markers of circadian function. Through Affymetrix microarray analysis, we identified 650 genes that shared circadian expression profiles in BAT, iWAT, and liver. Furthermore, we have demonstrated that temporally restricted feeding causes a coordinated phase-shift in circadian expression of the major oscillator genes and their downstream targets in adipose tissues. The presence of circadian oscillator genes in fat has significant metabolic implications, and their characterization may have potential therapeutic relevance with respect to the pathogenesis and treatment of diseases such as obesity, type 2 diabetes, and the metabolic syndrome.

Adiponectin↗

Differential RNA expression of hepatic tissue in lean and obese mice after LPS-induced systemic inflammation.

Mortality of obese patients with sepsis has been reported to be significantly higher than lean patients. The underlying basis for this difference is not currently known. However, it has been suggested that obesity is associated with an altered immune response to a septic or inflammatory insult. Since obesity is based on exclusion in many sepsis trials, little is known about how obesity affects mortality or whether obese individuals respond differently to therapeutic interventions. In this study, obese and non-obese mice were given intra-peritoneal injection of saline or LPS and the livers were harvested 2 hours later. RNA from these livers were subjected to DNA microarray. Analysis showed distinct differences in gene expression between lean and obese animals. The expression of one hundred and seventeen genes was found to be different among the groups. In the obese animals treated with LPS, the expression of 20 genes showed a significant change. Ontology analysis revealed increased expression of 15 genes and significant decrease in expression of 5 genes. This study shows different gene expression of liver in response to LPS in lean versus obese animals. These genes might play a role in the outcome of sepsis.

Animals↗

Update on extracorporeal life support 2004.

Since its beginnings in 1989, the Extracorporeal Life Support Organization (ELSO) Registry has collated and reported data on over 30,000 patients. The majority of patients entered into the Registry have been neonates with respiratory failure from meconium aspiration, persistent pulmonary hypertension, or congenital diaphragmatic hernia. These patients suffer from refractory hypoxemia; thus, this supportive technique came to be called "Extracorporeal Membrane Oxygenation (ECMO)" for its ability to provide excellent gas exchange. With advances in prevention, diagnosis, and treatment measures for neonatal respiratory failure, need for ECMO support has fallen from the peak of 1500 cases in the early 1990s to 800 cases annually. Sixty-six percent (over 19,000) of patients in the Registry are under the category of neonatal respiratory failure, with a 77% overall survival reported to discharge. The success of neonatal ECMO has led to expansion of the field to pediatric, cardiac, and adult patients. An average of 200 pediatric patients receive ECMO for respiratory failure per year with an overall survival of 55%. Adult respiratory failure patients form a smaller group, with less than 100 cases reported to the ELSO registry per year. Survival mirrors that noted in the pediatric ECMO population. The application of ECMO or related techniques continues to increase for cardiac failure across all age groups. Overall survival in cardiac patients ranges from 33% to 43%. A novel form of extracorporeal support is "ECPR" or ECMO during cardiac arrest. Bypass circuits and equipment can be set up and instituted within a very short period of time in this circumstance, thus the name "rapid deployment ECMO" has become associated with this form of support. Overall survival in the near-600 patients placed on ECMO during resuscitation is 40%.

Adolescent↗

Randomized, double-blind comparison of immediate-release omeprazole oral suspension versus intravenous cimetidine for the prevention of upper gastrointestinal bleeding in critically ill patients.

OBJECTIVE: To demonstrate that a new immediate-release omeprazole oral suspension is effective in preventing upper gastrointestinal bleeding in critically ill patients. DESIGN: A noninferiority analysis was used to compare rates of clinically significant upper gastrointestinal bleeding in a prospective, phase 3, double-blind trial with parallel omeprazole suspension and cimetidine treatment groups. SETTING: A total of 47 intensive care units in the United States. PATIENTS: A total of 359 critically ill patients who required mechanical ventilation for > or =48 hrs, had an Acute Physiology and Chronic Health Evaluation score of > or =11 at baseline, had an intact stomach with a nasogastric or orogastric tube in place, and had at least one additional risk factor for upper gastrointestinal bleeding. INTERVENTIONS: Patients were randomized to treatment with omeprazole suspension (two 40-mg doses on day 1, via orogastric or nasogastric tube, and 40 mg each day thereafter) or intravenous cimetidine (300-mg bolus and 50 mg/hr thereafter) for up to 14 days. Gastric aspirates were sampled for bleeding and pH. Medication doses were doubled for failure of pH control (two successive aspirates with pH < or = 4). MEASUREMENTS AND MAIN RESULTS: Clinically significant upper gastrointestinal bleeding (bright red blood not clearing after 5-10 mins of lavage or persistent Gastroccult-positive "coffee-grounds" material for 8 hrs on days 1-2 or for 2-4 hrs on days 3-14 and not clearing with > or =100 mL of lavage) was the primary end point of the trial. The rate of clinically significant bleeding in the per-protocol population was 4.5% with omeprazole suspension and 6.8% with cimetidine, meeting the criteria for the noninferiority of omeprazole suspension. Median gastric pH was > or =6 on all trial days with omeprazole suspension treatment and on 50% of days with cimetidine treatment (p < .001, all trial days). In the omeprazole suspension group, median gastric pH was >4 on each trial day in 95% of patients. CONCLUSIONS: Immediate-release omeprazole suspension is effective in preventing upper gastrointestinal bleeding and more effective than intravenous cimetidine in maintaining gastric pH of >4 in critically ill patients.

Administration, Oral↗

Protective effects of low respiratory frequency in experimental ventilator-associated lung injury.

OBJECTIVE: To determine whether ventilator-associated lung hyperinflation injury can be attenuated by a reduction in respiratory frequency. DESIGN: Prospective comparative laboratory investigation. SETTING: University medical center research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Eight groups of isolated, perfused rat lungs were exposed to cyclic ventilation at different respiratory frequencies and tidal volumes. Each group of six to eight lung preparations was assigned to one of four respiratory frequencies (10, 20, 40, or 80 breaths/min) and one of two tidal volumes (5 or 20 mL.kg). Measurement of capillary filtration coefficient (Kf,c), a sensitive index of lung microvascular permeability and injury, was made at baseline and at 30, 60, and 90 mins of the experimental conditions. MEASUREMENTS AND MAIN RESULTS: Lungs exposed to 5 mL.kg tidal volume had no elevation in Kf,c at any time point regardless of respiratory frequency. Lungs exposed to 20 mL. kg tidal volume and a respiratory frequency of 80 had significant elevations in Kf,c at all times after baseline compared with lungs exposed to respiratory frequencies of 10, 20, or 40 (0.14 +/- 0.03, 0.16 +/- 0.02, 0.31 +/- 0.05 vs. 0.76 +/- 0.16). Furthermore, the Kf,c at 90 mins was significantly higher than permeability at baseline in this group (1.53 +/- 0.45 vs. 0.12 +/- 0.02 mL.min.cm H2O.100 g of lung tissue). CONCLUSIONS: Reduction in respiratory frequency to values much lower than normal ameliorated experimental ventilator-induced hyperinflation lung injury as determined by pulmonary capillary filtration coefficient.

Animals↗

Brain RNA expression in obese vs lean mice after LPS-induced systemic inflammation.

Mortality of obese patients with severe sepsis is higher than non-obese patients. Thus far, a pathophysiologic mechanism has not been identified that explains this higher mortality. The central nervous system is now becoming increasingly recognized as a target organ in sepsis and the systemic inflammatory response syndrome and may hold clues to the deleterious affects of obesity in patients with sepsis syndrome. In this study, obese and non-obese mice were given LPS IP and the brains were harvested 2 hours after injection. The brains were processed and mRNA isolated and hybridized to a microarray chip and processed. Analysis of gene expression demonstrated distinct expression difference between the lean and obese animals. Ontology data supports clear differences between the lean and obese groups in the coagulation system, neuro-endocrine system, lipid transport and insulin receptors. Approximately eighty genes were identified to show 10-fold differential expression between the obese and lean mice.

Animals↗

Near-infrared spectroscopy: a tool to monitor cerebral hemodynamic and metabolic changes after cardiac arrest in rats.

INTRODUCTION: Cardiac arrest (CA) is associated with poor neurological outcome and is associated with a poor understanding of the cerebral hemodynamic and metabolic changes. The objective of this study was to determine the applicability of near-infrared spectroscopy (NIRS), to observe the changes in cerebral total hemoglobin (T-Hb) reflecting cerebral blood volume, oxygenation state of Hb, oxidized cytochrome oxidase (Cyto-C), and brain water content following CA. METHODS: Fourteen rats were subjected to normothermic (37.5 degrees C) or hypothermic (34 degrees C) CA induced by 8 min of asphyxiation. Animals were resuscitated with ventilation, cardiopulmonary resuscitation (CPR), and epinephrine (adrenaline). Hypothermia was induced before CA. NIRS was applied to the animal head to measure T-Hb with a wavelength of 808 nm (n = 10) and oxygenated/deoxygenated Hb, Cyto-C, and brain water content with wavelengths of 620-1120 nm (n = 4). RESULTS: There were no technical difficulties in applying NIRS to the animal, and the signals were strong and consistent. Normothermic CA caused post-resuscitation hyperemia followed by hypoperfusion determined by the level of T-Hb. Hypothermic CA blunted post-resuscitation hyperemia and resulted in more prominent post-resuscitation hypoperfusion. Both, normothermic and hypothermic CA resulted in a sharp decrease in oxygenated Hb and Cyto-C, and the level of oxygenated Hb was higher in hypothermic CA after resuscitation. There was a rapid increase in brain water signals following CA. Hypothermic CA attenuated increased water signals in normothermic CA following resuscitation. CONCLUSION: NIRS can be applied to monitor cerebral blood volume, oxygenation state of Hb, Cyto-C, and water content following CA in rats.

Animals↗

Cerebral cortical aquaporin-4 expression in brain edema following cardiac arrest in rats.

OBJECTIVES: Brain edema occurs following clinical as well as experimental cardiac arrest (CA) and predicts a poor neurologic outcome. The objective of this study was to determine the expression of cerebral cortex aquaporin (AQP)-4, a member of a family of membrane water-channel proteins, in brain edema formation following normothermic or hypothermic CA. METHODS: Twenty-four rats were subjected to time-matched normothermic (N-Sham, 37.5 degrees C +/- 0.5 degrees C, n = 6) or hypothermic (H-Sham, 34 degrees C +/- 0.5 degrees C, n = 6) sham experiments and normothermic (N-CA, n = 6) or hypothermic (H-CA, n = 6) CA induced by asphyxiation for 8 minutes. Hypothermia was induced before CA. The animals were resuscitated with cardiopulmonary resuscitation, ventilation, and epinephrine administration. Brain edema was determined by brain wet-to-dry weight ratio at one hour of resuscitation. AQP4 immunoactivity in the cerebral cortex was determined using immunohistochemical staining and was semiquantified as an intensity of staining with an automated cell imaging system. RESULTS: Mild hypothermia in the sham experiments did not alter cerebral cortex AQP4 immunoactivity (mean +/- SD) (55.0 +/- 3.7 in H-Sham vs. 53.3 +/- 1.7 in N-Sham, p > 0.05). N-CA resulted in a significant increase in AQP4 immunoactivity (61.8 +/- 4.5) compared with N-Sham (p = 0.01) and H-Sham (p = 0.03). H-CA attenuated AQP4 compared with N-CA (53.4 +/- 1.3, p = 0.01). Brain wet-to-dry weight ratios were 4.41 +/- 0.07 in N-Sham, 4.40 +/- 0.08 in H-Sham (p > 0.05 vs. N-Sham), 4.55 +/- 0.04 in N-CA (p = 0.004 vs. N-Sham; p = 0.005 vs. H-Sham), and 4.43 +/- 0.09 in H-CA (p = 0.02 vs. N-CA; p > 0.05 vs. N-Sham and H-Sham). CONCLUSIONS: Cerebral cortical AQP4 expression is up-regulated after normothermic CA, which is attenuated by hypothermia induced before CA.

Animals↗

Extracorporeal carbon dioxide removal to control arterial pH and PACO2 in a heart-beating donor with acute lung injury.

BACKGROUND: Arteriovenous carbon dioxide (AVCO2R) removal is a technique of pumpless extracorporeal carbon dioxide removal. This system has been used successively to control pH and PaCO2 in patients with acute lung injury who could not be adequately ventilated. This report describes the use of this technology in an organ donor awaiting harvesting. METHODS: AVCO2R was implanted using a hollow-fiber oxygenator attached to 12 F and 14 F vascular cannulas that were inserted into the femoral artery and vein, respectively. Oxygen was attached to the oxygenator to provide the sweep gas. RESULTS: The PaCO2 and arterial pH promptly corrected after support was initiated (from 83-42 mm Hg and 7.18-7.38, respectively). CONCLUSION: This case describes the successful use of pumpless arteriovenous extracorporeal removal of CO2 in a heart-beating donor awaiting organ harvest.

Accidents, Traffic↗

Pressure-controlled ventilation attenuates lung microvascular injury in a rat model of activated charcoal aspiration.

BACKGROUND: Previous animal data suggest that aspiration of activated charcoal is associated with pulmonary microvascular injury that may be related to excessive ventilator-induced airway pressures. The purpose of this study was to test the hypothesis that ventilator-induced airway trauma contributes to the lung vascular injury observed following activated charcoal aspiration. METHODS: Capillary filtration coefficient (Kf,c), a sensitive measure of lung microvascular permeability, was determined isogravimetrically prior to and after intratracheal instillation of 0.4 ml/kg (12% weight/vol. solution, pH 7.4) activated charcoal oran equal volume of sterile water in isolated, perfused rat lungs in which ventilation was either pressure-controlled at 10cm H2O or volume-controlled at 5 ml/kg. RESULTS: There was significant lung injury in both activated charcoal groups regardless of ventilation method compared to control lungs or lungs administered sterile water (p < 0.05 ANOVA). However, injury to pressure-controlled ventilated lungs was significantly less than lungs ventilated with traditional, volume-controlled ventilation. CONCLUSION: The results of this investigation demonstrate that pressure-controlled ventilation reduces the lung microvascular injury observed following aspiration of activated charcoal as compared to traditional volume-controlled ventilation methods.

Administration, Inhalation↗

Serum procalcitonin concentration as a negative predictor of serious bacterial infection in acute sickle cell pain crisis.

BACKGROUND: A pilot study was designed to determine if serum procalcitonin levels would assist in the diagnosis of severe bacterial infections in patients presenting to an emergency department (ED) with acute sickle cell pain crisis and evidence of acute inflammatory response. MATERIAL/METHODS: Prospective single cohort study evaluating measured procalcitonin levels in patients with sickle cell pain crisis and evidence of acute inflammation. Acute inflammation was defined as fever (>38 degrees C) and/or elevation in the white blood cell count (>4000 above baseline) and tachycardia (heart rate >100). Procalcitonin was measured using a semi-quantitative monoclonal antibody test. Patients were followed clinically to determine if procalcitonin has predictive value in excluding severe bacterial infections. RESULTS: Twenty four subjects were enrolled and completed the study. Sixteen had levels 0.5 ng/ml or less, two had levels 0.5 to 2 ng/ml, one had a level of 2 but less than 10 ng/ml, and four had levels 10 ng/ml or greater. All subjects with documented infections at presentation had procalcitonin levels > or =2.0 ng/ml. The sensitivity of the test in this study sample was 1, and the specificity was 0.95 (95% CI, 0.75-0.99). CONCLUSIONS: A serum procalcitonin less than 2 ng/ml appears to have good negative predictive value in excluding serious bacterial infections in patients that present with acute sickle cell pain crisis and evidence of acute inflammatory response. Further study is needed to investigate if procalcitonin has positive predictive value in identifying patients with serious bacterial infections in this patient population.

Acute Disease↗

Management of the acute respiratory distress syndrome.

Significant advances have occurred in the knowledge of the pathogenesis of ARDS. It is now recognized that ARDS is a manifestation of a diffuse process that results from a complicated cascade of events following an initial insult or injury. Mechanical ventilation and PEEP are still important components of supportive therapy. To avoid ventilator-associated lung injury there is emphasis on targeting ventilator management based on measurement of pulmonary mechanics. For those with resistant hypoxia and severe pulmonary hypertension adjunctive modalities, such as prone positioning and low-dose iNO, may provide important benefit. Alternative modes of supporting gas exchange, such as with partial liquid ventilation and extracorporeal gas-exchange, may serve as rescue therapies. Advances in cell and molecular biology have contributed to a better understanding of the role of inflammatory cells and mediators that contribute to the acute lung injury and the pathophysiology of the syndrome that manifests as ARDS. Based on this new understanding, the potential targets for intervention to ameliorate the systemic inflammatory response have proliferated. Examples include the cytokine network and its receptors, antioxidants, and endothelins. Apart from the challenge of testing these agents in experimental models, it seems likely that determination of the optimum combination of agents will become an equally important endeavor. A particular challenge is to develop better methods of predicting which of the many at-risk patients will go on to full-blown ARDS and MODS, thereby targeting subgroups of patients most likely to benefit from anti-inflammatory therapies. Similarly, the adverse effects of immunosuppressive therapy may be diminished by improved, perhaps molecular, techniques to detect microbial pathogens and permit differentiation between Systemic inflammatory response syndrome and sepsis.

Animals↗