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Biomedical subjects

Timothy W Evans

Publications and source records attributed to Timothy W Evans.

At least 19 recordsLinked to original sources
PubMed2007

Elucidation of toll-like receptor and adapter protein signaling in vascular dysfunction induced by gram-positive Staphylococcus aureus or gram-negative Escherichia coli.

Pathogens contain specific pathogen-associated molecular patterns, which activate pattern recognition receptors of the innate immune system such as Toll-like receptors (TLRs). Although there is a clear evidence of how macrophages sense pathogens, we know less about such processes in vessels. This is critical to understand because activation of vascular cells and the subsequent induction of inflammatory genes by bacteria are crucial events in the development of septic shock. In the current study we have used genetically modified mice to investigate the role of TLRs, adapter proteins, tumor necrosis factor alpha (TNFalpha), and nitric oxide synthase II (NOSII) in vascular dysfunction induced by Gram-positive (Staphylococcus aureus) or Gram-negative (Escherichia coli) bacteria. Our data show that Gram-positive S. aureus or Gram-negative E. coli causes vascular dysfunction via the induction of NOSII. For S. aureus, this process requires TLR2, TLR6, myeloid differentiation factor 88 (MyD88) adapter-like, MyD88, and TNF, but not TLR4 or TLR1. Vascular dysfunction induced by E. coli requires TLR4 but has no requirement for TLR2, TLR1, TLR6, or TNF, and a partial but incomplete requirement of MyD88 and TIR domain-containing adapter inducing interferon-beta. Staphylococcus aureus induced NOSII protein expression in vascular smooth muscle cells but not in macrophages, whereas E. coli induced NOSII in both cell types. Our data are the first to establish the definitive roles of specific TLRs in the sensing of Gram-positive and Gram-negative bacteria by vessels and demonstrate that macrophages and blood vessels may differ in their response to pathogens.

Animals↗
PubMed2006

Persistently low plasma thioredoxin is associated with meningococcal septic shock in children.

OBJECTIVE: To compare plasma levels of thioredoxin (Trx), TNF-alpha and IL-1 beta in children during the acute phase of meningococcal septic shock (MSS) and in convalescence. DESIGN AND SETTING: Retrospective, observational study in the paediatric intensive care unit of a postgraduate teaching hospital. PATIENTS: Thirty-five children requiring intensive care for meningococcal sepsis; paired convalescent samples from 30 survivors (median interval between samples 62 days); 25 healthy control children. MEASUREMENTS AND RESULTS: Plasma Trx levels were significantly lower in the children with MSS, both during the acute illness (5.5 ng/ml, IQR 1.4-11.4) and in convalescence (2.5 ng/ml, IQR 0.4-6.9) than controls (18.8 ng/ml, IQR 7.9-25.0). Levels of IL-1 beta and TNF-alpha were higher in patients with acute MSS (30.3 pg/ml, IQR 3.6-63.6, and 145.9 pg/ml, IQR 31.8-278.1 respectively) than controls (3.7 pg/ml, IQR 0-36.9, and 23.8 pg/ml, IQR 0-124.3, respectively). Levels fell in convalescence (3.7 pg/ml, IQR 0-25.5, 3.7 pg/ml, IQR 0-304.8, respectively). Plasma Trx was higher in non-survivors, albeit a small group (n=5), than in survivors (n=30). Trx, IL-1 beta, and TNF-alpha levels were not correlated with predicted mortality as assessed by the paediatric risk of mortality (PRISM) score. CONCLUSIONS: Children with MSS exhibit persistently low plasma levels of Trx during acute illness and in convalescence.

Case-Control Studies↗
PubMed2006

Incidence, duration and causes of intensive care unit admission following pulmonary resection for malignancy.

BACKGROUND: We assessed the overall incidence and duration of ICU admission following pulmonary resection and attempted to identify patients requiring prolonged ICU stay. METHODS: Analysis of prospectively collected data on all patients undergoing pulmonary resection for suspected malignant disease that subsequently required ICU admission between March 2002 and October 2003. RESULTS: Of 170 patients 52 (30%) needed intensive care post-operatively: 21 (12%) for less than 24 h and 31 (18%) for more, for which group the average length of stay was 11.3 days. There was no significant difference between the patient groups at ICU admission in terms of median APACHE II scores (12 vs. 14), gas exchange (PaO2/FIO2, 441 vs. 364 mmHg), estimated post-operative absolute FEV1 (1.62 vs. 1.31 l) or predicted percentage FEV1 (61.8% vs. 44.3%). Mean ICU cost was 1,838 sterling pounds vs. 25,974 sterling pounds per admission, respectively. CONCLUSIONS: Following pulmonary resection some 18% of patients need a protracted ICU stay at considerable cost. Neither severity of illness scoring, indices of gas exchange at ICU admission, nor predicted post-operative FEV1 identifies such patients.

APACHE↗
PubMed2006

Organ dysfunction during sepsis.

BACKGROUND: Multiple organ dysfunction syndrome is the commonest reason for sepsis-associated mortality. DISCUSSION: In the 40 years since it was first described understanding of its pathophysiology has improved, and novel methodologies for monitoring and severity of illness scoring have emerged. These, together with the development of systematic strategies for managing organ dysfunction in sepsis, and potentially effective new therapeutic interventions, should assist in reducing sepsis-associated mortality. CONCLUSION: These historical developments are discussed, and the reader is directed to these references for further guidance.

Humans↗
PubMed2006

Abdominal compartment syndrome: a rare complication of plication of the diaphragm.

Abdominal compartment syndrome is an increasingly recognized phenomenon. We report the case of an otherwise fit and healthy 42-year-old man who underwent plication of the right hemidiaphragm for idiopathic phrenic paresis. His postoperative recovery was complicated by abdominal compartment syndrome, which was managed conservatively. We believe this is the only report of this complication after diaphragmatic plication and one of very few reported thoracic causes of abdominal compartment syndrome.

Abdomen↗
PubMed2005

Redox regulation of neutrophil apoptosis and the systemic inflammatory response syndrome.

SIRS (systemic inflammatory response syndrome) may result from a wide variety of non-infective insults. Surgery is a recognized cause of SIRS, the onset of which can have adverse prognostic significance. Neutrophil activation is a key histopathological feature of SIRS, and neutrophil clearance through programmed cell death or apoptosis is an essential step in its resolution. Increasingly, it is recognized that ROS (reactive oxygen species), such as those generated by activated neutrophils during cardiac surgery, may have a regulatory role, influencing neutrophil lifespan and thus inflammation. In this review, we discuss the continuing importance of SIRS as a herald of inflammation and the role of neutrophil longevity in the resolution of inflammation, and we consider recent evidence for the regulation of neutrophil apoptosis by ROS.

Apoptosis↗
PubMed2005

Epidemiology of acute lung injury.

PURPOSE OF REVIEW: Acute lung injury and its extreme manifestation, acute respiratory distress syndrome, complicate a wide variety of serious medical and surgical conditions, only some of which affect the lung directly. Despite recent evidence-based advances in clinical management, acute lung injury and acute respiratory distress syndrome are associated with significant mortality. Detailed epidemiology is essential in guiding the recruitment of patients into trials of new therapeutic interventions, thereby improving outcome and allowing directed allocation of scarce resources. RECENT FINDINGS: The incidence of acute lung injury in the United States overall (17-64 per 100,000 person-years) seems to be higher than in Europe, Australia, and other developed countries (17-34 per 100, 000 person-years). The mortality rates for patients with acute respiratory distress syndrome range from 34 to 58%. The hypothesis that pulmonary and extrapulmonary acute respiratory distress syndromes are different disease entities continues to gain momentum. A genetic predisposition to acute respiratory distress syndrome may contribute to its pathogenesis and outcome. SUMMARY: Recent epidemiologic studies of the incidence of acute lung injury and acute respiratory distress syndrome have indicated a similar incidence in developed societies, and they confirm that mortality is falling in comparison with a decade ago. The awaited publication of new consensus guidelines for the definition of acute lung injury and acute respiratory distress syndrome may render new studies necessary.

Australia↗
PubMed2004

Fluids reverse the early lipopolysaccharide-induced albumin leakage in rodent mesenteric venules.

OBJECTIVE: Volume resuscitation is clinically beneficial in patients with sepsis, but few data exist concerning the effects of fluid administration on early events in the inflammatory process. Vascular permeability, leukocyte rolling and leukocyte adhesion in the rodent mesenteric microcirculation were assessed in vivo using intravital microscopy, and the effect of fluid administration on lipopolysaccharide (LPS)-induced changes recorded. DESIGN: Prospective, repeated measures study. SETTING: University hospital laboratory. SUBJECTS: Male Wistar rats in six groups. INTERVENTIONS: All animals underwent intravital microscopic examination of mesenteric post-capillary venules. LPS or vehicle was applied topically. Animals received either no additional fluids, 0.9% saline (16 ml/kg per h) or 5% human albumin (16 ml/kg per h) commencing 30 min prior to LPS/vehicle administration. MEASUREMENTS AND MAIN RESULTS: Leukocyte rolling, firm adhesion and blood velocity were observed directly. Vascular permeability was assessed using the flux of fluorescently labelled albumin into the interstitium. LPS significantly increased the median (IQR) number of leukocytes rolling and firmly adherent relative to baseline (at 60 min rolling increased from 12.0 (10.3-13.8) to 40.3 (36.0-47.5) cells/min; adhesion increased from 1 (1-2) to 17 (12-26) cells/100 microm; n=5, p<0.01). Transvascular albumin flux was significantly increased 45 min after LPS application (p<0.01), but not after vehicle. Administration of either 0.9% saline (n=5) or 5% human albumin (n=6), significantly attenuated LPS-induced increases in albumin flux (p<0.05), leukocyte rolling (p<0.01) and adhesion (p<0.01). Fluid administration did not appear to alter shear rates. CONCLUSIONS: Pre-emptive volume administration with either saline or albumin prevented early LPS-induced microcirculatory changes by an undefined effect that is unrelated to changes in microvascular flow.

Albumins↗
PubMed2004

Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute and mid-term effects.

AIM: The treatment of patients with pulmonary arterial hypertension remains a challenge. We set out to investigate the use of sildenafil, a selective inhibitor of phosphodiesterase type 5, in patients with this disease. METHODS AND RESULTS: Ten patients (8 females, mean age 34.5+/-3.3 years) with pulmonary hypertension underwent right heart catheterisation with vasodilator testing using incremental doses of intravenous sildenafil without adverse events. All patients were subsequently commenced on oral sildenafil 50 mg t.d.s. Nine patients had repeat right heart catheterisation 3 months after the commencement of oral therapy. There was a significant reduction in mean pulmonary artery pressure (from 55.8+/-5.9 to 50.4+/-6.1 mmHg, p=0.038 ) and pulmonary vascular resistance (from 10.1+/-1.7 to 8.6+/-1.5 Wood units, p=0.009 ), and an increase in cardiac output (from 4.7+/-0.3 to 5.0+/-0.4 l/min, p=0.15 ). Furthermore, there was a significant increase in the 6-minute walk test, a mean of 112 m. In response to a quality-of-life questionnaire, patients indicated marked clinical improvement on sildenafil. Sildenafil was discontinued in 1 patient due to a transient visual disturbance. The only patient previously awaiting transplantation was removed from the active transplantation list. CONCLUSIONS: Sildenafil is well tolerated in its intravenous and oral forms and appears to improve both pulmonary haemodynamics and the clinical status of patients with pulmonary hypertension after 3 months of oral therapy.

Administration, Oral↗
PubMed2004

Albumin influences total plasma antioxidant capacity favorably in patients with acute lung injury.

OBJECTIVE: To ascertain the influence of albumin on antioxidant status in patients with acute lung injury. DESIGN: Prospective, randomized, placebo-controlled study. SETTING: Intensive care units, teaching hospitals. PATIENTS: Twenty patients meeting the American European Consensus criteria for acute lung injury. INTERVENTIONS: Ten patients received albumin (25 g of a 25% solution every 8 hrs for a total of nine doses) and ten received placebo (normal saline administered in identical fashion and volume). All received supportive therapy appropriate for patients with acute lung injury. Plasma samples were obtained sequentially from all patients before, 30 mins after, and 4 hrs after albumin/placebo administration. MEASUREMENTS AND MAIN RESULTS: Serum albumin and total protein, total antioxidant status, iron-binding antioxidant protection, iron-oxidizing antioxidant protection, lipid hydroperoxides, protein carbonyls, and plasma thiols were measured. Albumin administration increased plasma albumin concentrations (p <.05 compared with placebo) and decreased concentrations of protein carbonyls (p <.05 compared with placebo). By contrast, plasma lipid hydroperoxide concentrations were similar in both groups, both in absolute terms and relative to albumin content. For all other variables, no significant differences were apparent. For all patients, there was a positive correlation between albumin and plasma thiol concentrations (r =.983, p <.01) and albumin and antioxidant capacity (r =.885, p =.01). In the albumin treatment group, there was a strong correlation between thiols and antioxidant capacity (r =.876, p =.01). No such correlation was apparent in the placebo group. Plasma iron-binding antioxidant protection was negatively correlated (r = -.741, p <.05) with albumin content in the treatment group but not the placebo group. CONCLUSIONS: In patients with acute lung injury, albumin administration favorably influences plasma thiol-dependent antioxidant status as well as levels of protein oxidative damage.

Adult↗
PubMed2004

Lung heme oxygenase-1 is elevated in acute respiratory distress syndrome.

OBJECTIVE: We aimed to quantify concentrations of inducible heme oxygenase (HO)-1 in the lungs of patients with acute respiratory distress syndrome (ARDS) and to investigate its role as a source of ferrous iron and as a signaling agent for iron regulation. Control of such processes by heme oxygenase has implications for the onset, progression, and resolution of ARDS. DESIGN: Retrospective analysis of archived samples. SETTING: Adult intensive care unit of a postgraduate teaching hospital. PATIENTS: Patients admitted to the adult intensive care unit who fulfilled the American-European Consensus Conference criteria for ARDS. INTERVENTIONS: Biochemical and immunohistochemical studies using bronchoalveolar lavage fluid or lung tissue were performed in patients with established ARDS and in those undergoing lung resection (controls). MEASUREMENTS AND MAIN RESULTS: Concentrations of heme oxygenase protein were significantly elevated in lung tissue (193.7 +/- 13.27 vs. 81.0 +/- 16.0%, p < .01) and in bronchoalveolar lavage fluid (2.4 x 10(5) vs. 1.4 x 10(5) densitometric units, p = .047) taken from patients with ARDS compared with controls. Concentrations of heme oxygenase protein in bronchoalveolar lavage fluid from patients with ARDS correlated positively and significantly with changes in the concentrations of ferritin (r = .697, p = .02) and the iron saturation of transferrin (r = .8, p = .014) but correlated negatively and significantly with concentrations of bleomycin-detectable (redox-active) iron (r = -.73, p = .031). Significantly elevated (p < .05) concentrations of heme oxygenase staining in cell types expressing this protein were detected in patients with ARDS, compared with concentrations in the same cells taken from controls undergoing lung resection. CONCLUSIONS: Heme oxygenase protein is elevated in the lungs of patients with ARDS and may contribute to the changes in iron mobilization, signaling, and regulation seen in this condition.

Adult↗
PubMed2003

Glucose control and mortality in critically ill patients.

CONTEXT: Hyperglycemia is common in critically ill patients, even in those without diabetes mellitus. Aggressive glycemic control may reduce mortality in this population. However, the relationship between mortality, the control of hyperglycemia, and the administration of exogenous insulin is unclear. OBJECTIVE: To determine whether blood glucose level or quantity of insulin administered is associated with reduced mortality in critically ill patients. DESIGN, SETTING, AND PATIENTS: Single-center, prospective, observational study of 531 patients (median age, 64 years) newly admitted over the first 6 months of 2002 to an adult intensive care unit (ICU) in a UK national referral center for cardiorespiratory surgery and medicine. MAIN OUTCOME MEASURES: The primary end point was intensive care unit (ICU) mortality. Secondary end points were hospital mortality, ICU and hospital length of stay, and predicted threshold glucose level associated with risk of death. RESULTS: Of 531 patients admitted to the ICU, 523 underwent analysis of their glycemic control. Twenty-four-hour control of blood glucose levels was variable. Rates of ICU and hospital mortality were 5.2% and 5.7%, respectively; median lengths of stay were 1.8 (interquartile range, 0.9-3.7) days and 6 (interquartile range, 4.5-8.3) days, respectively. Multivariable logistic regression demonstrated that increased administration of insulin was positively and significantly associated with ICU mortality (odds ratio, 1.02 [95% confidence interval, 1.01-1.04] at a prevailing glucose level of 111-144 mg/dL [6.1-8.0 mmol/L] for a 1-IU/d increase), suggesting that mortality benefits are attributable to glycemic control rather than increased administration of insulin. Also, the regression models suggest that a mortality benefit accrues below a predicted threshold glucose level of 144 to 200 mg/dL (8.0-11.1 mmol/L), with a speculative upper limit of 145 mg/dL (8.0 mmol/L) for the target blood glucose level. CONCLUSIONS: Increased insulin administration is positively associated with death in the ICU regardless of the prevailing blood glucose level. Thus, control of glucose levels rather than of absolute levels of exogenous insulin appear to account for the mortality benefit associated with intensive insulin therapy demonstrated by others.

APACHE↗
PubMed2003

Heme oxygenase is expressed in human pulmonary artery smooth muscle where carbon monoxide has an anti-proliferative role.

Heme oxygenase is the rate-limiting enzyme in the catabolism of heme to carbon monoxide, bilirubin and free iron. Many cell types express heme oxygenase-2 constitutively while heme oxygenase-1 is induced at sites of inflammation and oxidative stress. In systemic blood vessels, carbon monoxide may have an important homeostatic role where, like its better-studied counterpart nitric oxide, it is emerging as a vasodilator and an inhibitor of proliferation. However, much less is known regarding the role of heme oxygenase and carbon monoxide in the pulmonary circulation where vascular responses are very different. Here, using primary cultures of human pulmonary artery smooth muscle cells, we present novel data showing that this cell type expresses heme oxygenase-2 constitutively and, in the presence of oxidants, can induce heme oxygenase-1. We also show that the carbon monoxide-releasing molecule, tricarbonyldichlororuthenium (II) dimer, potently and profoundly inhibits proliferation of human pulmonary artery smooth muscle cells. Pulmonary hypertension is a disease characterised by abnormal vascular smooth muscle cell growth and remodelling of the pulmonary vasculature. Our observations support the growing evidence that the heme oxygenase/carbon monoxide system may play a role in the pathology of pulmonary hypertension.

Blotting, Western↗
PubMed2003

Type II nitric oxide synthase activity is cardio-protective in experimental sepsis.

Overproduction of nitric oxide (NO) via the induction of NO synthase (NOS) II is implicated in the pathogenesis of the refractory hypotension that characterizes septic shock. However, clinical trials of nonselective NOS inhibitors have failed to afford a mortality benefit in patients with sepsis, and in those with depressed left ventricular function, death rates were increased. Such observations have led to the suggestion that a selective inhibitor of NOSII would be more effective in treating septic shock, although precisely how NO modulates cardiac function in these circumstances remains unclear. We therefore used an isolated ejecting rodent heart model to study the effects of NO and experimental sepsis (endotoxin 20 mg kg i.p.) on cardiac functions. Coronary flow and cardiac output and ventricular functions were reduced by LPS, effects that were partially obviated by supplementation of perfusate with the NO substrate, L-arginine. These improvements were partially blocked by the selective NOSII inhibitor N-(3-(aminomethyl)benzyl)acetamidine (1400W) and further reduced by the combined NOSI, II and III inhibitor L-nitro L-arginine methyl ester (L-NAME). These findings suggest that NOSII is cardio-protective in the heart in sepsis and explain why its inhibition in man led to increased mortality in a subpopulation of patients.

Amidines↗