Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to lipid lowering effects, statins appear to have pleiotropic immunomodulatory properties. As they particularly affect monocyte functions, we tested the influence of statin treatment on the monocyte activating toll-like receptors (TLR) 4 and 2 in response to lipopolysaccharides (LPS) in vivo. In this double-blind, placebo-controlled study, 20 healthy, male subjects were randomized to receive either simvastatin (80 mg/day) or placebo for 4 days before intravenous LPS administration (20 IU/kg). Simvastatin did not influence the increase in TLR transcripts after LPS administration measured in mRNA isolated from whole blood by quantitative RT-PCR. In contrast, the parallel upregulation of TLR4 and TLR2 on the surface of monocytes determined by flow cytometry was attenuated by more than half after LPS challenge (P<0.02). Suppressed TLR4 and TLR2 expression was associated with diminished circulating concentrations of tumor necrosis factor-alpha and monocyte chemoattractant protein-1. In conclusion, high-dose simvastatin pretreatment blunted TLR4 and TLR2 expression on monocytes in a human endotoxemia model on a posttranscriptional level. This suppressive effect of statins on key receptors of the innate immunity which was associated with a reduction of effector cytokines reveals a potential mechanism for their beneficial effects in sepsis and cardiovascular disease.
 ...
PMID:Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo. 1644 29

An understanding of energy expenditure in hospitalized patients is necessary to determine optimal energy supply in the care of individuals who require nutritional support. A review was conducted of 19 studies in which resting energy expenditure (REE) had been measured using indirect calorimetry and compared with estimated basal energy expenditure (BEE) from the Harris-Benedict equation. Studies of patients with burns, head injuries, and fever were excluded because REE is known to be increased in these conditions. The studies reported data on 1256 patients with the following diagnoses: postoperative (28%), trauma or sepsis (26%), cancer (18%), pulmonary disease (9%), cardiovascular disease (2%), miscellaneous (9%), and unspecified (6%). The average REE in the 19 studies was 113% of the BEE. The mean +/- SD REE/BEE ratio was higher in 11 studies in which the REE was measured during feeding than in 5 studies in which the measurement was made during fasting (117% +/- 3% vs 105% +/- 4%; P = .047). In those 11 studies, overfeeding may have contributed to higher REE values than otherwise would have been observed. Some evidence indicated that the REE/BEE ratio is higher in more severe illness, but results were inconsistent. Unfortunately, little information is available concerning total energy expenditure, which includes the contribution of physical activity. It appears that most patients can be fed adequately with energy equal to 100% to 120% of estimated BEE. Hypoenergetic feeding may be appropriate in some overweight and obese individuals. Additional research in hospitalized patients on total energy expenditure and on the relationship between severity of illness and energy expenditure is needed.
 ...
PMID:Energy expenditure in hospitalized patients: implications for nutritional support. 1677 Sep 81

The future perspectives of cardiovascular intensive care medicine (CVICM) are affected by an ever increasing number of elderly (> 65 years), old (> 75 years) and very old (> 85 years) patients with the incidental clinical consequences, by an increase in inpatient days due to the increasing number of patients who have to be treated despite cost pressure, and by the attempts to integrate CVICM into one interdisciplinary intensive care unit (ICU) including medical and surgical patients, although proof of equal or even superior outcome, process or structural quality is lacking presently. To overcome all the problems mentioned, CVICM must develop from a mainly consensus-oriented to a more evidence-oriented medicine; CVICM must find ways to improve the poorly validated hemodynamic monitoring concept by pulmonary artery catheter and look for additional, less invasive monitoring techniques and better monitoring parameters; CVICM must support the search for new and hopefully better pharmacotherapeutic agents and cardiovascular assist devices as presently available to support the failing heart and the impaired vascular system; and CVICM must also learn to control noncardiac processes like inflammation and multi-organ failure, which often are responsible for the fatal outcome of the ICU patient with cardiovascular disease. Real challenges for the cardiovascular intensivist are refractory shock and refractory septic cardiomyopathy, these cardiovascular disease entities being responsible for every other fatality in the wake of severe sepsis and septic shock. To handle these tremendous challenges of CVICM, training of the young cardiologists in CVICM must be intensified, and much more attention to cardiovascular topics and techniques must be paid when training our colleagues in medical intensive care medicine.
 ...
PMID:[Future perspectives of cardiovascular intensive care medicine]. 1680 27

We analyzed survival rates of 144 prevalent patients on maintenance hemodialysis from 1998 to 2003 at the Department of Nephrology and Dialysis, Rijeka University Hospital, Rijeka, Croatia, and evaluated risk factors predicting their survival. Included were only end-stage renal disease (ESRD) patients on maintenance hemodialysis treatment dialysed more than 6 months before entering the study and who were clinically stable. The patients were randomised in two groups according to the presence or absence of diabetic nephropathy as the cause of ESRD and followed-up. The patient's death as outcome measure was recorded. The survival rates were estimated by the Kaplan-Meier method. The major causes of death were cardiovascular disease in 40 (60.6%) patients. An acute myocardial infarction in 15 (22.7%) patients was the major single cause of death. We found a significantly lower survival of diabetic patients than non-diabetic patients (P=0.0013). The most important predictors of death among diabetic patients on maintenance hemodialysis were hyperglycaemia (P<0.001), ischemic heart disease (P=0.004), hypercholesterolemia (P=0.013), and low delivered dialysis dose (P=0.013). The survival of diabetic patients undergoing hemodialysis was much worse than survival of non-diabetic patients. The cardiovascular disease remained the major cause of death in both groups. Early detection of pre-existing cardiovascular risk factors and diseases, and treatment of infections leading to sepsis, are of great importance, as they may influence the survival rates. Intensive management of diabetic patients is essential.
 ...
PMID:Comparison of survival between diabetic and non-diabetic patients on maintenance hemodialysis: a single-centre experience. 1682 39

Among non-traditional cardiovascular risk factors both malnutrition and inflammation appear to be strong predictors of mortality and morbidity in haemodialysis (HD) patients. Our study objective was to determine predictors of all-cause and cardiovascular mortality, considering the nutritional and immunologic parameters, in a cohort of HD patients treated in a single haemodialysis centre. 216 patients on HD were analyzed for clinical, nutritional-serum albumen and BMI, immunologic-serum CRP (C-reactive protein) and fibrinogen and dialysis parameters -- ultrafiltration, length of dialysis in hours, HD dose (using spKt/V and eKt/V). Mortality was monitored prospectively over a two-year period. Fifty-five of the 216 HD patients died during the follow-up period and the main cause of death was cardiovascular disease (CVD) -- 33 patients out of 55 (60%), followed by infection/sepsis (13 pts, 24%). The patients who died were significantly older, had a significantly shorter duration of HD in hours, ultrafiltration was significantly less, HD doses were significantly lower, as were serum levels of albumin (36.06 +/- 4.17 vs. 39.74 +/- 3.31; p=0.000) and Hg (93.14 +/- 15.43 vs. 109,16 +/- 12,08; p=0.000), but they had significantly higher serum levels of CRP (40.26 +/- 34.75 vs. 8.71 +/- 7.68, p=0.000) and fibrinogen (5.28 +/- 1.28 vs. 4.42 +/- 0.97, p=0.000). Kaplan-Meier survival estimates showed that the group with the lowest levels of albumin (< 3.5 g/L), and with the greatest levels of CRP (>20 mg/l) and fibrinogen (>5 g/L) had the lowest survival (log-rank test p=0.0008, p=0.00000, p=0.0000). However, in the Cox proportional hazards model, a high CRP and low Hg level (chi-square=96.467, p=0.0000) were predictors of all-cause mortality, whereas serum level of albumin did not show to be predictive. When only cardiovascular mortality is entered into the Cox model, CRP and Hg levels are still more important in predicting mortality (chi-square=70.055, p=0.0000) and only if CRP is not taken into account in the multivariate analysis, serum albumin level remains, after Hg, the strongest predictor for both overall and cardiovascular mortality (chi-square=76,564, p=0.0000; chi-square 50.619 p=0.0000). It can be concluded that inflammation predicted all-cause and cardiovascular mortality in our study group, because high CRP, as a marker of inflammation and low haemoglobin, as a result of inflammation, remained powerful predictors of both overall and cardiovascular death.
 ...
PMID:Inflammation predicts all-cause and cardiovascular mortality in haemodialysis patients. 1698 87

Sepsis, septic shock and organ failure are common among patients with moderate to severe burns. The inability of demographic and clinical factors to identify patients at high risk for such complications suggests that genetic variation may influence clinical outcome. Moreover, the genetic predisposition to death from infection has been estimated to be greater than for cardiovascular disease or cancer . While it is widely accepted that genetic factors influence many complex disease processes, controversy has emerged regarding the most appropriate methods for detection and even the validity of many published allelic associations . This article will review the few studies of genetic predisposition that have been conducted in the setting of burn injury, then discuss some of the obstacles and potential approaches for the discovery of additional allelic associations.
 ...
PMID:Detecting genetic predisposition for complicated clinical outcomes after burn injury. 1700 25

Adrenomedullin (AM) is a 52-amino-acid multifunctional peptide that circulates in the plasma in the low picomolar range and can exert a multitude of biological effects through an autocrine/paracrine mode of action. The mechanism by which AM transduces its signal represents a novel and pharmacologically tractable paradigm in G protein-coupled receptor signaling. Since its discovery in 1993, the study of AM has emerged into a new field of research with nearly 1800 publications that rivals the renown of other common factors like angiopoetin (1015 publications) and ghrelin (1550 publications). Despite the tremendous strides made in recent years toward unveiling the biochemical and cellular functions of AM, we are still lagging in our understanding of the essential roles of AM in normal and disease physiology. As discussed in this current review, a concerted effort to combine information from clinical, genomic, biochemical, and genetic mouse model sources can provide a focused view to help define the physiological functions of AM. Specifically, we find that certain conditions, such as pregnancy, cardiovascular disease, and sepsis, are associated with robust and dynamic changes in the expression of AM and AM receptor proteins, which together represent an elegant mechanism for altering the physiological responsiveness or function of AM. Thus, the modulation of AM signaling may be further exploited for therapeutic strategies in the management and treatment of human disease.
 ...
PMID:Receptor activity-modifying proteins: RAMPing up adrenomedullin signaling. 1705 41

Analyses describing outcomes of kidney transplantation usually exclude the survival of wait-listed patients and dialysis patients with failed kidney transplants, and thus reflect only a portion of the typical transplant process. We determined death rates during the continuum of wait-listing, transplantation, and after allograft failure among adult end-stage renal disease patients in the United States between 1995 and 2003. Before transplantation, death rates increased with longer waiting times. Death rates were lowest during the period of allograft function and highest after allograft failure. Patients were at particularly high risk during periods of transition between dialysis and transplantation (death rates during the peri-transplant period and during the re-initiation of dialysis after transplant failure were 8.2/100 patient-years (95% confidence interval (CI) 7.7, 8.8) and 17.9/100 patient-years (95% CI 15.7, 20.3), respectively compared to 6.4/100 patient-years (95% CI 6.25, 6.51) during the period of wait-listing. Diabetic patients and older patients were at increased risk at all time points. The most common known cause of death in all age subgroups was cardiovascular disease. The proportion of death owing to sepsis was greatest after allograft failure (16.8% of all deaths were due to sepsis compared to 14.0% during wait-listing, and 12.7% during the period of allograft function). Consideration of the entire transplant experience as a whole should help to focus patient care on periods of particularly high risk, and emphasizes opportunities to improve outcomes by strategies aimed at preventing death owing to cardiovascular and infectious causes.
 ...
PMID:The importance of transitions between dialysis and transplantation in the care of end-stage renal disease patients. 1722 66

Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA) are endogenously produced amino acids that inhibit all three isoforms of nitric oxide synthase (NOS). ADMA accumulates in various disease states, including renal failure, diabetes and pulmonary hypertension, and its concentration in plasma is strongly predictive of premature cardiovascular disease and death. Both L-NMMA and ADMA are eliminated largely through active metabolism by dimethylarginine dimethylaminohydrolase (DDAH) and thus DDAH dysfunction may be a crucial unifying feature of increased cardiovascular risk. However, despite considerable interest in this pathway and in the role of ADMA as a cardiovascular risk factor, there is little evidence to support a causal role of ADMA in pathophysiology. Here we reveal the structure of human DDAH-1 and probe the function of DDAH-1 both by deleting the DDAH1 gene in mice and by using DDAH-specific inhibitors which, as we demonstrate by crystallography, bind to the active site of human DDAH-1. We show that loss of DDAH-1 activity leads to accumulation of ADMA and reduction in NO signaling. This in turn causes vascular pathophysiology, including endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure. Our results also suggest that DDAH inhibition could be harnessed therapeutically to reduce the vascular collapse associated with sepsis.
 ...
PMID:Disruption of methylarginine metabolism impairs vascular homeostasis. 1787 60

Although comprehension of postburn pathophysiology has grown in recent years, we are still unable to accurately identify burn patients who are at an increased risk of infectious complications and death. This unexplained variation is likely influenced by heritable factors; the genetic predisposition for death from infection has been estimated as greater than that for cardiovascular disease or cancer. Identify genetic variants associated with increased mortality after burn injury. A total of 233 patients with burns of 15% of total body surface area or greater or smoke inhalation injury who survived more than 48 h after admission and were without significant nonburn-related trauma (injury severity score > or = 16), traumatic or anoxic brain injury, or spinal cord injury. We examined the influence of genotype at five candidate loci (interleukin [IL]-1beta, IL-6, tumor necrosis factor-alpha, toll-like receptor 4, CD14) on mortality risk after burn injury. DNA was isolated from residual blood from laboratory draws and candidate genotypes were determined by real-time polymerase chain reaction using TaqMan probes. Clinical data were prospectively collected into a local, curated database. Allelic associations were analyzed by multivariate logistic regression. After adjustment for age, full-thickness burn size, inhalation injury, ethnicity, and sex, carriage of the CD14-159 C allele imparted at least a 1.3-fold increased risk for death after burn injury, relative to TT homozygotes (adjusted odds ratio, 2.9; 95% confidence interval, 1.3-6.8; P = 0.01). This association was stronger (adjusted odds ratio, 3.3; 95% confidence interval, 1.3-8.4; P = 0.01) when the analysis was conducted only on deaths accompanied by severe sepsis. In addition, a gene dosage effect for increased mortality was apparent for carriage of the CD14-159 C allele (P = 0.006). The gene dosage effect remained when white, Hispanic, or African American patients were analyzed independently, although statistical significance was not achieved in the subgroup analysis. None of the other single nucleotide polymorphisms examined were significantly associated with mortality. These data provide strong evidence that a CD14 promoter allele that is known to impart lower baseline and induced CD14 transcription also affects mortality risk after burn injury. A potential (although untested) mechanism for our observation is that reduced signaling through CD14/toll-like receptor 4 in response to challenge by gram-negative bacteria after burns results in a blunted innate immune response and subsequent increased likelihood for systemic infection and death.
 ...
PMID:CD14-159 C allele is associated with increased risk of mortality after burn injury. 1730 2


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>