Clinical Chemistry Variables Research Articles

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on hormones of energy balance in a TCDD-sensitive and a TCDD-resistant rat strain.

One of the hallmarks of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a drastically reduced feed intake by an unknown mechanism. To further elucidate this wasting syndrome, we followed the effects of a single large dose (100 μg/kg) of TCDD on the serum levels of several energy balance-influencing hormones, clinical chemistry variables, and hepatic aryl hydrocarbon receptor (AHR) expression in two rat strains that differ widely in their TCDD sensitivities, for up to 10 days. TCDD affected most of the analytes in sensitive Long-Evans rats, while there were few alterations in the resistant Han/Wistar strain. However, analyses of feed-restricted unexposed Long-Evans rats indicated several of the perturbations to be secondary to energy deficiency. Notable increases in ghrelin and glucagon occurred in TCDD-treated Long-Evans rats alone, which links these hormones to the wasting syndrome. The newly found energy balance regulators, insulin-like growth factor 1 and fibroblast growth factor 21 (FGF-21), appeared to function in concert in body weight loss-induced metabolic state, and FGF-21 was putatively linked to increased lipolysis induced by TCDD. Finally, we demonstrate a reverse set of changes in the AHR protein and mRNA response to TCDD and feed restriction, suggesting that AHR might function also as a physiological regulator, possibly involved in the maintenance of energy balance.

Endogenous Thrombin Potential and Examination of a Further 31 Analytes in Liver Transplant Candidates

BackgroundTo predict the change in patient status and differentation of the basic diseases, endogenous thrombin potential (ETP), clinical chemistry, and coagulation variables were measured in liver transplant–listed patients with different etiologies. MethodsDifferences in values of ETP and analytes of 30 control persons and 164 cirrhotic patients were examined by means of binary logistic regression. The relationship between the analytes and ETP parameters were analyzed by means of Spearman correlation. The different etiologies of cirrhosises were studied by factor and discriminant analyses. Binary logistic regression was applied to forecast changes in clinical status. Survival analysis was carried out with the appropriate variable. ResultsInternational Normalized Ratio and activated partial thromboplastin time values were higher, whereas the area-under-the-curve values were lower in cirrhosis than in healthy subjects. A strong relationship was found only between the peak height and the anti-thrombin III (ATIII) values. In the factor analysis, 3 factors were found, which explained 81.6% of the total variance. Combination of aspartate aminotransferase and ATIII mostly separated the basic disease groups from each other in the discriminant analysis. From 35 variables, the lactate dehydrogenase (LDH) and ATIII have been suited for predicting the change in patient status. Eighty percent of patients with low ATIII and high LDH levels had deterioration of their clinical status. ConclusionsOur study demonstrated that the ETP parameters did not provide additional information compared with “conventional” coagulation tests in cirrhosis. On the basis of our study, LDH and ATIII appear to be promising analytes to assess the clinical status of patients with cirrhosis. In our opinion, the classification system of liver transplant–listed patients can be improved with their use.

Prognostic value of the neutrophil-to-lymphocyte ratio in patients with acute-on-chronic liver failure

The neutrophil-to-lymphocyte ratio (NLR) is a novel inflammation index that has been shown to independently predict poor clinical outcomes. We aimed to evaluate the role of NLR in the prediction of 3-month mortality in patients with acute-on-chronic liver failure (AoCLF). One hundred and twenty-seven patients, including 46 patients with chronic hepatitis B (CHB), 81 with AoCLF and 58 healthy controls (HCs), were enrolled in the study. All patients were followed up for 4months. The primary end-point was in-hospital mortality at the end of 90days. A blood sample was collected for all subjects at admission to examine liver function, renal function, international normalised ratio, C-reactive protein and neutrophil and lymphocyte counts, and NLRs were calculated. A total of six clinical chemistry and biochemical variables were analysed for potential associations with outcomes using Cox proportional hazards and multiple regression models. Acute-on-chronic liver failure patients had significantly higher NLRs on admission compared with HCs and CHB patients (all p=0.001). Patients with elevated NLRs were associated with increased severity of liver disease and 3-month mortality rates. According to multivariate analysis, only NLR was an independent predictor for mortality (p=0.025). The NLR measured at admission can serve as an independent predictor for 3-month mortality rate in AoCLF patients.

Serum Ferritin Concentration Predicts Mortality in Patients with Hepatitis B Virus-related Acute on Chronic Liver Failure

This study was designed to investigate the association between serum ferritin concentration (SF) and hepatitis B virus infected patients with acute-on-chronic liver failure (AoCLF). In addition, we analyzed whether SF levels are associated with mortality in AoCLF patients. One hundred and seventeen patients, including 46 patients with chronic hepatitis B (CHB), 71 with AoCLF, and 55 healthy controls (HCs) were enrolled in this study. All patients were followed for 4 months. In all subjects, a blood sample was collected at admission to examine liver function, renal function, international normalized ratio, and SF levels. A total of six clinical chemistry and biochemical variables (e.g., model for end-stage liver disease [MELD] score, age, levels of SF, total protein, albumin, and alanine aminotransferase) were measured and analyzed for their association with outcomes by using Cox proportional hazards and multiple regression models. AoCLF patients had significantly higher SF levels at admission compared to HCs and CHB (all p = 0.001). Elevated SF levels were associated with increased severity of liver disease and 3-month mortality rate. Multivariate analysis demonstrated that SF levels and MELD score were independent predictors for mortality (both p <0.001). The SF measured at admission may serve as an independent predictor for 3-month mortality rate in AoCLF patients.

Physical Exercise Induces Specific Adaptations Resulting in Reduced Organ Injury and Mortality During Severe Polymicrobial Sepsis

High physical activity levels are associated with wide-ranging health benefits, disease prevention, and longevity. In the present study, we examined the impact of regular physical exercise on the severity of organ injury and survival probability, as well as characteristics of the systemic immune and metabolic response during severe polymicrobial sepsis. Animal study. University laboratory. Male C57BL/6N mice. Mice were trained for 6 weeks by treadmill and voluntary wheel running or housed normally. Polymicrobial sepsis in mice was induced by injection of fecal slurry. Subsequently, mice were randomized into the following groups: healthy controls, 6 hours postsepsis, and 24 hours postsepsis. Blood and organ samples were collected and investigated by measuring clinical chemistry variables, cytokines, plasma metabolites, and bacterial clearance. Organ morphology and damage were characterized by histological staining. Physical exercise improved survival and the ability of bacterial clearance in blood and organs. The release of pro- and anti-inflammatory cytokines, including interleukin-6 and interleukin-10, was diminished in trained compared to untrained mice during sepsis. The sepsis-associated acute kidney tubular damage was less pronounced in pretrained animals. By metabolic profiling and regression analysis, we detected lysophosphatidylcholine 14:0, tryptophan, as well as pimelylcarnitine linked with levels of neutrophil gelatinase-associated lipocalin representing acute tubular injury (corrected R=0.910; p<0.001). We identified plasma lysophosphatidylcholine 16:0, lysophosphatidylcholine 17:0, and lysophosphatidylcholine 18:0 as significant metabolites discriminating between trained and untrained mice during sepsis. Regular physical exercise reduces sepsis-associated acute kidney injury and death. As a specific mechanism of exercise-induced adaptation, we identified various lysophosphatidylcholines that might function as surrogate for improved outcome in sepsis.

Lingonberry juice lowers blood pressure of spontaneously hypertensive rats (SHR)

Lingonberries (Vaccinium vitis-idaea) are rich in polyphenols, such as proanthocyanidins, anthocyanins, flavonols and flavanols. Polyphenol-rich foods affect vascular health. We previously described improved endothelium-dependent vascular function as well as anti-inflammatory and anti-atherothrombotic effects in spontaneously hypertensive rats (SHR) fed with lingonberry juice. In the present study, we investigated the effects of lingonberry juice dose on blood pressure, vascular function and vascular inflammation in SHR in an 8weeks’ study. Diluted (1:5) cold-compressed lingonberry juice was given as drinking fluid ad libitum to 5week old SHR for 8weeks. Control group (SHR) and normotensive reference group (Wistar-Kyoto) received tap water. Systolic blood pressure (SBP) was monitored weekly. Function of mesenteric artery rings was assessed in standard organ-bath chambers after 8weeks. Biochemical and clinical chemistry variables were measured from plasma and urine. Lingonberry juice lowered SBP of SHR (p=0.007). Endothelium-dependent vascular relaxation was not improved. Lingonberry treatment slightly affected plasma inflammatory markers (reduction of NOx and sICAM-1) and clinical chemistry variables (decreased alkaline phosphatase and increased chloride and calcium levels). In conclusion, Lingonberry juice at small concentrations lowers blood pressure in a long-term treatment in SHR.

Influence of Previous Use of Inhaled Corticoids on the Development of Pleural Effusion in Community-acquired Pneumonia

Previous use of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease has been associated with increased risk of community-acquired pneumonia. However, ICS have been associated with fewer pneumonia complications and decreased risk of pneumonia-related mortality. The objective of the study was to assess the influence of previous use of ICS on the incidence of parapneumonic effusion in patients with different baseline respiratory disorders. We conducted a single-center cohort study of 3,612 consecutively collected patients diagnosed with community-acquired pneumonia. We assessed clinical, radiographic, and pleural-fluid chemistry and microbiologic variables. Patients were classified according to whether or not they received prior ICS treatment. A total of 633 patients (17%) were treated with corticosteroids before the diagnosis of pneumonia (chronic obstructive pulmonary disease, 54%; asthma, 13%). Incidence of parapneumonic effusion was lower in patients with ICS use compared with non-ICS patients (5% vs. 12%; P < 0.001). After matching according to propensity scores (n = 640), prior treatment with corticosteroids was still significantly associated with a lower incidence of parapneumonic effusion (odds ratio, 0.40; 95% confidence interval, 0.23-0.69; P = 0.001) compared with patients without ICS treatment. Prior ICS treatment was associated with higher levels of glucose (P = 0.003) and pH (P = 0.02), and lower levels of protein (P = 0.01) and lactic acid dehydrogenase (P = 0.007) in the pleural fluid. Prior treatment with ICS in a population of patients with different respiratory chronic disorders who develop pneumonia is associated with lower incidence of parapneumonic effusion.

The association between circulating oestradiol levels and severity of liver disease in males with hepatitis B virus infection

Males have a strikingly increased risk of advanced liver disease. This study was designed to investigate the association between sex hormone levels and different disease states in hepatitis B virus (HBV)-infected male patients. Two hundred and fifty-two male patients, including 30 with acute hepatitis B (AHB), 127 with chronic hepatitis B (CHB) and 95 with chronic severe hepatitis B (CSHB), and 48 healthy controls (HCs) were enroled in this study. All patients were followed for 4 months. The primary end point was in-hospital mortality at the end of 90 days. At study entry, a blood sample was collected from all subjects to examine liver function, renal function and sex hormone levels (serum total testosterone and oestradiol). A total of nine clinical chemistry and biochemical variables were analyzed for possible association with outcomes by using Cox proportional hazards and multiple regression models. We demonstrated that in CSHB and CHB patients, oestradiol levels were significantly increased compared with HCs and AHB patients, whereas no significant differences were observed in AHB patients and HCs. All male patients had normal levels of testosterone which were not significantly different compared with those of HCs. Increased oestradiol levels were clinically associated with severe liver disease, and increased 3-month mortality rate. Multivariate analysis demonstrated that oestradiol and the model for end-stage liver disease (MELD) score were independent predictors for mortality (both P < 0.001). Oestradiol levels are significantly increased in male patients with hepatitis B, and were associated with the severity of liver disease. Moreover, elevation of oestradiol is an independent predictive factor for the 3-month mortality rate in male patients with hepatitis B.

Effects of Food or Sleep Deprivation During Civilian Survival Training on Clinical Chemistry Variables

To describe clinical chemistry and weight changes after short-term food or sleep deprivation or multiple deprivations during civilian survival training. Data from one baseline-controlled two-period crossover study designed to compare sleep deprivation for up to 50 hours with food deprivation for up to 66 hours (n = 12) and data from regular multiple-deprivations survival training comparing participants (n = 33) with nondeprived instructors (n = 10). Food deprivation was associated with decreased body weight, blood glucose, serum triglycerides, sodium, chloride, and urine pH, and there were increases in blood and urine ketones and serum free fatty acids. Sleep deprivation was associated with a minor decrease in hemoglobin and erythrocyte particle count and volume fraction and an increase in leukocytes. The clinical chemistry and body weight changes associated with food deprivation were qualitatively similar to those observed in fasting obese patients but developed quicker in the survival training setting. Sleep deprivation had few effects on the clinical chemistry profile except for hematological variables. Physicians evaluating clinical chemistry data from patients subjected to short-term food or sleep deprivation should take the physiological state into account in their assessment.

Nutritional status influences peripheral immune cell phenotypes in healthy men in rural Pakistan

Immune status is influenced by malnutrition, but how this factor interacts in developing countries and whether these differences are similar to those determined in industrialized countries, is unclear. To establish whether malnutrition-associated immune profiles in a developing country are similar to those in industrialized countries we analyzed peripheral blood immune cell phenotypes by polychromatic flow cytometry in 50 young and 50 elderly subjects. Data on anthropometrics and diet were collected through interviews. Plasma samples were analyzed for common clinical chemistry variables. Subjects in 4 BMI categories differed in their immune parameters demonstrating influence of nutritional status on immunity. This was greater within the young group and affected the CD4 subset more profoundly than the CD8 subset. No nutrition-associated differences were seen in B or NK cells. CD8+ cells as a percentage of CD3+ T cells were positively associated with plasma CRP levels but not other factors. We conclude that there are differences in the immune signatures of obese, overweight and underweight versus normal-weight young and elderly, which seem broadly similar to the more extensively-documented state reported in industrialized countries, despite the marked societal, nutritional and many other differences.

Serum vitamin B12 levels as indicators of disease severity and mortality of patients with acute‐on‐chronic liver failure

BackgroundThe study was designed to investigate the association between vitamin B12 levels and patients with acute-on-chronic liver failure (AoCLF). In addition, we analyzed whether B12 is associated with mortality in the AoCLF patients. MethodsOne hundred five patients with AoCLF and 44 healthy controls (HCs) were prospectively studied. In all subjects, a blood sample was collected at admission to examine liver function, renal function, international normalized ratio and B12 levels. A total of 9 clinical chemistry and biochemical variables were analyzed for possible association with outcomes by using Cox proportional hazards and multiple regression models. ResultsAoCLF patients had significantly higher B12 levels at admission compared with HCs (AoCLF patients vs HCs, median 1218pg/ml, mean 1736.2pg/ml, SD, 1294.6 vs 504pg/ml, 529.8±149.8pg/ml, P<0.001). Elevated B12 levels were associated with increased severity of liver disease and 3-month mortality rate. Multivariate analysis demonstrated that B12 levels and the model for end-stage liver disease score were independent predictors for mortality (both P<0.001). ConclusionB12 levels were significantly higher in AoCLF patients than in HCs and elevated B12 were associated with increased severity of disease. Moreover, B12 levels are an independent predicting factor for the 3-month mortality rate in AoCLF patients.

Subchronic feeding study of stacked trait genetically-modified soybean (3Ø5423 × 40-3-2) in Sprague–Dawley rats

The genetically-modified (GM) soybean 3Ø5423×40-3-2 expresses siRNA for the fatty acid desaturase-2 enzyme which results in higher concentrations of oleic acid (18:1) relative to linoleic acid (18:2) compared with non-GM soybeans. It also expresses the CP4 EPSPS protein for tolerance to glyphosate. In this study, three different dietary concentrations (7.5%, 15% and 30% wt/wt) of 3Ø5423×40-3-2 or non-GM soybeans were fed to Sprague–Dawley rats for 90days during which in-life nutritional and growth performance variables were evaluated followed by analysis of standard clinical chemistry, hematology and organ variables. Compared with rats fed the non-GM control diet, some statistically significant differences were observed in rats fed the 3Ø5423×40-3-2 diet. However the differences were not considered treatment-related and commonly fell within the normal ranges of the control group consuming the commercial diet. These results demonstrated that the GM soybean 3Ø5423×40-3-2 is as safe as non-GM soybeans.

Evaluation of Oral Robenacoxib for the Treatment of Postoperative Pain and Inflammation in Cats: Results of a Randomized Clinical Trial

The efficacy and safety of robenacoxib were assessed for the control of postoperative pain and inflammation in cats. The study was a multicenter, prospective, randomized, blinded, and parallel group clinical trial. A total of 249 client-owned cats scheduled for forelimb onychectomy plus either ovariohysterectomy or castration surgeries were included. All cats received butorphanol prior to anesthesia and forelimb four-point regional nerve blocks with bupivacaine after induction of general anesthesia. Cats were randomized to receive daily oral tablet robenacoxib, at a mean (range) dosage of 1.84 (1.03–2.40) mg/kg (n = 167), or placebo (n = 82), once prior to surgery and for two days postoperatively. Significantly (P < 0.05) fewer robenacoxib cats received additional analgesia rescue therapy (16.5%) than placebo cats (46.3%). Pain elicited on palpation of the soft tissue incision site, behavior following social interaction, and posture assessed during the first 8 hours after extubation were significantly (P < 0.05) improved in cats receiving robenacoxib. Frequency of reported adverse clinical signs, hematology, serum chemistry and urinalysis variables, and body weight changes weresimilar between groups. In conclusion, robenacoxib was effective and well tolerated in the control of postoperative pain and inflammation in cats undergoing onychectomy with ovariohysterectomy or castration.

Prevalence and progression of cardiovascular calcifications in peritoneal dialysis patients: A prospective study

BackgroundPatients on dialysis may have abnormal serum levels of Ca, P and parathyroid hormone, with related bone diseases. This population has an increased risk of death, with cardiovascular calcification (CC) a contributing factor. Patients on peritoneal dialysis appear to be at increased risk of hyperlipidemia, a contributing factor to atherosclerotic plaque formation. Although several studies have described the presence and progression of CC in hemodialysis populations, there are fewer data in patients on peritoneal dialysis. Study designThe Renal Osteodystrophy and Calcifications: Key factors in Peritoneal Dialysis (ROCK-PD) study was a 36-month, prospective observational study conducted in Italy. The study examined the presence and progression of CC in two cardiac valves and five arterial sites. The potential associations of serum Ca and P with mortality and cardiovascular morbidity, demographic, clinical and blood chemistry variables was investigated. ResultsCC was present in 77% of patients at baseline (N=369) and in 90% of patients by study end (N=145), progressing in 73% of patients. There were 42 deaths (11%). Analyses showed a marked correlation between baseline P levels and the presence of left ventricular hypertrophy. However, there were no consistent correlations between serum Ca or P with mortality or morbidity. ConclusionsCC was common in peritoneal dialysis patients and progressed in a majority of patients.

Clinical Usefulness of Measuring Red Blood Cell Distribution Width in Patients with Hepatitis B

BackgroundRed blood cell distribution width (RDW), an automated measure of red blood cell size heterogeneity (e.g., anisocytosis) that is largely overlooked, is a newly recognized risk marker in patients with cardiovascular diseases, but its role in persistent viral infection has not been well-defined. The present study was designed to investigate the association between RDW values and different disease states in hepatitis B virus (HBV)-infected patients. In addition, we analyzed whether RDW is associated with mortality in the HBV-infected patients.Methodology/Principal FindingsOne hundred and twenty-three patients, including 16 with acute hepatitis B (AHB), 61 with chronic hepatitis B (CHB), and 46 with chronic severe hepatitis B (CSHB), and 48 healthy controls were enrolled. In all subjects, a blood sample was collected at admission to examine liver function, renal function, international normalized ratio and routine hematological testing. All patients were followed up for at least 4 months. A total of 10 clinical chemistry, hematology, and biochemical variables were analyzed for possible association with outcomes by using Cox proportional hazards and multiple regression models. RDW values at admission in patients with CSHB (18.30±3.11%, P<0.001), CHB (16.37±2.43%, P<0.001) and AHB (14.38±1.72%, P<0.05) were significantly higher than those in healthy controls (13.03±1.33%). Increased RDW values were clinically associated with severe liver disease and increased 3-month mortality rate. Multivariate analysis demonstrated that RDW values and the model for end-stage liver disease score were independent predictors for mortality (both P<0.001).ConclusionRDW values are significantly increased in patients with hepatitis B and associated with its severity. Moreover, RDW values are an independent predicting factor for the 3-month mortality rate in patients with hepatitis B.

Safety of oral robenacoxib in the cat

The safety of robenacoxib, a nonsteroidal anti-inflammatory drug with high selectivity for inhibition of the cyclooxygenase (COX)-2 isoform of COX, was investigated in the cat in two randomized, blinded, placebo-controlled, parallel-group studies. Robenacoxib was administered orally to healthy young domestic short-hair cats at dosages of 0 (placebo), 5 and 10 mg/kg once daily for 28 days (study 1) and at 0 (placebo), 2, 6 and 10 mg/kg twice daily for 42 days (study 2). The recommended minimum dosage for robenacoxib tablets in cats is 1 mg/kg once daily (range 1-2.4 mg/kg). Relative to placebo treatment, no toxicologically significant effects of robenacoxib were recorded in either study, based on general observations of health, haematological and clinical chemistry variables and urinalyses in life, and by post mortem organ weight, gross pathology and histopathology assessments. Pharmacokinetic-pharmacodynamic simulations indicated that all dosages of robenacoxib were associated with marked inhibition of COX-2 at peak effect (median I(max) 97.8-99.4% inhibition) with lesser inhibition of COX-1 (median I(max) 26.8-58.3% inhibition). Inhibition of the COXs was short lasting, with >10% median inhibition persisting for 4.0 h for COX-2 and 1.5 h for COX-1. These levels of inhibition of COX-1 and COX-2 twice daily with robenacoxib were not associated with any detectable toxicity, suggesting that, as previously described in dogs, the high safety index of robenacoxib in cats may be related to a combination of its high COX-2 selectivity and short residence time in the central compartment.

Robenacoxib in the dog: target species safety in relation to extent and duration of inhibition of COX-1 and COX-2

The safety of robenacoxib, a nonsteroidal anti-inflammatory drug with high selectivity for inhibition of the cyclooxygenase (COX)-2 isoform of COX, was investigated in the dog in two randomized, placebo-controlled, parallel group studies. Robenacoxib was administered orally once daily to healthy young beagle dogs at 0 (placebo), 10, 20 and 40 mg/kg for 1 month (Study 1) and at 0 (placebo), 2, 4, 6 and 10 mg/kg for 6 months (Study 2). Relative to placebo treatment, no significant adverse effects of robenacoxib were recorded in either study for clinical observations, haematological and clinical chemistry variables or macroscopic or microscopic lesions at necropsy. In Study 2, additional examinations identified no adverse effects of robenacoxib on buccal bleeding time, electrocardiographic and ophthalmoscopic examinations, urinalysis or stifle joint tissues. Pharmacokinetic-pharmacodynamic simulations indicated that all dosages of robenacoxib were associated with marked inhibition of COX-2 (median Emax 74-99% inhibition). For the highest dosage of robenacoxib (40 mg/kg in Study 1), the upper limit of the 90% tolerance interval was associated with 71% inhibition of COX-1 at Emax, but 50% inhibition persisted for only 3.5 h. This level of inhibition of COX-1 with robenacoxib was not associated with any detectable toxicity, suggesting that the high safety index of robenacoxib in dogs is a function of both its high COX-2 selectivity and short residence time in the central compartment.

Robenacoxib vs. carprofen for the treatment of canine osteoarthritis; a randomized, noninferiority clinical trial

Robenacoxib is a member of the coxib class of nonsteroidal anti-inflammatory drugs (NSAID), with high selectivity for the cyclooxygenase (COX)-2 isoform of COX. In this study, the efficacy and tolerability of robenacoxib were compared with those of carprofen in canine osteoarthritis in a multi-centre, prospective, randomized, blinded, positive-controlled noninferiority clinical trial. Both drugs were administered orally once daily at recommended dosages: robenacoxib at 1-2 mg/kg (n = 125 dogs) and racemic carprofen at 2-4 mg/kg (n = 63 dogs) for a total of 12 weeks. The efficacy of the test compounds was assessed by veterinary investigators and owners using numerical rating scales at baseline and days 7, 14, 28, 56 and 84. In both groups, all scores were significantly (P < 0.0001) improved compared with baseline at all time points (days 7-84). Robenacoxib had noninferior efficacy to carprofen for the primary endpoint, the global functional disability, both for all dogs and for the subgroup of dogs in which robenacoxib was not administered during meals. Noninferiority was also demonstrated for three of six veterinary investigator secondary endpoints and four of six owner efficacy endpoints. For haematology and clinical chemistry variables, there were some significant differences from baseline levels but no differences between groups. There were no differences between groups in the frequencies of adverse events, which were reported in 46% dogs with robenacoxib and 52% with carprofen (P = 0.44), which were most frequently mild events affecting the gastrointestinal tract. In conclusion, noninferior efficacy and tolerability of robenacoxib compared with carprofen was demonstrated in dogs with osteoarthritis.

Efficacy, safety and pharmacokinetics of 1,2,4-trioxolane OZ78 against an experimental infection with Fasciola hepatica in sheep

The synthetic peroxide OZ78 is an effective flukicide in the rodent model, but the potential of OZ78 in target animals has not been studied to date. In the present study, OZ78 was administered at 50 mg/kg orally and subcutaneously to sheep harbouring an experimental Fasciola hepatica infection and the efficacy, tolerability and pharmacokinetic profiles were monitored. OZ78 given orally or subcutaneously revealed no effect neither on faecal egg counts nor on worm burdens. Apart from significant subcutaneous swelling at the injection sites of most of the treated animals, no other treatment related adverse events occurred. OZ78 had no significant effect on any haematological, coagulation or clinical chemistry variables tested. Following oral administration, a mean C max of 45.8 ± 13 μg/ml was reached after 1 h. An estimated elimination half-life of 1.0 h and a mean AUC of 116.2 ± 47 μg min/ml was calculated for the oral administration. Following subcutaneous treatment with OZ78 C max and t max were 13.7 ± 6.1 μg/ml and 0.9 ± 0.4 h, respectively. The α and β half-lives were 4.5 ± 4.3 h and 56.5 ± 36 h, respectively and the mean AUC was 219.1 ± 74 μg min/ml. Further studies are needed to determine whether the excellent activity observed with OZ78 in the rat model can be translated into efficacy in larger mammals .

Red cell distribution width in heart failure: Prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state

The goal of this study was to independently validate the recent observations on the predictive role of red cell distribution width (RDW) for outcomes in chronic heart failure and to provide epidemiologic data on the biological correlates of RDW in heart failure (HF). Understanding the mechanism underlying this observation is unclear, largely hampered by the lack of epidemiologic studies demonstrating factors that are associated with anisocytosis in cardiovascular diseases. One hundred ninety-five patients (145 men, 50 women) with systolic HF were enrolled and followed up for a median of 14.5 months. Primary end points were all-cause mortality and hospital readmission due to worsening HF symptoms. A total of 19 clinical chemistry, hematology, and biochemical variables were considered for analysis together with clinical parameters in Cox proportional hazards and multiple regression models. Red cell distribution width was found to be an N-terminal pro-brain natriuretic peptide independent predictor of all-cause mortality (adjusted HR 1.61 per 1 SD increase) in our study. Multiple correlations between biomarkers of ineffective erythropoiesis (serum iron, ferritin, and soluble transferrin receptor levels), inflammation and acute-phase reaction (interleukin-6, soluble tumor necrosis factor (TNF) receptor I and soluble TNF receptor II, C-reactive protein, and prealbumin concentrations), undernutrition (total cholesterol and albumin levels), and renal function were observed. In the multiple regression model, the strongest relationship for RDW was obtained with soluble transferrin receptor, soluble TNF receptor I, soluble TNF receptor II, and total cholesterol. Here we validate the strong, independent prediction of morbidity and mortality in HF by RDW. The described correlations between RDW and inflammation, ineffective erythropoiesis, undernutrition, and impaired renal function may facilitate the understanding why this marker is associated with adverse outcomes in HF.