A novel method for the analysis of clinical biomarkers to investigate the effect of diet on health in a rat model

Experiments into the relationship between diet and health have been an area of high interest for a long time. In this study, we investigate the application of multivariate data analysis to differentiate between rat populations fed on two different diets: normal rat diet (control) and Western affluent diet (WAD). Two sets of data were acquired and analysed: one from a biochemical clinical analyser, taking measurements of blood-based biochemical markers; the other from the analysis of the volatile organic compounds (VOCs) emitted from faecal samples from the same animals using selected ion flow tube mass spectrometry (SIFT-MS). Five classes were considered: weanlings, 12 month controls, 12 month WADs, 18 month controls, and 18 month WADs. Data from the biochemical analyser, weanlings and 18 month WAD fed rats showed significant differences from the other measurement classes. This was shown in both the exploratory analysis and through multivariate classification. Classification of control diet versus WAD diets suggested there are differences between classes with 92% accuracy for the 12 month classes and 91% for the 18 month classes. Cholesterol markers, especially as low density lipoprotein-cholesterol (LDL), were the main factor in influencing WAD samples. The data from the SIFT-MS analysis also produced very good classification accuracies. Classification of control diet versus WAD diets using the H3O+ precursor ion data suggested there are differences between classes with 71% accuracy for the 12 month classes and 100% for the 18 month classes. These findings confirm that total cholesterol and LDL-cholesterol are elevated in the 18 month WAD-fed rats. We therefore suggest that the analysis of VOCs from faecal samples in conjunction with multivariate data analysis may be a useful alternative to blood analysis for the detection of parameters of health

An unexpected and serious complication of treatment with the atypical antipsychotic drug clozapine

A 49-year-old man developed acute renal failure due to interstitial nephritis during treatment with the drug clozapine. Referral and diagnosis were delayed through a failure to consider complications of treatment other than neuroleptic malignant syndrome. Although this association has not previously been reported in the literature, we include details of a further 7 cases of acute renal failure in association with clozapine therapy reported to the Committee On Safety Of Medicines in the UK

Exertional Fatigue in Patients With CKD

Background: Fatigue is one of the most prevalent symptoms in chronic kidney disease (CKD). However, fatigue mechanisms are poorly understood due in part to nonspecific definitions. This study investigates exertional fatigue during simulated activities of daily living, focusing on oxygen delivery and utilization. Study Design: "Explanatory" matched-cohort study. Participants & Setting: 13 patients with CKD (stages 3b-4; mean age, 62 \ub1 13 [SD] years) and 13 healthy controls, mean matched for age, height, body mass and composition, and physical activity level. Participants completed an incremental cycle ergometer test to simulate energy expenditure of typical activities of daily living. Factor: 4 exercise intensities: 1, 1.8, 2.4, and 3.1 metabolic equivalent tasks (METs). Outcomes: The primary outcome was exertional fatigue by rating of perceived exertion (RPE) on a 6-20 scale. Measurements: Other multidimensional measures of fatigue: UK Short Form Health Survey 36 (UK SF-36) Vitality and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) subscales. Physiologic measures of the oxygen transport and utilization chain (expired gas analysis, cardiac output, and arterial oxygen content) and blood lactate. Results: RPE was increased in patients compared with controls at 2.4 (10.5 [ie, light] \ub1 2.7 vs 8.7 [very light] \ub1 1.7 units) and 3.1 (12.5 [somewhat hard] \ub1 2.6 vs 10.2 [light] \ub1 1.7 units) METs (interaction P = 0.03), which was consistent with higher chronic fatigue in patients by both the UK SF-36 Vitality (P = 0.01) and FACIT-Fatigue (P = 0.004) subscales. Arterial oxygen content was decreased in patients (P = 0.001), but cardiac output and oxygen extraction ratio were unchanged, decreasing oxygen delivery (P = 0.04). Respiratory exchange ratio (P = 0.004) and blood lactate production (P = 0.002) were increased. Limitations: Those inherent to a matched-cohort study. Conclusions: Using a novel application of the outcome measure RPE, patients with non-dialysis-dependent CKD reported considerable exertional fatigue during simulated activities of daily living. Poor compensation for mild anemia contributed to this symptom. In addition to anemia, the entire oxygen transport chain needs to be targeted to treat fatigue in patients with CKD. \ua9 2012 National Kidney Foundation, Inc

Hydration Marker Diagnostic Accuracy to Identify Mild Intracellular and Extracellular Dehydration

Identifying mild dehydration (/=0.7 receiver operating characteristic-area under the curve (ROC-AUC)). Thus, in 15 young healthy men, we determined the diagnostic accuracy of 15 hydration markers after three randomized 48-h trials; euhydration (EU, water 36 ml.kg.d(-1)), intracellular dehydration caused by exercise and 48 h of fluid restriction (ID, water 2 ml.kg.d(-1)), and extracellular dehydration caused by a 4 h diuretic-induced diuresis, begun at 44 h (ED, Furosemide 0.65 mg.kg(-1)). Body mass was maintained on EU and dehydration was mild on ID and ED (1.9 (0.5)% and 2.0 (0.3)% of body mass, respectively). Urine color, urine specific gravity, plasma osmolality, saliva flow rate, saliva osmolality, heart rate variability and dry mouth identified ID (ROC-AUC; range 0.70-0.99) and postural heart rate change identified ED (ROC-AUC 0.82). Thirst 0-9 scale (ROC-AUC 0.97 and 0.78 for ID and ED) and urine osmolality (ROC-AUC 0.99 and 0.81 for ID and ED) identified both dehydration types. However, only thirst 0-9 scale had a common dehydration threshold (>/=4; sensitivity and specificity of 100%, 87% and 71%, 87% for ID and ED). In conclusion, using a common dehydration threshold >/=4, the thirst 0-9 scale identified mild intracellular and extracellular dehydration with adequate diagnostic accuracy. In young healthy adults' thirst 0-9 scale is a valid and practical dehydration-screening tool

Muscle insulin-like growth factor status, body composition, and functional capacity in hemodialysis patients

Hemodialysis (HD) patients typically have reduced muscle mass and diminished functional capacity. The role of the muscle insulin-like growth factors (IGFs), a principal anabolic system that is involved in protein synthesis and that has downregulation that is implicated in muscle loss in animal models of uremia, has previously not been assessed in vivo in HD patients. Seventeen HD patients were compared cross-sectionally with 17 age-, sex-, and body mass index-matched healthy controls. Body composition was assessed by dual energy x-ray absorptiometry and bioelectrical impedance spectrometry; functional capacity by hand grip strength, quadriceps strength, and 30-second sit-to-stand test; systemic inflammation by tumor necrosis factor-\u3b1 (TNF-\u3b1) and TNF receptor 1 (TNFR1); serum and muscle IGF-I and IGFBP-3 by radioimmunoassay; and fragmentation of serum IGFBP-3 by Western immunoblotting. Appendicular lean mass was significantly decreased in HD patients compared with controls (17.6 \ub1 0.9 versus 21.5 \ub1 1.5 kg, P <. 05), as were all measures of functional capacity (P <. 01 to. 001), and highly significant positive correlations between appendicular lean mass and functional capacity were evident (appendicular lean mass and hand-grip strength, quadriceps strength, 30-second sit-to-stand test, all P <. 001). TNF-\u3b1 and TNFR1 were elevated in patients (P <. 001). Although serum IGF-I and IGFBP-3 levels did not differ between the groups (P =. 295 and. 379 respectively), fragmented IGFBP-3 levels were increased (53.1 \ub1 16.0 versus 29.81 \ub1 15.3%, P <. 005). In contrast, muscle IGF-I was substantially diminished in the patient group (n = 7) relative to control (n = 5) levels (0.84 \ub1 0.06 versus 2.78 \ub1 1.80 pg/\u3bcg, P <. 05). We provide evidence of reduced IGF-I in HD patients' skeletal muscle that may be a causal factor in the muscle wasting characteristic of this population. Future research should determine the exact consequences and causes of alterations to the muscle IGF system in HD patients. \ua9 2004 by the National Kidney Foundation, Inc