l-Theanine extends lifespan of adult Caenorhabditis elegans

Purpose

Compounds that delay aging in model organisms may be of significant interest to anti-aging medicine, since these substances potentially provide pharmaceutical approaches to promote healthy lifespan in humans. We here aimed to test whether pharmaceutical concentrations of l-theanine, a putative anti-cancer, anti-obesity, blood pressure-lowering, and neuroprotective compound contained in green tea (Camellia sinensis), are capable of extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans.

Methods

Adult C. elegans roundworms were maintained on agar plates, were fed E. coli strain OP50 bacteria, and l-theanine was applied to agar to test (1) whether it may increase survival upon paraquat exposure and (2) whether it may promote longevity by quantifying survival in the presence and absence of the compound.

Results

l-theanine increases survival of C. elegans in the presence of paraquat at a concentration of 1 micromolar. l-theanine extends C. elegans lifespan when applied at concentrations of 100?nM, as well as 1 and 10 micromolar.

Conclusions

In the model organism C. elegans, l-theanine is capable of promoting paraquat resistance and longevity suggesting that this compound may as well promote healthy lifespan in mammals and possibly humans.     

Effects of l-arginine supplementation on blood flow, oxidative stress status and exercise responses in young adults with uncomplicated type I diabetes

Background and aims

Vascular disease is the principal cause of death and disability in patients with diabetes, and endothelial dysfunction seems to be the major cause in its pathogenesis. Since l-arginine levels are diminished in conditions such as type 1 and type 2 diabetes, in this work we aimed to verify the effects of l-arginine supplementation (7 g/day) over the endothelial function and oxidative stress markers in young male adults with uncomplicated type 1 diabetes. We also investigated the influences of l-arginine administration on vascular/oxidative stress responses to an acute bout of exercise.

Methods

Ten young adult male subjects with uncomplicated type 1 diabetes and twenty matched controls volunteered for this study. We analysed the influence of l-arginine supplementation (7 g/day during 1 week) over lower limb blood flow (using a venous occlusion plethysmography technique), oxidative stress marker (TBARS, Carbonyls), anti-oxidant parameters (uric acid and TRAP) and total tNOx in rest conditions and after a single bout of submaximal exercise (VO₂ at 10 % below the second ventilatory threshold). Data described as mean ± standard error (SE). Alpha level was P < 0.05.

Results

Glycaemic control parameters were altered in type 1 diabetic subjects, such as HbA1c (5.5 ± 0.03 vs. 8.3 ± 0.4 %) and fasted glycaemia (94.8 ± 1.4 vs. 183 ± 19 mg/dL). Oxidative stress/damage markers (carbonyls and TBARS) were increased in the diabetic group, while uric acid was decreased. Rest lower limb blood flow was lower in type 1 diabetic subjects than in healthy controls (3.53 ± 0.35 vs. 2.66 ± 0.3 ml 100 ml^?¹ min^?¹). l-Arginine supplementation completely recovered basal blood flow to normal levels in type 1 diabetics’ subjects (2.66 ± 0.3 to 4.74 ± 0.86 ml 100 ml^?¹ min^?¹) but did not interfere in any parameter of redox state or exercise.

Conclusion

Our findings highlight the importance of l-arginine for the improvement of vascular function in subjects with diabetes, indicating that l-arginine supplementation could be an essential tool for the treatment for the disease complications, at least in non-complicated diabetes. However, based on our data, it is not possible to draw conclusions regarding the mechanisms by which l-arginine therapy is inducing improvements on cardiovascular function, but this important issue requires further investigations.     

Changes in mineral status are associated with improvements in insulin sensitivity in obese patients following l-arginine supplementation

Purpose

The aim of this study is to evaluate the long-term influence of l-arginine intake on mineral concentration in patients with obesity and to assess the changes in lipid serum levels, fat content, and insulin resistance that result.

Methods

A randomized double-blind placebo-controlled study was conducted. 88 obese patients were randomly assigned to receive either 9 g of l-arginine or placebo daily, for 6 months. At baseline and after 6 months, selected anthropometrical measurements and blood biochemical analyses were performed and mineral levels were assessed. To assess insulin sensitivity, the gold-standard euglycemic clamp methodology was used.

Results

We found that 6 months of l-arginine supplementation resulted in significant increases in insulin sensitivity (Δ1.1 mg/kg/min, P < 0.01) and zinc levels (Δ1.5 μmol/L, P < 0.001). Moreover, a positive correlation between the change in zinc concentration in serum and the change in insulin sensitivity was observed (R = 0.80, P < 0.01). In the group of patients treated with l-arginine, a negative correlation between the change in zinc concentration in serum and the change in body fat content was noted (R = ?0.38, P < 0.05).

Conclusions

l-Arginine supplementation affects zinc status in obese patients. One beneficial influence is related to the improvements in insulin sensitivity.     

Long-term dietary l-arginine supplementation increases endothelial nitric oxide synthase and vasoactive intestinal peptide immunoexpression in rat small intestine

Background and aims

Nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) are important intestinal neurotransmitters that coexist in the gut enteric nervous system and play an important role in intestinal physiology (e.g., absorption, motility, fluid secretion and smooth muscle relaxation). It is also known that cold exposure alters several aspects of gastrointestinal physiology and induces hyperphagia to meet increased metabolic demands, but there are no data regarding NO and VIP involvement in intestinal response during acclimation to cold. The objective of this study was to determine the influence of long-term l-arginine supplementation on the expression of the three isoforms of nitric oxide synthase (NOS) and VIP in small intestine of rats acclimated to room temperature or cold.

Methods

Animals (six per group) acclimated to room temperature (22 ± 1 °C) and cold (4 ± 1 °C), respectively, were treated with 2.25 % l-arginine, a substrate for NOSs, or with 0.01 % N ^ω-nitro-l-arginine methyl ester, an inhibitor of NOSs, for 45 days. The topographical distribution of VIP and NOSs expression in small intestine was studied by immunohistochemistry, and ImageJ software was used for semiquantitative densitometric analysis of their immunoexpression.

Results

Long-term dietary l-arginine supplementation increases VIP and NOSs immunoexpression at room temperature while at cold increases the endothelial NOS, inducible NOS and VIP but decrease neuronal NOS in rat small intestine.

Conclusion

Our results demonstrate that long-term dietary l-arginine supplementation modulates NOSs and VIP immunoexpression in rat small intestine with respect to ambient temperature, pointing out the eNOS as a predominant NOS isoform with an immunoexpression pattern similar to VIP.     

Fructo-oligosaccharide attenuates the production of pro-inflammatory cytokines and the activation of JNK/Jun pathway in the lungs of d-galactose-treated Balb/cJ mice

Purpose

This study determined the effects of long-term d-galactose (DG) injection on the lung pro-inflammatory and fibrotic status and whether fructo-oligosaccharide (FO) could attenuate such effects.

Methods

Forty Balb/cJ mice (12 weeks of age) were divided into four groups: control (s.c. saline) (basal diet), DG (s.c. 1.2 g DG/kg body weight) (basal diet), DG + FO (FO diet, 2.5 % w/w FO), and DG + E (vitamin E diet, α-tocopherol 0.2 % w/w) serving as an antioxidant control group. These animals were killed after 49 day of treatments. Another group of naturally aging (NA) mice without any injection was killed at 64 weeks of age to be an aging control group.

Results

d-galactose treatment, generally similar to NA, increased the lung pro-inflammatory status, as shown in the IL-6 and IL-1β levels and the expression of phospho-Jun and phospho-JNK, and the fibrotic status as shown in the hydroxyproline level compared to the vehicle. FO diminished the DG-induced increases in the lung IL-1β level and expressions of total Jun, phospho-JNK, and attenuated DG effects on lung IL-6 and hydroxyproline, while α-tocopherol exerted anti-inflammatory effects on all parameters determined. FO, as well as α-tocopherol, modulated the large bowel ecology by increasing the fecal bifidobacteria and cecal butyrate levels compared with DG.

Conclusions

d-galactose treatment mimicked the lung pro-inflammatory status as shown in the NA mice. FO attenuated the DG-induced lung pro-inflammatory status and down-regulated JNK/Jun pathway in the lung, which could be mediated by the prebiotic effects and metabolic products of FO in the large intestine.     

Chlorella pyrenoidosa ameliorated L-NAME-induced hypertension and cardiorenal remodeling in rats

Purpose

Hypertension is one of the main factors causing cardiovascular diseases. The aim of the study is to investigate the effects of Chlorella pyrenoidosa on blood pressure and cardiorenal remodeling in rats with N _ω-nitro-l-arginine methyl ester hydrochloride (L-NAME)-induced endothelial dysfunction.

Methods

Rats were fed a diet containing L-NAME (40 mg/kg) with or without chlorella (4 or 8 %) for 5 weeks. We found that chlorella retarded the development of hypertension and cardiorenal remodeling during the 5-week experimental period.

Results

Although there was no difference in NO _x levels or plasma arginine concentrations, plasma and tissues ACE activities were significantly lower in the chlorella groups than in the L-NAME group. Moreover, tissue tumor necrosis factor-α concentrations and renal CYP4A expression were also lower in the chlorella group.

Conclusion

These results suggest that chlorella might ameliorate the elevation of blood pressure and show cardiorenal-protective effects in nitric oxide-deficient rats, and one possible mechanism might be mediated by its ACE inhibitory activity.     

Functional relevance of d,l-sulforaphane-mediated induction of vimentin and plasminogen activator inhibitor-1 in human prostate cancer cells

Purpose

d,l-Sulforaphane (SFN) is a promising chemopreventive agent with in vivo efficacy against prostate cancer in experimental rodents. This study was undertaken to determine the role of vimentin and plasminogen activator inhibitor-1 (PAI-1) in anticancer effects of SFN.

Methods

Effect of SFN on levels of different proteins was determined by Western blotting or immunofluorescence microscopy. RNA interference of vimentin and PAI-1 was achieved by transient transfection. Apoptosis was quantified by flow cytometry. Transwell chambers were used to determine cell migration.

Results

Exposure of PC-3 and DU145 human prostate cancer cells to SFN resulted in induction of vimentin protein, which was accompanied by down-regulation of E-cadherin protein expression. The SFN-mediated induction of vimentin was also observed in a normal human prostate epithelial cell line. RNA interference of vimentin did not have any appreciable effect on early or late apoptosis resulting from SFN exposure. On the other hand, SFN-mediated inhibition of PC-3 and DU145 cell migration was significantly augmented by knockdown of the vimentin protein. Knockdown of vimentin itself was inhibitory against cell migration. The SFN-treated cells also exhibited induction of PAI-1, which is an endogenous inhibitor of urokinase-type plasminogen activator system. Similar to vimentin, PAI-1 knockdown resulted in a modest augmentation of PC-3 cell migration inhibition by SFN. Tumors from SFN-treated transgenic adenocarcinoma of mouse prostate mice showed a 1.7-fold increase in vimentin protein level compared with control tumors.

Conclusion

The present study indicates that vimentin and PAI-1 inductions confer modest protection against SFN-mediated inhibition of prostate cancer cell migration.     

4-Hydroxyisoleucine stimulates glucose uptake by increasing surface GLUT4 level in skeletal muscle cells via phosphatidylinositol-3-kinase-dependent pathway

Purpose

To determine the effect of 4-Hydroxyisoleucine (4-HIL), an unusual amino acid isolated from the seeds of Trigonella foenum-graecum, on glucose uptake and the translocation of glucose transporter 4 (GLUT4) to plasma membrane in skeletal muscle cells and to investigate the underlying mechanisms of action.

Methods

Rat skeletal muscle cells (L6-GLUT4myc) were treated with 4-HIL, and the effect on glucose uptake was determined by measuring the incorporation of radio-labeled 2-deoxy-[³H]-d-glucose (2-DG) into the cell. Translocation of GLUT4myc to plasma membrane was measured by an antibody-coupled colorimetric assay.

Results

The prolonged exposure (16?h) of L6-GLUT4myc myotubes to 4-HIL caused a substantial increase in the 2-DG uptake and GLUT4 translocation to the cell surface, without changing the total amount of GLUT4 and GLUT1. Cycloheximide treatment reversed the effect of 4-HIL on GLUT4 translocation to the basal level suggesting the requirement of new protein synthesis. The 4-HIL-induced increase in GLUT4 translocation was completely abolished by wortmannin, and 4-HIL significantly increased the basal phosphorylation of AKT (Ser-473), but did not change the mRNA expression of AKT, IRS-1, GLUT4, and GSK3β.

Conclusion

Results suggest that 4-HIL stimulates glucose uptake in L6-GLUT4myc myotubes by enhancing translocation of GLUT4 to the cell surface in a PI-3-kinase/AKT-dependent mechanism.     

d-Allulose Improves Endurance and Recovery from Exhaustion in Male C57BL/6J Mice

d-Allulose, a rare sugar, improves glucose metabolism and has been proposed as a candidate calorie restriction mimetic. This study aimed to investigate the effects of d-allulose on aerobic performance and recovery from exhaustion and compared them with the effects of exercise training. Male C57BL/6J mice were subjected to exercise and allowed to run freely on a wheel. Aerobic performance was evaluated using a treadmill. Glucose metabolism was analyzed by an intraperitoneal glucose tolerance test (ipGTT). Skeletal muscle intracellular signaling was analyzed by Western blotting. Four weeks of daily oral administration of 3% d-allulose increased running distance and shortened recovery time as assessed by an endurance test. d-Allulose administration also increased the maximal aerobic speed (MAS), which was observed following treatment for >3 or 7 days. The improved performance was associated with lower blood lactate levels and increased liver glycogen levels. Although d-allulose did not change the overall glucose levels as determined by ipGTT, it decreased plasma insulin levels, indicating enhanced insulin sensitivity. Finally, d-allulose enhanced the phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase and the expression of peroxisome proliferator-activated receptor γ coactivator 1α. Our results indicate that d-allulose administration enhances endurance ability, reduces fatigue, and improves insulin sensitivity similarly to exercise training. d-Allulose administration may be a potential treatment option to alleviate obesity and enhance aerobic exercise performance.     

Yeast (1,3)-(1,6)-beta-glucan helps to maintain the body’s defence against pathogens: a double-blind, randomized, placebo-controlled, multicentric study in healthy subjects

Purpose

The effect of brewers’ yeast (1,3)-(1,6)-beta-d-glucan consumption on the number of common cold episodes in healthy subject was investigated.

Methods

In a placebo-controlled, double-blind, randomized, multicentric clinical trial, 162 healthy participants with recurring infections received 900 mg of either placebo (n = 81) or an insoluble yeast (1,3)-(1,6)-beta-d-glucan preparation (n = 81) per day over a course of 16 weeks. Subjects were instructed to document each occurring common cold episode in a diary and to rate ten predefined infection symptoms during an infections period, resulting in a symptom score. The subjects were examined by the investigator during the episode visit on the 5th day of each cold episode.

Results

In the per protocol population, supplementation with insoluble yeast (1,3)-(1,6)-beta-glucan reduced the number of symptomatic common cold infections by 25 % as compared to placebo (p = 0.041). The mean symptom score was 15 % lower in the beta-glucan as opposed to the placebo group (p = 0.125). Beta-glucan significantly reduced sleep difficulties caused by cold episode as compared to placebo (p = 0.028). Efficacy of yeast beta-glucan was rated better than the placebo both by physicians (p = 0.004) participants (p = 0.012).

Conclusion

The present study demonstrated that yeast beta-glucan preparation increased the body’s potential to defend against invading pathogens.     

Circulating leptin levels are associated with physical activity or physical fitness in Japanese

Objective

The aim of this study was to evaluate the link between circulating leptin levels and physical activity and/or physical fitness in apparently healthy Japanese.

Methods

A total of 85 men and 111 women who were not taking any medication were enrolled in this cross-sectional study. Circulating leptin levels, physical activity measured by tri-axial accelerometers and peak oxygen uptake were evaluated. We also assessed anthropometric data, blood pressure, blood examinations and energy intake.

Results

Circulating leptin levels were 3.2 ± 2.3 ng/mL in men and 5.9 ± 3.8 ng/mL in women. Circulating leptin levels were significantly and positively correlated with body weight, body mass index, abdominal circumference, insulin and the homeostasis model assessment index, and significantly and negatively correlated with peak oxygen uptake in both sexes. Stepwise multiple regression showed that peak oxygen uptake in men and physical activity evaluated by \(\sum {\left[ {{\text{metabolic equivalents }} \times \rm h {\text{ per week}}({\text{METs}}\;\;h/w)} \right]}\) in women were determinant factors for circulating leptin levels after adjusting for confounding factors.     

Promoting voluntary help-seeking among doctors with mental disorders

Objectives

To explore if the Barcelona Integral Care Program for Doctors with mental disorders (PAIMM, in Catalan) has achieved its goal of enhancing earlier and voluntary help-seeking amongst sick doctors.

Material and Methods

We conducted a retrospective chart review of 1363 medical records of physicians admitted to the inpatient and outpatient units of the PAIMM from February 1st, 1998 until December 31st, 2011. The sample was divided into 3 time periods: 1998–2004, 2005–2007 and 2008–2011 (477, 497, and 389 cases, respectively).

Results

The mean age at admission decreased (F = 77.57, p < 0.001) from the first period ( \(\bar x = 54.18\) ; SD = 10.28 years) to the last period ( \(\bar x = 44.81\) ; SD = 10.65 years), while voluntary referrals increased from 81.3% to 91.5% (Chi² = 17.85, p < 0.001). Mental disorders other than substance use disorders grew from 71% during the 1998–2003 period, to 87.4% (2004–2007), and 83.9% in the last period (Chi₂ = 29.01, p < 0.001). Adjustment disorders increased their prevalence, while inpatient treatment progressively represented less of the overall clinical activity.

Conclusions

Sick doctors may feel encouraged to seek help in non-punitive programs specially designed for them and where treatment becomes mandatory only when there is risk or evidence of malpractice.     

Renal impairment caused by chronic occupational chromate exposure

Purpose

To determine the nephritic toxicity of chromate after chronic occupational exposure.

Methods

The environmental contamination was assessed by measuring the chromium (Cr) in 8-h airborne sampler. The integrated level of Cr was determined by Cr concentrations in the whole blood (WB-Cr) and the urine (U-Cr). The renal glomerular and tubule impairment was evaluated by determination of cystatin C (Cys-C) in the serum and microalbumin (mALB), urinary beta₂-microglobulin (??₂M), N-acetyl-beta-d-glucosaminidase (NAG) activity in the urine.

Results

The mean occupational exposure time to Cr was 12.86?years with average daily air level of 27.13???g/m³ comparing to 0.11???g/m³ of the background level. The WB-Cr and U-Cr were 23.49???g/L and 17.41???g/g creatinine (Cre), respectively in the chromate-exposed workers comparing to 3.32???g/L and 1.52???g/g Cre in the controls. The serum Cys-C and urinary mALB were significantly increased in the chromate-exposed workers. Exposure to Cr seems to induce an enhanced level of urinary NAG activity and ??₂M concentration. The increased serum Cys-C concentration was positively correlated with the level of serum Cre. The U-Cr was positively correlated to the concentrations of urinary mALB, ??₂M, and the activity of NAG.

Conclusions

Chronic occupational exposure to chromate causes comprehensive renal impairment though more severity could occur in the tubule than in the glomeruler.     

Regional survey of image quality and radiation dose in computed tomography examinations in Saudi Arabia

This study is the first regional investigation in Najran, Saudi Arabia aimed at investigating radiation dose and image quality of computed tomography (CT) examinations. The survey data was collected from five scanners in four hospitals. For all CT scanners, a correction factor was calculated to measure the weighted computed tomography dose index (CTDI $_{w}$ ) using standard dosimetry phantoms. The CTDI $_{w}$ were reported in this study and compared with other countries. It was found that most CTDI $_{w}$ values were close to the European reference levels and in line with the results of similar surveys in the other parts of world. Concerning image quality, 80 % of the scanners were found to be in compliance with the relative international guidelines for all the examined parameters     

The flavonoid luteolin induces nitric oxide production and arterial relaxation

Purpose

Luteolin, a flavone present in many foods and medicinal plants, may have beneficial effects on various human chronic diseases. In the present study, we investigated the hypothesis that luteolin can directly act on vascular endothelial cells (ECs), leading to nitric oxide (NO) production and subsequent vascular relaxation.

Methods

Rat aortic rings were mounted in organ bath. Luteolin was added cumulatively, and vessel relaxation of rat aortic rings precontracted with phenylephrine (PE) or potassium was recorded. Endothelial nitric oxide synthase (eNOS) phosphorylation at Ser1177 and NO production from aortic rings and primary human aortic endothelial cells (HAECs) exposed to luteolin were measured by using Western blot and fluorometric assay, respectively.

Results

Luteolin dose-dependently (10–100 μmol/L) elicited relaxation of PE- or potassium-contracted aortic rings. The vasorelaxation effect of luteolin was attenuated by the eNOS inhibitor, N-nitro-l-arginine methyl ester, suggesting that this luteolin action is at least partially mediated by activating eNOS activity. We further found that luteolin dose-dependently (10–100 μmol/L) increased eNOS phosphorylation at Ser1177 (up to 1.9-fold) in isolated rat rings. Consistently, exposure of HAECs to luteolin also increased eNOS phosphorylation and NO production.

Conclusions

Luteolin may be a vascular protective agent by directly acting on vascular ECs to stimulate NO-dependent vascular dilatation.     

Study on the cytochrome P-450- and glutathione-dependent biotransformation of trichloroethylene in humans

Objectives: To investigate in humans the contribution of the cytochrome P-450- and glutathione-dependent biotransformation of trichloroethylene (TRI) under controlled repeated exposure in volunteers, and under occupational conditions. Methods: Volunteers were exposed to TRI, using repeated 15?min exposures at 50 and 100?ppm. This exposure schedule resulted in internal doses of 1.30 and 2.40?mmol of TRI respectively. Urine samples were collected for a minimum of 45?h. Urine samples were also collected from occupationally exposed workers. The samples were analysed for the known human metabolites of TRI, trichloroethanol (TCE), trichloroacetic acid (TCA) and both regio-isomeric forms of the mercapturic acid N-acetyl-S-(dichlorovinyl)-l-cysteine (DCV-NAC), and for (dichlorovinyl)-l-cysteine (DCVC). In order to further elucidate the metabolism of TRI in humans, we analysed samples for dichloroacetic acid and for the proposed break-down products of 1,2 and 2,2-dichlorovinyl-L-cysteine after deamination: the S-conjugates of 3-mercaptolactic acid, 3-mercaptopyruvic acid and 2-mercaptoacetic acid. Results: None of the glutathione metabolites was found in urine of volunteers. In workers occupationally exposed to TRI at levels between 0.4 and 21?ppm [8-h time-weighted average (TWA)], levels of DCV-NAC in urine samples collected at the end of the 4th working day and also next morning were below detection limit (0.04?μmol/l). This confirms the findings of Bernauer et?al. (1996) that these metabolites are excreted at very low levels in humans. Urinary levels of DCVC and six postulated metabolites of dichlorovinyl-S-cysteine conjugates via deamination were also below 0.04?μmol/l, indicating that at most 0.05% of the dose is excreted in the form of these metabolites. These data further strengthen the argument for a very low activity of glutathione-mediated metabolism for chronically exposed workers. Conclusions: This study gives additional data which indicate that glutathione-mediated metabolism is of minor importance in humans exposed to TRI. In spite of indications to the contrary, significant metabolism of the cysteine conjugate via ß-lyase, which could result in a toxic metabolite, cannot be ruled out completely.     

The utility of the behavioral risk factor surveillance system (BRFSS) in testing quality of life theory: an evaluation using structural equation modeling

Purpose

This study uses structural equation modeling to assess the utility of the behavioral risk factor surveillance system (BRFSS)—the Centers for Disease Control’s premier surveillance tool for monitoring behavioral risk factors—in predicting health-related quality of life (HRQoL).

Methods

Using SPSS/AMOS (version 18), the study utilizes New York State data extracted from the 2007 BRFSS national dataset to test a well-known HRQoL model developed by Wilson and Cleary (J Am Med Assoc 59–65, 2). The analysis represents an exploratory study that seeks to identify new applications for this important epidemiological database as well as a theoretical evaluation that examines the robustness of our current understanding of HRQoL.

Results

Findings support the Wilson and Cleary (J Am Med Assoc 59–65, 2) model, with the final model producing fit indices well within the thresholds traditionally used as benchmarks of good fit.

Conclusions

The integrity of the Wilson and Cleary (J Am Med Assoc 59–65, 2) model was substantiated, and the utility of BRFSS data for operationalization of HRQoL concepts was demonstrated successfully. This study has: (1) expanded the role of epidemiological research to include whole theory testing; and (2) successfully operationalized the Wilson and Cleary (J Am Med Assoc 59–65, 2) model using available, non-clinical data, which represents a major methodological contribution to the study of HRQoL.