[Show abstract][Hide abstract] ABSTRACT: AbstrAct The prevalence of therapeutic failures (TFs) and ad-verse drug reactions (ADRs) markedly increased in older subjects. However, both TFs and ADRs did not al-ways appear related to the presence of multiple phar-macologic treatments, a common status in subjects aged 65 and over. Instead, they seem more related to variations in the genes encoding protein metabolizing and transporting drugs. Thus, variations in these pro-teins may account for the inter-individual differences observed in drug efficacy, including the most severe clinical consequences TFs and ADRs. The genetics of drug metabolizing enzymes (DMEs) and drug trans-porters (DTs) is a very active area of multidisciplinary research, overlapping the fields of medicine, biology, pharmacology, and genetics. These proteins are virtu-ally responsible for metabolism and disposition, and thus the efficacy, of a number of drugs currently used in clinical practice. This article explored some basic concepts of the pharmacogenetics of DMEs and DTs. We also focused current knowledge of the genetic basis of TFs and ADRs of the most common drugs currently used in geriatric clinics. The knowledge of what we know and what we need to know is needed to advance the application of pharmacogenetics in clini-cal practice, in order to introduce personalized treat-ments for elderly people.
Journal of nephrology 04/2012; · 2.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prevalence of therapeutic failures (TFs) and adverse drug reactions (ADRs) markedly increased in older subjects. However, both TFs and ADRs did not always appear related to the presence of multiple pharmacologic treatments, a common status in subjects aged 65 and over. Instead, they seem more related to variations in the genes encoding protein metabolizing and transporting drugs. Thus, variations in these proteins may account for the inter-individual differences observed in drug efficacy, including the most severe clinical consequences TFs and ADRs. The genetics of drug metabolizing enzymes (DMEs) and drug transporters (DTs) is a very active area of multidisciplinary research, overlapping the fields of medicine, biology, pharmacology, and genetics. These proteins are virtually responsible for metabolism and disposition, and thus the efficacy, of a number of drugs currently used in clinical practice. This article explored some basic concepts of the pharmacogenetics of DMEs and DTs. We also focused current knowledge of the genetic basis of TFs and ADRs of the most common drugs currently used in geriatric clinics. The knowledge of what we know and what we need to know is needed to advance the application of pharmacogenetics in clinical practice, in order to introduce personalized treatments for elderly people.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND AIMS: Several studies have reported that the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) K121Q polymorphism (rs1044498) interacts with increased adiposity in affecting glucose homeostasis and insulin sensitivity. Conversely, one would expect that the amelioration of glucose homeostasis observed after weight loss is modulated by the ENPP1 K121Q polymorphism. The aim of our study was to test such hypothesis, in non-diabetic overweight-obese individuals. METHODS AND RESULTS: Two hundred eleven non-diabetic overweight-obese individuals were studied. Body mass index (BMI), fasting glucose, homeostasis model assessment of insulin resistance (HOMA-IR index) and lipid levels were obtained before and after 6-week lifestyle intervention (LI; diet and exercise) and their changes calculated as baseline minus 6-week values. LI decreased BMI, glucose, HOMA-IR and triglyceride levels (p < 0.001 for all). No difference across genotype groups (160 KK and 51 KQ or QQ - named as XQ - individuals) was observed in these changes. In a multivariate model, BMI changes predicted fasting glucose changes (β = 0.139 mmol/L (2.50 mg/dl) for 1 unit BMI change, p = 0.005). This correlation was not significant among KK individuals (β = 0.082; p = 0.15), while much steeper and highly significant among XQ individuals (β = 0.336; p = 0.00008) (p-value for Q121-by-weight loss interaction = 0.047). CONCLUSION: Individuals carrying the ENPP1 Q121 variant are highly responsive to the effect of weight loss on fasting glucose. This reinforces the previously suggested hypothesis that the Q121 variant interacts with adiposity in modulating glucose homeostasis.
[Show abstract][Hide abstract] ABSTRACT: Aim We investigated inpatients with and without type 2 diabetes mellitus, aged over 60 years, to compare their vitamin D status and calcium homeostatic parameters Materials and Methods We studied 140 patients consecutively admitted to our Internal Medicine Unit during the year 2010 (61 from November to April, 79 from May to October). The sample encompassed 70 patients with and 70 without diabetes. At admission we measured serum calcium (Ca), phosphate (P), sodium (Na), potassium (K), creatinine (Cr), alkaline phosphatase total activity (AP), albumin adjusted serum calcium (Caalb adj), 25 hydroxy-vitamin D (25OHD), parathyroid hormone (PTH), and 24-h urinary sodium/creatinine (uNa/Cr), potassium/creatinine (uK/Cr), calcium/creatinine (uCa/Cr), phosphate/creatinine (uP/Cr) ratios and calcium excretion (Ca ex). Results 25OHD levels of patients with and without diabetes did not significantly differ. In patients without diabetes recruited from November to April, 25OHD levels were significantly lower than those from May to October, whilst patients with diabetes did not show a significant seasonal variation. PTH had opposite non-significant seasonal variations, and negatively correlated with 25OHD in both groups of patients. This correlation was lost after adjusting for age and BMI in patients with diabetes. These inpatients had higher serum P and lower uP/Cr, according to lower PTH. Their serum glucose negatively correlated with uCa/Cr and Ca ex, contrary to inpatients with other diseases. Instead, uCa/Cr and Ca ex correlated with uNa/Cr only in patients without diabetes. Conclusions Inpatients with diabetes did differ from those with other disorders for vitamin D status and calcium-phosphate homeostatic mechanism.
[Show abstract][Hide abstract] ABSTRACT: Cytochrome P450 (CYP) 2D6 enzyme is the major responsible for the metabolism of donepezil, an inhibitor of acetyl cholinesterase currently used for the symptomatic treatment of mild-to-moderate Alzheimer's disease (AD). Functional polymorphisms in the CYP2D6 gene may affect enzyme activity and thus, the metabolism of donepezil. The aim of this study was to evaluate the effect of 16 functional polymorphisms in the CYP2D6 gene on the clinical response to donepezil treatment in patients with mild-to-moderate AD.
In this multicenter prospective cohort study we evaluated 57 unrelated Caucasians clinically diagnosed as AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association Work Group criteria. Patients were treated with donepezil (5-10 mg/daily) for 6 months. The response to donepezil treatment was evaluated at 6-month follow-up according to the National Institute for Health and Clinical Excellence requirements. The identification of 16 clinically relevant CYP2D6 gene variants was performed by a high-throughput genetic analysis.
Thirty-eight of 57 patients (67%) were responders and 19 patients (33%) were nonresponders to donepezil treatment. A significantly higher frequency of gene variants conferring decreased or absent enzyme activity was observed in responder than in nonresponder patients (73.68% vs. 36.84%; P=0.005). The presence of gene variants conferring decreased or absent activity of the CYP2D6 enzyme was significantly associated with a clinical response to donepezil treatment (odds ratio=6.286; 95% confidence interval=1.828-21.667).
Functional polymorphisms in the CYP2D6 gene can influence the clinical efficacy of donepezil. The analysis of CYP2D6 genotypes may be useful in identifying subgroups of AD patients with different clinical response to donepezil treatment.
Pharmacogenetics and Genomics 04/2011; 21(4):225-30. DOI:10.1097/FPC.0b013e32833f984c · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent studies investigating the single cytochrome P450 (CYP) 2D6 allele *2A reported an association with the response to drug treatments. More genetic data can be obtained, however, by high-throughput based-technologies. Aim of this study is the high-throughput analysis of the CYP2D6 polymorphisms to evaluate its effectiveness in the identification of patient responders/non-responders to CYP2D6-metabolized drugs.
An attempt to compare our results with those previously obtained with the standard analysis of CYP2D6 allele *2A was also made. Sixty blood samples from patients treated with CYP2D6-metabolized drugs previously genotyped for the allele CYP2D6*2A, were analyzed for the CYP2D6 polymorphisms with the AutoGenomics INFINITI CYP4502D6-I assay on the AutoGenomics INFINITI analyzer.
A higher frequency of mutated alleles in responder than in non-responder patients (75.38 % vs 43.48 %; p = 0.015) was observed. Thus, the presence of a mutated allele of CYP2D6 was associated with a response to CYP2D6-metabolized drugs (OR = 4.044 (1.348 - 12.154). No difference was observed in the distribution of allele *2A (p = 0.320).
The high-throughput genetic analysis of the CYP2D6 polymorphisms better discriminate responders/non-responders with respect to the standard analysis of the CYP2D6 allele *2A. A high-throughput genetic assay of the CYP2D6 may be useful to identify patients with different clinical responses to CYP2D6-metabolized drugs.
[Show abstract][Hide abstract] ABSTRACT: Previous papers investigating vitamin D status have often outlined the significant relationships between serum parathyroid hormone (PTH) and 25-hydroxyvitamin D (25OHD), but the influence of ionized calcium levels has not been concomitantly considered.
In 1050 healthy men (547) and women (503), serum ionized calcium (iCa), creatinine (Cr), albumin, 25OHD, and PTH were measured. After conventional analysis, a regression tree was fitted on the data set.
25OHD and PTH values showed significant opposite seasonal changes. 25OHD levels negatively correlated with PTH, which in turn negatively correlated with iCa. A regression tree was fitted to the whole data set using PTH as the response variable and 25OHD and iCa as covariates. PTH concentration depended on that of iCa only in subjects with 25OHD levels>16.35 ng/mL, while for 25OHD<16.35 ng/mL it depended on 25OHD values.
Our results indicated that PTH levels were highly conditioned by those of 25OHD in subjects with 25OHD values lower than 16.35 ng/mL and by those of iCa only for higher 25OHD concentration.
Bone 09/2010; 47(3):626-30. DOI:10.1016/j.bone.2010.06.013 · 4.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the recent decades, oxidative stress has become focus of interest in most biomedical disciplines and many types of clinical research. Increasing evidence from research on several diseases show that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart failure. Based on this research, the emerging concept is that oxidative stress is the "final common pathway", through which risk factors of several diseases exert their deleterious effects. Oxidative stress causes a complex dysregulation of cell metabolism and cell-cell homeostasis. In this review, we discuss the role of oxidative stress in the pathogenesis of insulin resistance and beta-cell dysfunction. These are the two most relevant mechanisms in the pathophysiology of type 2 diabetes, and in the pathogenesis of diabetic vascular complications, the leading cause of death in diabetic patients.
The Review of Diabetic Studies 01/2010; 7(1):15-25. DOI:10.1900/RDS.2010.7.15
[Show abstract][Hide abstract] ABSTRACT: To explore the role of asymmetric-dimethyl-L-arginine (ADMA), an endogenous nitric oxide synthetases (NOS) inhibitor, and nitrite/nitrate (NOx) in the pathogenesis of oxidative stress in early stages of type 1 diabetes mellitus.
We measured in 99 female subjects with uncomplicated type 1 diabetes (duration disease <10 years) and in 44 sex-matched controls (comparable for age, smoking habit, diet and physical activity) plasma levels of NOx, glycosylated haemoglobin (HbA1c), glucose, uric acid, total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides and serum ADMA.
Type 1 diabetic subjects have higher levels of glycemia, HbA1c, LDL cholesterol and NOx, but lower ADMA and serum uric acid (UA), compared with the control group; no further differences were found. A significant linear and inverse correlation was found between NOx and ADMA levels (R(2)=0.237, p<0.001).
This study suggests a reduced ADMA inhibition of NOS as possible mechanism involved in the pathogenesis of oxidative stress in female subjects with a short duration and uncomplicated type 1 diabetes.
Diabetes research and clinical practice 12/2009; 86(3):173-6. DOI:10.1016/j.diabres.2009.09.019 · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The development of non-invasive procedure to determine HER2 status may represent a powerful method for monitoring disease progression and response to the treatment.
Serum samples and RNA from peripheral blood were evaluated in 85 breast cancer patients (49 HER2 positive and 36 HER2 negative) and 22 healthy controls. HER2 mRNA levels were measured by real-time quantitative PCR (QPCR) and serum HER2 protein by immunoenzimatic assay (EIA). ROC curve analyses were used to determine the optimal cut off values.
A statistically significant difference was detected for both QPCR and EIA in HER2 positive patients as compared with both healthy controls and HER2 negative tumours. QPCR showed a 91% (CI95%: 84%-98%) specificity and a 78% (CI95%: 68%-88%) sensitivity for an optimal cut off value of 4.74. The optimal cut off value for EIA was 22 ng/ml yielding a 95% (CI95%: 90%-100%) specificity and a 59% (CI95%: 48%-70%) sensitivity. The QPCR assay was slightly less specific than EIA in discriminating HER2 positive breast cancers from HER2 negative tumours (78% CI95%: 69%-87% versus 86% CI95%: 79%-93%), but it was more sensitive (76% CI95%: 67%-85% versus 55% CI95%: 44%-66%).
Our results indicate that QPCR performs better than EIA in the determination of HER2 status of breast cancer patients and could be useful in monitoring the disease during follow up.
Cellular oncology: the official journal of the International Society for Cellular Oncology 02/2009; 31(3):203-11. DOI:10.3233/CLO-2009-0468 · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study, we evaluated the modifications of nasal function in type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]) by active anterior rhinomanometry (AAR) to understand if involvement of the nasal nervous system and microcirculation could be detected in nasal mucosa.
We studied 35 nonsmoking IDDM patients without diabetic complications, nasal pathology, or septal deviation. We measured serum levels of nitric oxide (NO) and nasal airway in three conditions: basal, supine, and after decongestion (phenylephrine hydrochloride 0.25 mg spray) by means of rhinomanometry, determining inspiratory total resistance and nasal airflow. The rhinomanometric results of the IDDM patients were compared with those of control normal subjects. In the IDDM patients, neuropathy was evaluated according to standardized procedures, including the vibration perception threshold test, cardiovascular autonomic tests, conduction velocity test, and fundoscopic examination.
The NO serum level was significantly higher in IDDM patients (12.5 +/- 3.8) compared with normal controls (4.8 +/- 1.4). The AAR results showed that in IDDM patients, inspiratory total resistance in the basal (0.82 +/- 0.4 Pa/cm3) and supine (0.94 +/- 0.7 Pa/cm3) positions and after decongestion (0.59 +/- 0.2 Pa/cm3) were increased compared with the control group in three conditions (basal, 0.52 +/- 0.2 Pa/cm3; supine, 0.58 +/- 0.3 Pa/cm3; after decongestion, 0.48 +/- 0.2 Pa/cm3). After decongestion, there was a greater decrease in nasal resistance in diabetic patients than in normal subjects.
Nasal function is involved in IDDM, rhinomanometry can also be considered an important test in the evaluation of this involvement in patients without other signs of diabetic neuropathy, and an increase in NO could partially explain these alterations.
Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale 11/2008; 37(5):611-5. · 0.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study is to verify whether, early in the course of type 1 diabetes and assuming hyperglycemia as the only risk factor, women demonstrate a change in oxidative status due to an interaction between nitric oxide (NO) and uric acid production.
Thirty-eight women with type 1 diabetes of less than 10 years' duration and with no diabetic complications were compared with 25 matched healthy female controls. Insulin, C-peptide, NO, HbA(1c) and oxidative stress metabolites were determined from venous blood samples taken from all patients after a 12 h overnight fast. Urine samples were used for urinary uric acid determination.
Most oxidative stress metabolites were significantly increased (p < 0.0001), while plasmatic and urinary uric acid levels were significantly lower (p < 0.0001) in patients with type 1 diabetes compared with controls. Mean NO levels were inversely related to uricemia. Bivariate regression analysis showed a significant correlation between plasmatic uric acid and NO (p = 0.004), ascorbic acid (p = 0.042), triglycerides (p = 0.014) and HbA(1c) (p < 0.0001). Linear multivariate regression analysis showed a significant relationship between HbA(1c) and plasmatic uric acid (beta = - 0.465, p = 0.0004).
Oxidative stress is already present in the early stages of type 1 diabetes. We conclude that the initial increase in oxidative stress could be linked to a reduction in plasmatic levels of uric acid, which is probably directly caused by an overproduction of NO.
Diabetes/Metabolism Research and Reviews 05/2008; 24(4):318-23. DOI:10.1002/dmrr.814 · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Type 2 deiodinase (D2) converts T4 in T3 in several human tissues, including hypothalamus and pituitary, and, therefore, plays a pivotal role in the negative feedback regulation of TSH secretion. A common variant of the gene, threonine (Thr) 92 alanine (Ala), has been identified and associated with decreased D2 enzymatic activity.
Our objective was to investigate whether this polymorphism predicts the T4 dosage needed to obtain target TSH levels in thyroidectomized patients.
Ambulatory patients were included in the study.
A total of 191 consecutive thyroid cancer patients, previously treated by near total thyroidectomy and radioiodine ablation, were studied. They were on stable T4 dose treatment aimed at obtaining either suppressed (supp) (n=117, <0.1 mU/liter) or near-supp (n=74, >or=0.1<0.5 mU/liter) serum TSH levels.
DNA genotyping for D2 Thr92Ala variant and evaluation of T4 dose (microg/kg) needed to obtain target TSH levels were determined.
Ala/Ala homozygous patients needed a higher T4 dose as compared with patients carrying the Thr92 variant (X/Thr patients) according to a recessive genetic model (2.08+/-0.43 vs. 1.90+/-0.35 microg/kg; P<0.05). This difference was observable in the near-supp group (P=0.002), but not in the supp group (P=0.4).
D2 Thr92Ala polymorphism seems to predict the need for higher T4 intake in thyroidectomized patients. If this finding is confirmed in additional studies, it may predict the T4 requirement to suppress TSH on the basis of the individual genetic background.
[Show abstract][Hide abstract] ABSTRACT: Objectives: To report a first case of 21-hydroxylase deficiency associated with anew genotype determined by V281+I172N/V281L mutations of the CYP21A2 gene. Design and methods: Direct genetic sequencing of CYP21A2 gene was performed. Results: Both siblings had the same genotype, namely V281+I172N/V281L, while their parents resulted as V281L and V281+I172N carriers, respectively. Conclusions: V281+I172N/V281L genotype should be included in the panel of mutations associated with the non-classical forms of 21-hydroxylase deficiency. (c) 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Hypercortisolism is known to cause osteoporosis.
To evaluate the prevalence of subclinical hypercortisolism in participants referred for evaluation of osteoporosis.
Two community hospitals and research institutes in Italy.
219 patients without clinically overt hypercortisolism or other secondary causes of osteoporosis who were referred for evaluation of osteoporosis between January 2005 and December 2005.
Bone mineral density was measured by using dual-energy x-ray absorptiometry, and hypercortisolism was assessed with serum cortisol levels after a dexamethasone suppression test. Also measured were 24-hour urinary free cortisol levels and midnight plasma cortisol levels.
Seven of 65 patients with T-scores of 2.5 or less and vertebral fractures had subclinical hypercortisolism (prevalence, 10.8% [95% CI, 3.23% to 18.31%]). This prevalence was 4.8% (CI, 1.32% to 8.20%) among patients with osteoporosis. In multivariable analyses adjusted for age, sex, and body mass index, a positive dexamethasone suppression test result was associated with the presence of osteoporosis (odds ratio, 3.37 [CI, 1.78 to 6.43]; P < 0.001) and vertebral fractures (odds ratio, 1.70 [CI, 1.04 to 2.79]; P = 0.035).
The study was conducted in a referral setting; its findings may not apply to the general population.
Subclinical hypercortisolism may be more common than is generally recognized in patients with osteoporosis in whom secondary causes of osteoporosis have been excluded.
Annals of internal medicine 10/2007; 147(8):541-8. · 16.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Amplification of the Her2neu oncogene is a well known indicator of poor prognosis in breast cancer patients. The implementation into the clinical setting of therapeutical strategies directly targeting the Her2neu gene product, has create the need for the development of non-invasive analytical techniques in order to monitoring minimal residual disease and response to the treatment.
To detect the expression of Her2neu mRNA in peripheral blood, we developed a specific real-time quantitative reverse transcription-PCR (QPCR) assay. The analyses were performed on blood samples obtained from 30 breast cancer patients positive for Her2neu overexpression by immunohistochemical analysis (IHC), 10 breast cancer patients negative for Her2neu overexpression, and 24 healthy controls.
Her2neu positive tumors showed a significant increase in mRNA transcripts as compared with both healthy controls (n=24) and Her2neu negative patients (n=10). After establishing a cut-off value, 18 out of the 30 Her2neu positive patient scored positive for Her2neu expression, whereas only 1 out of the 10 Her2neu negative patients was weakly positive.
Her2neu QPCR is suitable method for Her2neu overexpression detection in peripheral blood from clinical samples of breast cancer patients. QPCR could be used to identify breast cancer patients with poor prognosis and for monitoring response to the therapy.
[Show abstract][Hide abstract] ABSTRACT: Mass spectrometry-based approaches are the reference techniques for the determination of nitrite and nitrate in plasma and serum. However, due to their simplicity and rapidity, assays based on the Griess reaction or HPLC are generally used in clinical studies, but they generate diverging values for nitrite/nitrate concentration. In this study, particular attention is paid to the optimization of the deproteinization procedure for plasma and serum samples prior to nitrite/nitrate analysis by an enzymatic batch Griess assay, HPLC and GC-MS. A method is reported to verify completeness of deproteinization and to correct for nonspecific contribution to the absorbance of the diazo dye at 540 nm. With the application of such optimized procedures, we were able to significantly improve the correlation between Griess and HPLC method or the GC-MS technique for nitrite+nitrate concentrations in human serum and plasma. Despite remaining potentially interfering pre-analytical and analytical factors, the procedures reported in the present study may be helpful in a critical evaluation of limits and possibilities of the enzymatic batch Griess assay as a large-scale method for nitrite/nitrate determination in human serum in clinical studies.
Journal of Chromatography B 06/2007; 851(1-2):257-67. DOI:10.1016/j.jchromb.2007.02.003 · 2.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with type 1 diabetes (T1DM) present lower serum free IGF and IGFBP-3 values than healthy people. T1DM patients often present with associated autoimmune diseases such as thyroiditis or coeliac disease, and over time they frequently develop proliferative retinopathy, neuropathy or nephropathy in different combinations.
The aim of this study was to evaluate the effect of two associated autoimmune diseases or three diabetic complications on the serum free IGF-I or IGFBP-3 levels in T1DM patients, who also have a family history of T1DM. Design. 246 T1DM patients were enrolled, and then subdivided into groups according to diabetic complications or associated autoimmune diseases. Demographic and clinical data were recorded. Serum free IGF-I and IGFBP-3 levels were determined by IRMA.
IGF-I and IGFBP-3 generally present correlated serum values as confirmed in this study. Those patients with autoimmune thyroiditis and coeliac disease presented with significantly lower serum values of IGFBP-3, whereas free IGF-I was significantly lower in patients with the different diabetic complications. Retinopathy presented a slightly significant reduction in serum free IGF-I, while neuropathy and nephropathy showed a more pronounced fall. The number of complications was related to progressively decreasing free IGF-I levels. T1DM family history was associated with lower serum free IGF-I concentrations. These findings were confirmed after correction for age, glycosylated haemoglobin levels, insulin treatment protocol, body mass index, serum creatinine and sex.
Despite a direct correlation between serum free IGF-I and IGFBP-3, the correlation between the two molecules in patients with associated autoimmune diseases was lost, possibly due to different mechanisms of metabolic regulation.
European cytokine network 10/2006; 17(3):167-74. · 1.80 Impact Factor