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ABSTRACT: Heterozygous patients with familial hypercholesterolemia (FH) are known to be associated with a high risk of coronary artery disease (CAD), which is a major determinant of their clinical outcome. The prognosis of heterozygous FH patients substantially varies, being dependent on the level of their CAD risk, and their therapeutic regimen should be individualized. We assessed critical levels of LDL-cholesterol (LDL-C) and Achilles tendon thickness (ATT) to identify heterozygous FH patients at "very high" risk for CAD.
One hundred and nine heterozygous FH patients who had no history of CAD and had had their plasma lipid profile and ATT assessed before treatment were followed up until their first CAD event or 31 December 2010. Multivariable logistic regression models were used to analyze the correlation of LDL-C and/or ATT levels with the risk of developing CAD.
During the follow-up period, 21 of the 109 patients had a CAD event, diagnosed by coronary angiogram. Individuals in the highest tertile of LDL-C had a CAD risk 8.29-fold higher than those in the lowest tertile. Individuals in the highest tertile of the ATT group had a 7.82-fold higher CAD risk than those in the lowest tertile. Those who had either LDL-C ≥ 260 mg/dL or ATT ≥ 14.5 had a 23.94-fold higher CAD risk than those with LDL-C < 260 mg/dL and ATT <14.5 mm.
In heterozygous FH patients, LDL-C 260 mg/dL or higher and/or ATT 14.5 mm or thicker are useful markers for extracting patients at "very high" risk for CAD.
Journal of atherosclerosis and thrombosis 02/2012; 19(4):369-75. · 2.69 Impact Factor
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Nippon rinsho. Japanese journal of clinical medicine 01/2011; 69 Suppl 1:473-7.
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Mariko Harada-Shiba,
Takako Sugisawa, Hisashi Makino,
Mitsuru Abe,
Motoo Tsushima,
Yasunao Yoshimasa,
Takahiro Yamashita,
Yoshihiro Miyamoto,
Akira Yamamoto,
Hitonobu Tomoike,
Shinji Yokoyama
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ABSTRACT: Familial hypercholesterolemia (FH) patients are at particular risk for premature coronary artery disease (CAD) caused by high levels of low density lipoprotein (LDL). Administration of statins enabled us to reduce LDL-C levels in heterozygous FH patients. To evaluate the impact of statins on the clinical fate of heterozygous FH, a retrospective study was performed.
We analyzed the clinical influence of statins on age at the first clinical onset of CAD in 329 consecutive FH patients referred to the lipid clinic of the National Cardiovascular Center. Among 329 heterozygous FH patients, the onset of CAD was identified in 101.
The age at onset of CAD was 58.8+/-12.5 years in the 25 patients on statins at onset, significantly higher than that in the 76 patients not on statins (47.6+/-10.5 years) (p <0.001). The average age at CAD onset was significantly higher after widespread use of statins (54.2+/-13.2 years in 48 patients, Group 1) compared to before October 1989 when statins were approved in Japan (46.9+/-9.6 years in 53 patients; Group 2, p=0.002). A significant difference was seen between Groups 1 and 2 in the variables, including sex, prevalence of smoking habit, LDL-C, and the use of statins, aspirin and probucol. After adjusting for these variables, only statin use was independently associated with the difference in age at CAD onset by multivariable analysis.
Statins have improved the clinical course of patients with heterozygous FH.
Journal of atherosclerosis and thrombosis 07/2010; 17(7):667-74. · 2.69 Impact Factor
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ABSTRACT: The effects of exercise intervention and to assess its long-term efficacy in preventing subsequent cardiovascular events in patients with type 2 diabetes were little known on randomized controlled trial.
Thirty-eight type 2 diabetic patients (21 men and 17 women) were assigned to either the exercise group (n=21) or the control group without exercise training (n=17) by simple randomization. The exercise training group was scheduled for aerobic and resistance exercise programs for 3 months. After the 3-month, we investigated endothelial function, insulin resistance, adipocytokines and inflammatory markers. The endothelial function was evaluated by examining a flow-mediated endothelium-dependent vasodilatation (FMD). Furthermore, we followed the incidence of cardiovascular events for 24 months.
After 3-month, HbA1C was decreased significantly in both groups. FMD was increased from 7.3+/-4.7% to 10.9+/-6.2% only in the exercise group (p<0.05). Long-term follow-up data showed that the control group developed cardiovascular events more frequently than did the exercise group (p<0.05).
Exercise improves endothelial dysfunction independently of glycemic control and insulin sensitivity in patients with type 2 diabetes. The beneficial effects of 3-month exercise to reduce cardiovascular events persist for 24 months.
Journal of atherosclerosis and thrombosis 05/2010; 17(8):828-33. · 2.69 Impact Factor
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ABSTRACT: The association between BMI and low levels of B-type natriuretic peptide (BNP), a marker of heart failure, has been demonstrated in a large population-based cohort. We examined the effects of obesity on BNP levels in patients with diabetes that are often associated with obesity and a higher risk for heart failure.
Plasma BNP levels, BMI, and cardiac function parameters were measured in 608 patients with type 2 diabetes. A computed tomography scan was performed to measure abdominal fat.
In multivariable regression analyses adjusted for age, sex, systolic blood pressure, pulse rate, serum creatinine, asynergy, left atrial dimension, percent fractional shortening, and left ventricular mass, there was an inverse relationship between BMI and BNP (p<0.001). Obese individuals with 25</=BMI<30 and 30</=BMI individuals were more likely to have lower BNP levels compared with BMI<22 individuals (multivariable-adjusted odds ratios (95% CIs): 1.61 (1.16-2.26) and 2.07 (1.35-3.22), respectively). Inverse associations were noted between BNP and visceral fat area (VFA) in both sexes (p=0.029 for men, p=0.024 for women).
In patients with type 2 diabetes, BNP levels are significantly lower in obese subjects after multivariable adjustments. Among various obesity parameters, visceral fat was most closely associated with BNP levels.
Diabetes research and clinical practice 04/2010; 89(2):174-80. · 2.16 Impact Factor
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Koji Harada,
Yoshihiro Miyamoto,
Hiroko Morisaki,
Naotaka Ohta,
Itaru Yamanaka,
Yoshihiro Kokubo, Hisashi Makino,
Mariko Harada-Shiba,
Akira Okayama,
Hitonobu Tomoike,
Tomonori Okamura,
Okamura Tomonori,
Yoshihiko Saito,
Yasunao Yoshimasa,
Takayuki Morisaki
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ABSTRACT: The autosomal recessive hypercholesterolemia (ARH) gene is located on chromosome 1p35 and encodes a 308-amino acid protein containing a phosphotyrosine-binding domain. Several researchers have identified mutations of ARH that cause autosomal recessive hypercholesterolemia; however, it remains unknown whether this gene is involved in common hypercholesterolemia.
We searched for polymorphisms of the ARH gene by denaturing high-performance liquid chromatography and direct sequencing. We identified 18 single nucleotide polymorphisms of the gene, including 9 novel polymorphisms, and determined 2 haplotype blocks. No association was observed between common hypercholesterolemia and any polymorphisms or haplotypes of the ARH gene; however, we newly identified a rare Thr56Met missense mutation located in the phosphotyrosine-binding domain, which is the functional domain responsible for cholesterol metabolism. Among 1,800 Japanese individuals enrolled in the Suita study, only 4 were heterozygous for Thr56Met and all had hypercholesterolemia. The total cholesterol level and low-density lipoprotein cholesterol level of diabetic patients with the Thr56Met missense mutation was 276.3+/-13.8 mg/dL and 185.3+/-7.37 mg/dL, respectively.
Because the Thr56Met missense mutation occurs in an orthologously conserved functional domain and all subjects with the mutation had hypercholesterolemia resembling familiar hypercholesterolemia, it may be a cause of familial hypercholesterolemia.
Journal of atherosclerosis and thrombosis 02/2010; 17(2):131-40. · 2.69 Impact Factor
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ABSTRACT: The inverse association between plasma B-type natriuretic peptide (BNP) levels and body mass index (BMI) has been reported in Western populations. Here we analyzed the relationship between plasma BNP and obesity in a general urban Japanese population. We recruited 1,759 subjects without atrial fibrillation or history of ischemic heart disease aged 38-95 years (mean age +/- standard deviation 64.5 +/- 10.9 years, 56.1% women, mean BMI 22.8 +/- 3.1 kg/m(2)) from the participants in the Suita Study between August 2002 and December 2003. In multivariable regression analyses adjusted for age, systolic blood pressure, pulse rate, serum creatinine, left ventricular hypertrophy in ECG, the inverse relationships between BNP levels and BMI (kg/m(2)) was found in both sexes (both p<0.001). Multivariable-adjusted mean plasma BNP levels in the group of BMI<18.5, 18.5< or =BMI< 22, 22< or =BMI<25, and 25< or =BMI were 23.4, 17.9, 14.0 and 13.0 pg/mL, respectively (trend p<0.001). The negative association of body fat (percentage and mass), skin fold thickness, or waist circumference with BNP levels was observed the negative associations in both sexes (p<0.01). Among the obesity indices, body fat mass is most tightly associated with BNP. In conclusion, plasma BNP was inversely associated with obesity related markers such as body fat mass, skinfold thickness and waist circumferences after adjusted for relevant covariates in a Japanese population.
Endocrine Journal 01/2010; 57(8):727-33. · 2.03 Impact Factor
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Makoto Kawamura,
Hiroaki Itoh,
Shigeo Yura,
Haruta Mogami,
Tsuyoshi Fujii, Hisashi Makino,
Yoshihiro Miyamoto,
Yasunao Yoshimasa,
Seiichiro Aoe,
Yoshihiro Ogawa,
Norimasa Sagawa,
Norio Kanayama,
Ikuo Konishi
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ABSTRACT: Epidemiologic studies have shown that in utero malnutrition is a risk factor for adult cardiovascular disease (CVD). Recently, we reported a mouse animal model of 30% maternal caloric reduction, in which offspring showed a significant increase in systolic blood pressure (SBP) as well as in cardiac remodeling-associated morphological parameters such as cardiac enlargement and coronary perivascular fibrosis in adulthood. Using a similar animal model, we here demonstrated that an increased level of protein consumption during an undernourished pregnancy (high-protein diet; HPD) corrected for the development of CVD risk factors found in fetal undernourishment with less protein consumption (standard-protein diet; SPD). In contrast, maternal ad libitum feeding with HPD resulted in significantly elevated SBP and cardiac enlargement in offspring at 16 wks. Appropriate maternal protein ingestion might partly protect against the development of CVD risk factors in offspring.
Endocrine Journal 06/2009; 56(5):679-89. · 2.03 Impact Factor
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Yoshihiro Kokubo,
Satoko Nakamura,
Tomonori Okamura,
Yasunao Yoshimasa, Hisashi Makino,
Makoto Watanabe,
Aya Higashiyama,
Kei Kamide,
Katsuyuki Kawanishi,
Akira Okayama,
Yuhei Kawano
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ABSTRACT: Chronic kidney disease (CKD) is increasingly recognized as an independent risk factor for stroke and myocardial infarction (MI). Few studies, however, have examined the relationship between blood pressure (BP) category and these diseases in subjects with and without CKD.
We studied 5494 Japanese individuals (ages 30 to 79, without stroke or MI at baseline) who completed a baseline survey and received follow-up through December 2005. The glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease study equation modified by the Japanese coefficient. CKD was defined as an estimated GFR <60 mL/min/1.73 m2. BP categories were defined by the European Society of Hypertension and European Society of Cardiology 2007 criteria.
In 64 395 person-years of follow-up, we documented 346 incidences of cardiovascular diseases (CVD; 213 strokes and 133 MI events). Compared with the GFR (> or =90 mL/min/1.73 m2) group, the hazard ratios (95% confidential intervals) for stroke were 1.9 (1.3 to 3.0) in the GFR 50 to 59 mL/min/1.73 m2 group and 2.2 (1.2 to 4.1) in the GFR <50 mL/min/1.73 m2 group. Results for cerebral infarction were similar. Compared with the optimal BP subjects without CKD, the normal BP, high-normal BP, and hypertensive subjects without CKD showed increased risks of CVD and stroke; however the impact of each BP category on CVD (P for interaction: 0.04 in men, 0.49 in women) and stroke (0.03 in men, 0.90 in women) was more evident in men with CKD.
CKD may increase the association of BP and CVD in a Japanese urban population.
Stroke 05/2009; 40(8):2674-9. · 5.73 Impact Factor
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ABSTRACT: Circulating bone marrow derived immature cells, including CD34-positive (CD34(+)) cells, contribute to maintenance of the vasculature, not only as a pool of endothelial progenitor cells (EPCs), but also as a source of growth/angiogenesis factor. We hypothesized that the thiazolidineone compound pioglitazone could stimulate the circulating CD34(+) cells in diabetic patients. Thirty-four patients with type 2 diabetes received 15-30 mg pioglitazone for 24 weeks. The number of circulating CD34(+) cells significantly increased at 12 and continued this effect for 24 weeks (1.08+/-0.39, 1.34+/-0.34 and 1.32+/-0.28cells/microl at 0, 12 and 24 weeks, respectively). The change of CD34(+) cell levels (DeltaCD34(+) cells) between 0 and 12 weeks was significantly correlated with the change of high sensitive C reactive protein levels (Deltahs-CRP) and change in adiponectin levels (Deltaadiponectin) (r=-0.412, r=0.359, respectively). Our study demonstrated that pioglitazone treatment increased circulating CD34(+) cells, suggesting that this effect may at least partly contribute to the anti-atherosclerotic action of pioglitazone.
Diabetes research and clinical practice 09/2008; 81(3):327-30. · 2.16 Impact Factor
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ABSTRACT: Statins have been shown to have beneficial effects on myocardial infarction, revascularization, stroke, and cardiovascular mortality in numerous clinical trials. Seven kinds of statins are available today and have different characteristics in their efficacy of LDLlowering, their metabolism and their adverse effects including hepatic injury, muscle disease, renal injury and neurologic injury. Muscle disease is the most discussed adverse effect with the use of statins including rhabdomyolysis, the most serious one. Hepatic injury with high dose statin use should be mentioned, although the incidence is low. Statins are well-tolerated and have been extremely well studied all over the world. As the contribution of statins in preventing cardiovascular events has already been proven, physicians should not hesitate to prescribe statins to patients not only with hypercholesterolemia, but also to those with high risks.
Immunology Endocrine & Metabolic Agents - Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology Endocrine & Metabolic Agents) 05/2008; 8(2):172-176.
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Sadanori Okada, Hisashi Makino,
Ayako Nagumo,
Takako Sugisawa,
Muneya Fujimoto,
Ichiro Kishimoto,
Yoshihiro Miyamoto,
Akie Kikuchi-Taura,
Toshihiro Soma,
Akihiko Taguchi,
Yasunao Yoshimasa
Diabetes care 02/2008; 31(1):157-8. · 8.09 Impact Factor
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ABSTRACT: An elevated urinary albumin excretion is associated with an increased risk of cardiovascular disease due to atherosclerosis, but the pathophysiological mechanism underlying this association is poorly understood. We studied 217 diabetic patients, that is, 121 normoalbuminuric patients, 71 microalbuminuric patients, and 25 macroalbuminuric patients. We evaluated flow-mediated dilatation of brachial artery (%FMD, one endothelial function marker associated with endogenous NO production), von Willebrand factor (vWF, endothelial activation marker), high-sensitive CRP (hsCRP, a low-grade inflammation marker), asymmetric dimethyl arginine (ADMA, an endogenous inhibitor of NO synthesis), and insulin sensitivity by steady-state plasma glucose method. %FMD was apparently decreased in microalbuminuric and macroalbuminuric patients compared with normoalbuminuric patients (p<0.001). Moreover, %FMD was significantly correlated with the degree of albuminuria (r=-0.38, p<0.05). On the other hand, vWF and hsCRP did not show significant difference between normoalbuminuric patients and microalbuminuric patients. In diabetic patients with macroalbuminuria, ADMA was significantly elevated compared to those with normoalbuminuria. Insulin sensitivity was significantly associated with urinary albumin excretion rate. These results suggested that endothelial dysfunction which may be due to impaired NO production and insulin resistance underlie the association between diabetic nephropathy and atherosclerosis in diabetic patients.
Diabetes research and clinical practice 02/2008; 79(1):177-82. · 2.16 Impact Factor
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ABSTRACT: Diabetic nephropathy is a leading cause of end-stage renal disease. Several pathways, including the renin-angiotensin system, have been postulated as potential mechanisms of diabetic nephropathy. In addition, glomerulogenesis-related molecules are involved in the pathogenesis of diabetic nephropathy, especially at the early stage. They can be divided into three groups by function, that is, fibrosis-related, podocyte differentiation-related and angiogenesis-related molecules. Most of the molecules are expressed in the podocyte and upregulated, even during the normoalbuminuric stage. Expression of several podocyte structure-related molecules are also altered at the normoalbuminuric stage. They can contribute to the structural alteration of the podocyte in diabetic nephropathy. Thus, normalization of the expression of glomerulogenesis-related molecules could be a new target for preventing the initiation and progression of diabetic nephropathy.
Expert Review of Endocrinology & Metabolism 08/2007; 2(5):615-622.
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Nippon rinsho. Japanese journal of clinical medicine 08/2007; 65 Suppl 7:504-8.
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ABSTRACT: Evidence has emerged that undernutrition in utero is a risk factor for cardiovascular disorders in adulthood, along with genetic and environmental factors. Recently, the local expression of angiotensinogen and related bioactive substances has been demonstrated to play a pivotal role in cardiac remodeling, i.e. fibrosis and hypertrophy. The aim of the present study was to clarify the possible involvement of the local cardiac angiotensin system in fetal undernutrition-induced cardiovascular disorders. We developed a mouse model of undernutrition in utero by maternal food restriction, in which offspring (UN offspring) showed an increase in systolic blood pressure (8 wk of age, P < 0.05; and 16 wk, P < 0.01), perivascular fibrosis of the coronary artery (16 wk, P < 0.05) and cardiac cardiomegaly (16 wk, P < 0.01), and cardiomyocyte enlargement, concomitant with a significant augmentation of angiotensinogen (P < 0.05) and endothelin-1 (P < 0.01) mRNA expression and a tendency to increase in immunostaining for both angiotensin II and endothelin-1 in the left ventricles (16 wk). These findings suggest that fetal undernutrition activated the local cardiac angiotensin system-associated bioactive substances, which contributed, at least partly, to the development of cardiac remodeling in later life, in concert with the effects of increase in blood pressure.
Endocrinology 03/2007; 148(3):1218-25. · 4.46 Impact Factor
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ABSTRACT: Glomerular injury plays a pivotal role in the development of diabetic nephropathy. To elucidate molecular mechanisms underlying diabetic glomerulopathy, we compared glomerular gene expression profiles of db/db mice with those of db/m control mice at a normoalbuminuric stage characterized by hyperglycemia and at an early stage of diabetic nephropathy with elevated albuminuria, using cDNA microarray. In db/db mice at the normoalbuminuric stage, hypoxia-inducible factor-1alpha (HIF-1alpha), ephrin B2, glomerular epithelial protein 1, and Pod-1, which play key roles in glomerulogenesis, were already upregulated in parallel with an alteration of genes related to glucose metabolism, lipid metabolism, and oxidative stress. Podocyte structure-related genes, actinin 4alpha and dystroglycan 1 (DG1), were also significantly upregulated at an early stage. The alteration in the expression of these genes was confirmed by quantitative RT-PCR. Through pioglitazone treatment, gene expression of ephrin B2, Pod-1, actinin 4alpha, and DG1, as well as that of oxidative stress and lipid metabolism, was restored concomitant with attenuation of albuminuria. In addition, HIF-1alpha protein expression was partially attenuated by pioglitazone. These results suggest that not only metabolic alteration and oxidative stress, but also the alteration of gene expression related to glomerulogenesis and podocyte structure, may be involved in the pathogenesis of early diabetic glomerulopathy in type 2 diabetes.
Diabetes 11/2006; 55(10):2747-56. · 8.29 Impact Factor
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Takayoshi Suganami,
Kiyoshi Mori,
Issei Tanaka,
Masashi Mukoyama,
Akira Sugawara, Hisashi Makino,
Seiji Muro,
Kensei Yahata,
Shuichi Ohuchida,
Takayuki Maruyama,
Shuh Narumiya,
Kazuwa Nakao
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ABSTRACT: One of the major causes of end-stage renal diseases is hypertensive renal disease, in which enhanced renal prostaglandin (PG) E2 production has been shown. PGE2, a major arachidonic acid metabolite produced in the kidney, acts on 4 receptor subtypes, EP1 through EP4, but the pathophysiological importance of the PGE2/EP subtypes in the development of hypertensive renal injury remains to be elucidated. In this study, we investigated whether an orally active EP1-selective antagonist (EP1A) prevents the progression of renal damage in stroke-prone spontaneously hypertensive rats (SHRSP), a model of human malignant hypertension. Ten-week-old SHRSP, with established hypertension but with minimal renal damage, were given EP1A or vehicle for 5 weeks. After the treatment period, vehicle-treated SHRSP showed prominent proliferative lesions in arterioles, characterized by decreased alpha-smooth muscle actin expression in multilayered vascular smooth muscle cells. Upregulation of transforming growth factor-beta expression and tubulointerstitial fibrosis were also observed in vehicle-treated SHRSP. All these changes were dramatically attenuated in EP1A-treated SHRSP. Moreover, EP1A treatment significantly inhibited both increase in urinary protein excretion and decrease in creatinine clearance but had little effect on systemic blood pressure. These findings indicate that the PGE2/EP1 signaling pathway plays a crucial role in the development of renal injury in SHRSP. This study opens a novel therapeutic potential of selective blockade of EP1 for the treatment of hypertensive renal disease.
Hypertension 01/2004; 42(6):1183-90. · 6.21 Impact Factor
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ABSTRACT: The klotho gene product and stanniocalcin (STC) 1 and 2 are recently identified molecules implicated in calcium and phosphorus homeostasis. In the present study, we investigated the regulation of STC1 and STC2 gene expression in the kidney by klotho gene expression. Mice deficient in klotho expression (klotho mice) have hypercalcemia and hyperphosphatemia, and increased renal gene expression of STC1 and STC2 compared with wild-type mice. Administration of vitamin D or CaCl(2) to wild-type mice causes upregulation of STC1 but STC2 gene expression is not altered significantly. On the other hand, treatment of klotho mice with low phosphorus diet results in partial decrease in STC2 gene expression with normalization of hyperphosphatemia. These findings indicate that klotho gene expression plays a crucial role in the regulation of renal stanniocalcin gene expression in vivo, at least partly, through the control of circulating calcium and phosphate concentrations.
Biochemical and Biophysical Research Communications 11/2003; 310(1):128-34. · 2.48 Impact Factor
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ABSTRACT: Patients that are homozygous for familial hypercholesterolemia (FH) exhibit severe hypercholesterolemia, cutaneous and tendon xanthomas and premature atherosclerosis beginning in childhood. They are resistant to drug therapy and low-density lipoprotein (LDL) apheresis is the practical treatment. Here we review the technique of LDL apheresis treatment, the long-term effects of LDL apheresis, the effect of apheresis on pregnancy, and the drugs that have proven beneficial in patients with homozygous FH. We also record our experiences of treating eight homozygous FH patients using the LDL apheresis treatment. Among the eight patients, one has been free from cardiovascular disease and two patients have each regressed once. In two patients, aortic valve stenosis developed and the other two patients died for acute myocardial infarction. Furthermore, two patients delivered healthy babies in spite of coronary artery disease. Thus, LDL apheresis therapy has the possibility of preventing the progression of atherosclerosis, but the prognosis assessed by long-term observation is still not satisfactory. A recent clinical trial showed some efficacy of the combination therapy of LDL apheresis and atorvastatin for reducing serum cholesterol levels in homozygous FH, suggesting that this combination therapy may be useful for prevention of atherosclerosis in patients homozygous for FH.
Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 09/2003; 7(4):397-401. · 1.39 Impact Factor
