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ABSTRACT: BACKGROUND: Minimal-change nephrotic syndrome has recently been attributed to an immature, dysfunctional T-cell population. CASE-DIAGNOSIS/TREATMENT: A woman, now 23 years old, developed nephrotic syndrome when she was 6 years old. Despite treatment with steroids and immunosuppressants such as cyclosporine, mizoribine, mycophenolate mofetil, and tacrolimus, the patient relapsed 14 times. At the age of 19 years, she developed chronic myelogenous leukemia, against which imatinib achieved cytogenetic remission. The patient received an allogeneic bone marrow graft transplantation from an unrelated marrow bank donor, with an uncomplicated recovery and molecular genetic remission. Immunosuppressants were withdrawn within 6 months. The patient is now without drug treatment. Complete remission of nephrotic syndrome has also been maintained for over 4 years without any drug administration. CONCLUSIONS: The patient's course supports suggestions that immunological dysfunction in nephrosis is associated with abnormality of immature, relatively unclassified T cells (CD34(+)) representing hematopoietic stem cells, as opposed to mature T cells (CD34(-)).
Pediatric Nephrology 02/2013; · 2.52 Impact Factor
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ABSTRACT: BACKGROUND: A syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA), as well as immunoglobulin A nephropathy (IgAN), may be caused by autoimmune reactivity nephropathy. CASE-DIAGNOSIS/TREATMENT: A 10-year-old boy presented with periodic fever, exudative tonsillitis, oral aphthous ulcer, and cervical lymph node inflammation. These conditions had occurred at intervals of about 2-6 weeks since the age of 3 years. Microscopic hematuria, first detected at age 8 years, worsened during episodes of PFAPA-related fever; since 10 years of age, the hematuria was accompanied by sustained proteinuria. Examination of a kidney biopsy specimen led to a diagnosis of IgAN. In the kidney specimen, fractalkine immunoreactivity and heavy macrophage infiltration were prominent. Multi-drug cocktail therapy improved the urinalysis findings, and subsequent tonsillectomy succeeded in controlling recurrences of PFAPA and IgAN. In a post-treatment renal biopsy specimen, mesangial proliferation was decreased, and fractalkine immunoreactivity was absent. CONCLUSION: Immunologic reactions against certain antigens in local mucosa, including tonsils, may be impaired in PFAPA and IgAN, as evidenced by the suppression of both diseases in our patient by tonsillectomy. Accordingly, the concurrence of PFAPA and IgAN in our patient appeared to be a consequence of shared autoimmune mechanisms and systemic and local increases in cytokine concentrations, rather than coincidence.
Pediatric Nephrology 09/2012; · 2.52 Impact Factor
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ABSTRACT: Venous thrombosis is a well-known complication of nephrotic syndrome (NS), while arterial thrombosis is rare. We know of no reports of children with this complication. Here we report a case of 14-year-old girl with NS, who complicated with renal and cerebral infarctions resulting from arterial thrombosis. Urinary examination showed heavy proteinuria. She had intravascular dehydration. Serum albumin was 0.9 g/dL. Contrast-enhanced computed tomography (CT) showed a low-attenuation area in the right kidney. Decreased blood flow in the right middle cerebral artery was observed on MRA and also on multi-detector-row head CT. Urokinase and heparin were given. Cerebral infarction was treated neuroprotectively by i.v. infusion of edaravone. Comprehensive assessment of intravascular dehydration and the coagulation-fibrinolysis system is needed to guide decisions concerning prophylactic anticoagulation therapy. Better understanding of NS and its risks, as well as the necessity of drug therapy, may help teenagers to accept and cooperate with treatment.
Pediatrics International 08/2012; 54(4):549-52. · 0.63 Impact Factor
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ABSTRACT: We investigated efficacy and therapeutic mechanisms of tonsillectomy for intractable childhood IgA nephropathy. Five patients refused tonsillectomy. Among 25 patients, 19 patients were able to evaluate histological findings before and after surgery. Patients with poor (n = 7) or relatively poor (n = 18) histologically determined prognosis and an age of at least 7 years, together with proteinuria of at least 0.3 g/day or severe persisting despite ongoing drug treatment, are candidates for surgery. Patients were grouped by interval between diagnosis of IgA nephropathy and tonsillectomy (within 3 years; early group vs 3 years or later; later group). Patients underwent kidney biopsy shortly before and 1 to 2 years after tonsillectomy.
Proteinuria was reduced after tonsillectomy over 2 years of follow-up in both early and later groups compared with proteinuria in the 6 months preceding surgery. Complete remission was achieved in 10 patients, most often among those having surgery within 3 years, while patients refusing surgery failed to attain complete remission of urinary findings. Histological activity decreased in both groups, significantly when surgery was early. Complement component C3 deposition and activated macrophages in glomeruli decreased after tonsillectomy, especially with early surgery.
Tonsillectomy improved clinicopathological features in relatively severe paediatric IgA nephropathy, especially with the early-surgery group. Therapeutic mechanisms may include inhibition of complement activity in glomeruli and glomerular infiltration by activated macrophages.
Nephrology 05/2012; 17(7):658-64. · 1.31 Impact Factor
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ABSTRACT: BACKGROUND: Secondary focal segmental glomerulosclerosis (FSGS) follows congenital or acquired tubulointerstitial alterations such as in Dent's disease, Lowe syndrome, and reflux nephropathy. Failure of adequate regeneration after tubulointerstitial injury, or abnormal tubulogenesis, can disturb intrarenal blood circulation, causing excessive glomerular filtration. The epithelial cell-transforming sequence 2 gene (ECT2) contributes to tight junction function in epithelial cells. METHODS: We encountered two patients with a nonfunctioning ECT2 genotype who later developed FSGS. Both developed proteinuria associated with acute renal failure in early childhood. RESULTS: Renal biopsy specimens showed marked tubulointerstitial nephritis at the onset of proteinuria, later progressing to FSGS consequent to tubulointerstitial injury. The patients did not respond to corticosteroids and attained only incomplete remission upon cyclosporine A administration. One patient received a maternal renal transplant with good function and no rejection. CONCLUSIONS: ECT2 is important for tight junction function and maintenance of cell polarity. Nonfunction of this gene may cause renal tubulointerstitial injury, progressing to glomerular sclerosis.
Clinical and Experimental Nephrology 05/2012; · 1.37 Impact Factor
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ABSTRACT: In addition to the urinary abnormalities, symptoms of left renal vein entrapment between the aorta and superior mesenteric artery (left renal vein entrapment syndrome, LRVES) may include abdominal and flank pain as well as chronic fatigue. We investigated various LRVES symptoms in this study.
In 53 pediatric LRVES patients treated at our department, 22 had a score of 5 points or higher on orthostasis. Initial evaluation of LRVES by abdominal ultrasonography showed a stenotic-to-prestenotic vein diameter ratio of 0.2 or less. Definitive diagnosis was made by computed tomography and magnetic resonance angiography. Cortisol, catecholamine (CA), and brain natriuretic peptide (BNP) were also measured.
The frequency of LRVES was 2.5 times higher in girls than in boys. Low or very low body mass indexes were seen in both sexes. The most common initial finding was urine abnormalities, followed by dizziness and malaise. In 6 patients, orthostasis precluded school attendance. Ten patients had orthostasis scores above 12. Patients unable to attend school had either low levels of plasma or urinary cortisol. Midodrine significantly decreased orthostasis scores. Some patients required treatment with fludrocortisone. Plasma CA, renin, and BNP levels were all normal.
Locally excessive venous pressure may cause reversible adrenal dysfunction with transitory Addisonian symptoms. Children with cryptogenic malaise or severe orthostasis should be evaluated for LRVES.
World Journal of Pediatrics 05/2012; 8(2):116-22. · 1.22 Impact Factor
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ABSTRACT: Imbalance between T-helper 1 (Th1) and 2 (Th2) lymphocytes and effects of reactive oxygen species (ROS) upon glomerular capillary walls have been implicated in minimal change nephrotic syndrome (MCNS).
By polymerase chain reaction and comparative genomic hybridization, we evaluated mutations of the GSTT1 gene (GSTT1), a member of the glutathione S-transferase (GST) supergene family associated with both protection of cells from ROS and control of allergic reactions and serum immunoglobulin (Ig) E.
Among 15 children with MCNS, IgE elevation (over 2,000 IU/l) and GSTT1 deletion was found in 2 who showed severe allergic symptoms. Serum ROS concentrations in these 2 patients were significantly higher than in healthy controls or other MCNS patients. In addition, a Th2 shift caused by increased serum interleukin (IL)- 4 was observed.
These results suggest presence of a GSTT1 abnormality in some children with MCNS having marked serum IgE elevations and various allergic complications. Defective ROS degradation and Th1/Th2 imbalance caused by GSTT1 abnormality could initiate proteinuria leading to MCNS.
Clinical nephrology 04/2012; 77(4):261-6. · 1.17 Impact Factor
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ABSTRACT: The complement system, the major component of the innate immune functions resisting microbial infection, includes the classical complement pathway, the alternate pathway, and the mannose-binding lectin pathway. All of these merge at the level of complement component (C) 3. Complement factor H (CFH), a soluble complement mediator in blood, regulates alternate pathway activation; a conformational change of C3 molecules by C3 convertases leads to an enzyme complex formation resulting in opsonization and cell lysis. Clinical manifestations arising from CFH gene (CFH) abnormalities include hemolytic uremic syndrome and membranoproliferative glomerulonephritis. We encountered a 24-year-old woman initially diagnosed with C3 glomerulonephritis associated with persistently low circulating C3. Definitive diagnosis of C3 glomerulonephritis was made from immunohistologic demonstration of isolated mesangial C3 deposits. The biopsy specimen showed moderately increased mesangial proliferation, without thickening of the glomerular capillary walls. Genetic analysis disclosed a homozygous CFH missense mutation, a G-to-T transversion at nucleotide 3,048 in exon 18, resulting in substitution of Asp for Glu at position 936. A low serum CFH concentration (110 µg/mL) might reflect the consequences of this CFH mutation. C3 glomerulonephritis is associated with a CFH mutation, the mutation of which results in the unexpected activation of alternate pathway complement with clinical laboratory fluctuations, such as varying reduction of serum CFH and C3. The finding of a patient with a CFH mutation associated with C3 glomerulonephritis represents an opportunity to expand the phenotypic spectrum of the CFH mutations.
The Tohoku Journal of Experimental Medicine 01/2012; 227(3):211-5. · 1.24 Impact Factor
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ABSTRACT: In two patients with steroid-resistant nephrotic syndrome (SRNS), we investigated the relationship between clinical findings during immunosuppressive therapy and multiple drug resistant gene-1 (MDR-1) expression. MDR-1 was detected by real-time polymerase chain reaction (PCR). In a boy who initially developed SRNS at 3years, we observed MDR-1 expression over 3years. Maximal and minimal MDR-1 expression were 90,000 and 7800 copies/µg RNA, respectively. In a 4-year-old boy who initially developed SRNS at 3years, we determined MDR-1 expression over 2years. Maximal and minimal MDR-1 expression were 42,000 and 6900, respectively. MDR-1 evaluation requires determination of MDR-1 expression at several time points in a clinical course. Establishment of a normal expression may be needed for each individual patient. Increasing MDR-1 during remission was followed soon by recurrences, an observation that may be a guide for therapeutic choice. LDL influences a humoral factor involved in MDR-1 expression. Both patients responded to LDL adsorption therapy because of elevated LDL levels. While cyclosporine A therapy gradually decreased MDR-1 expression, LDL adsorption therapy decreased expression sharply. Based on the results of the present study, LDL adsorption therapy could contribute to the amelioration of drug sensitivity for immunosuppressants including corticosteroids via inhibitory effects on MDR-1 expression.
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 10/2011; 15(5):499-503. · 1.39 Impact Factor
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ABSTRACT: Focal segmental glomerular sclerosis (FSGS) is a leading cause of the nephrotic syndrome and characterized by the sclerosing lesions that affect one or more segments of some glomeruli. We encountered a female patient with a partial deletion of chromosome 6p, who presented proteinuria at age 3 years. Detailed chromosomal analysis disclosed an interstitial deletion of 6p: del(6)(p22.1p22.3). No abnormality such as hydronephrosis or renal agenesis was disclosed by imaging, but FSGS was present in a renal biopsy specimen. The patient is currently 11 years old and shows mental retardation with mild deterioration in the renal function. To address the defective genes in the present patient, we carried out comparative genomic hybridization (CGH), showing that E2F3 on chromosome 6p is absent in this patient. E2F3, a member of the E2F family transcription factors, inhibits expression of vascular endothelial growth factor (VEGF) and induces apoptosis during vascular development. The deletion of E2F3 was also detected by employing a PCR method, suggesting that glomerular architecture had been compromised in this patient. Serum VEGF concentrations were elevated to 177 ± 21.4 pg/mL (upper limit of 33.3 pg/mL), when she was 6 years old, associated with the enhanced expression of VEGF in glomeruli. These findings suggest that the dysregulation of VEGF synthesis caused by the deletion of E2F3 may be associated with development of FSGS. In conclusion, among patients with idiopathic FSGS, an abnormality of E2F3 may exist on chromosome 6p. Therefore, one might consider chromosomal analyses in children with FSGS who have mental retardation.
The Tohoku Journal of Experimental Medicine 01/2011; 223(3):187-92. · 1.24 Impact Factor
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ABSTRACT: The relationship between abnormalities of tubular architecture and tubulointerstitial nephritis antigen (TIN-ag) in juvenile nephronophthisis (J-NPH) was evaluated.
Sixteen J-NPH patients were examined. Nephrocystin-1, TIN-ag, type IV collagen, Fas antigen and the C5b-9 complement complex were stained by immunohistochemical methods.
Renal tubules of patients with J-NPH showed morphological abnormalities of tubular basement membranes (TBM) and frequent apoptosis of tubular epithelial cells. Additionally, the C5b-9 complement complex was deposited within the TBM in the absence of immunoglobulin deposition, suggesting complement-dependent TBM injury. Localization of TIN-ag in the TBM of J-NPH patients disclosed a partial defect or discontinuity in 14 of the 16 patients, while type IV collagen immunoreactivity was relatively preserved. These findings suggest that tubulogenesis is disturbed during nephronogenesis in J-NPH patients because of a defect in nephrocystin, an NPHP gene product. TBM defects induce further morphological abnormalities such as cystic dilation of tubules; as tubular function impairment advances, the incomplete tubules may be injured by C5b-9 complement complexes, followed by apoptotic cell death.
TIN-ag, which is important in early nephrogenesis, lacks normal activity, and vulnerable and incomplete tubules with deficient TIN-ag expression are formed. Removal of these defective tubules by apoptosis combined with the C5b-9 complement complex could be the primary reason for progression to end-stage renal disease in J-NPH patients.
Nephrology 01/2011; 16(5):495-501. · 1.31 Impact Factor
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ABSTRACT: We evaluated and treated a girl with Henoch-Schönlein purpura (HSP), who initially developed redness, swelling, and pain in all 4 limbs accompanied by Raynaud syndrome and then had convulsions and disturbance of consciousness. HSP was diagnosed based on later findings of purpura in both legs and a decrease in factor XIII activity not accompanied by thrombocytopenia. She was normotensive. A skin biopsy specimen showed small-vessel vasculitis accompanied by immunoglobulin A deposition. The cause of erythema and limb pain, convulsions, and disturbed consciousness presumably was vasculitis. The possibility of HSP should be considered in patients with limb pain despite initial absence of purpura and in patients with central nervous system symptoms such as convulsions.
Journal of clinical rheumatology: practical reports on rheumatic & musculoskeletal diseases 10/2010; 16(7):338-40. · 1.19 Impact Factor
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ABSTRACT: We analyzed renal histologic and immunohistologic findings in children with nephrotic syndrome (NS) who did (n=5) or did not (n=17) develop cyclosporine A (CyA) nephropathy despite appropriately low serum CyA concentrations being maintained over 2 years.
To discriminate embryonic-type from mature glomeruli, we performed staining for type IV collagen a1, laminin ß1 and laminin ß2. Staining patterns were used to semiquantitatively assess glomerular immaturity (glomerular immaturity index, or GII).
In follow-up biopsy specimens, residual embryonic-type, collapsed embryonic-type and sclerotic glomeruli that had failed to differentiate were observed. Patients with early-onset CyA nephropathy had a high GII. In patients with a high GII, arteriopathy developed early in CyA treatment. Arteriopathy was observed mostly near embryonic-type glomeruli. Taken together, these glomeruli (surviving embryonic-type, collapsing embryonic-type, and sclerotic glomeruli) essentially equaled the total number of embryonic-type glomeruli in specimens obtained before CyA treatment.
Our findings indicate a need for caution in CyA therapy for patients with NS, even for a relatively short course of administration, because some patients may have embryonic-type glomeruli or immature arterioles that predispose them to CyA nephropathy.
Journal of nephrology 10/2010; 24(4):474-81. · 1.65 Impact Factor
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ABSTRACT: Tubulointerstitial nephritis antigen (TIN-ag), which has been localized to the renal tubular basement membrane, is a target antigen in some forms of TIN. Physiologically, TIN-ag is thought to be important in maintaining the structure of renal tubular basement membrane. Here we describe a child with chronic renal failure showing a human TIN-ag gene (hTIN-ag) deletion. Immunohistochemical examination using an antihuman TIN-ag monoclonal antibody showed attenuation or lack of TIN-ag staining along the renal tubular basement membrane, whereas nephrocystin staining was normal in renal tubules. Polymerase chain reaction detected no amplification band corresponding to hTIN-ag in this patient. Testing for a deletion in this gene showed nearly complete deletion. By using array-comparative genomic hybridization method, large deletion of a gene mapped on chromosome 6p11-6p12 was demonstrated, corresponding to the locus where hTIN-ag is located. Therefore, an hTIN-ag defect may be a potent cause of end-stage renal failure in childhood.
Pediatric Nephrology 02/2010; 25(7):1349-53. · 2.52 Impact Factor
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ABSTRACT: Gene mutations in COL4A5 located on Xq22 are believed to cause X-linked Alport syndrome, whereas mutations in COL4A3 and COL4A4 located on chromosome 2 are associated with autosomal inherited Alport syndrome or benign familial hematuria. A family with benign familial hematuria caused by COL4A5 mutation, implying X-linked transmission, is reported here for the first time. This result suggests that COL4A5 should be added to the list of causative genes for benign familial hematuria, although the mechanism(s) by which the same mutation leads to the distinct phenotypes, i.e. X-linked Alport syndrome or benign familial hematuria, remains unknown.
Pediatric Nephrology 11/2009; 25(3):545-8. · 2.52 Impact Factor
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Pediatrics International 09/2009; 51(5):759-60. · 0.63 Impact Factor
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ABSTRACT: Although still incompletely understood, the etiology of systemic lupus erythematosus (SLE) is considered to involve both genetic and environmental factors. We encountered two boys with severe SLE from unrelated families and analyzed the gene that encodes cytotoxic T-lymphocyte-associated (CTLA)-4, a protein important in T-cell activation and immune tolerance. Abnormal function of the gene may participate in causation of autoimmune disease, including SLE. In family 1, a boy showed serious cardiovascular complications associated with heart failure, and his mother also had clinically active SLE, including nephritis. A boy in family 2 developed severe renal complications and peripheral vasculitis accompanied by disseminated petechiae in the lower extremities. His paternal grandfather had died from fibrinous pneumonia caused by SLE. They showed high SLE Disease Activity Index (SLEDAI) score. Analysis of the CTLA-4 gene indicated that the boy in family 1 and his mother and the boy in family 2 possess a GG genotype in CTLA-4 exon 1 at +49 together with a 106-bp fragment length of the 3' untranslated region (UTR) in exon 4. No association with disease activity was found for polymorphism of the promoter region in exon 1 at -318 in either family. Disorders of the CTLA-4 gene, especially a GG genotype in exon 1 at +49 and/or 106-bp fragment length of the 3'UTR in exon 4, may be involved in early development of SLE in Japanese children, such as the boys described here.
Clinical and Experimental Nephrology 05/2008; 12(2):149-54. · 1.37 Impact Factor
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ABSTRACT: Cyclosporin A (CyA) can suppress relapses and reduce proteinuria in frequent-relapse nephrotic syndrome (FRNS) and steroid-resistant nephrotic syndrome (SRNS). However, some patients remain resistant to CyA therapy. The purpose of the present paper was to evaluate mycophenolate mofetil (MMF) treatment in pediatric patients with CyA-resistant intractable nephrotic syndrome.
MMF therapy was given to 11 patients with FRNS who had relapse despite CyA therapy, and one patient with SRNS who had been receiving combined therapy using steroid and CyA until immediately before the start of MMF. MMF was administered at a daily dose of 750-1000 mg/m(2) in two divided doses.
Ten of the 11 patients with FRNS were able to maintain remission. Among them, seven patients remained relapse free for 1 year, and two patients had a decrease in the frequency of relapse after initiation of MMF therapy. One patient, however, had repeated cycles of remission and relapse, and was considered resistant to MMF therapy. The total prednisolone dose during the period from month 6 to month 12 after the start of MMF therapy was significantly lower than that during the 6 month period before the start of MMF therapy. The patient with SRNS, who had not achieved remission despite CyA administration, had complete remission on MMF. No serious adverse effects were seen in any of the present patients.
MMF could be useful in CyA-treatment-refractory FRNS and CyA-resistant SRNS.
Pediatrics International 01/2008; 49(6):933-7. · 0.63 Impact Factor
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ABSTRACT: The incidence of tuberculosis (TBC) in patients undergoing maintenance hemodialysis is reported to be higher than that in the general population. We report an 8-year-old boy receiving such treatment for chronic renal failure who developed mediastinal lymph node TBC. He showed only intermittent fever, recurring every 2 weeks, with no other symptoms suggesting TBC. Although staining and culture of pharyngeal swab and gastric juice specimens failed to provide evidence of TBC, a lymph node biopsy specimen disclosed typical pathologic findings of tuberculoma, including caseating granulomas. Antituberculous therapy with isoniazid (INH), rifampicin, pyrazinamide, and ethambutol was given for 12 months, resulting in complete resolution of the TBC, with no subsequent recurrence. To our knowledge, mediastinal lymph node localization of TBC is relatively rare, in a patient on maintenance hemodialysis, especially in a child.
Clinical and Experimental Nephrology 07/2006; 10(2):152-5. · 1.37 Impact Factor
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ABSTRACT: Since isolated C3 mesangial proliferative glomerulonephritis in the absence of systemic disease (i-C3-GN) is an uncommon chronic glomerular disease, long-term prognosis and optimal therapeutic intervention for it are not yet fully defined, especially in children. We report clinical features, outcome, and interventions in 4 patients, ranging from 6 to 18 years old, with i-C3-GN. Microscopic or macroscopic hematuria with or without proteinuria was first noted between 3 and 8 years. When present, proteinuria ranged from 0.2 to 1.0 g/24 h. Persistent hypocomplementemia and circulating immune complexes were found in 1 patient. None of the patients had nephrotic syndrome or hypertension. Percutaneous renal biopsy specimens showed varying degrees of mesangial proliferative glomerulonephritis; 2 patients showed mild mesangial proliferation, while others exhibited moderate histologic severity. In 1 patient with a mild mesangial increase, tubulointerstitial changes were associated. Both patients exhibiting mild mesangial changes followed a benign clinical course with normal renal function over 10 years of follow-up. Patients with moderately severe mesangial alteration manifested slight renal function loss and moderate proteinuria at the time of biopsy, but these largely resolved after a six-month course of prednisolone combined with cyclophosphamide, warfarin, and an angiotensin-converting enzyme inhibitor. Thus, clinical manifestations and the need for aggressive treatment appear to vary among pediatric patients with i-C3-GN. Therapy combining prednisolone with immunosuppression seemed to reduce proteinuria and improve glomerular function in patients with moderately severe mesangial proliferation.
Pediatric Nephrology 10/2005; 20(9):1273-8. · 2.52 Impact Factor
