Comparison of mycophenolic acid with cyclophosphamide for the treatment of pediatric lupus nephritis: A retrospective study from a tertiary center hospital in Taiwan.

BACKGROUND: This study aimed to compare the efficacy of mycophenolic acid (MPA) and cyclophosphamide (CYC) for treating pediatric lupus nephritis (pLN). METHODS: Data on patients with pLN class III, IV, and V, diagnosed by renal biopsy, were collected from the Databank of Kaohsiung Veterans General Hospital between February 2005 and December 2020. The study included 31 pLN patients. Of these, 15 received MPA (MPA group) and 16 received CYC (CYC group). Systemic lupus erythematosus disease activity index score, laboratory findings, complete remission (CR), and partial remission (PR) were assessed at 6, 12, and 24 months. RESULTS: In the MPA group, CR occurred in 7/15 (47%) patients at month 6 and in 11/15 (73%) at months 12 and 24. In the CYC group, CR was reached in 5/16 (31%) patients at month 6, in 8/16 (50%) at month 12, and in 9/16 (56%) at month 24. PR was seen in 3/15 (20%) patients in the MPA group and in 3/16 (19%) in the CYC group at month 24. The cumulative probability of CR and PR showed no statistically significant difference between the two groups. However, the estimated glomerular filtration rate (eGFR) improved significantly in the MPA group at months 6, 12 and 24 compared to that in the CYC group (p < 0.05). CONCLUSION: The efficacy of MPA is similar to that of CYC for pLN treatment, with MPA providing a significant improvement in eGFR after pLN induction therapy at months 6,12 and 24.

Effects of early aminophylline therapy on clinical outcomes in premature infants.

BACKGROUND: Aminophylline use and the association between clinical outcomes and therapy timing have been less investigated. The objective of this study was to determine the efficacy of early aminophylline use (within the first two days of life) in premature infants. METHOD: A retrospective observational cohort of infants weighing <1500 g and <30 weeks of gestational age at Kaohsiung Veterans General Hospital received aminophylline either within the first two days of life (EA, early aminophylline group), after the third day of life (LA, late aminophylline group), or without aminophylline during the first month of life (WA, without aminophylline group). Demographic data and neonatal clinical outcomes were compared among the three groups. RESULTS: This study included 89 preterm infants (EA = 33, LA = 38, WA = 18). The EA group had a lower incidence of bronchopulmonary dysplasia (BPD) than the WA group (adjusted odds ratio [aOR] = 8.86(1.56-59.32); P = 0.024). Although there was no significant difference in BPD incidence between the EA and LA groups (aOR = 2.66(0.51-13.81), P = 0.244), a trend remained. Birth body weight less than 1000 g was also a significant risk factor for BPD (aOR = 8.86(1.32-47.41), P = 0.014). The duration of mechanical ventilation was shorter in the infants in the EA group compared to the WA group (estimated beta = -11.344(-19.57-3.12); P = 0.008). CONCLUSION: Early aminophylline administration may be associated with a decreased incidence of BPD in preterm infants. However, the clinical benefits of aminophylline treatment require further investigation. In addition, a birth body weight of less than 1000 g was a crucial risk factor for BPD.

Nomogram for diagnosing acute pyelonephritis in pediatric urinary tract infection.

BACKGROUND: For risk stratification and individualized treatment for children with urinary tract infection (UTI), they must be assessed for the presence of acute pyelonephritis (APN). Our study aimed to combine variables that can predict APN and establish a nomogram for clinical use. METHODS: In total, 111 children <5 years old hospitalized at Kaohsiung Veterans General Hospital for UTI were classified into APN and simple UTI groups based on a technetium-99 m dimercaptosuccinic acid scan. Their demographic, laboratory test, and renal and urinary bladder sonography (RUBS) data were compared. RESULTS: Fever peak of >39 °C, serum procalcitonin (PCT) ≥ 0.52 pg/mL, C-reactive protein (CRP) ≥ 2.86 mg/dL, and abnormal RUBS findings were independent variables for predicting APN in children. The nomogram established using the aforementioned variables had an area under the receiver operating characteristic curve (AUC) of 0.89, which was higher than those of PCT and CRP alone (0.776 and 0.774, respectively). CONCLUSION: The combination of four variables had the highest power in predicting APN in children with UTI. The established nomogram is practical for clinical use.

Urine metabolic phenotyping in children with nocturnal enuresis and comorbid neurobehavioral disorders.

Nocturnal enuresis (NE) is a common problem among 10% school-aged children. The etiologies underlying childhood NE is complex and not fully understood nowadays. Nevertheless, increasing evidence suggests a potential link between neurobehavioral disorders and enuresis in children. In this study, we aimed to explore novel metabolomic insights into the pathophysiology of NE and also, its association with pediatric psychiatric problems. Urine collected from 41 bedwetting children and 27 healthy control children was analyzed by using 1H-nuclear magnetic resonance spectroscopy from August 2017 to December 2018. At regular follow-up, there were 14 children with refractory NE having a diagnosis of attention deficient hyperactivity disorder (ADHD) or anxiety. Eventually, we identified eight significantly differential urinary metabolites and particularly increased urinary excretion of betaine, creatine and guanidinoacetate linked to glycine, serine and threonine metabolism were associated with a comorbidity of neurobehavioral disorders in refractory bedwetting children. Notably, based on physiological functions of betaine acting as a renal osmolyte and methyl group donor, we speculated its potential role in modulation of renal and/or central circadian clock systems, becoming a useful urinary metabolic marker in diagnosis of treatment-resistant NE in children affected by these two disorders.

Incidence and risk factors for chronic kidney disease in patients with congenital heart disease.

BACKGROUNDS: Chronic kidney disease (CKD) is underdiagnosed in children with congenital heart disease (CHD). Our aim was to study the incidence of CKD in CHD children and identify risk factors for CKD. METHODS: CHD patients were enrolled from the Kaohsiung Veterans General Hospital database between 2010 and 2019. Patient age at enrollment was age at first visit to the hospital. The end of follow-up was marked by the last measurement of serum creatinine, urine protein-to-creatinine ratio (UPCR), or urine microalbumin-to-creatinine ratio (UACR) after enrollment, and only patients who underwent the aforementioned tests in 2 different years were included. Patients with an estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73m2 were diagnosed as having CKD and were further classified into clinically recognized CKD (CR-CKD, defined as eGFR <60 mL/min/1.73m2, UPCR >0.5, or UACR >30 mg/g) and non-clinically recognized CKD (NCR-CKD). Their demographic data, CHD category, heart surgery types, medications, and contrast-related examinations during follow-up were collected. RESULTS: The study included 359 CHD patients, of whom 167 (46.5%) developed CKD (18 patients with CR-CKD and 341 with NCR-CKD). Patients with CR-CKD were significantly older at enrollment than patients with NCR-CKD. Corrective heart surgery may be a protective factor for CKD. Furthermore, cyanotic heart disease, two or more image-related contrast exposures, and diuretic use may be associated with CKD. CONCLUSION: CHD patients have a high incidence of CKD. The early detection of CKD and prompt corrective heart surgery for CHD may be beneficial for kidney function.

Epigallocatechin-3-gallate downregulates PDHA1 interfering the metabolic pathways in human herpesvirus 8 harboring primary effusion lymphoma cells.

Primary effusion lymphoma (PEL) is an aggressive neoplasm correlated with human herpesvirus 8 (HHV8). Metabolic reprogramming is a hallmark of cancers. The alterations in cellular metabolism are important to the survival of HHV8 latently infected cells. Pyruvate dehydrogenase (PDH) controls the flux of metabolites between glycolysis and the tricarboxylic acid cycle (TCA cycle) and is a key enzyme in cancer metabolic reprogramming. Glutaminolysis is required for the survival of PEL cells. Glutamate dehydrogenase 1 (GDH1) converts glutamate into α-ketoglutarate supplying the TCA cycle with intermediates to support anaplerosis. Previously we have observed that epigallocatechin-3-gallate (EGCG) can induce PEL cell death and N-acetyl cysteine (NAC) attenuates EGCG induced PEL cell death. In this study, results showed that EGCG upregulated the expression of glucose transporter GLUT3, and reduced the expression of pyruvate dehydrogenase E1-alpha (PDHA1), the major regulator of PDH, and GDH1. NAC could partially reverse the effects of EGCG in PEL cells. Overexpression of PDHA1 in PEL cells or supplement of α-ketoglutarate attenuated EGCG induced cell death. EGCG also reduced the levels of oncometabolite D-2-hydroxyglutarate (D2HG). These results suggest that EGCG may modulate the metabolism of PEL cells leading to cell death.

Pediatric Kikuchi-Fujimoto disease: A clinicopathologic study and the therapeutic effects of hydroxychloroquine.

BACKGROUND: To investigate the clinical features of Kikuchi-Fujimoto disease (KFD) in children, and place an emphasis on the therapeutic effects of hydroxychloroquine as monotherapy. METHODS: We retrospectively reviewed the medical records of all children diagnosed with KFD during the period January 1992 to September 2016 at a tertiary medical center in Taiwan. RESULTS: 40 patients were histopathologically confirmed as KFD, and the mean age of the patients was 13.9 ± 3.1 years. The male to female ratio was 1:1. The lymph node involvements were often cervical (95%) with features of unilateral predisposition (75%), polyadenopathy (84.4%) and tenderness (56.3%). Fever, cough, rhinorrhea, and tonsillitis were other common presentations. Laboratory findings included leukopenia (56.5%), monocytosis (63.6%), with positive results of EB-VCA IgG (88.9%), EB-VCA IgM (22.2%), EBEA IgG (22.2%) and EBNA IgG (88.9%). The univariate analyses of prolonged fever with lymphopenia, monocytosis, thrombocytopenia and necrotizing type in histopathology were disclosed as statistically significant (P < 0.05). Corticosteroids and hydroxychloroquine were administered in 15.6% of patients respectively, along with symptomatic treatments for the rest. Recurrence occurred in 13.0% of patients without corticosteroids or hydroxychloroquine treatment. There were neither recurrences nor relevant major adverse effects in all the five KFD cases treated with hydroxychloroquine. CONCLUSION: KFD should be suspected in children with febrile cervical lymphadenopathy, especially when concomitant with leukopenia and monocytosis. Lymphopenia, monocytosis, thrombocytopenia and necrotizing type in histopathology are reliable predictors for prolonged fever. Hydroxychloroquine may be an alternative choice to corticosteroids for its favorable effects and safety.

Epigallocatechin-3-Gallate Suppresses Human Herpesvirus 8 Replication and Induces ROS Leading to Apoptosis and Autophagy in Primary Effusion Lymphoma Cells.

Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, has been shown to induce cell death in cancer cells. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by human herpesvirus 8 (HHV8). In this study, we examined the role of EGCG on PEL cells in cell death and HHV8 replication. We performed trypan blue exclusion assay to assess the cell viability of PEL cells, flow cytometry analysis to examine the cell cycle distribution and reactive oxygen species (ROS) generation, caspase-3 activity to assay apoptosis, acridine orange staining to determine autophagy, and immunoblotting to detect the protein levels involved in apoptosis and autophagy as well as mitogen activated protein kinases (MAPKs) activation upon EGCG treatment. The expression of the HHV8 lytic gene was determined by luciferase reporter assay and reverse transcription-PCR, and viral progeny production was determined by PCR. Results revealed that EGCG induced cell death and ROS generation in PEL cells in a dose-dependent manner. N-acetylcysteine (NAC) inhibited the EGCG-induced ROS and rescued the cell from EGCG-induced cell death. Even though EGCG induced ROS generation in PEL cells, it reduced the production of progeny virus from PEL cells without causing HHV8 reactivation. These results suggest that EGCG may represent a novel strategy for the treatment of HHV8 infection and HHV8-associated lymphomas.

Effectiveness of Parenteral Glutamine on Methotrexate-induced Oral Mucositis in Children with Acute Lymphoblastic Leukemia.

High-dose methotrexate (HDMTX) is important for children with acute lymphoblastic leukemia (ALL). There is no effective treatment for patients with oral mucositis, which is a major side effect associated with HDMTX. Here, we reviewed the medical records of patients younger than 18 yr with newly diagnosed ALL in our hospitals from 2002 to 2013. According to the nationwide protocol (TPOG-ALL-2002), each patient received four courses of HDMTX (2.5 or 5 g/m2) during consolidation therapy. HDMTX courses with glutamine therapy were as the glutamine group, and intravenous glutamine (0.4 g/kg/day) was started within 48 h after the initiation of HDMTX for 3 consecutive days. HDMTX courses without glutamine were as the control group. A total of 347 HDMTX courses were administrated in the 96 children with ALL during the study period. The incidence of oral mucositis was significantly lower in the glutamine group than in the control group (3.8% vs. 17.6%; P = 0.004). In the glutamine group, no patients suffered from severe oral mucositis. No severe adverse effects associated with glutamine administration were noted. Accordingly, parenteral glutamine appears to be feasible and safe to prevent oral mucositis in patients receiving HDMTX.

Resveratrol induces cell death and inhibits human herpesvirus 8 replication in primary effusion lymphoma cells.

Resveratrol (3,4',5-trihydroxy-trans-stilbene) has been reported to inhibit proliferation of various cancer cells. However, the effects of resveratrol on the human herpesvirus 8 (HHV8) harboring primary effusion lymphoma (PEL) cells remains unclear. The anti-proliferation effects and possible mechanisms of resveratrol in the HHV8 harboring PEL cells were examined in this study. Results showed that resveratrol induced caspase-3 activation and the formation of acidic vacuoles in the HHV8 harboring PEL cells, indicating resveratrol treatment could cause apoptosis and autophagy in PEL cells. In addition, resveratrol treatment increased ROS generation but did not lead to HHV8 reactivation. ROS scavenger (N-acetyl cysteine, NAC) could attenuate both the resveratrol induced caspase-3 activity and the formation of acidic vacuoles, but failed to attenuate resveratrol induced PEL cell death. Caspase inhibitor, autophagy inhibitors and necroptosis inhibitor could not block resveratrol induced PEL cell death. Moreover, resveratrol disrupted HHV8 latent infection, inhibited HHV8 lytic gene expression and decreased virus progeny production. Overexpression of HHV8-encoded viral FLICE inhibitory protein (vFLIP) could partially block resveratrol induced cell death in PEL cells. These data suggest that resveratrol-induced cell death in PEL cells may be mediated by disruption of HHV8 replication. Resveratrol may be a potential anti-HHV8 drug and an effective treatment for HHV8-related tumors.

Brain Stem Hemorrhage in a 2-Year-10-Month-Old Child with Renovascular Hypertension Related to Fibromuscular Dysplasia.

UNLABELLED: Renovascular hypertension due to fibromuscular dysplasia is an uncommon but important cause of pediatric hypertension. It is usually ignored and diagnosed after a long delay because blood pressure is infrequently measured in children. We report a case of previously undiagnosed renovascular hypertension complicated with right renal infarction in a 2-year-10-month-old child, who initially presented as a case of conscious disturbance. The patient's brain CT displayed brain stem hemorrhage, and a brain MRI showed acute hemorrhage and multiple old intracerebral hemorrhage. Therefore, intimal fibromuscular dysplasia of the right renal artery was diagnosed by computed tomography and confirmed after renal angiography. Her blood pressure was gradually normalized after medical therapy, including use of Losartan. She is presently asymptomatic on OPD follow-up. The importance of BP measurement can not be overemphasized in pediatric patients less than three years of age with underlying diseases. KEY WORDS: Conscious disturbance; Fibromuscular dysplasia; Renovascular hypertension.

Perinatal factors in patent ductus arteriosus in very low-birthweight infants.

BACKGROUND: The relationship between hemoglobin and patent ductus arteriosus (PDA) has not been discussed before. The aim of this study was to assess the influence of hemoglobin and perinatal factors on PDA in very low-birthweight (VLBW) infants. METHODS: Using data from the Premature Baby Foundation of Taiwan (PBFA), the characteristics, perinatal factors, and hemoglobin of VLBW infants with and without PDA and treatment were compared. RESULTS: Between January 2008 and December 2010, 89 VLBW infants were admitted to hospital. The overall survival rate was 87.6%. Twelve infants were excluded. Compared to those without PDA, the 34 infants with PDA received oral indomethacin or surgery, had smaller mean gestational age (GA; 27.93 ± 1.818 weeks, P = 0.000003), lower mean birthweight (BW; 1031 ± 259 g, P = 0.0001), significantly lower Apgar score at 5 min, more severe respiratory distress syndrome (RDS; grade 3 or 4), greater use of surfactants, and lower mean hemoglobin (P = 0.018) after birth than those without PDA. Compared to those with indomethacin, the seven infants with surgery had lower mean GA (26.43 ± 1.718 weeks, P = 0.011), significantly lower Apgar scores at 1 min, but higher platelet count (P = 0.002) after birth, and more red blood cell transfusions (P = 0.039). CONCLUSIONS: Smaller GA, lower BW, lower Apgar score at 5 min, more severe RDS, greater use of surfactants, and lower hemoglobin after birth place VLBW infants at greater risk of PDA. Proper prenatal care, and prevention of premature labor and delivery may be the most important preventative factors. The appropriate hemoglobin level for PDA closure requires further investigation.

Urinary tract infection in infants: a single-center clinical analysis in southern Taiwan.

BACKGROUND: This study summarized the epidemiology, etiology, and susceptibility of pathogens to antibiotics, and specific characteristics in infants aged less than 4 months diagnosed with urinary tract infection in the past decade in Taiwan. METHODS: The medical charts of patients aged less than 4 months admitted for urinary tract infection to Kaohsiung Veterans General Hospital between January 2001 and December 2009 were retrospectively reviewed. RESULTS: A total of 132 patients, with male predominance (68.9%), were enrolled. The top three pathogens were similar to those identified in previous studies in Taiwan. The most common pathogen, Escherichia coli (85.3%), was resistant to ampicillin (75.9%), followed by sulfamethoxazole/trimethoprim (31.7%), and cefazolin (28.5%). Dimercaptosuccinic acid (DMSA) renal scan revealed 34.5% positive findings, while the vesicoureteral reflux (VUR) rate was 37.8% by direct radionuclide voiding cystography and/or voiding cysto-urethrography. Positive DMSA findings significantly correlated with VUR (p<0.001) and higher C-reactive protein level (p<0.05). CONCLUSIONS: E coli was the most common pathogen in the present cohort, and the top three pathogens were similar to those found in general pediatric population in Taiwan. VUR was the most common genitourinary tract anomaly in this age group. Positive DMSA was well correlated with VUR and higher C-reactive protein level.

Cisplatin disrupts the latency of human herpesvirus 8 and induces apoptosis in primary effusion lymphoma cells.

Human herpesvirus 8 (HHV8) is the etiologic agent for primary effusion lymphoma (PEL). The aim of this study is to investigate the effects of cisplatin on the PEL cells. Cisplatin treatment induced apoptosis and inhibited the growth of PEL cells, and the effect was more profound in the HHV8-positive lymphoma cells compared with the EBV-positive lymphoma cells. Cisplatin treatment decreased the expression of HHV8 latent genes and activated p53 at serine 15 in PEL cells. Our results indicate that cisplatin can disrupt HHV8 latency and induce reactivation of p53 and highly selective treatment modality for this virally induced lymphoma.

Invasive pneumococcal pneumonia is the major cause of paediatric haemolytic-uraemic syndrome in Taiwan.

AIM: Streptococcus pneumoniae-associated haemolytic uraemic syndrome (SP-HUS) is a major concern of paediatric acute renal failure in Taiwan; it leads to significant morbidity and mortality during the acute phase and to long-term morbidity after an acute episode. METHODS: Twenty children diagnosed with HUS between 1 May 1995, and 31 December 2008 was enrolled. Clinical variables related to laboratory data, organ involved, and outcomes were examined between patients with and without SP-HUS. RESULTS: Thirteen of the 20 (13/20, 65%) patients required dialysis, nine (9/20, 45.0%) developed hepatic dysfunction, disseminated intravascular coagulation (DIC), gastrointestinal bleeding, and hypertension, respectively. They were the second most common extrarenal complication except empyema (11/20, 55%). Two (10%) died and seven (35%) of the survivors developed long-term renal morbidity. Twelve of the 20 patients (60%) were diagnosed with SP-HUS. Younger age, female children, higher white blood cell count, higher alanine transaminase, higher lactate dehydrogenase and high incidence of DIC were significantly common in SP-HUS cases. All SP-HUS cases were complicated with pleural effusion, empyema, or both. Positive Thomsen-Freidenreich antigen (T-Ag) activation was 83% sensitive and 100% specific for SP-HUS, and a positive direct Coombs' test was 58% sensitive and 100% specific. CONCLUSION: Invasive pneumococcal infection is the most common cause of HUS in Taiwan. Positive T-Ag activation and a direct Coombs' test are rapid predictors of SP-HUS in children with invasive pneumonia.

Non-vitrectomizing vitreous surgery for premacular haemorrhage.

PURPOSE: We report three cases illustrating an alternative treatment option for premacular haemorrhage. METHODS: This retrospective interventional case study included three eyes in three patients with premacular haemorrhage caused by idiopathic thrombocytopenic purpura in the first case, trauma in the second case and retinal arterial macroaneurysm in the third case. All patients underwent non-vitrectomizing vitreous surgery. Visual acuity as well as slit-lamp and indirect ophthalmoscopic examinations were performed pre- and postoperatively to evaluate the resolution of premacular haemorrhage and changes in lenticular opacity. RESULTS: At postoperative day 1, visual acuity had improved from counting fingers (CF) to 6/12 in case 1, from CF to 6/20 in case 2 and from CF to 3/60 in case 3. Examination of the fundus showed resolution of the premacular haemorrhage with mild vitreous haemorrhage in all cases. Final best corrected visual acuities were 6/6, 6/7.5 and 6/15, respectively. The lens remained clear in two of two phakic eyes at the last follow-up visit. CONCLUSIONS: In these selected cases, non-vitrectomizing vitreous surgery was a useful and safe alternative for the treatment of premacular haemorrhage.

Human herpesvirus 8 viral FLICE-inhibitory protein retards cell proliferation via downregulation of Id2 and Id3 expression.

Death receptor-mediated apoptosis is potently inhibited by viral FLIP (FLICE/caspase 8 inhibitory protein) through reduced activation of procaspase 8. In this study, we show that the human herpesvirus 8-encoded vFLIP retards cell proliferation. Overexpression of vFLIP caused cell cycle arrest, with an apparent decrease of cells in the S phase. The Id (inhibitor of DNA binding) proteins are considered as dominant negative regulators of differentiation pathways, but positive regulators of cellular proliferation. The mechanisms by which Id proteins promote the cell cycle are diverse, but appear to involve affecting the expression of cell cycle regulators. RT-PCR results demonstrated that the expression of vFLIP decreased the expression levels of Id2 and Id3 as well as cyclin E and cyclin A compared with the vFLIP-null cells. These indicate that vFLIP affects cell proliferation by decreasing the expression levels of cell cycle regulatory proteins.