Ji Nan Sheu

Melatonin inhibits microglial activation, reduces pro-inflammatory cytokine levels, and rescues hippocampal neurons of adult rats with acute Klebsiella pneumoniae meningitis.

Abstract:  Acute bacterial meningitis caused by Klebsiella pneumoniae (K. pneumoniae) is a major health threat with a high mortality rate and severe neuro‐cognitive sequelae. The intense pro‐inflammatory cytokine released from calcium‐mediated microglial activation plays an important role in eliciting neuronal damage in the hippocampal region. Considering melatonin possesses anti‐inflammatory and immuno‐modulatory properties, the present study determined whether melatonin can effectively decrease inflammatory responses and prevent hippocampal damage in animals subjected to K. pneumoniae. Adult rats inoculated with K. pneumoniae received a melatonin injection immediately thereafter at doses of 5, 25, 50, or 100 mg/kg. Following 24 h of survival, all experimental animals were processed for time‐of‐flight secondary ion mass spectrometry (for detecting glial calcium intensity), isolectin‐B4 histochemistry (reliable marker for microglial activation), pro‐inflammatory cytokine measurement as well as cytochrome oxidase and in situ dUTP end‐labeling (representing neuronal bio‐energetic status and apoptotic changes, respectively). Results indicate that in K. pneumoniae‐infected rats, numerous calcium‐enriched microglia, enhanced pro‐inflammatory cytokine, and various apoptotic neurons with low bio‐energetic activity were detected in hippocampus. Following melatonin administration, however, all parameters including glial calcium intensity, microglial activation, pro‐inflammatory cytokine levels, and number of apoptotic neurons were successfully decreased with maximal change observed at a melatonin dose of 100 mg/kg. Enzymatic data corresponded well with above findings in which all surviving neurons displayed high bio‐energetic activity. As effectively reducing glia‐mediated inflammatory response is neuro‐protective to hippocampal neurons, the present study supports the clinical use of melatonin as a potential therapeutic agent to counteract K. pneumoniae meningitis‐induced neuro‐cognitive damage.

Cotransplantation of umbilical cord-derived mesenchymal stem cells promote hematopoietic engraftment in cord blood transplantation: a pilot study.

Background Delayed hematopoietic reconstitution after cord blood transplantation (CBT) may lead to increased risk of complications and longer hospitalization. Bone marrow–derived mesenchymal stem cells (MSCs) have been found to promote engraftment after hematopoietic stem cell transplantation. However, harvesting MSCs from bone marrow involves an invasive procedure. Then again, MSCs can be easily obtained from umbilical cords without harm to the donors. Methods Umbilical cord–derived MSCs (UCMSCs) were isolated from Wharton’s jelly and then ex vivo cultured. After showing normal karyotype and negative for infectious contamination, culture-expanded UCMSCs were intravenously infused into the recipients on the day of CBT. The control patients were those receiving CBT alone. Adverse effects and efficacy of intravenous UCMSCs were evaluated. Results A total of five patients received cotransplantation of UCMSCs at the time of CBT. No serious adverse events were observed. The time to achieve neutrophil engraftment ranged from 7 to 13 days (median, 11 days) and platelet engraftment ranged from 22 to 41 days (median, 32 days). Compared with the nine patients receiving CBT alone, patients receiving cotransplantation of UCMSCs had significantly faster hematopoietic recovery of neutrophils and platelets (P=0.02 and 0.01, respectively). Conclusions This pilot study is the first report of cotransplantation of UCMSCs in CBT. Intravenous infusion of UCMSCs appeared to be a feasible and safe modality to enhance hematopoietic engraftment in patients receiving CBT. Further studies were warranted.

The Role of Procalcitonin for Acute Pyelonephritis and Subsequent Renal Scarring in Infants and Young Children

PURPOSE We assessed the usefulness of procalcitonin as a biological marker in diagnosing acute pyelonephritis and for predicting subsequent renal scarring in young children with a first febrile urinary tract infection. MATERIALS AND METHODS Children 2 years old or younger with a first febrile urinary tract infection were prospectively studied. Renal parenchymal involvement was assessed by (99m)Tc-dimercaptosuccinic acid scan within 5 days of admission and after 6 months. Serum samples from all patients were tested for procalcitonin, C-reactive protein and white blood cell count measurements. RESULTS The 112 enrolled patients (age range 24 days to 24 months old) were divided into acute pyelonephritis (76) and lower urinary tract infection (36) groups according to the results of (99m)Tc-dimercaptosuccinic acid scans. Median values of procalcitonin, C-reactive protein and white blood cell count at hospitalization were significantly higher in patients with acute pyelonephritis than in those with lower urinary tract infection. The area under receiver operating characteristic curves showed that procalcitonin was superior to C-reactive protein and white blood cell count as a marker for diagnosing acute pyelonephritis. Initial and post-antibiotic treatment procalcitonin values were significantly higher in children with renal scarring than in those without scarring (p <0.001). Procalcitonin values at hospitalization and after treatment were independent predictors of later renal scarring on logistic regression analysis. CONCLUSIONS Our results indicate the superior diagnostic accuracy of procalcitonin for predicting acute pyelonephritis in children 2 years old or younger. Higher initial and posttreatment procalcitonin values are independent risk factors for later renal scarring.

Acute 99mTc DMSA scan predicts dilating vesicoureteral reflux in young children with a first febrile urinary tract infection: a population-based cohort study.

Objective This study aimed to examine the ability of acute 99mTc DMSA scan for predicting dilating (grades III-V) vesicoureteral reflux (VUR) after a first febrile urinary tract infection in children aged 2 years or younger. Patients and Methods All children underwent ultrasonography (US), 99mTc DMSA scan, and voiding cystourethrography. Sensitivity, specificity, positive and negative predictive values, likelihood ratios, and receiver operating characteristic curves were performed to assess the diagnostic accuracy for predicting dilating VUR. Follow-up scan was performed at least 6 months after the acute infection to evaluate the presence of renal scarring (RS) or new scars. Results Of the 473 children analyzed (289 boys and 184 girls; median age, 5 months), 282 (59.6%) had abnormal acute 99mTc DMSA scan findings. There was VUR in 153 children (32.3%), whereas 95 (20.1%) had dilating VUR. The sensitivity and negative predictive value in predicting dilating VUR were 95.8% and 97.9%, respectively, for 99mTc DMSA and 97.9% and 98.6%, respectively, for combined US and 99mTc DMSA, whereas the positive and negative likelihood ratios were 1.90 and 0.08, respectively, for 99mTc DMSA and 1.57 and 0.06, respectively, for combined studies. On multivariate analysis, dilating VUR was a predictor for developing RS and new scars. Conclusions Our results reveal the usefulness of acute 99mTc DMSA scan for predicting dilating VUR in children with a first febrile urinary tract infection. A voiding cystourethrography is indicated in only children with abnormalities found on a 99mTc DMSA and/or a US. The presence of dilating VUR predisposes to developing RS and new scars.

Role of procalcitonin in predicting dilating vesicoureteral reflux in young children hospitalized with a first febrile urinary tract infection

Objective: The aim of this article was to assess the usefulness of procalcitonin (PCT) as a marker for predicting dilating (grades III–V) vesicoureteral reflux (VUR) in young children with a first febrile urinary tract infection. Methods: Children ⩽2 years of age with a first febrile urinary tract infection were prospectively evaluated. Serum samples were tested for PCT at the time of admission to a tertiary hospital. All children underwent renal ultrasonography (US), 99mTc-dimercaptosuccinic acid renal scan, and voiding cystourethrography. The diagnostic characteristics of PCT test for acute pyelonephritis and dilating VUR were calculated. Results: Of 272 children analyzed (168 boys and 104 girls; median age, 5 months), 169 (62.1%) had acute pyelonephritis. There was VUR demonstrated in 97 (35.7%), including 70 (25.7%) with dilating VUR. The median PCT value was significantly higher in children with VUR than in those without (P < 0.001). Using a PCT cutoff value of ≥1.0 ng/mL, the sensitivity and negative predictive value for predicting dilating VUR were 94.3% and 95.4%, respectively, for PCT, and 97.1% and 97.8%, respectively, for the combined PCT and US studies, whereas the positive and negative likelihood ratios were 2.03 and 0.107, respectively, for PCT, and 1.72 and 0.067, respectively, for the combined studies. By multivariate analysis, high PCT values and abnormalities on US were independent predictors of dilating VUR. Conclusions: PCT is useful for diagnosing acute pyelonephritis and predicting dilating VUR in young children with a first febrile urinary tract infection. A voiding cystourethrography is indicated only in children with high PCT values (≥1.0 ng/mL) and/or abnormalities found on a US.

Sleep deprivation impairs Ca2+ expression in the hippocampus: ionic imaging analysis for cognitive deficiency with TOF-SIMS.

Sleep deprivation causes cognitive dysfunction in which impaired neuronal plasticity in hippocampus may underlie the molecular mechanisms of this deficiency. Considering calcium-mediated NMDA receptor subunit 1 (NMDAR1) and neuronal nitric oxide synthase (nNOS) activation plays an important role in the regulation of neuronal plasticity, the present study is aimed to determine whether total sleep deprivation (TSD) would impair calcium expression, together with injury of the neuronal plasticity in hippocampus. Adult rats subjected to TSD were processed for time-of-flight secondary ion mass spectrometry, NMDAR1 immunohistochemistry, nNOS biochemical assay, cytochrome oxidase histochemistry, and the Morris water maze learning test to detect ionic, neurochemical, bioenergetic as well as behavioral changes of neuronal plasticity, respectively. Results indicated that in normal rats, strong calcium signaling along with intense NMDAR1/nNOS expression were observed in hippocampal regions. Enhanced calcium imaging and neurochemical expressions corresponded well with strong bioenergetic activity and good performance of behavioral testing. However, following TSD, both calcium intensity and NMDAR1/nNOS expressions were significantly decreased. Behavioral testing also showed poor responses after TSD. As proper calcium expression is essential for maintaining hippocampal neuronal plasticity, impaired calcium expression would depress downstream NMDAR1-mediated nNOS activation, which might contribute to the initiation or development of TSD-related cognitive deficiency.

Diagnostic performance of procalcitonin for hospitalised children with acute pyelonephritis presenting to the paediatric emergency department

Objectives Urinary tract infection (UTI) is a common bacterial infection in children that can result in permanent renal damage. This study prospectively assessed the diagnostic performance of procalcitonin (PCT) for predicting acute pyelonephritis (APN) among children with febrile UTI presenting to the paediatric emergency department (ED). Methods Children aged ≤10 years with febrile UTI admitted to hospital from the paediatric ED were prospectively studied. Blood PCT, C reactive protein (CRP) and white blood cell (WBC) count were measured in the ED. Sensitivity, specificity, predictive values, multilevel likelihood ratios, receiver operating characteristic (ROC) curve analysis and multivariate logistic regression were used to assess quantitative variables for diagnosing APN. Results The 136 enrolled patients (56 boys and 80 girls; age range 1 month to 10 years) were divided into APN (n=87) and lower UTI (n=49) groups according to 99mTc-dimercaptosuccinic acid scan results. The cut-off value for maximum diagnostic performance of PCT was 1.3 ng/ml (sensitivity 86.2%, specificity 89.8%). By multivariate regression analysis, only PCT and CRP were retained as significant predictors of APN. Comparing ROC curves, PCT had a significantly greater area under the curve than CRP, WBC count and fever for differentiating between APN and lower UTI. Conclusions PCT has better sensitivity and specificity than CRP and WBC count for distinguishing between APN and lower UTI. PCT is a valuable marker for predicting APN in children with febrile UTI. It may be considered in the initial investigation and therapeutic strategies for children presenting to the ED.

Resveratrol suppresses calcium-mediated microglial activation and rescues hippocampal neurons of adult rats following acute bacterial meningitis

Acute bacterial meningitis (ABM) is a serious disease with severe neurological sequelae. The intense calcium-mediated microglial activation and subsequently pro-inflammatory cytokine release plays an important role in eliciting ABM-related oxidative damage. Considering resveratrol possesses significant anti-inflammatory and anti-oxidative properties, the present study aims to determine whether resveratrol would exert beneficial effects on hippocampal neurons following ABM. ABM was induced by inoculating Klebsiella pneumoniae into adult rats intraventricularly. The time-of-flight secondary ion mass spectrometry (TOF-SIMS), Griffonia simplicifolia isolectin-B4 (GSA-IB4) and ionized calcium binding adaptor molecule 1 (Iba1) immunohistochemistry, enzyme-linked immunosorbent assay as well as malondialdehyde (MDA) measurement were used to examine the calcium expression, microglial activation, pro-inflammatory cytokine level, and extent of oxidative stress, respectively. In ABM rats, strong calcium signaling associated with enhanced microglial activation was observed in hippocampus. Increased microglial expression was coincided with intense production of pro-inflammatory cytokines and oxidative damage. However, in rats receiving resveratrol after ABM, the calcium intensity, microglial activation, pro-inflammatory cytokine and MDA levels were all significantly decreased. Quantitative data showed that much more hippocampal neurons were survived in resveratrol-treated rats following ABM. As resveratrol successfully rescues hippocampal neurons from ABM by suppressing the calcium-mediated microglial activation, therapeutic use of resveratrol may act as a promising strategy to counteract the ABM-induced neurological damage.

Bladder agenesis and bilateral ectopic ureters draining into the vagina in a female infant: demonstrated by MR imaging

Complete agenesis of the bladder and urethra is an extremely rare congenital anomaly and most of these patients are stillborn or die during infancy. We report the case of a 1-month-old female infant with bladder and urethral agenesis who presented with bilateral dilated and tortuous ectopic ureters draining into the vagina diagnosed using MR imaging. Our patient was maintained on antibiotic prophylaxis and she remained well during the 3-year follow-up. MR imaging can be used as a valuable modality for genitourinary abnormalities, particularly in cases of inconclusive ultrasound or retrograde pyelography findings.

Multicystic Dysplastic Kidney Disease Presenting With a Single Large Cyst in a Fetus–Anatomical Basis and Radiological Aspects

Multicystic dysplastic kidney (MCDK) is a congenital maldevelopment in which the renal cortex is characteristically replaced by numerous cysts of multiple sizes. MCDK presenting as a single predominant large cyst in morphology is less common. We report on the prenatal imaging findings and perinatal management of a fetus with MCDK unusually presenting as a single predominant large cyst, erroneously interpreted as a severe fetal hydronephrosis. Details of the perinatal history, radiological evaluation, morphological characteristic, and clinical aspect of this case are presented. We also discuss a few studies addressing the sensitivity of magnetic resonance urography for the prenatal diagnosis of MCDK.