Search

With the advancement in technology and increasing familiarity, the use of extracorporeal membrane oxygenation (ECMO) has expanded in the past decade. Although ECMO can be lifesaving for critically ill children, it is an invasive therapy associated with complications that may necessitate rehabilitation and long-term follow-up. Paediatric clinicians play an essential role in managing these children, especially after the acute phase of their illness. This review provides an overview of ECMO and will provide a basic understanding of ECMO and its principles. [ABSTRACT FROM AUTHOR]

In recent years, cardiovascular immuno-imaging by positron emission tomography (PET) has undergone tremendous progress in preclinical settings. Clinically, two approved PET tracers hold great potential for inflammation imaging in cardiovascular patients, namely FDG and DOTATATE. While the former is a widely applied metabolic tracer, DOTATATE is a relatively new PET tracer targeting the somatostatin receptor 2 (SST2). In the current study, we performed a detailed, head-to-head comparison of DOTATATE-based radiotracers and [18F]F-FDG in mouse and rabbit models of cardiovascular inflammation. For mouse experiments, we labeled DOTATATE with the long-lived isotope [64Cu]Cu to enable studying the tracer's mode of action by complementing in vivo PET/CT experiments with thorough ex vivo immunological analyses. For translational PET/MRI rabbit studies, we employed the more widely clinically used [68Ga]Ga-labeled DOTATATE, which was approved by the FDA in 2016. DOTATATE's pharmacokinetics and timed biodistribution were determined in control and atherosclerotic mice and rabbits by ex vivo gamma counting of blood and organs. Additionally, we performed in vivo PET/CT experiments in mice with atherosclerosis, mice subjected to myocardial infarction and control animals, using both [64Cu]Cu-DOTATATE and [18F]F-FDG. To evaluate differences in the tracers' cellular specificity, we performed ensuing ex vivo flow cytometry and gamma counting. In mice subjected to myocardial infarction, in vivo [64Cu]Cu-DOTATATE PET showed higher differential uptake between infarcted (SUVmax 1.3, IQR, 1.2–1.4, N = 4) and remote myocardium (SUVmax 0.7, IQR, 0.5–0.8, N = 4, p = 0.0286), and with respect to controls (SUVmax 0.6, IQR, 0.5–0.7, N = 4, p = 0.0286), than [18F]F-FDG PET. In atherosclerotic mice, [64Cu]Cu-DOTATATE PET aortic signal, but not [18F]F-FDG PET, was higher compared to controls (SUVmax 1.1, IQR, 0.9–1.3 and 0.5, IQR, 0.5–0.6, respectively, N = 4, p = 0.0286). In both models, [64Cu]Cu-DOTATATE demonstrated preferential accumulation in macrophages with respect to other myeloid cells, while [18F]F-FDG was taken up by macrophages and other leukocytes. In a translational PET/MRI study in atherosclerotic rabbits, we then compared [68Ga]Ga-DOTATATE and [18F]F-FDG for the assessment of aortic inflammation, combined with ex vivo radiometric assays and near-infrared imaging of macrophage burden. Rabbit experiments showed significantly higher aortic accumulation of both [68Ga]Ga-DOTATATE and [18F]F-FDG in atherosclerotic (SUVmax 0.415, IQR, 0.338–0.499, N = 32 and 0.446, IQR, 0.387–0.536, N = 27, respectively) compared to control animals (SUVmax 0.253, IQR, 0.197–0.285, p = 0.0002, N = 10 and 0.349, IQR, 0.299–0.423, p = 0.0159, N = 11, respectively). In conclusion, we present a detailed, head-to-head comparison of the novel SST2-specific tracer DOTATATE and the validated metabolic tracer [18F]F-FDG for the evaluation of inflammation in small animal models of cardiovascular disease. Our results support further investigations on the use of DOTATATE to assess cardiovascular inflammation as a complementary readout to the widely used [18F]F-FDG. [ABSTRACT FROM AUTHOR]

In many parts of Southeast Asia, opencast hydraulic tin mining has been carried out since the colonial era. Regardless of its scale, this mining method has significantly affected microtopography and left extremely degraded soil surfaces, where vegetation can hardly grow. Therefore, the identification of a feasible method for the rehabilitation and reforesting of these areas is a long‐term issue. In this study, we aimed to clarify the subsurface geological (soil properties and distribution) and hydrological conditions at a post‐tin mining site on an Indonesian island using an electrical resistivity survey combined with microtopographic information. The electrical resistivity survey of the study site provided information about the distribution of bedrock and sandy and clayey soils, reflecting mining activities. Furthermore, direct and continuous groundwater level monitoring showed the ranges of groundwater fluctuation depending on the soil and climate conditions. Our study demonstrates that subsurface assessment by electrical resistivity survey can provide essential information, contributing to the development of feasible plans for reforestation or transformation to agricultural land at post‐tin mining sites through the improvement of physical conditions and soil fertility. [ABSTRACT FROM AUTHOR]

A kidney biopsy revealed tubulointerstitial nephritis with foreign body granuloma in the medulla, as well as reddish-brown crystalline material (Figure 1C). The patient had a history of 2,8-dihydroxyadenine (DHA) urolithiasis and adenine phosphoribosyltransferase (APRT) deficiency. [Extracted from the article]

We previously performed genetic analysis in six unrelated families with infantile limb pain episodes, characterized by cold-induced deterioration and mitigation in adolescence, and reported two new mutations p.R222H/S in SCN11A responsible for these episodes. As no term described this syndrome (familial episodic pain: FEP) in Japanese, we named it as”小児四肢疼痛発作症”. In the current study, we recruited an additional 42 new unrelated Japanese FEP families, between March 2016 and March 2018, and identified a total of 11 mutations in SCN11A: p.R222H in seven families, and p.R225C, p.F814C, p.F1146S, or p.V1184A, in independent families. A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan. We also identified two novel missense variants of SCN11A, p.F814C and p.F1146S. To evaluate the effects of these latter two mutations, we generated knock-in mouse models harboring p.F802C (F802C) and p.F1125S (F1125S), orthologues of the human p.F814C and p.F1146S, respectively. We then performed electrophysiological investigations using dorsal root ganglion neurons dissected from the 6–8 week-old mice. Dissected neurons of F802C and F1125S mice showed increased resting membrane potentials and firing frequency of the action potentials (APs) by high input–current stimulus compared with WT mice. Furthermore, the firing probability of evoked APs increased in low stimulus input in F1125S mice, whereas several AP parameters and current threshold did not differ significantly between either of the mutations and WT mice. These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations. It can be expected that a considerable number of potential patients with FEP may be the result of gain of function SCN11A mutations. [ABSTRACT FROM AUTHOR]

Circulating microRNAs (miRNAs) could represent sensitive and specific biomarkers for tissue injury. However, their utility as biomarkers in nonclinical toxicological studies using nonhuman primates is limited by a lack of information on their organ specificity and circulating levels under resting condition of the animals. Herein, liver, heart, and skeletal muscle-specific expression patterns of miRNAs were determined in 27 tissues/organs from male and female monkeys (n =2/sex) by next-generation sequencing (NGS) analysis. This analysis revealed organ-specific miRNAs in the liver (miR-122), heart (miR-208a and miR-499a), and skeletal muscle (miR-206). Next, plasma was collected from conscious-naive male and female cynomolgus monkeys (n = 25/sex) to better understand the expressions of organ-specific circulating miRNAs. The absolute values of circulating miRNAs were quantified using a Taqman microRNA assay. MiR-1, miR-133a, and miR-208b showed preferential expression in the heart and skeletal muscles, whereas miR-192 was abundant in the liver, stomach, small intestine, and kidney. These miRNAs had identical sequences to their human counterparts. Six organ-specific miRNAs (miR-1, miR-122, miR-133a, miR-192, miR-206, and miR-499a) could be evaluated quantitatively by quantitative real-time reverse transcription polymerase chain reaction with or without preamplification. No significant sex differences were noted for these circulating miRNAs. For their circulation levels, miR-133a showed more than 900-fold interindividual variation, whereas miR-122 showed only a 20-fold variation. In conclusion, we profiled circulating organ-specific miRNAs for the liver, heart, and skeletal muscle of cynomolgus monkeys. [ABSTRACT FROM AUTHOR]

To characterize microRNAs (miRNAs) involved in testicular toxicity in cynomolgus monkeys, miRNA profiles were investigated using next-generation sequencing (NGS), microarray and reverse transcription-quantitative real-time-PCR (RT-qPCR) methods. First, to identify organ-specific miRNAs, we compared the expression levels of miRNAs in the testes to those in representative organs (liver, heart, kidney, lung, spleen and small intestine) obtained from naïve mature male and female monkeys ( n = 2/sex) using NGS analysis. Consequently, miR-34c-5p, miR-202-5p, miR-449a and miR-508-3p were identified to be testicular-specific miRNAs in cynomolgus monkeys. Next, we investigated miRNA profiles after testicular-hyperthermia (TH) treatment to determine which miRNAs are involved in testicular injury. In this experiment, mature male monkeys were divided into groups with or without TH-treatment ( n = 3/group) by immersion of the testes in a water bath at 43 °C for 30 min for 5 consecutive days. As a result, TH treatment induced testicular injury in all animals, which was characterized by decreased numbers of spermatocytes and spermatids. In a microarray analysis of the testis, 11 up-regulated (>2.0 fold) and 13 down-regulated (<0.5 fold) miRNAs were detected compared with those in the control animals. Interestingly, down-regulated miRNAs included two testicular-specific miRNAs, miR-34c-5p and miR-449a, indicating their potential use as biomarkers for testicular toxicity. Furthermore, RT-qPCR analysis revealed decreased expression levels of testicular miR-34b-5p and miR-34c-5p, which are enriched in meiotic cells, reflecting the decrease in pachytene spermatocytes and spermatids after TH treatment. These results provide valuable insights into the mechanism of testicular toxicity and potential translational biomarkers for testicular toxicity. Copyright © 2016 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

To establish a method for estimating the glomerular filtration rate (GFR) in conscious monkeys, the radiographic contrast medium iodixanol and the standard agent inulin were coadministered as tracers tomale cynomolgus monkeys (Macaca fascicularis) as a bolus injection; blood was collected after 60, 90 and 120min. An equation based on a single-blood-sample method derived from Jacobsson's formula was prepared using the data from healthy and saline- and gentamicin-treated monkeys by a multisample strategy with iodixanol. The GFR using the equation with iodixanol was in agreement with that from the multisamplemethod with inulin or iodixanol. When the GFR decreased tomore than 60% of the basal reference level, serum creatinine concentrations tended to increase, whereas serum blood urea nitrogen concentrations fluctuated. The results suggest that the single-sample-blood method with iodixanol is a practical tool for estimating the monkey GFR in a toxicological research setting therefore minimizing animal sufferings. [ABSTRACT FROM AUTHOR]

Phosphoglycerate kinase (PGK) deficiency, a rare X-linked inherited disorder, manifests as various combinations of hemolytic anemia, neurological dysfunction, and myopathy. We report a Japanese boy with PGK deficiency presenting as chronic hemolytic anemia. The diagnosis of PGK1 deficiency was made at 11 months of age on the basis of low PGK enzyme activity (36.7 IU/g Hb; normal, 264-326 IU/g Hb) and the identification through PGK1 gene sequencing of a novel missense mutation: c. 1180A>G at exon 10. The mutation, which has been designated PGK-Aoto, results in a Thr394Ala amino-acid substitution at β-strand L. Because β-strand L plays an important role in the function of the hinge connecting the two domains of PGK, the Thr394Ala substitution may perturb this motion. At 3 years of age the patient has transfusion-dependent hemolytic anemia but no evidence of neuromuscular disease or developmental delay. Long-term follow-up will be needed to identify possible future clinical manifestations. [ABSTRACT FROM AUTHOR]

Increased incidence of headless sperms (HS) was spontaneously observed in the urine of adolescent naïve male SPF/VAF Crl:CD(SD) rats. To clarify the factors contributing to this event, the HS incidence in urine and the epididymis was periodically examined in conjunction with measurements of testis and epididymis weights, motility and morphology of sperms and testosterone, transferrin or follicle-stimulating hormone (FSH) concentrations in serum and/or the testis. The urinary HS incidence was 61%, 69%, 44%, 30%, 14%, 9% and 7% in 100 sperms counted at ages 8, 9, 10, 11, 12, 13 and 14 weeks, respectively; namely, HS peaked at 9 weeks, gradually decreased from 10 weeks and became almost a plateau from 12 weeks onwards. The epididymal HS incidence, which was lower than that in urine, peaked at 8 weeks, decreased from 10 weeks and became almost zero from 12 weeks. By scanning electron microscopy of HS in the epididymis, a narrow gap between the sperm head and neck was clearly seen along with the posterior ring. Concentrations of testicular testosterone and transferrin, a marker for Sertoli cell maturation, reached mature animal levels at 12 weeks. In contrast, no change in serum FSH concentration was seen throughout the study period. These results demonstrate that a marked increase in urinary HS incidence in naïve rats at ages 8–11 weeks would be a physiological phenomenon seen in connection with the process of Sertoli cell maturation. [ABSTRACT FROM AUTHOR]

Background Brain-directed prenatal gene therapy may benefit some lysosomal storage diseases that affect the central nervous system (CNS) before birth. Our previous study showed that intrauterine introduction of recombinant adenoviruses into cerebral ventricles results in efficient gene transfer to the CNS in the mouse. However, transgene expression decreased with time due to the non-integrative property of adenoviral vectors. In this study, in order to obtain permanent gene transduction, we investigated the feasibility of retrovirus-mediated in utero gene transduction. Methods Concentrated retrovirus encoding the LacZ gene was injected into the cerebral ventricles of the embryos of normal and twitcher mice (a murine model of Krabbe disease) at embryonic day 12. The distribution and maintenance of the transgene expression in the recipient brain were analyzed histochemically, biochemically and by the quantitative polymerase chain reaction method pre- and postnatally. Results Efficient and highly persistent gene transduction to the brain was achieved both in normal and the twitcher mouse. Transduced neurons, astrocytes and oligodendrocytes were distributed throughout the brain. The transduced LacZ gene, its transcript and protein expression in the brain were maintained for 14 months without decrement. In addition, gene transduction to multiple tissues other than the brain was also detected at low levels. Conclusions This study suggests that brain-directed in utero gene transfer using retrovirus vector may be beneficial to the treatment of lysosomal storage diseases with severe brain damage early in life, such as Krabbe disease. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article presents a case study of a two year old Japanese girl with a diagnosis of Allgrove syndrome resulting from a novel homozygous mutation of the AAAS gene. On admission, hyperpigmentation was observed on her lips, tongue and skin. The article discusses about the Allgrove syndrome, also known as triple A syndrome, rare autosomal recessive disorder characterized by the triad of adrenocorticotropic hormone (ACTH) resistant adrenal insufficiency, achalasia and alacrima and AAA gene.

Background: Hilar biliary stricture caused by isolated fungal infections in immunocompetent patients are considered to be extremely rare and difficult to the diagnose from the outset.Case Presentation: We report a unique case of granulomatous cholangitis based on isolated biliary fungal infection manifesting as obstructive jaundice and mimicking hilar cholangiocarcinoma in an immunocompetent woman. A 67-year-old Japanese woman was referred to our hospital for obstructive jaundice. She had been followed up for hypochondroplasia by the referring physician. Her total bilirubin level was 5.4 mg/dL. Viral hepatitis screening was found to be negative, and serum IgG4 was within normal limits; however, her CA19-9 level was high. Abdominal computed tomography revealed dilatation of the intrahepatic bile ducts. Abdominal echogram detected a solid mass in the hilar bile duct. Her magnetic resonance cholangiopancreatography has also revealed an abrupt stenosis of the primary biliary confluence with upstream dilatation of the intrahepatic bile ducts. Endoscopic nasobiliary drainage was then performed to improve the obstructive jaundice. Although biliary cytology did not reveal malignant findings, the bile duct in the hilum showed severe stenosis, and hilar cholangiocarcinoma could not be completely excluded. The patient had a developmental disorder based on chondrodystrophy. To avoid excessive surgical stress, such as hepatic lobectomy, we performed resection of the extrahepatic bile duct and Roux-en-Y hepaticojejunostomy reconstruction. Intraoperative frozen sections of the resection margins were determined to be negative for tumor. The resected specimen showed multiple strictures inside the common bile duct, numerous calculi in the lumen, and little free space. The final pathological diagnosis was granulomatous cholangitis due to fungal infection. The patient's postoperative course was deemed uneventful. She was discharged from our hospital 23 days after surgery without antifungal treatment.Conclusions: For a unique case of granulomatous cholangitis based on isolated biliary fungal infection mimicking hilar cholangiocarcinoma, we were able to avoid excessive invasion and performed appropriate surgical management. [ABSTRACT FROM AUTHOR]

Examines the application of allogenic bone marrow transplantation (BMT) in the treatment of late-infantile neuronal ceroid lipofuscinosis in a pediatric patient. Medical background of the subject; Importance of choosing drugs with less neurotoxic side-effects in conditioning the patient; Difficulty in timing the BMT.