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Background: Inherited glycosylphosphatidylinositol (GPI) deficiency is an autosomal recessive disease and a set of syndromes caused by different genes involved in the biosynthesis of phosphatidylinositol characterized by severe cognitive disability, elevated serum alkaline phosphatase (ALP) levels, and distinct facial features. This report presents a patient with inherited GPI deficiency caused by a homozygous frameshift variant of PGAP3 due to uniparental isodisomy (UPiD) on chromosome 17. Method: Clinical characteristics of the patient were collected. Microarray analysis followed by adaptive sampling sequencing targeting chromosome 17 was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. Results: The patient was born at 38 weeks of gestation with a birthweight of 3893 g. He had a distinctive facial appearance with hypertelorism, wide nasal bridge, and cleft soft palate. Postnatal head magnetic resonance imaging revealed a Blake's pouch cyst. The serum ALP level was 940 IU/L at birth and increased to 1781 IU/L at 28 days of age. Microarray analysis revealed region of homozygosity in nearly the entire region of chromosome 17, leading to the diagnosis of UPiD. Adaptive sampling sequencing targeting chromosome 17 confirmed the homozygous variant NM_033419:c.778dupG (p.Val260Glyfs*14) in the PGAP3 gene, resulting in a diagnosis of inherited GPI deficiency. Conclusion: This is the first report of inherited GPI deficiency caused by UPiD. Inherited GPI deficiency must be considered in patients with unexplained hyperphosphatasemia. [ABSTRACT FROM AUTHOR]

When a mixture containing 1‐halo‐1‐alkyne, a dinucleophilic agent, and a base (Cs2CO3 or K3PO4) was heated in DMF, regio‐ and stereo‐selective nucleophilic addition of the dinucleophilic agent to the acetylenes occurred. This reaction yielded (Z,Z)‐bis(haloalkene), which subsequently underwent Pd‐catalyzed cyclization through C−H bond activation, resulting in the formation of two‐oxygen‐ or ‐nitrogen‐containing hetero‐π‐conjugated compounds. N‐(5‐Hydroxynaphthalen‐1‐yl)methanesulfonamide was treated with 2‐phenyl‐1‐chloroethyne followed by 1‐chloro‐1‐hexadecyne. After these reactions, Pd‐catalyzed double C−H cyclization was employed to produce 1H‐2‐phenyl‐7‐tetradecylbenzofuro[7,6‐g]indole. Notably, this compound transformed into a fan‐shaped structure at 86 °C and transitioned into a smectic A phase characterized by a layered structure. [ABSTRACT FROM AUTHOR]

Summary: Anti‐CD20 antibody in combination with chemotherapy extends overall survival (OS) in untreated advanced‐stage follicular lymphoma (FL), yet the optimal associated therapy is unclear. Data on the cumulative incidence of secondary malignancies postrelapse after conventional immunochemotherapy are scarce. A long‐term analysis of rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) as first‐line treatment was conducted in a randomised clinical trial. A six‐cycle R‐CHOP regimen was administered every 2 or 3 weeks without rituximab maintenance. A prespecified evaluation was conducted 15 years after the completion of enrolment, following initial analysis results that showed no significant differences in outcomes at the 3‐year mark. In‐depth analyses were performed on the cohort of 248 patients with FL who were allocated to the two treatment arms. With a median follow‐up period of 15.9 years, the 15‐year OS was 76.2%. There were no protocol treatment‐related deaths, nor were there any fatal infections attributable to subsequent lymphoma treatment. At 15 years, the cumulative incidence of non‐haematological and haematological malignancies was 12.8% and 3.7% respectively. Histological transformation appeared after a median of 8 years. R‐CHOP maintains safety and efficacy in patients with advanced FL over extended follow‐up, making it a viable first‐line option for patients with advanced‐stage FL. [ABSTRACT FROM AUTHOR]

Aim: Surgical site infection (SSI) is one of the most common postoperative complications in gastrointestinal surgery. To clarify the superiority of 1.5% olanexidine, we conducted a randomized prospective clinical trial that enrolled patients undergoing gastrointestinal surgery with operative wound classes II–IV. Methods: To evaluate the efficacy of 1.5% olanexidine in preventing SSIs relative to 10% povidone‐iodine, we enrolled 298 patients in each group. The primary outcome was a 30‐day SSI, and the secondary outcomes were incidences of superficial and deep incisional SSI and organ/space SSI. In addition, subgroup analyses were performed. Results: The primary outcome of the overall 30‐day SSI occurred in 38 cases (12.8%) in the 1.5% olanexidine group and in 53 cases (18.0%) in the 10% povidone‐iodine group (adjusted risk ratio: 0.716, 95% confidence interval: 0.495–1.057, p = 0.083). Organ/space SSI occurred in 18 cases (6.1%) in the 1.5% olanexidine group and in 31 cases (10.5%) in the 10% povidone‐iodine group, with a significant difference (adjusted risk ratio: 0.587, 95% confidence interval: 0.336–0.992, p = 0.049). Subgroup analyses revealed that SSI incidences were comparable in scheduled surgery (relative risk: 0.809, 95% confidence interval: 0.522–1.254) and operative wound class II (relative risk: 0.756, 95% confidence interval: 0.494–1.449) in 1.5% olanexidine group. Conclusion: Our study revealed that 1.5% olanexidine reduced the 30‐day overall SSI; however, the result was not significant. Organ/space SSI significantly decreased in the 1.5% olanexidine group. Our results indicate that 1.5% olanexidine has the potential to prevent SSI on behalf of povidone‐iodine. [ABSTRACT FROM AUTHOR]

Background: The immunomodulatory drug lenalidomide, which is now widely used for the treatment of multiple myeloma (MM), exerts pharmacological action through the ubiquitin‐dependent degradation of IKZF1 and subsequent down‐regulation of interferon regulatory factor 4 (IRF4), a critical factor for the survival of MM cells. IKZF1 acts principally as a tumour suppressor via transcriptional repression of oncogenes in normal lymphoid lineages. In contrast, IKZF1 activates IRF4 and other oncogenes in MM cells, suggesting the involvement of unknown co‐factors in switching the IKZF1 complex from a transcriptional repressor to an activator. The transactivating components of the IKZF1 complex might promote lenalidomide resistance by residing on regulatory regions of the IRF4 gene to maintain its transcription after IKZF1 degradation. Methods: To identify unknown components of the IKZF1 complex, we analyzed the genome‐wide binding of IKZF1 in MM cells using chromatin immunoprecipitation‐sequencing (ChIP‐seq) and screened for the co‐occupancy of IKZF1 with other DNA‐binding factors on the myeloma genome using the ChIP‐Atlas platform. Results: We found that c‐FOS, a member of the activator protein‐1 (AP‐1) family, is an integral component of the IKZF1 complex and is primarily responsible for the activator function of the complex in MM cells. The genome‐wide screening revealed the co‐occupancy of c‐FOS with IKZF1 on the regulatory regions of IKZF1‐target genes, including IRF4 and SLAMF7, in MM cells but not normal bone marrow progenitors, pre‐B cells or mature T‐lymphocytes. c‐FOS and IKZF1 bound to the same consensus sequence as the IKZF1 complex through direct protein‐protein interactions. The complex also includes c‐JUN and IKZF3 but not IRF4. Treatment of MM cells with short‐hairpin RNA against FOS or a selective AP‐1 inhibitor significantly enhanced the anti‐MM activity of lenalidomide in vitro and in two murine MM models. Furthermore, an AP‐1 inhibitor mitigated the lenalidomide resistance of MM cells. Conclusions: C‐FOS determines lenalidomide sensitivity and mediates drug resistance in MM cells as a co‐factor of IKZF1 and thus, could be a novel therapeutic target for further improvement of the prognosis of MM patients. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Ectopia cordis is a rare condition with expected low survival rate based on past studies. We encountered a case of a preterm and low birth weight infant with ectopia cordis. When the infant cried, the prolapse of the heart, liver, and intestinal tract worsened. A pressure‐applying protector was used to protect the organs and reduce the prolapse. Upon application, the infant's tachypnea and desaturation worsened. Fluoroscopic examination suggested that the pressure from the prolapsed regions was impeding pulmonary expansion and negatively affecting circulation. It is essential to carefully design a protector that accommodates the infant's growth. [ABSTRACT FROM AUTHOR]

The effects of polymorphisms of ABCB1 and ABCG2 on the dose‐adjusted plasma trough concentrations and cerebrospinal fluid (CSF)‐to‐plasma ratios of ponatinib were evaluated. Blood (C4) and CSF (CSF4) concentrations at 4 h after administration were determined. The median (95% confidence interval) CSF4‐to‐C4 ratio of ponatinib in subjects homozygous for ABCB1 variants 1236T/T, 2677T/T + T/A or 3435T/T were significantly higher than that in a group of subjects with other genotypes (P =.026,.012 and.015, respectively). The median (95% confidence interval) CSF4‐to‐C4 ratio of ponatinib in 4 patients with the combination of ABCB1 variants 1236T/T‐2677T/T + T/A‐3435T/T was 2.62% (1.42–3.42%); this ratio was significantly higher than that in subjects with other genotypes (1.08% [0.89–1.47%]; P =.006). The brain distribution of ponatinib was affected by ABCB1 polymorphisms and therefore seems to be modulated by P‐glycoprotein at the blood–brain and blood–CSF barriers. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma (MM) is a hematopoietic malignancy for which proteasome inhibitors have become available in recent years. However, many patients develop resistance to these drugs during treatment. Therefore, it is important to elucidate the mechanisms underlying resistance acquisition by proteasome inhibitors. Side population (SP) cells, which have a high drug efflux capacity and hypoxic responses in the microenvironment have both provided important insights into drug resistance in MM; however, little is known about the characteristics of SP cells in hypoxic microenvironments. Methods: We performed cDNA microarray analysis for SP and non‐SP obtained from RPMI‐8226 and KMS‐11 cell lines cultured for 48 h in normoxic and hypoxic conditions (1% O2). Genes specifically upregulated in hypoxic SP were examined. Results: Our comprehensive gene expression analysis identified HMOX1, BACH2, and DUX4 as protein‐coding genes that are specifically highly expressed in SP cells under hypoxic conditions. We have shown that HMOX1/heme oxygenase‐1 (HMOX1/HO‐1) is induced by hypoxia‐inducible reactive oxygen species (ROS) and reduces ROS levels. Furthermore, we found that HMOX1 contributes to hypoxia‐induced resistance to proteasome inhibitors in vitro and in vivo. Excessive ROS levels synergistically enhance bortezomib sensitivity. In clinical datasets, HMOX1 had a strong and significantly positive correlation with MAFB but not MAF. Interestingly, hypoxic stimulation increased MAFB/MafB expression in myeloma cells; in addition, the knockdown of MAFB under hypoxic conditions suppressed HMOX1 expression. Conclusion: These results suggest that the hypoxia‐ROS‐HMOX1 axis and hypoxia‐induced MafB may be important mechanisms of proteasome inhibitor resistance in hypoxic microenvironments. [ABSTRACT FROM AUTHOR]

Aim: Acute chest pain is a commonly encountered symptom in hospital medical/surgical units; however, almost half of nurses in their second year of clinical experience in our facility have reported struggling to care for acute chest pain patients. We developed, implemented, and examined the effectiveness of a simulation‐based, mastery learning clinical nursing educational program to improve self‐efficacy and performance in caring for patients with acute chest pain. Methods: The study adopted a single‐site, single‐cohort design using simulation‐based performance assessment and self‐efficacy surveys on a convenience sample of 37 second‐year clinical nurse participants in multi‐stage hybrid mastery learning educational intervention using asynchronous e‐learning, and hands‐on simulation training and assessment with feedback on caring for chest pain patients. Performance assessments and self‐efficacy surveys were administered pre‐, post‐, and 5 months post‐intervention. Results: Clinical performance on the post‐ and 5 months follow‐up assessments were significantly higher than those for the pre‐test (P <.0001). The self‐efficacy scores for the post‐ and the 5 months follow‐up assessments were significantly higher than the pre‐course scores (P <.0001). Participants' self‐efficacy perceptions were positively correlated with their performances at 5 months post‐intervention. Conclusion: Performance and self‐efficacy of novice nurses in caring for acute chest pain patients improved significantly with the multi‐stage hybrid mastery learning educational intervention, with improvements retained 5 months post‐intervention. The results suggest the applicability of simulation‐based mastery learning in a clinical setting for novice nurses to attain specific skills, and raise their self‐perception of competence to care for patients in acute settings. [ABSTRACT FROM AUTHOR]

Age and comorbidities are important factors to be considered in the selection of tyrosine kinase inhibitors (TKIs) for first‐line treatment in patients with chronic myeloid leukemia in chronic phase (CML‐CP). However, it is yet unclear whether TKI selection, particularly, imatinib versus second‐generation TKIs (2GTKIs), impacts treatment outcomes in the clinical practice. To address this, we compared the clinical outcomes of prospectively registered 452 patients with CML‐CP treated with imatinib and 2GTKIs, taking into consideration their age and/or comorbidities. A total of 136 patients (30.1%) were classified into an older cohort (≥65 years) and 316 (69.9%) into a younger cohort (18‐64 years). The TKI selection did not vary based on age (70.6% received 2GTKIs in the younger cohort and 66.2% in the older cohort). The median follow‐up period was 5.4 years. Treatment responses including the cumulative incidence of deep molecular response (BCR‐ABL1 international scale ≤0.0032%) at any time were similar between the two age cohorts regardless of the type of TKI. The 5‐year overall survival (OS) in the older cohort was lower than that in the younger cohort (95.9% vs 83.8%; p < 0.0001), whereas the 5‐year OS in patients treated with 2GTKIs was not influenced by age factors and comorbidities. Therefore, our results suggest that the selection of 2GTKIs as first‐line treatment is an effective option for both younger and older CML‐CP patients with or without comorbidities. This trial was registered at UMIN‐CTR as 00003581. [ABSTRACT FROM AUTHOR]

Background: We recently showed that pharmacological inhibition of plasminogen activator inhibitor‐1 (PAI‐1) activity, based on TM5614, increases cell motility and induces the detachment of hematopoietic stem cells from their niches. In this TM5614 phase II clinical trial, we investigated whether the combination of a PAI‐1 inhibitor and tyrosine kinase inhibitors (TKIs) would induce a deep molecular response (DMR) in patients affected by chronic myeloid leukemia (CML) by quantifying BCR‐ABL1 transcripts. Methods: Patients with chronic phase CML treated with a stable daily dose of TKIs for at least 1 year and yielding a major molecular response (MMR) but not achieving MR4.5 were eligible for this study. After inclusion, patients began to receive TM5614 as well as a TKI. The primary objective was an evaluation of the cumulative incidence of patient progression from an MMR/MR4 to MR4.5 by 12 months. Results: Thirty‐three patients were enrolled in the study. The median age was 59.0 years and 58% were male. No Sokal high‐risk patients were enrolled in this trial. The median TKI treatment duration was 4.8 years. At the start of this study, seven patients and 26 patients received imatinib and second‐generation TKIs, respectively. The cumulative MR4.5 incidence by 12 months was 33.3% (95% confidence interval, 18.0%–51.8%). The cumulative MR4.5 spontaneous conversion over 12 months was estimated as 8% with TKIs alone based on historical controls. The halving time of BCR‐ABL1 at 2 months was significantly shorter for patients who achieved an MR4.5, by 12 months than for the other patients (cutoff value: 48 days; sensitivity: 0.80; specificity: 0.91; ROC‐AUC: 0.83). During this study, bleeding events and abnormal coagulation related to the drug were not reported, and TM5614 was found to be highly safe. Conclusion: TM5614 combined with TKI was well tolerated and induced MR4.5 in more patients than stand‐alone TKI treatment. [ABSTRACT FROM AUTHOR]

Asciminib, a first‐in‐class, allosteric inhibitor of BCR‐ABL1 that acts by STAMP (Specifically Targeting the ABL Myristoyl Pocket), is a novel therapeutic option for patients with chronic myeloid leukemia (CML). In the global, phase 3, open‐label ASCEMBL study in patients with CML in chronic phase (CML‐CP) pretreated with ≥2 tyrosine kinase inhibitors (TKIs) (NCT03106779), asciminib (40 mg twice‐daily) demonstrated significant superiority over the ATP‐competitive TKI bosutinib (500 mg once daily) for the primary endpoint of major molecular response (MMR; BCR::ABL1 transcript levels on the international scale [BCR::ABL1IS] ≤0.1%) at week 24. Here, we report results from a descriptive subgroup analysis of Japanese patients enrolled in ASCEMBL study (data cut‐off: May 25, 2020). Overall, 16 Japanese patients were randomized (asciminib, n = 13; bosutinib, n = 3). At week 24, the MMR rate with asciminib was 30.8% (4/13; 95% confidence interval [CI], 9.09–61.43). BCR::ABL1IS ≤1% and complete cytogenic response (CCyR) at week 24 were 61.5% (8/13 patients) and 50.0% (4/8 patients), respectively. In the bosutinib group, no patient achieved MMR, CCyR, or BCR::ABL1IS ≤1%, but results were limited by the low number of patients. The safety profile of asciminib was comparable to that previously observed in the overall study population. Findings from this Japanese subgroup analysis of the ASCEMBL study support the use of asciminib for the treatment of Japanese patients with CML‐CP previously treated with ≥2 TKIs. ClinicalTrials.gov Identifier: NCT03106779. [ABSTRACT FROM AUTHOR]

Background: An increasing number of infants are being conceived using assisted reproductive technology (ART). The effects of infertility treatments (IFTs) on infant outcomes have been extensively debated; however, a consensus has not yet been reached. In the present study, we investigated the impact of IFTs on neonatal intensive care unit (NICU) managements using data collected at a single large NICU center. Methods: We retrospectively investigated patients admitted to the University of Tokyo Hospital NICU during three different time periods (2010, 2015, and 2020). We included 131, 201, and 323 infants, respectively, and compared a number of factors among groups classified by the mode of conception: spontaneous pregnancy (SP), non‐ART (conceived with assisted ovulation or artificial insemination), and ART. We also compared the mode of conception among inborn singletons. Results: The rate of admission of ART infants significantly increased from 2010 (9.1%) to 2015 (22.9%) and 2020 (25.7%) (p values of <0.05 and <0.01, respectively). When compared among inborn singletons, ART infants were more often admitted to NICU (p < 0.01). Congenital anomalies and surgical interventions were significantly more frequent in the SP group than in the ART group (p < 0.01). No significant differences were observed in neonatal outcomes among ART infants from 2010 to 2015/2020. Conclusions: The rate of ART infants admitted to the NICU has significantly increased, with ART pregnancies now accounting for 25% of admissions to the perinatal medical center. ART procedure may be a risk factor for NICU admission. Neonatal intensive care is becoming increasingly indispensable for ART pregnancies. [ABSTRACT FROM AUTHOR]

Background: This non‐randomized intervention study aimed to evaluate the effect of supplementing infant formula with biotin on biotin metabolism and on development. Methods: We enrolled healthy Japanese infants (n = 84) and assigned them to groups offered Formula A (total biotin, 0.5 μg/100 kcal) or Formula B (total biotin, 2.4 μg/100 kcal) until they were 6 months of age, and completed an additional follow up to age 36 months. Urinary biotin concentrations were measured at 1 and 6 months, and were compared among breast‐fed, Formula A‐fed, and Formula B‐fed infants at each age. In a follow‐up subgroup analysis, we compared scores on the Ages and Stages Questionnaire, version 3 (ASQ‐3), from 9 to 36 months among infants continuously fed Formula A, Formula B, or breastmilk. Results: No adverse events occurred during the intervention period. At 1 month, urinary biotin concentrations were highest in Formula B‐fed infants and lowest in Formula A‐fed infants. At 6 months, Formula B‐fed infants retained higher biotin levels than Formula A‐fed and breast‐fed infants. Both differences were statistically significant (P < 0.05). The breast‐fed, Formula A‐fed, and Formula B‐fed groups had similar ASQ scores at 9–36 months. Conclusions: Biotin supplementation of infant formula contributed to improving biotin status in formula‐fed infants. The results support the official approval of the use of biotin in infant formula by the government of Japan in 2014. [ABSTRACT FROM AUTHOR]

Background: In Japan, the mortality rate of extremely low birth weight (ELBW) infants is notably low in comparison with other developed countries, but the prevalence of chronic lung disease (CLD) and retinopathy of prematurity (ROP) is relatively high. This study aimed to estimate the mortality and morbidity of ELBW infants born in 2015 who were admitted to neonatal intensive care units (NICUs) in Japan and to examine the factors that affected the short‐term outcomes of these infants. We also compared the mortality of ELBW infants born in 2005, 2010, and 2015. Methods: We analyzed the mortality, morbidity, and factors related to short‐term outcomes of ELBW infants, using data from 2782 infants born in 2015 and registered at NICUs in Japan. Results: The mortality rates during NICU stays were 17.0%, 12.0%, and 9.8% for ELBW infants born in 2005, 2010, and 2015, respectively. Among ELBW infants born in 2015, multiple logistic regression analysis showed that short gestational age and low birthweight Z‐score contributed to the increased risk of death. Births by cesarean section and antenatal corticosteroid administration were significantly associated with a reduced risk of death. Among infants who survived, CLD was observed in 53.1% and ROP requiring treatment was observed in 30.4%. Conclusions: Mortality in ELBW infants decreased significantly from 2005 to 2015. As CLD and ROP may affect quality of life and long‐term outcomes of infants who survived, prevention strategies and management for these complications are critical issues in neonatal care in Japan. [ABSTRACT FROM AUTHOR]

It has been reported that certain microRNAs (miRNA) are associated with the pathogenesis of lymphoma. We have previously demonstrated that histone deacetylase inhibitors restore tumor‐suppressive miRNAs, such as miR‐16, miR‐29, miR‐150, and miR‐26, in advanced cutaneous T‐cell lymphoma (CTCL). Among these, the function of miR‐26 remains unclear. In this study, we aimed to reveal the function of miR‐26 in CTCL oncogenesis. First, we confirmed that the miR‐26 family was markedly dysregulated in CTCL cell lines and primary samples. In vivo analysis using miR‐26a‐transduced CTCL cells injected into immunodeficient NOG mice demonstrated the significant prolonged survival of the mice, suggesting that the miRNA had a tumor‐suppressive function. We performed gene expression assays and identified 12 candidate miR‐26 targets, namely RGS13, FAM71F1, OAF, SNX21, CDH2, PTPLB, IL22, DNAJB5, CASZ1, CACNA1C, MYH10, and CNR1. Among these, IL22 was the most likely candidate target because the IL‐22–STAT3–CCL20–CCR6 cascade is associated with tumor invasion and metastasis of advanced CTCL. In vitro analysis of IL22 and IL22RA knockdown and miR‐26 transduction demonstrated inhibited CTCL cell migration. In particular, IL22 knockdown induced cell apoptosis. Finally, we conducted in vivo inoculation analysis of mice injected with shIL22‐transfected CTCL cells, and found no tumor invasion or metastasis in the inoculated mice, although the control mice showed multiple tumor invasions and metastases. These results, along with our previous data, demonstrated that miR‐26 is a tumor suppressor that is associated with tumor invasion and the metastasis of advanced CTCL by regulating the IL‐22–STAT3–CCL20 cascade. Therefore, a IL‐22‐targeting therapy could be a novel therapeutic strategy for advanced CTCL. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 38-year-old asymptomatic man with mucopolysaccharidosis II (MPS II), a rare X-linked lysosomal storage disease. Topics discussed include the association between MPS II and RDS, the importance of early diagnosis through newborn screening, and the initiation of enzyme replacement therapy (ERT) for better developmental outcomes.

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti‐CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)‐associated immature plasma cell phenotype, and particularly in those expressing B–cell‐associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B–cell‐associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B–cell‐associated genes were indeed less sensitive to daratumumab‐mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all‐trans‐retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B‐cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable hematopoietic neoplasm derived from plasma cells, and existing in the bone marrow. Recent developments in the field of myeloma onco‐biology have enabled the use of proteasome inhibitors (PIs) as key drugs for MM. PIs can increase cell sensitivity to endoplasmic reticulum stress, leading to apoptosis of myeloma cells. PI cannot kill all myeloma cells, however; one reason of this might be activation of autophagy via hypoxic stress in the bone marrow microenvironment. Hypoxia‐inducible gene(s) that regulate autophagy may be novel therapeutic target(s) for PI‐resistant myeloma cells. Here, a hypoxia‐inducible glycolytic enzyme hexokinase‐2 (HK2) was demonstrated to contribute by autophagy activation to the acquisition of an anti‐apoptotic phenotype in myeloma cells. We found that hypoxic stress led to autophagy activation accompanied by HK2 upregulation in myeloma cells. Under hypoxic conditions, HK2 knockdown inhibited glycolysis and impaired autophagy, inducing apoptosis. The cooperative effects of a PI (bortezomib) against immunodeficient mice inoculated with HK2‐knocked down myeloma cells were examined and significant tumor reduction was observed. An HK2 inhibitor, 3‐bromopyruvate (3‐BrPA), also induced apoptosis under hypoxic rather than normoxic conditions. Further examination of the cooperative effects between 3‐BrPA and bortezomib on myeloma cells revealed a significant increase in apoptotic myeloma cells. These results strongly suggested that HK2 regulates the activation of autophagy in hypoxic myeloma cells. Cooperative treatment using PI against a dominant fraction, and HK2 inhibitor against a minor fraction, adapted to the bone marrow microenvironment, may lead to deeper remission for refractory MM. [ABSTRACT FROM AUTHOR]

Comorbidities at diagnosis among patients with chronic myeloid leukemia in chronic phase (CML‐CP) may affect their overall survival (OS) rate even in the tyrosine kinase inhibitor (TKI) era. However, the prognostic impact of comorbidities in patients with CML‐CP treated with a second‐generation TKI (2GTKI) has not been elucidated. We evaluated the effect of comorbidities on survival using the Charlson Comorbidity Index (CCI) in patients with CML‐CP treated with imatinib or a 2GTKI (nilotinib and dasatinib). From April 2010 to March 2013, 506 patients with CML‐CP were registered for the population‐based cohort study, and 452 with a median age of 56 y were assessable. Treatment groups included 139 patients receiving imatinib, 169 receiving nilotinib, and 144 receiving dasatinib. Comorbidities were diagnosed in 99 patients. CCI scores were stratified as follows: 2, 353 patients; 3, 72 patients; and ≥4, 27 patients. Treatment response did not vary relative to CCI scores. However, across the entire cohort, the OS rate was significantly lower among patients with higher CCI scores than in those with a CCI score of 2 (94.4% in score 2, 89.0% in score 3, and 72.8% in score ≥4; P <.001). Multivariate analysis identified a CCI score of ≥4 as a strong adverse prognostic factor for OS rather than the disease‐specific risk factor, older age, performance status, or selection of TKI (Wald test, P <.01). Our results demonstrated that comorbidities at diagnosis were the most important predictive factor for successful treatment, regardless of the TKI type used in CML‐CP. This trial was registered at UMIN‐CTR as 00003581. [ABSTRACT FROM AUTHOR]

Background: The precise mechanism of hyponatremia in Kawasaki disease (KD) remains elusive because assessment of volume status based on serial changes in body weight is lacking in previous reports. Methods: Seventeen patients who were diagnosed with KD and hyponatremia (serum sodium levels <135 mmol/L) were analyzed. Volume status was assessed based on serial changes in body weight. Plasma arginine vasopressin (ADH), urine electrolytes, and serum cytokine levels were measured on diagnosis of hyponatremia. An increase in body weight by >3% was defined as hypervolemia and a decrease in body weight by >3% was defined as hypovolemia. Results: The volume status was hypervolemic in three patients (18%), euvolemic in 14 (82%), and hypovolemic in none (0%). Five (29%) patients were diagnosed with "syndrome of inappropriate secretion of antidiuretic hormone" (SIADH) and no patients were diagnosed with hypotonic dehydration. The contribution of decreased total exchangeable cations (salt loss) to hyponatremia (5.9% [interquartile range, 4.3%, 6.7%]) was significantly larger than that of increased total body water (−0.7% [−1.8%, 3.1%]) (P = 0.004). Serum interleukin‐6 levels were elevated in all of the nine patients who were evaluated. Among the 12 (71%) patients who did not meet the criteria of SIADH and hypotonic dehydration, plasma ADH levels were inappropriately high in ten patients. These patients were also characterized by euvolemic or hypervolemic hyponatremia and salt loss, which might be compatible with a diagnosis of SIADH. Conclusions: Our study shows that hyponatremia in KD is euvolemic or hypervolemic and is associated with nonosmotic secretion of ADH and salt loss in the majority of patients. [ABSTRACT FROM AUTHOR]

The article presents a case of a 58-year-old female with lymphoid chronic myeloid leukaemia (CML)-blast crisis who switched to nilotinib as treatment due to intolerance to imatinib and dasatinib maintenance therapy. She was also diagnosed with isolated central nervous system relapse (ICNSR) based on bone marrow (BM) and cerebrospinal fluid (CSF) findings and underwent intrathecal chemotherapy twice a month. She experienced BM relapse and nilotinib was discontinued.

Background and purpose: We started performing sentinel node navigation surgery (SNNS) for patients with early gastric cancer (EGC) using infrared ray electronic endoscopy (IREE) with indocyanine green injection from year 2000. The EGCs usually have complex lymphatic drainage, unidirectional or multidirectional lymphatic flow. In this study, we investigated and clarified factors that affect the direction of gastric lymphatic drainage.Patients and method: Consecutive 60 patients with EGC who underwent SNNS by IREE from year 2006 to 2014 were enrolled to this study. Patients’ age, gender, location of tumors, operative method, previous treatment by endoscopic submucosal dissection (ESD), presence of pathological ulcerative scar and maximum tumor diameter were enrolled as parameters which may affect direction of lymphatic drainage and analyzed.Result: Bivariate analysis demonstrated that the presence of pathological ulcerative scar (P = 0.01), tumor location (g.c vs. a.w vs. p.w vs. l.c, P = 0.01), and maxim tumor diameter (P = 0.0003) were relevant to direction of gastric lymphatic drainage. Multivariate analysis showed that tumor location (g.c/a.w/p.w vs. l.c, odds ratio 8.227, P = 0.011) and the maximum tumor diameter (odds ratio 1.057, P = 0.037) are independent factors that affect direction of gastric lymphatic flow. Of tumors, 78% located at lesser curvature had unidirectional lymphatic drainage, and 93% of tumors whose diameter was 40 mm and more had multidirectional lymphatic drainage.Conclusion: Our investigation revealed that the tumor location and tumor diameter were the key factors which affect the direction of lymphatic drainage, which is useful fact to understand the complexity of gastric lymphatic drainage. [ABSTRACT FROM AUTHOR]

Multiple myeloma ( MM) is characterized by the accumulation of a population of malignant plasma cells within the bone marrow and its microenvironment. A hypoxic niche is located within the microenvironment, which causes myeloma cells to become quiescent, anti-apoptotic, glycolytic, and immature. Cell heterogeneity may be related to distinct gene expression profiles under hypoxic and normoxic conditions. During hypoxia, myeloma cells acquire these phenotypes by downregulating interferon regulatory factor 4 ( IRF4), an essential transcription factor in myeloma oncogenesis. To identify essential micro RNAs and their targets regulated under hypoxic conditions, we undertook micro RNA and c DNA microarray analyses using hypoxia-exposed primary MM samples and myeloma cell lines. Under hypoxia, only miR-210 was highly upregulated and was accompanied by direct downregulation of an 18S r RNA base methyltransferase, DIMT1. This inverse expression correlation was validated by quantitative RT- PCR for primary MM samples. We further determined that DIMT1 has an oncogenic potential as its knockdown reduced tumorigenicity of myeloma cells through regulation of IRF4 expression. Notably, by analyzing gene expression omnibus datasets in the National Center for Biotechnology Information database, we found that DIMT1 expression increased gradually with MM progression. In summary, by screening for targets of hypoxia-inducible micro RNA-210, we identified DIMT1 as a novel diagnostic marker and therapeutic target for all molecular subtypes of MM. [ABSTRACT FROM AUTHOR]

Occult hepatitis B virus (HBV) infection is a clinical challenge, but its relationship to clinicopathologic features and the risk of progression to malignant lymphoma (ML) are poorly defined. We estimated the prevalence of HBV infection of 1,358 patients with newly diagnosed ML. HBV infection was more prevalent in ML than in control patients. The occult HBV infection group had a higher median onset age, no liver or spleen involvement, and higher prevalence of diffuse large B-cell lymphoma than the other groups, indicating that occult HBV infection is a distinct clinicopathologic entity. J. Med. Virol. 88:2206-2210, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The article presents a case study of a mother of the patient who had an intrauterine infection with elevation of serum C-reactive protein (CRP) and white blood cell (WBC) count, but blood culture and cervical culture were negative. She was diagnosed with partial placental abruption, and immediately strong labor began, and the baby was born transvaginally. It notes the association of high mobility group box-1 (HMGB-1) with the development of neonatal leukemoid reaction (NLR).

The article presents a case study of a male preterm neonate weighing 1,915 g was delivered at 32 weeks and 1 day of gestation by induced delivery due to a history of prolonged premature rupture of membranes. It mentions about the after birth, an ileostomy was created after resecting part of the intestine for an idiopathic, localized, intestinal perforation; and antibiotics were discontinued on day 26 and no additional treatment was required.

We studied the cytokine profile of two siblingswith neonatal lupus erythematosus (NLE) born to amother positive for serum anti-Ro and -La antibodies, who did not receive any medication during the two pregnancies. The first sibling was found to have complete atrioventricular block in utero and became severely ill after birth. He fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis on day 2. The second sibling did not have any fetal symptoms. He was generally stable after birth, but with typical skin rash. Laboratory data suggested that they both had hypercytokinemia during the neonatal period, requiring corticosteroid treatment. Interleukin (IL)-6, interferon-γ, IL-8 and monocyte chemotactic protein-1 were elevated in both cases, while IL-12, IL-13 and IL-17 were elevated only in the second sibling. Comparison of the cytokine profiles suggests the potential roles of different cytokines in the onset and clinical manifestations of NLE. [ABSTRACT FROM AUTHOR]

Background Preterm infants are at significant risk of reduced bone mineral content and subsequent bone disease (metabolic bone disease of prematurity, MBDP). MBDP is frequently found in very low-birthweight (VLBW) infants, but long-term height prognosis is not well known. Methods VLBW infants from two major neonatal intensive care units were studied. Medical records were reviewed. A total of 143 subjects were analyzed after excluding subjects who died, or who had severe complications that could affect linear growth, Silver-Russell syndrome, severe cholestasis, and/or chromosomal abnormality. The relationship between MBDP and height at age 3 was investigated. Results Height standard deviation score (SDS) at age 3 negatively correlated with peak serum alkaline phosphatase (ALP) activity in early life ( r = −0.30, P = 0.0003) and positively correlated with serum phosphorus (P) at peak ALP ( r = 0.33, P = 0.0002). In addition, serum P independently affected height SDS at 3 years of age (β = 0.19, P = 0.018), and was significantly different between infants with and without catch-up growth in height (difference: 0.23 mmol/L, 95%CI: 0.09-0.36, P = 0.0010). Conclusions MBDP, particularly hypophosphatemia in the early period of life, is associated with linear growth until 3 years of age in VLBW infants. [ABSTRACT FROM AUTHOR]

Background The pathogenesis of abdominal symptoms in premature infants with hypothyroxinemia is not understood; therefore, we investigated changes in gut hormones before and after levothyroxine sodium ( T4- Na) supplementation in preterm infants with abdominal symptoms and hypothyroxinemia. Methods In eight preterm study subjects and 14 gestational age-matched controls, fasting serum concentration of leptin, glucose-dependent insulinotropic polypeptide ( GIP), glucagon-like peptide-1 ( GLP-1), peptide YY ( PYY), pancreatic polypeptide, insulin, amylin and ghrelin was measured using a bead array system. Results Serum GLP-1, GIP and PYY in the subjects before T4- Na supplementation were lower than in controls at age 2 weeks. After improvement of abdominal symptoms and free thyroxine, serum levels of the three gut hormones in the subjects were increased and were not different from those in the control patients. Conclusions In preterm infants with abdominal symptoms, serum GLP-1, GIP and PYY might be related to thyroid function. [ABSTRACT FROM AUTHOR]

Herein is described a case of neonatal neuroblastoma with cyclic blood pressure fluctuation and elevated catecholamines. The fluctuations stabilized after treatment with α-adrenergic blocker and the perioperative course was uneventful. The possibility of catecholamine-related symptoms including hypertension, heart failure, and blood pressure fluctuations should be considered in the treatment for neuroblastoma; if they are present, treatment with α-blockers is effective. [ABSTRACT FROM AUTHOR]

Key Clinical Message Nilotinib, a BCR- ABL tyrosine kinase inhibitor, is a known inhibitor of CYP3A4 and could increase the concentration of drugs metabolized by CYP3A4. An immunosuppressive drug for nilotinib-treated patients following transplant should be administered with careful pharmacokinetic monitoring because of its interaction with nilotinib. [ABSTRACT FROM AUTHOR]

Background The neonatal intensive care unit ( NICU) is a high-risk setting for transmission of methicillin-resistant Staphylococcus aureus ( MRSA). The recent prevalence of colonization with MRSA in patients and its control measures are unknown in Japanese NICU. We investigated the prevalence of MRSA colonization in patients and measures to control and prevent health-care-associated transmission in Japanese NICU in 2011. Methods A nationwide survey was performed in facilities certified as training hospitals for neonatologists. Data in NICU and growing care units ( GCU) were collected and analyzed regarding surveillance cultures for MRSA and the proportion of MRSA-colonized patients in September 2011. Trends in the proportion of MRSA-colonized patients and the measures to control and prevent health-care-associated MRSA transmission were investigated in the surveyed NICU in 2000, 2003, and 2011. Results A total of 168 NICU and 158 GCU were analyzed. The proportions of NICU and GCU that conducted regular surveillance cultures for MRSA were 81% and 66%, respectively. MRSA colonization was not found in 53% of NICU and in 45% of GCU. The percentage of NICU reported to be free of MRSA colonization increased over time. Use of alcohol-based hand rub and gloves by clinical staff and cohorting for identified MRSA-positive patients became more common in 2011 than in 2000 or 2003. Conclusions Approximately half of Japanese NICU did not observe any patients with MRSA colonization in September 2011. Control and prevention measures have changed to use of alcohol-based hand rub and gloves in the last decade. [ABSTRACT FROM AUTHOR]

ABSTRACT Since 1992, many neonates in neonatal intensive care units in Japan have been developing fever and systemic exanthema. Immunological analyses of neonates with these symptoms has revealed that the bacterial superantigen, toxic shock syndrome toxin-1 (TSST-1) is the cause. The name neonatal TSS-like exanthematous disease (NTED) has been applied to this condition. The most striking clinical finding has been that none of the term neonates have developed shock or died of NTED. The timing of NTED epidemics has coincided with the spread of emerging TSST-1-producing methicillin-resistant Staphylococcus aureus clones in Japan. The low frequency of pregnant women with positive anti-TSST-1 antibody titers could be one reason for the spread of NTED in Japan. Neonates have immune tolerance against TSST-1 and may actively suppress the immune response to NTED with interleukin-10. According to the T cell responses in infants or young children with diseases induced by TSST-1, the pathophysiology of TSST-1-related diseases may be age-dependent. The precise mechanism of anergy and deletion of specific T cells stimulated with TSST-1 should be investigated in neonates infected with NTED. Both NTED and TSS might provide good models for analyzing the mechanism(s) of neonatal immune tolerance and the age-dependence of human immunity. This disease has not only become representative of diseases caused by superantigens, but has also yielded a considerable amount of evidence about human immune reactions against superantigens. [ABSTRACT FROM AUTHOR]

Aim Assisted reproductive technology ( ART) has increased the incidences of multiple gestations and low birth weights, which frequently warrant pediatric surgery. ART may have also increased the rate of birth defects. In this study, we aimed to determine whether infants conceived after ART required neonatal surgery more frequently compared with naturally conceived infants. Material and Methods Our study population comprised 1891 infants (160 ART (+) and 1731 ART (−)) who were admitted to our neonatal intensive care unit during a 5-year period ( January 2006- December 2010); of these, 198 infants (9 ART (+) and 189 ART (−)), with diseases requiring surgery, were referred to pediatric surgeons (consultation cases). We examined the following: (i) factors potentially increasing the requirement for surgery; (ii) frequency of birth defects; and (iii) maternal factors that may increase the need for surgery. Results A significantly higher incidence of multiple gestation and low birth weight was observed in the ART (+) group than the ART (−) group. However, ART did not yield a higher rate of surgery and birth defects: overall, the rate of surgery was 4% (7/160) in the ART (+) group and 8% (143/1731) in the ART (−) group. Of 198 consultation cases, the percentage of infants actually requiring surgery was approximately the same in the ART (+) group (7/9 [78%]) and the ART (−) group (143/189 [76%]). Conclusion Infants conceived after ART comprised a small proportion of neonatal surgery cases, and did not require surgery more frequently. [ABSTRACT FROM AUTHOR]

The article presents a case study of a female neonate diagnosed with disseminated herpes simplex virus (HSV) infection. It is inferred that the patient was also diagnosed with hemophagocytic lymphohistiocytosis (HLH). The patient showed white-matter damage despite of no evidence of viral involvement of the central nervous system (CNS).

Background: Respiratory syncytial virus (RSV) infection is a major cause of hospitalization during the winter among infants and young children. In 2002 palivizumab was introduced to high-risk infants for RSV hospitalization in Japan. It is important to characterize the hospitalized children due to RSV infection after the introduction of palivizumab. Methods: A survey was conducted to collect the data from the hospitalized children at 12 participating hospitals during the winter of 2007. Results: From October 2007 through April 2008, 8163 children were admitted to participating hospitals, with RSV infection accounting for 811 of those hospitalizations. Mean age in children with RSV infection at hospitalization was 12.4 1 12.7 months, and children under 24 months of age accounted for 86.4%. The mean gestational age of those at birth was 38.0 1 2.6 weeks, with 82.4% of the children born at term. Palivizumab was administered in 24 cases of RSV infection, while there were 28 patients who were not treated with palivizumab, even though they met the indication for palivizumab. Death, in a total of five cases, occurred in children who were not treated with palivizumab. Conclusions: Palivizumab has been widely used in high-risk infants who were covered by health insurance, and most of the hospitalized children with RSV infection in the study hospitals were not treated with palivizumab. [ABSTRACT FROM AUTHOR]

The article presents a case study of a preterm female infant diagnosed with early onset listeriosis. Her mother had a high fever and was diagnosed with chorioamnionitis where antibiotics were administered to the mother. The infant was delivered having signs of respiratory distress and circulatory disturbance. The infant's serum cytokine profile is determined to evaluate her immune response and the immunological pathophysiology of early onset listeriosis in preterm infants is discussed.

Although cladribine has been reported to be an active purine analog against indolent B-cell non-Hodgkin lymphoma (B-NHL), there are few reports of combination use of cladribine and rituximab. This multicenter phase II study evaluated the efficacy and toxicity of cladribine with rituximab (R-2-CdA) therapy in relapsed or refractory indolent B-NHL. Twenty patients with the median age of 58.5 yrs (range, 42-72) were enrolled and received R-2-CdA therapy from April 2005 to July 2007. The median number of prior regimens was 2 (range, 1-3), and fifteen patients (75%) were previously treated with rituximab-containing regimens. Disease histology included follicular lymphoma in 16 patients, MALT lymphoma in two patients, nodal marginal B-cell lymphoma in one patient, and lymphoplasmacytic lymphoma in one patient. The overall response rate (ORR) was 90%, with a complete response rate (CRR) of 70%. Estimated median progression-free survival (PFS) time was 22.4 months (95%CI, 10.9-32.6 months) at a median follow-up time of 27 months (range, 12-43). Two-year PFS and 2-yr overall survival (OS) were 52.6% (95%CI, 31.0-73.2%) and 89.5% (95%CI, 66.1-97.3%), respectively. Grade 3 or grade 4 toxicities were neutropenia in 74% and thrombocytopenia in 11%. R-2-CdA therapy was demonstrated to have a high activity with durable PFS and acceptable toxicity in relapsed or refractory indolent B-NHL mostly pretreated with rituximab-containing therapy. Although a large-scale trial is needed for confirmation, R-2-CdA therapy could be a good salvage therapy option in relapsed or refractory indolent B-NHL. [ABSTRACT FROM AUTHOR]

A simple, rapid and sensitive high-performance liquid chromatography (HPLC)-based method with ultraviolet detection was developed for the quantitation of nilotinib, a tyrosine kinase inhibitor, in human plasma. Nilotinib and the internal standard dasatinib were separated using a mobile phase of 0.5% KH2PO4 (pH2.5)-acetonitrile-methanol (55:25:20, v/v/v) on a Capcell Pak MG II column (250 × 4.6 mm) at a flow rate of 0.5 mL/min and optical measurement at 250 nm. Analysis required only 100 μL of plasma and involved a rapid and simple solid-phase extraction with an Oasis HLB cartridge, which gave recoveries from 72 to 78% for nilotinib and from 74 to 76% for dasatinib. The lower limit of quantification for nilotinib was 10 ng/mL. The linear range of this assay was between 10 and 5000 ng/mL ( r2 > 0.9992 for the regression line). Intra- and inter-day coefficients of variation were less than 10.0% and accuracies were within 10.4% over the linear range. Our results indicate that this method is applicable to the monitoring of plasma levels of nilotinib in a clinical setting. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Reported herein is an autopsy case of mast cell leukemia, a rare form of systemic mastocytosis, complicated with portal hypertension. A 52-year-old woman presented with urticaria-like skin symptoms, anemia, and thrombocytopenia. Atypical mast cells (CD2+, CD25+, CD117+) with toluidine blue metachromasia were found in the peripheral blood and on bone marrow aspiration smears. Chemotherapy with cytosine arabinoside and idarubicin was ineffective and the patient died of multi-organ failure with rapidly progressing hepatosplenomegaly and large-volume ascites 3 months after admission. At autopsy the bone marrow, spleen, liver, and lymph nodes were extensively infiltrated by atypical tumor cells with occasional bi- or multi-lobated nuclei. They were positive for mast cell tryptase and possessed an activating mutation of the c-kitgene (D816V). Ascites (2200 mL) and non-ruptured esophageal varices with submucosal hemorrhage indicated the presence of severe portal hypertension. Although there was no evidence of liver cirrhosis, the hepatic sinusoids were clogged with tumor cells, with a tendency to be more severe in the perivenular areas, and the lumens of central veins were obliterated by tumor cell infiltration. The present case demonstrates that non-cirrhotic portal hypertension due to blocking of sinusoidal and venous flow could be a serious complication in mast cell leukemia. [ABSTRACT FROM AUTHOR]

A new epidemic, NTED, has recently occurred in Japan. The cause of NTED is a bacterial superantigen, TSST-1. The aim of the present study was to analyze the change in Vβ2+ T cells reactive to TSST-1 in NTED in order to establish T-cell-targeted diagnostic criteria for NTED. Blood samples from 75 patients with clinically diagnosed NTED were collected from 13 neonatal intensive care units throughout Japan. We investigated the percentages of Vβ2+, Vβ3+ and Vβ12+ T cells and their CD45RO expressions in the samples using flow cytometry. In 18 of the 75 patients, we conducted multiple examinations of the T cells and monitored serial changes. The Vβ2+ T-cell population rapidly changed over three phases of the disease. Whereas the percentage of Vβ2+ T cells was widely distributed over the entire control range, CD45RO expression on Vβ2+ T cells in CD4+ in all 75 patients was consistently higher than the control range. Patients cannot necessarily be diagnosed as having NTED based on expansion of Vβ2+ T cells alone in the early acute phase. Instead, CD45RO expression on specific Vβ2+ cells is a potential diagnostic marker for a rapid diagnosis of NTED. We present three diagnostic categories of NTED. Fifty patients (66.7%) were included in the category ‘definitive NTED’. It is important to demonstrate an increase of Vβ2+ T cells in the following phase in cases of ‘probable NTED’ or ‘possible NTED’. [ABSTRACT FROM AUTHOR]

Ehlers–Danlos syndrome (EDS) type IV is an autosomal dominantly inherited connective tissue disorder caused by abnormal type III collagen resulting from heterogenous mutations of the type III procollagen gene ( COL3A1). The maternal mortality rate per pregnancy in EDS type IV has been reported as 11.5% to 25%. A 30-year-old Japanese primiparous woman, with a brother who had suffered a bowel rupture due to EDS type IV, became pregnant. She also suffered from myocardial infarction due to coronary artery dissections at 24 years old, and underwent coronary artery bypass grafting. Due to uncontrollable uterine contractions, beta 2-stimulants were administered during 18 to 29 weeks of gestation. Therefore, we performed a cesarean section at 29 weeks of gestation to prevent uterine rupture. She and her baby were discharged without any complications. It was revealed that she had the same mutation as her brother, Gly220Trp, in the (Gly-X-Y)n repeat of the triple-helical domain of COL3A1. [ABSTRACT FROM AUTHOR]

Background: Extremely preterm infants, especially those <24 weeks of gestation, displayed extremes in changes of fluid/electrolyte balance. The purpose of the present study was to retrospectively investigate abnormalities in fluid/electrolyte balance during the first postnatal week. Methods: Of 32 subjects admitted during 20 years, 17 infants with no severe complications were examined, and 72 appropriate-for-dates infants at 24–28 weeks of gestation were taken as controls. The subjects were managed in closed incubators in a highly humidified environment and fluid/electrolyte balances were monitored in retrospect. Results: The subjects had higher urine contents, while the insensible water loss was higher than in controls. As for weight loss, no remarkable changes were noted between the two groups. On day 4 and thereafter, serum Na+ levels were high, indicating a high complication rate of hypernatremia without differences in hyperkalemia. The decrease in blood base excess was rapid, requiring supplementation of sodium bicarbonate up to postnatal day 5 in all preterm infants. Conclusion: Due to the relatively higher urine output and insensible water loss in extremely preterm infants during postnatal week 1, higher water intake was required. As such, metabolic acidosis was bound to have occurred. [ABSTRACT FROM AUTHOR]

Background: Recent studies of chronic lung disease (CLD) of newborns emphasize the contribution of antenatal infection. However, the association of Ureaplasma urealyticum infection and CLD has been controversial. The purpose of the present paper was to determine whether U. urealyticum is associated with chorioamnionitis (CAM) and a certain type of CLD. Methods: One hundred and five infants <32 weeks of gestation who were admitted to the neonatal intensive care unit at Jichi Medical School Hospital, who underwent both histological and microbiological examinations and who survived to discharge were included. CAM was determined by histological examination. Placenta, gastric and tracheal aspirates, and nasopharyngeal swabs were cultured for Mycoplasma and other microorganisms. CLD was defined as oxygen needed at 28 days of age with symptoms of persistent respiratory distress and hazy or emphysematous and fibrous appearance upon X-ray. CLD was further divided into two subtypes according to the presence of antenatal infection. Results: CAM was associated with premature rupture of membrane (odds ratio [OR], 10.19; 95% confidence interval [CI]: 3.10–33.56), placental colonization of U. urealyticum (OR 6.73, 95%CI: 1.89–23.91), neonatal colonization of other microorganisms (OR 7.33, 95%CI: 1.22–44.13) and level of IgM (OR 1.06, 95%CI: 1.01–1.11). Comparisons between CLD and non-CLD patients showed that gestational age (OR 0.43, 95%CI: 0.30–0.61) and white blood cell count (WBC) at birth (OR 1.06, 95%CI: 1.01–1.11) were risk factors for CLD, while gestational age (OR 0.38, 95%CI: 0.23–0.64), neonatal colonization of U. urealyticum (OR 5.98, 95%CI: 1.17–30.6) and WBC (OR 1.08, 95%CI: 1.01–1.15) were independent risk factors for infection-related CLD compared with non-CLD. Within CLD, infection-related CLD was associated with neonatal colonization of U. urealyticum (OR 43.7, 95%CI: 2.84–673.8) and WBC (OR 1.27, 95%CI: 1.07–1.50). Conclusions: Placental colonization of U. urealyticum was significantly related to CAM; and neonatal colonization of U. urealyticum and leukocytosis at birth were risk factors for infection-related CLD. [ABSTRACT FROM AUTHOR]