Low prevalence of maternal microchimerism in peripheral blood of Japanese children with type 1 diabetes.

AIM: To clarify the prevalence and degree of maternal microchimerism in Japanese children with type 1 diabetes, as well as its effect on phenotypic variation. METHODS: We studied 153 Japanese children with type 1 diabetes, including 124 children positive for ß-cell autoantibodies, and their 71 unaffected siblings. The number of circulating microchimeric cells per 105 host cells was estimated by the use of quantitative-polymerase chain reaction targeting non-transmitted maternal human leukocyte antigen alleles. The results were compared to previous data from white European people. Phenotypic comparison was performed between maternal microchimerism carriers and non-carriers with diabetes. RESULTS: Maternal microchimerism was detected in 15% of children with autoantibody-positive type 1 diabetes, 28% of children with autoantibody-negative type 1 diabetes, and 16% of unaffected siblings. There were no differences in the prevalence or levels of maternal microchimerism among the three groups or between the children with type 1 diabetes and their unaffected siblings. Furthermore, maternal microchimerism carriers and non-carriers exhibited similar phenotypes. CONCLUSIONS: Maternal microchimerism appears to be less common in Japanese children with type 1 diabetes than in white European people. Our data indicate that maternal microchimerism is unlikely to be a major trigger or a phenotypic determinant of type 1 diabetes in Japanese children and that the biological significance of maternal microchimerism in type 1 diabetes may differ among ethnic groups.

Comparison of oncological outcomes after open and laparoscopic re-resection of incidental gallbladder cancer.

BACKGROUND: The safety and oncological efficacy of laparoscopic re-resection of incidental gallbladder cancer have not been studied. This study aimed to compare laparoscopic with open re-resection of incidentally discovered gallbladder cancer while minimizing selection bias. METHODS: This was a multicentre retrospective observational cohort study of patients with incidental gallbladder cancer who underwent re-resection with curative intent at four centres between 2000 and 2017. Overall survival (OS) and recurrence-free survival (RFS) were analysed by intention to treat. Inverse probability of surgery treatment weighting using propensity scoring was undertaken. RESULTS: A total of 255 patients underwent re-resection (190 open, 65 laparoscopic). Nineteen laparoscopic procedures were converted to open operation. Surgery before 2011 was the only factor associated with conversion. Duration of hospital stay was shorter after laparoscopic re-resection (median 4 versus 6 days; P < 0·001). Three-year OS rates for laparoscopic and open re-resection were 87 and 62 per cent respectively (P = 0·502). Independent predictors of worse OS were residual cancer found at re-resection (hazard ratio (HR) 1·91, 95 per cent c.i. 1·17 to 3·11), blood loss of at least 500 ml (HR 1·83, 1·23 to 2·74) and at least four positive nodes (HR 3·11, 1·46 to 6·65). In competing-risks analysis, the RFS incidence was higher for laparoscopic re-resection (P = 0·038), but OS did not differ between groups. Independent predictors of worse RFS were one to three positive nodes (HR 2·16, 1·29 to 3·60), at least four positive nodes (HR 4·39, 1·96 to 9·82) and residual cancer (HR 2·42, 1·46 to 4·00). CONCLUSION: Laparoscopic re-resection for selected patients with incidental gallbladder cancer is oncologically non-inferior to an open approach. Dissemination of advanced laparoscopic skills and timely referral of patients with incidental gallbladder cancer to specialized centres may allow more patients to benefit from this operation.

ANTECEDENTES: No se conoce la seguridad y la eficacia oncológica de la re-resección laparoscópica del cáncer incidental de vesícula biliar. Este estudio tiene como objetivo comparar las re-resecciones del cáncer incidental de vesícula biliar por vía laparoscópica y vía abierta, minimizando el sesgo de selección. MÉTODOS: Estudio de cohortes observacional, retrospectivo y multicéntrico de pacientes con cáncer incidental de vesícula biliar que se sometieron a una re-resección con intención curativa en 4 centros entre 2000 y 2017. Se analizó la supervivencia global (overall survival, OS) y la supervivencia libre de recidiva (recurrence free survival, RFS) según intención de tratamiento. Se calculó la probabilidad inversa de la ponderación del tratamiento quirúrgico utilizando puntuación de propensión. RESULTADOS: Se incluyeron 255 pacientes con re-resección (190 por vía abierta y 65 por vía laparoscópica). Se convirtieron 19 pacientes del grupo laparoscópico. El único factor relacionado con la conversión fue la realización de la cirugía antes de año 2011. La mediana de la estancia hospitalaria fue más corta tras la re-resección laparoscópica (4 versus 6 días; P < 0,001). La OS a tres años fue del 87% y del 62% (P = 0,502) para las re-resecciones laparoscópicas y abiertas, respectivamente). Los factores predictivos independientes relacionados con una peor OS fueron el hallazgo de cáncer residual en el momento de la re-resección (cociente de riesgos instantáneos, hazard ratio, HR 1,91; i.c. del 95% 1,17-3,11), una pérdida hemática > 500 ml (HR 1,83; i.c. del 95% 1,23-2,74) y la presencia de ≥ 4 ganglios positivos (HR 3,11; i.c. del 95% 1,46-6,65). En el análisis de riesgo competitivo, la RFS fue mayor para la resección laparoscópica (P = 0,038), pero no hubo diferencias en la OS entre ambos grupos. Los factores predictivos independientes de peor RFS fueron la detección de 1-3 ganglios positivos (HR 2,16; i.c. del 95% 1,29-3,60), ≥ 4 ganglio positivos (HR 4,39; i.c. del 95% 1,96-9,82) y el cáncer residual (HR 2,42; i.c. de 95% 1,46-4,0). CONCLUSIÓN: En pacientes seleccionados, los resultados oncológicos de la re-resección laparoscópica de un cáncer incidental de vesícula biliar no son inferiores a los que se obtienen por vía abierta. Una mayor difusión de las técnicas laparoscópicas avanzadas y una oportuna derivación de los pacientes con cáncer de vesícula biliar incidental a centros especializados podrían permitir que un mayor número de pacientes se beneficiaran de este abordaje.

Prognostic impact of perihepatic lymph node metastases in patients with resectable colorectal liver metastases.

BACKGROUND: Although perihepatic lymph node metastases (PLNMs) are known to be a poor prognosticator for patients with colorectal liver metastases (CRLMs), optimal management remains unclear. This study aimed to determine the risk factors for PLNMs, and the survival impact of their number and location in patients with resectable CRLMs. METHODS: Data on patients with CRLM who underwent hepatectomy during 2003-2014 were analysed retrospectively. Recurrence-free (RFS) and overall (OS) survival were calculated according to presence, number and location of PLNMs. Risk factors for PLNM were evaluated by logistic regression analysis. RESULTS: Of 1485 patients, 174 underwent lymphadenectomy, and 54 (31·0 per cent) had PLNM. Ten patients (5·7 per cent) who had lymphadenectomy and 176 (13·4 per cent) who did not underwent repeat hepatectomy. Survival of patients with PLNM was significantly poorer than that of patients without (RFS: 5·3 versus 13·8 months, P < 0·001; OS: 20·5 versus 71·3 months; P < 0·001). Median OS was significantly better in patients with para-aortic versus hepatoduodenal ligament PLNMs (58·2 versus 15·5 months; P = 0·011). Patients with three or more PLNMs had significantly worse median OS than those with one or two (16·3 versus 25·4 months; P = 0·039). The presence of primary tumour lymph node metastases (odds ratio 2·35; P = 0·037) and intrahepatic recurrence requiring repeat hepatectomy (odds ratio 5·61; P = 0·012) were significant risk factors for PLNM on multivariable analysis. CONCLUSION: Patients undergoing repeat hepatectomy and those with primary tumour lymph node metastases are at significant risk of PLNM. Although PLNM is a poor prognostic factor independent of perihepatic lymph node station, patients with one or two PLNMs have a more favourable outcome than those with more PLNMs.

Protein-altering variants of PTPN2 in childhood-onset Type 1A diabetes.

AIM: To examine the contribution of PTPN2 coding variants to the risk of childhood-onset Type 1A diabetes. METHODS: PTPN2 mutation analysis was carried out for 169 unrelated Japanese people with childhood-onset Type 1A diabetes. We searched for coding variants that were absent or extremely rare in the general population and were scored as damaging by multiple in silico programs. We performed mRNA analysis and three-dimensional structural prediction of the detected variants, when possible. We also examined possible physical links between these variants and previously reported risk SNPs as well as clinical information from variant-positive children. RESULTS: One frameshift variant (p.Q286Yfs*24) and two probably damaging missense substitutions (p.C232W and p.R350Q) were identified in one child each. Of these, p.Q286Yfs*24 and p.C232W were hitherto unreported, while p.R350Q accounted for 2/121,122 alleles of the exome datasets. The p.Q286Yfs*24 variant did not encode stable mRNA, and p.C232W appeared to affect the structure of the tyrosine-protein phosphatase domain. The three variants were physically unrelated to known risk SNPs. The variant-positive children manifested Type 1A diabetes without additional clinical features and invariably carried risk human leukocyte antigen alleles. CONCLUSIONS: The results provide the first indication that PTPN2 variants contribute to the risk of Type 1A diabetes, independently of known risk SNPs. PTPN2 coding variants possibly induce non-specific Type 1A diabetes phenotypes in individuals with human leukocyte antigen-mediated disease susceptibility. Our findings warrant further validation.

Does response rate of chemotherapy with molecular target agents correlate with the conversion rate and survival in patients with unresectable colorectal liver metastases?: A systematic review.

PURPOSE: This study aimed to evaluate whether the response rate of chemotherapy with molecular target agents correlates with the conversion rate, R0 resection rate, and survival in patients with initially unresectable colorectal liver metastases (CRLM). METHODS: We reviewed the literature of prospective, controlled trials of systemic chemotherapy for patients with unresectable liver-only CRLM, including resectable extrahepatic metastases. Pearson's correlation coefficients were calculated. RESULTS: A total of 26 patient groups from 18 studies were reviewed. The response rate was significantly correlated with the conversion rate (r = 0.66) and R0 resection rate (r = 0.43) in overall patients. In subgroup analysis, only the conversion rate in patients with chemotherapy only (r = 0.75) and anti-EGFR therapy (r = 0.78) were significantly strongly correlated with the response rate. A non-significant strong trend toward correlation between response and conversion rates was observed in patients with bevacizumab (r = 0.73, p = 0.10). The regression line in the scatter plot of patients using bevacizumab showed a less steep slope. This indicated that conversion rates were relatively less affected by response rates under anti-VEGF therapy compared with the other patient groups. The response rate in chemotherapy-only patients was significantly correlated with median progression-free survival (r = 0.61) and overall survival (r = 0.66). CONCLUSIONS: Chemotherapy without molecular target agents and with anti-EGFR agents shows similar results of correlation between response and conversion/R0 resection rates. Under anti-VEGF therapy, conversion would be expected, even with a relatively lower response rate.

An abscess mimicking a left incarcerated groin hernia.

We present the case of a 79-year-old man with an irreducible and painful left groin mass. Obtaining a detailed history of present illness and assessment of radiological findings revealed an abscess in a groin hernia sac, which was formed secondary to perforation of the descending colon. Various examinations, however, failed to reveal the cause of the bowel perforation. Percutaneous drainage improved his symptoms. He was discharged home 24 days after admission with no further sequelae. An abscess in a groin hernia sac is very rare. Although neither bowel perforation nor hernia is rare, surgeons do not sufficiently consider the possibility of an abscess in a groin hernia sac. Thus, surgeons often encounter unexpected abscesses in the groin hernia sac during operations. Our case points to the necessity of obtaining a detailed history of present illness as well as assessment of radiological findings, and presents a therapeutic option for an abscess in a groin hernia sac.

Unsedated transnasal ultrathin esophagogastroduodenoscopy may provide better diagnostic performance in gastroesophageal reflux disease.

Transnasal ultrathin esophagogastroduodenoscopy (N-EGD) with less gagging reflexes under non-sedation is likely suitable for the diagnosis of gastroesophageal reflux disease (GERD), however, N-EGD might have drawbacks, including its low image resolution. Limited information is available regarding the diagnosability of N-EGD for GERD. We compared the utility and gagging reflexes of three different endoscopies, including N-EGD, ultrathin transoral EGD (UTO-EGD) and conventional oral EGD (CO-EGD), in the diagnosis of GERD. We performed screening endoscopy in 1580 patients (N-EGD n=727, UTO-EGD n=599, CO-EGD n=254) and compared the frequency distributions of the severity of reflux esophagitis, hiatus hernia, and Barrett's epithelium to estimate the diagnostic performance of each endoscopy. We also analyzed patients' tolerability of endoscopy by the subjective evaluation of gagging reflexes. In the diagnosis of reflux esophagitis and Barrett's epithelium, there was no significant difference in the frequency distributions of the severity of the diseases among three EGDs. However, the incidence of Barrett's epithelium was higher than that in the previous nationwide survey of GERD in Japan. The evaluated size of hiatus hernia was smaller in N-EGD than in two other peroral endoscopies. The size of hiatus hernia correlated significantly with severity of gagging reflexes that was also lowest when diagnosed with N-EGD. N-EGD had an equivalent performance in the diagnosis of reflux esophagitis and Barrett's epithelium compared with CO-EGD. Enlargement of hiatus hernia induced by gagging reflexes was minimal in N-EGD, resulting in its better performance in the diagnosis of Barrett's epithelium.

Integrated photonic decoder with complementary code processing and balanced detection for two-dimensional optical code division multiple access.

We propose a novel integrated photonic decoder for two-dimensional (time spreading, wavelength hopping) optical code division multiple access. The decoder is composed of multiplexers-demultiplexers, variable delay lines, and a coupler, which processes complementary codes and utilizes balanced detection to reduce unwanted cross-correlation interference. We successfully carried out a 10 Gbit/s transmission that demonstrated its effectiveness.

K+-independent initiation of motility in chum salmon sperm treated with an organic alcohol, glycerol.

Sperm of salmonid fishes are quiescent in the presence of millimolar concentrations of extracellular K+, but motility initiation occurs when sperm are suspended in K+-free medium. In this study, glycerol (CH2OHCHOHCH2OH) treatment of intact sperm in the presence of K+ induced the initiation of motility even though a large amount of K+ was present. Another organic alcohol, erythritol (CH2OH(CHOH)2CH2OH), had a similar effect, but ethylene glycol (CH2OHCH2OH) did not initiate sperm motility. Furthermore, this glycerol-treated sperm showed motility without subsequent addition of ATP and cAMP. CCCP, an uncoupler of the mitochondrial electron-transport chain involved in ATP synthesis, suppressed motility of glycerol-treated sperm, suggesting that ATP synthesis is required for dynein to slide microtubules in glycerol-treated sperm. The amount of intracellular cAMP ([cAMP]i) in glycerol-treated sperm did not increase on motility activation, but a protein kinase A (PKA) inhibitor, H-89, inhibited glycerol-treated sperm motility. In addition, phosphorylation of protein associated with motility initiation also occurred in glycerol-treated sperm, suggesting that the glycerol treatment induces activation of PKA without an increase in [cAMP]i. Taken together, it can be concluded that organic alcohol, glycerol and erythritol induce phosphorylation for motility initiation, bypassing the increase in [cAMP]i as a result of a decrease in extracellular K+ concentration.

Requirement of Ca2+ on activation of sperm motility in euryhaline tilapia Oreochromis mossambicus.

Euryhaline tilapia Oreochromis mossambicus acclimates to the external spawning environment by modulating its mechanism for regulating sperm motility. Adaptation of sperm was performed by acclimating fish in various environments. In this paper, regulatory mechanisms of freshwater-acclimated tilapia were studied in detail. Tilapia sperm motility was vigorous in hypotonic conditions and decreased with increasing osmolality. Sperm motility was reduced in hypotonic conditions when extracellular Ca(2+) was chelated; however, extracellular Ca(2+) was not a major factor for motility activation since sperm were motile even when extracellular Ca(2+) levels were nominally depleted by EGTA. The Ca(2+) indicator, fluo 3, showed that intracellular [Ca(2+)] increased on motility activation independently of extracellular [Ca(2+)], accompanied by swelling of the sperm neck region called the sleeve structure. Intracellular [Ca(2+)] was not increased under hypertonic conditions, in which sperm were immotile, even on addition of extracellular Ca(2+). It is possible that Ca(2+) is stored in the neck region. Demembranated sperm were reactivated in the presence of Ca(2+), but cAMP failed to reactivate the motility. Furthermore, we detected phosphorylation and dephosphorylation of three proteins at serine and threonine residues on motility activation. It is likely that hypotonic shock causes an increase in intracellular [Ca(2+)] that activates motility activation via phosphorylation of some flagellar proteins.

Different mutation status of the beta-catenin gene in carcinogen-induced colon, brain, and oral tumors in rats.

Mutations in the region corresponding to the N-terminal phosphorylation sites (codons 1-51) of the rat beta-catenin gene (Ctnnb1) were investigated in rat colon tumors induced by 1-hydroxyanthraquinone (1-HA) plus methylazoxymethanol (MAM) acetate, by using polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis. The beta-catenin gene was also screened for mutations in rat brain and oral tumors induced by ethyl nitrosourea (ENU) and 4-nitroquinoline 1-oxide (4-NQO), respectively. In colon tumors, beta-catenin gene mutations were found in two of three adenomas (67%) and 26 of 28 adenocarcinomas (93%), with a total incidence of 90% (28 of 31 adenomas plus adenocarcinomas). Eight (29%) were (34)G-->T (second position), eight (29%) were (32)G-->A (first position), five (18%) were (34)G-->A (first position), five (18%) were (41)C-->T (second position), one (4%) was (34)G-->A (second position), and one (4%) was (32)A-->G (second position), mutations, resulting in the substitutions of Gly(34)-->Val, Asp(32)-->Asn, Gly(34)-->Arg, Thr(41)-->Ile, Gly(34)-->Glu, and Asp(32)-->Gly, respectively. The (34)G-->T (second position) mutations found in this study were unique compared to those found in other carcinogen-induced rat colon carcinogenesis models. In contrast, beta-catenin gene mutations were not found in either the brain or oral tumors. These results suggest that mutations in the beta-catenin gene in rat tumors occur in specific tissues or organ sites and in a carcinogen-specific manner. Thus, the mutation spectrum in the beta-catenin gene is organ- and chemical carcinogen-specific.

Bioresorbable devices made of forged composites of hydroxyapatite (HA) particles and poly L-lactide (PLLA). Part II: practical properties of miniscrews and miniplates.

Miniscrews and miniplates made of forged composites composed of raw hydroxyapatite (u-HA) particles (particle size 0.2-20 microm, averaging 3.0 microm, Ca/p = 1.69 and containing CO3(2-)) and a poly L-lactide (PLLA, Mv: about 180 kDa, containing residual 0.05 wt% lactide) with osteological bioactivity such as direct bonding to bone and osteoconductivity, total resorbability and radiopacity were examined for various mechanical properties in order to evaluate their usefulness for cranio-, oral and maxillo-facial as well as plastic and reconstructive surgeries with PLLA-only or titanium devices. The composites containing u-HA particles at 30wt% for miniscrews and 40wt% for miniplates were selected based on total mechanical strengths and bioactivity, respectively. It was found that the composite devices generally had slightly different mechanical properties than forged PLLA-only devices of which strengths are ranked the highest among the reinforced PLLA-only ones that having been used in many clinical cases to date, in spite of their approximate 2 or 3 times lower absolute strengths than those of titanium ones. However, a remarkable distinction that makes the composite miniplates stand above the titanium ones was confirmed on their fatigue resistance to alternate bendings such that they retained 70% of their initial strength even after 60 times without revealing any damage, whereas the metallic devices fully broke off at only 8 times. This behavior was similar to that of forged PLLA-only devices but is unique as composites made of organic polymers divided by inorganic particles. In addition, profile plates such as L-, T-, X, T, C-, Mesh-, Box-, and Barhole types which were processed by forging twice exhibited nearly directional isotropy in strength and could be deformed in situ at ordinary temperatures to adjust their shapes along the surface undulations of the skull, mandible, maxilla, zygomatic bone and the like without thermoforming and did not return to their original shapes inside an alive body due to the high PLLA's Tg (65 degrees C) over an alive body temperature (37 degrees C). Since it had already been confirmed in previous papers that these stiff and tough composites have the osteological bioactivity which is missing from both PLLA-only and titanium ones, and radiopacity which is wanting in PLLA-only ones, these various small and thin screws and plates have conclusively less objectionable practicality for use in oral-maxillo and craniofacial as well as plastic and reconstructive surgeries.

Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma.

Retinoids induce apoptosis and differentiation of hepatocellular carcinoma (HCC) cells and are used clinically in the chemoprevention of HCC. We have shown previously that hepatocarcinogenesis is accompanied by accumulation of full-length retinoid X receptor alpha (RXRalpha), although the underlying mechanisms and biological implications have remained unclear. The present studies were based on the finding that the accumulated full-length RXRalpha was phosphorylated at serine/threonine residues both in all human HCC tissues examined and in human HCC-derived HuH7 cells. Phosphorylation at serine 260 of RXRalpha, a consensus site of mitogen-activated protein kinase, was closely linked to its retarded degradation, low transactivating activity, and the promotion of cancer cell growth. There was no genomic mutation in the RXRalpha gene, and abrogation of phosphorylation by mitogen-activated protein kinase-specific inhibitors restored the degradation of RXRalpha in an RXR ligand-dependent manner. These results suggest that phosphorylation of RXRalpha may interfere with its metabolism and signaling in human HCC, which could lead to growth promotion of these tumors.

Apoptosis induction by acyclic retinoid: a molecular basis of 'clonal deletion' therapy for hepatocellular carcinoma.

We have shown previously that administration of acyclic retinoid to cirrhotic patients who had undergone curative treatment of preceding hepatocellular carcinoma (HCC) induced the disappearance of serum lectin-reactive alpha-fetoprotein (AFP-L3) and subsequently reduced the incidence of second liver cancers. AFP-L3 is a tumor marker that indicates the presence of occult tumors below the detection limit by diagnostic images. Therefore, we have proposed a new concept of 'clonal deletion' therapy with acyclic retinoid for the cancer chemoprevention against HCC. Such eradication of AFP-L3-producing latent malignant (or premalignant) cells from the liver suggested a new strategy to prevent HCC, which may be involved in the same category as cancer chemotherapy. In the present series of studies, we explored the molecular mechanism of 'clonal deletion' and found a novel mechanism of apoptosis induction by the retinoid. We have demonstrated a modification of a retinoid receptor, RXRalpha, by mitogen-activated protein (MAP) kinase-dependent phosphorylation, resulting in the loss of transactivating activity. This may lead HCC cells to be resistant to natural retinoic acid. However, acyclic retinoid restored the function of phosphorylated RXRalpha and induced its downstream pro-apoptotic genes including tissue transglutaminase, an enzyme that is implicated in apoptosis. Tissue transglutaminase-dependent apoptosis in HCC cells was independent of the activation of caspases. This novel mechanism of retinoid-induced apoptosis may give a clue to understand the molecular mechanism of clonal deletion.

A comparison of vibration magnitudes on the tool with different subject according to the ISO 8662-7 standard.

Recently, ISO has defined the guidelines for the evaluation of the measurement and exposure limits of hand-transmitted vibrations at the handle of hand-held portable power tools. In a measurement of vibrations at pneumatic impact wrenches that tighten and remove screws. ISO 8862-7 standard: 1997 and ISO 5349 standard: 1986 are set as international standards. In order to make an exact measurement of the quantities of vibrations exposed to the hand-arm system of a human body, ISO 8662-7 gives specifications to a measurement device and a loading device. As to a measurement device, for instance, the mass, installation method etc. of transducers and mechanical filters are defined. In addition, it specifies with each tolerance the working conditions of a pneumatic tool, the number of revolutions of socket in a loading device, the feed force, the number of subjects, and such an evaluation method as how to decide a declaration value of vibrations. These specifications give toolmakers a comparative measurement of vibration values of their tools before shipment. Meanwhile, although the measurement condition described in ISO8662-7: 1997 is that skilled operators conduct vibration measurement, no provisions as to operators are made in detail. Hence, this study focuses its concern on ambiguous work experience years in measuring vibrations of the tools in conformity with ISO 8662-7, and hereby the effect of years of work experience upon measurement values is considered and at the same time a knowledge of how to select operators is made clear.