Magnesium sulphate and perinatal mortality and morbidity in very-low-birthweight infants born between 24 and 32 weeks of gestation in Japan.

OBJECTIVE: Maternal exposure to magnesium sulphate has a neuroprotective effect in premature infants. This study aimed to examine this neuroprotective effect and the dose-response relationship in very-low-birthweight infants born between 24 and 32 weeks of gestation. STUDY DESIGN: A retrospective cohort study compared the rates of mortality and brain damage between three groups: no magnesium sulphate, low-dose (<50g) magnesium sulphate and high-dose (≥50g) magnesium sulphate. RESULTS: Japanese maternal and neonatal databases were linked using six key parameters from 2003 to 2007. Of 298,514 deliveries, 9101 were very-low-birthweight infants. Among these, full matching was possible for 5562 infants. Of the fully-matched infants, 3763 were born between 24 and 32 weeks of gestation, and 1813 (48%) were followed-up beyond 18 months. A multivariate analysis of the data, including gestational age, sex, fetal growth restriction, antenatal steroids and low pH (<7.1), showed that the low-dose group had no beneficial effects in terms of a reduction in mortality or incidence of brain damage (cerebral palsy or mental retardation). The high-dose group showed a significantly higher mortality rate [odds ratio (OR) 1.9, 95% confidence interval (CI) 1.2-2.9]. A stratified subgroup analysis of infants born between 28 and 32 weeks of gestation showed that survivors in the low-dose group had significantly lower rates of cerebral palsy (OR 0.4, 95% CI 0.2-0.98) and brain damage (OR 0.2, 95% CI 0.1-0.9), while the high-dose group did not show any significant changes. CONCLUSION: This study found that antepartum exposure to magnesium sulphate did not reduce the infant mortality rate or influence neurological outcomes. However, among infants born between 28 and 32 weeks of gestation, rates of cerebral palsy and brain damage were found to be significantly lower among survivors in the low-dose group.

Maternal IgG avidity, IgM and ultrasound abnormalities: combined method to detect congenital cytomegalovirus infection with sequelae.

OBJECTIVE: We used maternal immunoglobulin M (IgM), immunoglobulin G (IgG) avidity index (AI) and fetal ultrasonography (US) to effectively detect a congenital cytomegalovirus-infected fetus that would suffer neurological sequelae after birth. STUDY DESIGN: The detecting method was prospectively adapted to 1163 unselected pregnant women. IgM, IgG and IgG-AI were measured at the first prenatal examination (10.8±2.2 weeks of gestation). Advanced US was performed for the IgM-positive women at our center. The urine of 1163 neonates was examined via PCR. All infected neonates were followed for neurological development. RESULT: Most women (83.3%) were seropositive. Among them, 40 (4.1%) were IgM positive. Nine of forty (22.5%) had low AI, of which one showed abnormal US and suffered severe sequelae. The remaining eight had a normal US; however, one infant had hearing impairment. There were another three infected infants with normal development. Their mothers' serological results were: IgM positive with high AI (n=1); IgG positive; IgM negative with high AI (n=1); and both IgG and IgM negative (n=1). CONCLUSION: This method enabled us to detect infected fetuses having severe sequelae. However, the problem remains of detecting infected fetuses that only have a hearing impairment.

Paediatric presentation and outcome of congenital protein C deficiency in Japan.

Severe heritable protein C (PC) deficiency is quite rare, although heterozygous PROC mutation is the second leading cause of genetic predisposition to thrombosis in Japanese adults. The aim of the study was to search the optimal management, the paediatric onset and outcomes of PC deficiency were characterized in Japan. The genetic study, postmarketing survey of activated PC(aPC) concentrate (Anact(®)C) and intensive review in Japan for 20 years enabled the analysis of the disease onset, genotype, treatment and prognosis. Symptomatic PC deficiency was determined in 27 Japanese children. All but two patients presented within 16 days after birth (three prenatal and six neonatal onsets). Postnatal-onset cases had normal growth at full-term delivery. Of the 27 patients, 19 suffered intracranial thrombosis or haemorrhage (ICTH) (three foetal hydrocephalies), 16 developed purpura fulminans (PF) and 10 had both at the first presentation. ICTH preceded PF in both affected cases. Low PC activities of 18 mothers and/or 12 fathers indicated 20 inherited PC deficiencies (2 homozygotes, 11 compound heterozygotes and 7 heterozygotes) and seven unidentified causes of PC deficiency. Nine of 11 patients studied had PROC mutations. Four unrelated patients (50%) carried PC nagoya (1362delG). No PC-deficient parents had experienced thromboembolism. Of the 18 patients with aPC therapy, two died and eight evaluable survivors had neurological sequelae. This first comprehensive study of paediatric PC deficiency suggested that perinatal ICTH was the major presentation, occurring earlier than neonatal PF. PC nagoya was prevalent in paediatric, but not adult, patients in Japan. Early maternal screening and optimal PC therapy are required for newborns at risk of PC deficiency.

Associations of intrauterine growth restriction with placental pathological factors, maternal factors and fetal factors; clinicopathological findings of 257 Japanese cases.

Intrauterine growth restriction (IUGR) is the leading cause of fetal mortality and morbidity. As an etiology, each of placental findings, maternal factors and fetal factors has been reported to be associated with IUGR, although a comprehensive approach to examine all of these parameters as a cause of IUGR has not been reported. In the present study, therefore, we comprehensively examined the placental findings and maternal and fetal factors in the cases of IUGR (n=257, mean maternal age, 30 years; gestational weeks, 34 weeks) and normal growth pregnancies (n=258, mean maternal age, 30 years; gestational weeks, 33 weeks), and determined risk factors for IUGR. The prevalence of pregnancy hypertension (PHT) (19% vs. 8%, P<0.01), smoking habit (3% vs. 0.7%, P<0.05) and fetal anomaly (3.5% vs. 0.8%, P<0.05) were higher in IUGR cases than normal growth pregnancies. Pathologically, the prevalence of infarction (33% vs. 14%, P<0.05), fetal vessel thrombosis (22% vs. 6%, P<0.001) and chronic villitis (11% vs. 3%, P<0.001) were higher in IUGR cases than those in normal growth pregnancies. A multivariable regression analysis revealed that maternal factors (PHT), fetal factors (anomaly), and placental findings (infarction, fetal vessel thrombosis, and chronic villitis) are independently associated with increased risk of IUGR (all P<0.01).

A mathematical model for predicting outcome in preterm labour.

OBJECTIVE: This study aimed to develop a model for predicting the outcome and evaluating the treatment of patients with threatened of preterm labour. METHODS: Clinical data from 236 patients at <32 weeks gestation who were in preterm labour were analysed to develop a discriminant function using multiple logistic regression to identify significant risk factors. The function was validated retrospectively in a further 501 patients and prospectively in 63 patients with premature labour. RESULTS: Factors that increased the risk of preterm birth were premature rupture of the membranes, intrauterine infection, dilatation of the cervix and uterine bleeding. Factors that decreased the risk of preterm birth were hospital admission after 28 weeks of gestation and intravenous administration of ritodrine. The predictive accuracy of the function was 75.4% in the 236 patients analysed, 84.8% in the further 501 retrospectively studied patients and 85.7% in the prospective group. CONCLUSIONS: The discriminant function described was clinically useful for predicting the outcome of threatened preterm labour before initiating treatment and for determining the medical care of patients, including maternal transfer to a high-level perinatal care centre.

Characteristics of the spin-trapping reaction of a free radical derived from AAPH: further development of the ORAC-ESR assay.

The characteristics of the spin-trapping reaction in the oxygen radical absorbance capacity (ORAC)-electron spin resonance (ESR) assay were examined, focusing on the kind of spin traps. 2,2-Azobis(2-amidinopropane) dihydrochloride (AAPH) was used as a free radical initiator. The spin adducts of the AAPH-derived free radical were assigned as those of the alkoxyl radical, RO· (R=H(2)N(HN)C-C(CH(3))(2)). Among the spin traps tested, 5,5-dimethyl-1-pyrroline N-oxide (DMPO), 5,5-dimethyl-4-phenyl-1-pyrroline N-oxide (4PDMPO), 5-(2,2-dimethyl-1,3-propoxycyclophosphoryl)-5-methyl-1-pyrroline N-oxide (CYPMPO), and 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DEPMPO) were applicable to the ORAC-ESR assay. Optimal formation of spin-trapped radical adduct was observed with 1 mM AAPH, 10 mM spin trap, and 5 s UV irradiation. The calibration curve (the Stern-Volmer's plot) for each spin trap showed good linearity, and their slopes, k (SB)/k (ST), were estimated to be 87.7±2.3, 267±15, 228±9, and 213±16 for DMPO, 4PDMPO, CYPMPO, and DEPMPO, respectively. Though the k (SB)/k (ST) values for selected biosubstances varied with various spin traps, their ratios to Trolox (the relative ORAC values) were almost the same for all spin traps tested. The ORAC-ESR assay also had a very good reproducibility. The ORAC-ESR assay was conducted under stoichiometric experimental conditions. The present results demonstrate the superiority of the ORAC-ESR assay.

Population-based study of asymptomatic infection with Chlamydia trachomatis among female and male students.

There are few epidemiological studies of asymptomatic chlamydial infection among students in non-medical settings with minimal bias and improved accuracy; thus, useful data from screening among students are limited. We aimed to obtain accurate epidemiological information about asymptomatic chlamydial infection among students in non-medical settings. A population-based cross-sectional survey of 10,440 >or=18-year-old asymptomatic students who volunteered for a urine screening test for chlamydia was conducted. The prevalences of asymptomatic infection were 9.5% for women and 6.7% for men. Multivariate analysis revealed the risk factors to be a lifetime history of >or=4 sexual partners for women (odds ratio [OR] 3.17) and inconsistent condom use for men (OR 4.18). For both sexes, younger age at first intercourse was associated with a higher rate of inconsistent condom use. This study produced accurate epidemiological information on asymptomatic chlamydial infection. These results may contribute to the establishment of preventive countermeasures against such infection.

Absence of tyrosine kinase mutations in Japanese colorectal cancer patients.

Tyrosine kinases, which are important regulators of intracellular signal-transduction pathways, have mutated forms that are often associated with oncogenesis and are attractive targets for therapeutic intervention. Recently, systematic mutational analyses of tyrosine kinases revealed that a minimum of 30% of colorectal cancer contain at least one mutation in the tyrosine kinases. To further explore these mutations, we examined all reported mutations of NTRK3, FES, KDR, EPHA3, NTRK2, JAK1, PDGFRA, EPHA7, EPHA8, ERBB4, FGFR1, MLK4 and GUCY2F genes in the 24 colorectal cancer cell lines. Unexpectedly, among 24 colorectal cancer cell lines, only two cell lines (LoVo and CaR1) harbored mutation C1408T (R470C) in MLK4 gene. The mutation rate was extremely low compared to that previously reported. Therefore, we analyzed mutations in 46 colorectal cancer samples resected from the same number of Japanese patients. Surprisingly, none of the 46 samples contained any of the mutations reported. Based on our study, we advise that a more comprehensive tyrosine kinase gene mutation assay is necessary in the future.

Absence of PIK3CA hotspot mutations in hepatocellular carcinoma in Japanese patients.

A recent study revealed that the p110alpha (PIK3CA), catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is somatically mutated in many types of cancer. For example, PIK3CA is mutated in an estimated 35.6% of hepatocellular carcinoma (HCC) cases. To measure the frequency of PIK3CA hotspot mutations in Japanese HCC patients, exons 9 and 20 of the PIK3CA gene were sequenced in 47 clinical HCC samples. Contrary to expectations, no hotspot mutations were found any of the HCC samples. In addition, we found abnormally migrating waves near the end of exon 9 in the PCR chromatograms from 13 of the 47 samples. PCR amplification and subsequent cloning and sequencing revealed that these chromatograms contained two distinct sequences, the wild-type p110alpha sequence and a different sequence found on human chromosome 22q11.2, the Cat Eye Syndrome region, which contains a putative pseudogene of PIK3CA. These abnormally migrating waves were also found in noncancerous liver tissue, indicating that this was not a result of HCC-associated mutations. Therefore, it is likely that the percentage of hotspot mutations in the PIK3CA gene of Japanese HCC patients is lower than was previously reported.

The hepatitis B virus X protein enhances AP-1 activation through interaction with Jab1.

Hepatitis B virus X protein (HBx) has many cellular functions and is a major factor in hepatitis and hepatocellular carcinoma caused by HBV infection. A proteomic approach was used to search for HBx-interacting proteins in order to elucidate the molecular mechanism of hepatocarcinogenesis. HBx was attached to myc and flag tags (MEF tags) and expressed in 293T cells; the protein complex formed within the cells was purified and characterized by mass spectrometry. COP9 signalosome (CSN) subunits 3 and 4 were subsequently identified as HBx-interacting proteins. In addition, CSN subunit 5, Jun activation domain-binding protein 1 (Jab1), was shown to be a novel cellular target of HBx. In vivo and in vitro interactions between HBx and Jab1 were confirmed by standard immunoprecipitation and GST pull-down assays. An analysis of HBx deletion constructs showed that amino acids 30-125 of HBx were responsible for binding to Jab1. Confocal laser microscopy demonstrated that HBx was mainly localized in the cytoplasm, while Jab1 was found mainly in the nucleus and partially in the cytoplasm, and that the two proteins colocalized in the cytoplasm. The cotransfection of HBx and Jab1 resulted in substantial activator protein 1 (AP-1) activation and knockdown of endogenous Jab1 attenuated AP-1 activation caused by HBx. In addition, the coexpression of HBx and Jab1 potentiated phosphorylation of JNK, leading to the subsequent phosphorylation of c-Jun, whereas the level of c-Jun and JNK phosphorylation induced by HBx was decreased in Jab1 knockdown cells. These results suggest that the interaction between HBx and Jab1 enhances HBx-mediated AP-1 activation.

Association between endometriosis and genetic polymorphisms of the estradiol-synthesizing enzyme genes HSD17B1 and CYP19.

BACKGROUND: Endometriosis, an estrogen-dependent disease, is believed to be influenced by multiple genetic and environmental factors. Here, we evaluated whether the risk and severity of endometriosis are associated with polymorphisms in estradiol-synthesizing enzyme genes: the Ser312Gly polymorphism in 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) and the Arg264Cys polymorphism in cytochrome P450, subfamily XIX (CYP19). METHODS: All participants underwent diagnostic laparoscopy, and the stage of endometriosis was determined according to the Revised American Fertility Society classification. Of the 138 women enrolled, 59 had no endometriosis, 21 had stage I, 10 had stage II, 23 had stage III and 25 had stage IV. SNPs were discriminated by allele-specific oligonucleotide hybridization. RESULTS: Individuals having at least one A-allele (A/G or A/A genotype) of HSD17B1 showed a significantly increased risk of endometriosis (A/G genotype: adjusted OR, 3.06; 95%CI 1.21-7.74; A/A genotype: adjusted OR, 3.02; 95%CI 1.08-8.43). There was a significant trend associating A/G + A/A genotypes with severity of endometriosis (P for trend < 0.01). No statistically significant association was found for the CYP19 polymorphism. CONCLUSIONS: Evidence for association between the Ser312Gly polymorphism in HSD17B1 and endometriosis was found in a Japanese population. The A-allele of HSD17B1 appears to confer higher risk for endometriosis.

Fibroblasts from the inner granulation tissue of the pseudocapsule in hips at revision arthroplasty induce osteoclast differentiation, as do stromal cells.

BACKGROUND: It has previously been shown that many osteoclast precursors are included in the granulation tissue within the pseudocapsule obtained at revision arthroplasty from hips with osteolysis. In vitro culture of only cells isolated from the granulation tissue has been previously shown to generate many mature osteoclasts. OBJECTIVE: To investigate the presence or otherwise of supporting cells, similar to stromal cells, which differentiate osteoclasts within the granulation tissue. METHODS: Cells isolated from the granulation tissue were cultured alone, and after four weeks fibroblast-like cells (granulation fibroblasts) remained. Rat non-adherent bone marrow cells (NA-BMCs) were co-cultured with the granulation fibroblasts with or without 1alpha,25(OH)2D3 (10(-8) M) or heat treated ROS 17/2.8 cell conditioned medium (ht ROSCM), or both. Multinucleated cells (MNCs), which formed, were assessed by biochemical and functional characterisation of osteoclasts. Receptor activator of NFkappaB ligand (RANKL) was investigated by immunohistochemistry. RESULTS: Co-culture of NA-BMCs and granulation fibroblasts caused the formation of tartrate resistant acid phosphatase (TRAP) positive MNCs, which had the calcitonin receptor (CTR), the Kat-1 antigen, which is specific to the surface of rat osteoclasts, and the ability to form pits in the presence of both 1alpha,25(OH)2D3 and ht ROSCM or in the presence of just ht ROSCM. RANKL was detected in fibroblast-like cells in the granulation tissue. CONCLUSION: These data suggest that granulation fibroblasts support osteoclast differentiation, as do osteoblasts/stromal cells, and may play a part in aseptic loosening.

Altered expressions of glutamate transporter subtypes in rat model of neonatal cerebral hypoxia-ischemia.

Glutamate transporters are essential for maintaining the extracellular levels of glutamate at synaptic clefts and are regulated developmentally in a subtype-specific manner. We investigated chronological changes of immunoreactivities for glial glutamate transporters GLAST and GLT-1 and a neuronal glutamate transporter, EAAC1, in postnatal 7-day-old rat neocortices and hippocampi at 12, 24, 48 and 72 h after hypoxia-ischemia. Glutamate transporter subtypes are differentially expressed in the ischemic core and the boundary area of the neonatal rat brain with hypoxia-ischemia. Expressions of these glutamate transporters decreased in the ischemic core at 12 h, then immunoreactivities for GLAST and GLT-1 were recovered at the hippocampus. This was accompanied by a GFAP-positive gliosis at 72 h, whereas these immunoreactivities were reduced at the neocortex in the ischemic core. Glial glutamate transporters, especially GLAST, were noted in some astrocytes appearing as apoptosis as well as shrunken pyramidal neurons mainly in the boundary area of the neocortex. Increased perikaryal expression of EAAC1 was associated with that of MAP2 at the border of the boundary area. These temporal and regional expressions of glutamate transporters may contribute towards understanding the excitotoxic cell death mechanism in hypoxic-ischemic encephalopathy during the perinatal period.

Systematic analysis of the TGF-beta-Smad signaling pathway in gastrointestinal cancer cells.

The transforming growth factor-beta (TGF-beta)-Smad signaling pathway has an important role in carcinogenesis. To study the frequency and mechanism of functional impairment of this pathway in human gastrointestinal cancers, we used a reporter assay to examine the response of 38 cell lines (11 colorectal, 9 pancreatic, 10 gastric, and 8 hepatic cancers) to TGF-beta. We then analyzed TGF-beta type II receptor (T beta RII) gene, immunoblots of Smad4, and restoration of the pathway by rescuing T beta R or Smad. We observed impaired signaling in 91% of colorectal, 67% of pancreatic, and 40% of gastric cancer cell lines, but in none of the hepatic cancer cells. We suggest that this pathway does not function as a tumor suppressor in hepatic carcinogenesis. The impairment is due to inactivation of T beta RII and Smad4 in colorectal and pancreatic cancers. However, because the signal was not recovered by rescuing T beta R or Smad genes in TGF-beta-response-defective gastric cancer cell lines, we suggest that novel molecules or mechanisms are involved in the impaired pathway in some gastric cancers.

Insulin-meal interval and short-term glucose fluctuation in tightly controlled gestational diabetes mellitus.

OBJECTIVE: To study the effect of two insulin-meal intervals on short-term glucose fluctuations in tightly controlled gestational diabetes mellitus (GDM). METHODS: We performed a prospective and paired study in 11 Japanese GDM women requiring insulin for good glycemic control during the third trimester. The women were subjected to test two insulin-meal intervals: 15 min and 30 min. Both regimens were examined in each patient in random order, 2 days apart. Blood glucose was measured by an automated glucose monitor every 2 min. Short-term glucose fluctuations of the two observations were analyzed by two-way ANOVA for repeated measurements with a post hoc t test (p < 0.05). Data were expressed as mean +/- SD. RESULTS: Daily glucose profiles of the two groups showed that their glycemic controls on the days of observation were good and that the two glucose profile curves were superimposable. A transient decrease in glucose (nadir 62 +/- 6 mg/dl) was observed at 6-10 min of meal ingestion in the 30-min regimen, which was significantly different from the glucose fluctuations during the 15-min regimen. The 2-h postprandial glucose levels were similar in both experiments. CONCLUSIONS: In women with tightly controlled GDM during the third trimester, insulin-meal intervals of 15 min are beneficial when compared with 30-min intervals, in that they avoid preprandial hypoglycemia without increasing 2-h postprandial hyperglycemia.

Reduced C-terminal Src kinase activity is correlated inversely with pp60(c-src) activity in colorectal carcinoma.

BACKGROUND: Specific kinase activity of the proto-oncogene product pp60(c-src) is reported to be elevated in patients with carcinoma of the colon, and a novel cytoplasmic protein-tyrosine kinase, C-terminal Src kinase (Csk), has been found to inactivate the members of the Src family protein-tyrosine kinase. In this study, Csk activity and pp60(c-src) activity were examined in colorectal tumors as well as in colon carcinoma cell lines. METHODS: Colorectal carcinoma tissue and adjacent nonneoplastic tissue from 24 patients, from 8 colon carcinoma cell lines, and from 1 normal colon cell line were used. The levels of pp60(c-src) and Csk in colorectal tissue and cell lines were analyzed by Western and/or Northern blot analysis, and their kinase activity levels were measured by in-gel kinase assay. RESULTS: In the samples from 24 patients with colorectal carcinoma, pp60(c-src) kinase activity and protein levels were increased by 7.8 +/- 0.55 and 2.6 +/- 0.13 times the control levels, respectively. Conversely, the Csk protein level and its kinase activity were reduced by 0.53 +/- 0.08 and 0.53 +/- 0.09 times the control levels, respectively. pp60(c-src) kinase activity was correlated inversely with Csk activity (correlation coefficient = -0.71; P < 0.0001). Of the cell lines, pp60(c-src) kinase activity and protein levels, respectively, were 7.4 +/- 1.22 and 1.86 +/- 0.28 times greater than normal control levels. Csk protein level and kinase activity, respectively, were 0.54 +/- 0.13 and 0.52 +/- 0.11 times less normal control levels and were correlated with mRNA amount. CONCLUSIONS: Csk mRNA, protein, and its kinase activity were reduced in colorectal carcinoma and were correlated with pp60(c-src) kinase activity level. The reduced activity of Csk may be involved in the transformation of a subset of colorectal carcinoma.

Effects of actinomycin D on fetal growth in rats.

OBJECTIVE: The goal of this study was to determine the effects of actinomycin D on fetal growth and prostaglandin dehydrogenase activity and to determine whether these effects could be obtained by administering extracts of fetal calf serum (SS-094). METHODS: Actinomycin D (7 microg/100 g body weight) was injected intraperitoneally on days 11 and 12 of pregnancy to induce growth restriction in rats. In another group, SS-094 was given (0.1 ml/100 g body weight) on days 12, 15, 17 and 19 of pregnancy, following the administration of actinomycin D. Placental prostaglandin dehydrogenase (PGDH) activity was measured on days 15 and 21 of pregnancy. Statistical analysis was performed by ANOVA and Dunnet's test. RESULTS: In the group injected with actinomycin D, fetal weight was significantly restricted (on day 15; p < 0.05; on day 21; p < 0.01), compared to the controls, and this restriction was successfully reversed by SS-094. PGDH activity in the placenta was significantly (p < 0.01) decreased in growth-restricted rats and remained low even after fetal weight recovered. CONCLUSIONS: Growth restriction in pregnant rats was successfully induced by actinomycin D, and SS-094 reversed this restriction. It does not seem that prostaglandin metabolism in the placenta is responsible for growth restriction.

Frameshift mutations at mononucleotide repeats in RAD50 recombinational DNA repair gene in colorectal cancers with microsatellite instability.

To identify additional genes targeted for microsatellite instability (MSI), we search for human genes which contain mononucleotide repeats in their coding region, selected 7 genes (RAD50, DNA-PKcs, FLASH, Apaf-1, XPG, CtIP, and MLSN1), and analyzed frameshift mutations in them. Here we report that 60% (3 out of 5) of human colorectal cancer cell lines exhibiting a high frequency of MSI (MSI-H) and 46% (6 out of 13) of MSI-H primary colorectal tumors had mutations in the (A)9 repeat of RAD50 recombinational repair gene. In contrast, no frameshift mutations were found in any of the 5 MSI-negative colorectal cancer cell lines, 8 colorectal tumors exhibiting a low frequency of MSI (MSI-L), or 28 MSI-negative colorectal tumors. No mutations were found in the mononucleotide repeats of 6 other genes, even in MSI-H cancers. These results suggest that RAD50 frameshift mutations may play a role in the tumorigenesis of MSI-H colorectal cancers.

Diagnosis and management of acute obstetrical DIC.

UNLABELLED: Obstetrical disseminated intravascular coagulation (DIC) is usually a very acute, serious complication of pregnancy. The DIC diagnostic criteria in obstetrics (the obstetrical DIC score) help with making a prompt diagnosis and starting treatment early. These DIC diagnostic criteria, in which higher scores are given for clinical parameters than for laboratory parameters, have three components: (1) the underlying disease, (2) clinical symptoms, and (3) laboratory findings. It is justified that it is appropriate to initiate therapy for DIC when the obstetrical DIC score reaches 8 points or more before obtaining the results of coagulation tests. MANAGEMENT: (1) Control of the underlying disease: because prolongation of exposure to the triggering factors worsens DIC, it is important to eliminate the etiologic factors as rapidly as possible. Elimination of the cause of DIC can be easily performed in obstetrics, for example, by cesarean section. (2) Antithrombin (AT) therapy: AT monotherapy (1,500 to 3,000 units/day, 2 days) is preferably employed instead of heparin monotherapy or heparin-AT therapy because of the hemorrhagic side effects of heparin. (3) Synthetic serine protease inhibitors: continuous infusion ofgabexate mesilate (FOY) or nafamostat mesilate (FUT) is effective for DIC. Controlled multicenter trials showed a significant improvement not only in clinical response but also in platelet counts and prothrombin time (PT) in the AT group compared with the FOY group. (4) Activated protein C (APC) can inhibit thrombin generation and accelerate fibrinolytic activity. APC (5,000 to 10,000 units) is administered for 2 days in patients with placental abruption complicated by DIC. APC is a very safe, effective, and useful agent for the treatment of DIC.