Impact of the 2017 revised Japanese obstetric hemorrhage management guidelines on tranexamic acid use in patients undergoing cesarean delivery: an interrupted time series analysis.

BACKGROUND: Tranexamic acid is one component of a complex management algorithm for postpartum hemorrhage. In Japan, the 2010 obstetric hemorrhage management guidelines was revised in 2017, adding the recommendation for the administration of tranexamic acid for postpartum hemorrhage. This research aims to delineate the temporal trends in tranexamic acid administration in patients undergoing cesarean deliveries and to examine the impact of the obstetric hemorrhage management guidelines implementation. METHODS: An interrupted time series analysis was conducted on data from patients who underwent cesarean deliveries from April 2012 to August 2021, sourced from Japan's nationwide health insurance claims database. We examined the trends of tranexamic acid usage and blood transfusion use before and after the implementation of the revised guidelines in 2017. RESULTS: The study cohort comprised 91 166 cesarean deliveries. Prior to the guideline implementation, the rate of tranexamic acid usage decreased. Post-guidelines implementation, there was a statistically significant increase in the rate of tranexamic acid use, with a quarterly percentage change of 0.48% (95% confidence interval: 0.36 to 0.60; P < 0.001). The guidelines implementation in 2017 was not significantly associated with a change in the rate of transfusions. CONCLUSIONS: This interrupted time series analysis demonstrated a significant increase in the rate of tranexamic acid administration following the implementation of the revised guidelines, reversing the previously observed downward trend. Our findings could reflect the impact of the revised guideline on the use of tranexamic acid for postpartum hemorrhage, but this did not translate to fewer blood transfusions.

Cyclic ADP-ribose in insulin secretion from pancreatic beta cells.

Inositol 1,4,5-trisphosphate (IP3) is thought to be a second messenger for intracellular calcium mobilization. However, in a cell-free system of islet microsomes, cyclic adenosine diphosphate-ribose (cADP-ribose), a nicotinamide adenine dinucleotide (NAD+) metabolite, but not IP3, induced calcium release. In digitonin-permeabilized islets, cADP-ribose and calcium, but not IP3, induced insulin secretion. Islet microsomes released calcium when combined with the extract from intact islets that had been incubated with high concentrations of glucose. Sequential additions of cADP-ribose inhibited the calcium release response to extracts from islets treated with high concentrations of glucose. Conversely, repeated additions of the islet extract inhibited the calcium release response to a subsequent addition of cADP-ribose. These results suggest that cADP-ribose is a mediator of calcium release from islet microsomes and may be generated in islets by glucose stimulation, serving as a second messenger for calcium mobilization in the endoplasmic reticulum.

Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice.

Vascular complications arising from multiple environmental and genetic factors are responsible for many of the disabilities and short life expectancy associated with diabetes mellitus. Here we provide the first direct in vivo evidence that interactions between advanced glycation end products (AGEs; nonenzymatically glycosylated protein derivatives formed during prolonged hyperglycemic exposure) and their receptor, RAGE, lead to diabetic vascular derangement. We created transgenic mice that overexpress human RAGE in vascular cells and crossbred them with another transgenic line that develops insulin-dependent diabetes shortly after birth. The resultant double transgenic mice exhibited increased hemoglobin A(1c) and serum AGE levels, as did the diabetic controls. The double transgenic mice demonstrated enlargement of the kidney, glomerular hypertrophy, increased albuminuria, mesangial expansion, advanced glomerulosclerosis, and increased serum creatinine compared with diabetic littermates lacking the RAGE transgene. To our knowledge, the development of this double transgenic mouse provides the first animal model that exhibits the renal changes seen in humans. Furthermore, the phenotypes of advanced diabetic nephropathy were prevented by administering an AGE inhibitor, (+/-)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195), thus establishing the AGE-RAGE system as a promising target for overcoming this aspect of diabetic pathogenesis.

Loss of Lewis antigen expression on erythrocytes in some cancer patients with high serum CA19-9 levels.

The Lewis (Le) phenotype of both erythrocytes and sera and serum CA19-9 levels were studied in 49 patients with pancreatic carcinoma, in 37 with gastric cancer, in 22 with colorectal cancer, in 21 with bile duct carcinoma, and in 19 with hepatocellular carcinoma. The Le phenotype was determined in sera with the use of the dot-immunobinding assay and on erythrocytes. The localizations of the Le antigen and CA19-9 were studied in pancreatic tissues from 22 patients with pancreatic carcinoma. The prevalence of Le(a-,b-) on erythrocytes was significantly higher in patients with pancreatic carcinoma than in normal controls. Nineteen of 21 patients with pancreatic carcinoma, whose Le phenotype on erythrocytes was Le(a-,b-), had Le antigen in tissues and sera, and they had a raised serum CA19-9 level. The remaining 2 patients were of the Le(a-,b-) phenotype for both erythrocytes and sera, and their serum CA19-9 levels were below 6 U/ml. Neither Le antigen nor CA19-9 could be localized in tissues of these 2 patients. Two patients with gastric cancer, 6 with colorectal cancer, and 6 with bile duct carcinoma had Le antigen in sera in spite of having Le(a-,b-) on erythrocytes. These results indicate that the Le phenotype on erythrocytes can undergo a change not infrequently in patients with pancreatic carcinoma as well as in patients with other gastrointestinal cancers, but patients with the Le(a-,b-) phenotype in sera cannot synthesize CA19-19.

Cloning and structural determination of human peptide YY cDNA and gene.

We have isolated two kinds of cDNAs and the gene encoding human peptide YY and determined their nucleotide sequences. The human peptide YY gene is composed of four exons and three introns spanning approx. 1.2 kbp. Two mRNA species are generated from the gene by alternative splicing of the third intron.

The primary structure of rat rig/ribosomal protein S15 gene.

We have isolated rat rig/ribosomal protein S15 gene from a DNA library derived from a rat insulinoma and determined the complete nucleotide sequence. The rat rig/S15 gene is composed of four exons and three introns spanning 2 kbp and exhibits distinctive structural features unique for a ribosomal protein gene.

Cloning and characterization of cDNA encoding rat ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase (homologue to human CD38) from islets of Langerhans.

We report the cloning and cDNA sequence of rat CD38, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase. Rat CD38 is composed of 303 amino acids and shares a high degree of homology with human and mouse CD38. Rat CD38 mRNA is expressed in various tissues including pancreatic islets but not in RINm5F cells.

Characterization of the 5'-regulatory region of rat Reg I gene.

We report here the characterization of the 5'-regulatory region of rat Reg I gene encoding a growth stimulating factor for pancreatic beta-cells. Transient expression assays of the 5'-flanking region/luciferase fusion gene in AR4-2J cells showed that the -304/-237 region contained positive cis-acting elements. Gel shift assays using AR4-2J and rat pancreas nuclear extracts showed the formation of a specific complex with the -256/-237 oligonucleotide.

Isolation, structural determination and expression of a novel reg gene, human regI beta.

We have isolated a novel human gene and cDNA encoding a member of the regI proteins, regI beta. The gene encodes a 166-amino acid protein which has 22 amino acid substitutions in comparison with the previously isolated human reg protein, regI alpha. RegI beta was expressed only in pancreas, whereas regI alpha was expressed in kidney and stomach as well as in pancreas.

Structure determination and evolution of the chicken cDNA and gene encoding prepropancreatic polypeptide.

We have previously demonstrated that the C-terminal regions of the rat and human pancreatic polypeptide (PPP) precursors exhibit a high degree of divergence, whereas the N-terminal regions are highly conserved. This blend of structural conservation and divergence in the precursors appears to be caused by splice junction sliding and translational frameshift in the 3'-region of the PPP gene [Yonekura et al., J. Biol. Chem. 263 (1988) 2990-2997]. In the present study, we determined the nucleotide (nt) sequences of the chicken PPP (cPPP) cDNA and gene, and compared them with those of the mammals. In cPPP, the C-terminal region of the precursor is quite heterologous with respect to the rat (rPPP) and human (hPPP) precursors, and this heterogeneity is accentuated by the large deletion in exon 3 of cPPP. Furthermore, mutational accumulation during evolution caused the structural organization of the 3'-region of cPPP to change; cPPP is terminated in exon 3, whereas rPPP and hPPP are terminated in exon 4. Thus, our previous observation regarding the possibility of 'mosaic evolution' [Yamamoto et al., J. Biol. Chem. 261 (1986) 6156-6159] of PPP has been extended and confirmed by this study. Available evidence suggests that 'mosaic evolution' is a phenomenon unique to PPP, and not to the genes encoding the other members of the PPP family, neuropeptide-Y and peptide-YY.

Cloning of a cDNA encoding rat bone marrow stromal cell antigen 1 (BST-1) from the islets of Langerhans.

We have isolated the rat bone marrow stromal cell antigen 1-encoding cDNA (BST-1) from a pancreatic islet cDNA library. The cDNA encodes a 319-amino-acid (aa) protein whose aa sequence shows homology with mammalian CD38 (33%), Aplysia ADP-ribosyl cyclases (33%), as well as mouse (86%) and human (72%) BST-1.

Structure and expression of a novel rat RegIII gene.

We have isolated a rat cDNA and a novel gene, Reg (regeneration-promoting gene). The cDNA encodes a 174-amino-acid (aa) RegIII protein with a 25-aa signal peptide. The RegIII gene spans 2.7 kb and consists of six exons and five introns. RegIII was expressed in regenerating pancreatic islets, but not in normal islets.

Sequence of the chicken rig gene encoding ribosomal protein S15.

The nucleotide sequence of the chicken rig gene encoding ribosomal protein S15 was determined. The 1.6-kb gene consists of four exons and three introns. The 5'-flanking region of the gene lacks TATA- or CAAT-box sequences. Several GC-box sequences were found around the transcription start point.

The structure of the Aplysia kurodai gene encoding ADP-ribosyl cyclase, a second-messenger enzyme.

The complete nucleotide (nt) sequences of the cDNA and gene encoding the marine mollusk Aplysia kurodai (Ak) ADP-ribosyl cyclase (ADRC) which synthesizes cyclic ADP-ribose (cADP-ribose), a second messenger for Ca2+ mobilization from endoplasmic reticulum, were determined. Ak ADRC consists of 258 amino acids (aa) (29 kDa). It shares 86% aa sequence homology with that from A. californica, and 31-32% homology with the human, rat and mouse cluster of differentiation 38 (CD38) that has both ADRC and cADP-ribose hydrolase activities. The Ak ADRC-encoding gene (ADRC) spans approx. 7 kb and contains eight exons and seven introns. The transcription start point (tsp) determined by primer extension analysis and S1 mapping is 28 bp downstream from the TATA box. This gene is expressed specifically in the ovotestis, although the mammalian CD38-encoding gene is expressed in many kinds of tissues and cells. The 5'-flanking region contains several consensus sequences responsible for the germ-cell-specific expression of the mouse zona pellucida 3 (ZP3) and Drosophila melanogaster chorion genes. The existence of the consensus sequences located at nt -1649, -1161, -234 and -90 may account for the ovotestis-specific expression of the Ak ADRC gene.

Structure, chromosomal localization and expression of mouse genes encoding type III Reg, RegIII alpha, RegIII beta, RegIII gamma.

Reg (regenerating gene), first isolated from a rat regenerating islet cDNA library, is expressed in regenerating islet beta-cells. Recently, it has been revealed that Reg and Reg-related genes constitute a multigene family, Reg family, which consists of three subtypes (type I, II, III) based on the primary structures of the encoded proteins of the genes. In mouse, type I and type II Reg genes (i.e. RegI and RegII gene) have so far been isolated. In the present study, the complete nucleotide (nt) sequences of the cDNAs and genes encoding murine type III Reg (regenerating gene product), RegIII alpha, RegIII beta and RegIII gamma were determined. RegIII alpha, RegIII beta and RegIII gamma encode 175-, 175- and 174-amino acid (aa) proteins, respectively, with 60-70% homology. All three genes are composed of six exons and five introns spanning approx. 3 kb, and exhibit distinctive structural features unique for members of the Reg gene family. All the mouse Reg genes, RegIII alpha, RegIII beta, RegIII gamma, RegI and RegII, are assigned to the adjacent site of chromosome 6C by fluorescence in situ hybridization (FISH). RegIII alpha, RegIII beta and RegIII gamma were expressed weakly in pancreas, strongly in intestinal tract, but not in hyperplastic islets, whereas both RegI and RegII were expressed in hyperplastic islets. These results suggest that genes of the mouse Reg family are derived from a common ancestor gene by several gene duplications, and have obtained divergency in expression and function in the process of genetic evolution.

Human gene encoding CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase): organization, nucleotide sequence and alternative splicing.

We have recently demonstrated that cyclic ADP-ribose (cADPR) serves as a second messenger for glucose-induced insulin secretion [Takasawa et al. (1993a) Science 259, 370-373] and that CD38 has both ADP-ribosyl cyclase (ADRC) and cADPR hydrolase activities [Takasawa et al. (1993b) J. Biol. Chem. 268, 26052-26054]. In this study, we determined the structure of the human CD38 gene, and showed that two mRNA forms originated by alternative splicing from the CD38 gene. The human CD38 gene consists of 8 exons that extend more than 77 kb on the human genome. Exon 1 encoded the 5'-untranslated region of the mRNA, the N-terminal end of CD38 and the putative transmembrane domain, and exon 2-8 encoded the remainder of CD38: the exon-intron organization of the human CD38 gene is similar to that of the Aplysia ADRC gene [Nata et al. (1995) Gene 158, 213-218]. This structural conservation between human and Aplysia genes suggests that both genes may have evolved from a common ancestral gene.

Isolation and functional expression of pituitary peptidylglycine alpha-amidating enzyme mRNA. A variant lacking the transmembrane domain.

We demonstrate that, in rat pituitary, peptidylglycine alpha-amidating enzyme was encoded by at least 5 distinct mRNAs. Southern blot and ribonuclease protection analyses revealed that the mRNAs arose through alternative splicing. A variant lacking the transmembrane domain-coding sequence was a major mRNA species for the enzyme in the pituitary. When the cDNAs were expressed in COS-7 cells, the variant was the most efficient in producing a secretory form (37 kDA) of the enzyme.

Structural determination of Saccharomyces cerevisiae rig gene and identification of its product as ribosomal protein S21.

rig was originally isolated from a rat insulinoma-derived cDNA library. The 145 amino acid sequence of the rig protein is invariant in mammalian cDNAs. In this paper, we have isolated the cDNA and genomic clones for yeast (Saccharomyces cerevisiae) rig, determined their nucleotide sequences, and identified the gene product. The gene and the mRNA encode a basic protein of 142 amino acids which has 61.3% amino acid identity with mammalian rig protein. On two-dimensional gel electrophoresis, the in vitro transcription/translation product of yeast rig cDNA co-migrated with yeast ribosomal protein S21. These results led to the conclusion that yeast rig ribosomal protein S21 and to the determination of the previously unknown primary structure of yeast S21 protein. Unlike most ribosomal protein genes of S. cerevisiae, the gene exists as a single copy in a haploid set of the yeast genome and has no intron, locating at chromosome VII or XV.

Structural determination and characterization of a 40 kDa protein isolated from rat 40 S ribosomal subunit.

We have purified a 40 kDa protein from the rat 40 S ribosomal subunit and determined its primary structure by amino acid and cDNA sequencing. The amino acid sequence of the 40 kDa protein shared 29-37% homology with prokaryotic ribosomal protein S2 of eubacteria and chloroplasts, indicating that the protein is a eukaryotic counterpart to prokaryotic S2. Moreover, the amino acid sequence shared 99% identity with those deduced from cDNAs for 68 kDa laminin binding proteins of human, murine and bovine origins. The cDNAs are capable of encoding polypeptides with predicted molecular mass of 33,000 which lacked typical signal sequences, N-linked glycosylation sites and putative transmembrane domains. These results indicate that the cDNAs for 68 kDa laminin binding proteins actually code for the 40 kDa ribosomal protein.

Human REG family genes are tandemly ordered in a 95-kilobase region of chromosome 2p12.

Reg, first isolated from a rat regenerating islet cDNA library, is expressed in regenerating islet beta-cells. Recently, it has been revealed that Reg and Reg-related genes constitute a multigene family, the Reg family. In human, the four REG family genes, i.e., REG 1 alpha, REG 1 beta, REG-related sequence (RS) and HIP/PAP, have so far been isolated. In this study, we analyzed YAC clones containing the four genes and performed two-color FISH to determine the map order of the genes. The human REG family genes are tandemly ordered in the 95-kbp DNA region of chromosome 2p12 as follows: 2cen-HIP/PAP-RS-REG I alpha-REG I beta-ptel.