ITPA genetic variants influence efficacy of PEG-IFN/RBV therapy in older patients infected with HCV genotype 1 and favourable IL28B type.

Inosine triphosphatase (ITPA) genetic variants are strongly associated with ribavirin (RBV)-induced anaemia during pegylated interferon (PEG-IFN) plus RBV therapy. However, the treatment efficacy of ITPA genetic variants has not been fully explored. We enrolled 309 individuals infected with hepatitis C virus genotype 1, who were treated with PEG-IFN plus RBV for 48 weeks. The ITPA SNP: rs1127354 and IL28B SNP: rs8099917 were genotyped. We examined the risk factors for severe anaemia up to week 12 after the start of treatment and treatment efficacy. The incidence of severe anaemia, ≥ 3 g/dL reduction or <10 g/dL of haemoglobin (Hb) up to week 12, was more frequent in patients with CC at rs1127354 [65% (145/224), 33% (73/224)] than in those with CA/AA [25% (21/85), 6% (8/85)] (P < 0.0001). ITPA genotype, pretreatment Hb level and age were independent predictive factors for severe anaemia: Hb < 10 g/dL. In IL28B favourable type, the sustained virologic response rate was higher in ≥ 60-year-old patients with CA/AA than in those with CC [71% (22/31) vs 40% (26/65), P = 0.005], although there was no significant difference in treatment efficacy according to ITPA genetic variants in the <60-year-old patients. The proportion of patients administered ≥ 80% of the dosage of RBV was significantly higher in the patients with CA/AA than in those with CC (P = 0.025), resulting in a lower relapse rate. In conclusion, ITPA genetic variants were associated with severe RBV-induced anaemia and could influence the efficacy of PEG-IFN plus RBV treatment among elderly patients with IL28B favourable type.

Mechanism of the dependence of hepatitis B virus genotype G on co-infection with other genotypes for viral replication.

Hepatitis B virus (HBV) is classified into several genotypes. Genotype G (HBV/G) is characterised by worldwide dispersion, low intragenotypic diversity and a peculiar sequence of the precore and core region (stop codon and 36-nucleotide insertion). As a rule, HBV/G is detected in co-infection with another genotype, most frequently HBV/A2. In a previous in vivo study, viral replication of HBV/G was significantly enhanced by co-infection with HBV/A2. However, the mechanism by which co-infection with HBV/A2 enhances HBV/G replication is not fully understood. In this study, we employed 1.24-fold HBV/A2 clones that selectively expressed each viral protein and revealed that the core protein expressing construct significantly enhanced the replication of HBV/G in Huh7 cells. The introduction of the HBV/A2 core promoter or core protein or both genomic regions into the HBV/G genome showed that both the core promoter and core protein are required for efficient HBV/G replication. The effect of genotype on the interaction between foreign core protein and HBV/G showed that HBV/A2 was the strongest enhancer of HBV/G replication. Furthermore, Western blot analysis of Dane particles isolated from cultures of Huh7 cells co-transfected by HBV/G and a cytomegalovirus (CMV) promoter-driven HBV/A2 core protein expression construct indicated that HBV/G employed HBV/A2 core protein during particle assembly. In conclusion, HBV/G could take advantage of core proteins from other genotypes during co-infection to replicate efficiently and to effectively package HBV DNA into virions.

Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels.

BACKGROUND/AIM: To examine the risks for hepatocellular carcinoma (HCC) with respect to hepatitis B virus (HBV) genotypes, specific viral mutations (MT), serum HBV DNA levels, and cirrhosis. METHODS: HBV genotypes, 1653/1753/core promoter (CP)/precore MT and HBV DNA levels were determined in 248 HBV patients with HCC and 248 HBV controls. RESULTS: Genotype C, CP-MT, T1653, HBV DNA levels >or=4 log(10) copies/ml and cirrhosis had a higher risk for HCC compared to patients with genotype B (p = 0.001, OR 1.9), CP wild-type (WT) (p<0.001, OR 4.1), C1653 (p = 0.028, OR 2.4), HBV DNA <4 log(10) copies/ml (p = 0.003, OR 2.1) and without cirrhosis (p<0.001, OR 4.0) respectively. Multivariate analysis showed that CP-MT, T1653, HBV DNA >or=4 log(10) copies/ml and cirrhosis were independent factors for HCC (all p<0.05). A receiver operating characteristics curve showed no cut-off HBV DNA level associated with minimal chance of HCC. Patients with CP-MT and cirrhosis had a 22.2-fold increased risk of HCC compared to patients with CP-WT and without cirrhosis. Patients with CP-MT and HBV DNA levels >or=4 log(10) copies/ml had a 7.2-fold increased risk of HCC compared to patients with CP-WT and HBV DNA levels <4 log(10) copies/ml. Patients with CP-MT and T1653 had a 9.9-fold increased risk of HCC compared to patients with wild-type for both regions. CONCLUSIONS: CP-MT, T1653, HBV DNA levels >or=4 log(10) copies/ml and cirrhosis are independent factors for development of HCC. The risks increased substantially in patients having these factors in combination.

Predictive role of serum HBsAg and HBcrAg kinetics in patients with HBeAg-negative chronic hepatitis B receiving pegylated interferon-based therapy.

OBJECTIVES: To investigate the role of serum hepatitis B core-related antigen (HBcrAg) kinetics in predicting long-term outcome of pegylated interferon (PEG-IFN)-based therapy in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). METHODS: A total of 121 Thai patients with HBeAg-negative CHB recruited from a previous randomized trial of 48-week PEG-IFN alone or combined with entecavir were enrolled. Hepatitis B surface antigen (HBsAg) and HBcrAg levels were serially examined. Paired biopsy samples taken at baseline and after treatment were assessed for intrahepatic covalently closed circular DNA (cccDNA). RESULTS: Persistent virologic remission (PVR, defined by persistent hepatitis B virus (HBV) DNA <2000 IU/mL) and HBsAg clearance at 3 years after treatment were 29% (35/121) and 9% (11/121) respectively. Baseline HBcrAg correlated with HBV DNA and cccDNA but not with HBsAg. Baseline HBsAg, as well as HBsAg and HBcrAg, declines were associated with PVR, while HBsAg decline was predictive of HBsAg clearance. High baseline antigen levels (HBsAg ≥3.4 log10 IU/mL plus HBcrAg ≥3.7 log10 U/mL) yielded high negative predictive values of PVR (45/50, 90%) and HBsAg clearance (50/50, 100%). At week 12, declines of HBsAg, HBcrAg and both antigens combined of <0.5 log10 yielded negative predictive values for PVR of 90% (71/79), 82% (61/74) and 96% (48/50) respectively. CONCLUSIONS: Quantitative HBcrAg was significantly associated with cccDNA in HBeAg-negative CHB. This novel antigen, together with HBsAg, could identify patients with low probability of PVR and HBsAg clearance in long-term follow-up.

The propensity to malignancy of dispermic heterozygous moles.

Complete hydatidiform moles may originate from either the fertilization of an empty egg by a haploid sperm followed by duplication (producing a monospermic, homozygous mole) or the fertilization of such an egg by two haploid sperms (producing a dispermic, heterozygous mole). This difference in the mechanism leading to the formation of complete moles raises the question of whether the risk of subsequent malignancy is influenced by the zygosity of the mole. We have compared the incidence of postmolar sequelae in patients with homozygous and heterozygous moles. Using chromosomal heteromorphisms, human lymphocyte antigen (HLA) and phosphoglucuromutase 1 (PGM1) polymorphisms, we established the androgenetic origin of complete mole in 84 of 91 cases. Homozygosity was confirmed in 51 moles, and we found ten heterozygous moles. Five of ten patients with heterozygous moles developed postmolar trophoblastic disease, whereas only two of the 51 patients with homozygous moles had postmolar trophoblastic disease (an additional five patients showed signs of degenerating residual trophoblasts). The XY sex chromosome constitution of the two in vitro choriocarcinoma cell lines examined here provides further evidence of the propensity to malignancy of heterozygous moles.

Asymmetry in the nonmesonic weak decay of polarized (5)(Lambda)He hypernuclei

We have measured the asymmetric emission of protons from the nonmesonic decay of polarized (5)(Lambda)He produced by the (pi(+), K+) reaction. (5)(Lambda)He is an s-shell hypernucleus and its polarization is due to the Lambda. One expects to obtain direct information on the elementary weak Lambda-->p-->np process. The asymmetry parameter has been determined to be 0.24+/-0.22. The implication of the result is discussed.

Effects of the kappa-opioid dynorphin A(1-13) on learning and memory in mice.

The effects of intracerebroventricular administration of dynorphin A(1-13) on scopolamine- and pirenzepine-induced amnesia were investigated in mice by observing the step-down-type passive avoidance response and spontaneous alternation performance. The pre- or post-training, or preretention administration of dynorphin A(1-13) (0.3-10 micrograms) alone failed to affect the passive avoidance response, while scopolamine (1 mg/kg) significantly inhibited it. Dynorphin A(1-13) (1 microgram) given 15 min before training and retention tests, but not immediately after training, significantly improved the scopolamine (1 mg/kg)-induced impairment of passive avoidance response, indicating the anti-amnesic effects of dynorphin A(1-13). A lower dose (1 mg/kg) of the kappa-opioid receptor antagonist (-)-(1R,5R,9R)-5,9-diethyl-2-(3-furyl-methyl)-2'-hydroxy-6,7-benzomorpha n reversed the anti-amnesic effects of dynorphin A(1-13) (1 microgram). In contrast, although dynorphin A(1-13) (1, 3 and 10 micrograms) did not influence spontaneous alternation performance, scopolamine (1 mg/kg) and the muscarinic M1 receptor antagonist pirenzepine (3 micrograms) markedly decreased spontaneous alternation performance. Dynorphin A(1-13) (3, 5.6 and/or 10 micrograms) significantly improved the scopolamine (1 mg/kg)- and pirenzepine (3 micrograms)-induced impairment of spontaneous alternation performance. The improving effects of dynorphin A(1-13) (3 micrograms) were almost completely reversed by pretreatment with nor-binaltorphimine (4 micrograms), a kappa-selective opioid receptor antagonist. These results suggest that the stimulation of kappa-opioid receptors improves memory dysfunctions resulting from the blockade of muscarinic M1 receptors.

Substance P markedly ameliorates scopolamine-induced impairment of spontaneous alternation performance in the mouse.

We investigated the effects of intracerebroventricular injection of substance P (SP) on the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance in the mouse. SP (0.001-3 micrograms) alone did not influence either spontaneous alternation performance or total arm entries. Scopolamine (1 mg/kg) impaired spontaneous alternation performance accompanied by an increment in total arm entries. In contrast, SP (0.01-1 micrograms) significantly improved the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance without influencing the scopolamine (1 mg/kg)-induced increase in total arm entries. The effects of SP (0.1 micrograms) on the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance were almost completely reversed by pretreatment with WIN 62577 (1 mg/kg), a tachykinin NK-1 receptor antagonist. These results suggest that SP improves the scopolamine-induced impairment of spontaneous alternation performance through the mediation of tachykinin NK-1 receptors.

kappa-Opioid receptor agonists improve pirenzepine-induced disturbance of spontaneous alternation performance in the mouse.

We investigated the effects of kappa-opioid receptor agonists such as dynorphin A-(1-13) and U-50,488H on the muscarinic M1-selective receptor antagonist pirenzepine (3 micrograms, i.c.v.)-induced impairment of spontaneous alternation performance in the mouse. Although dynorphin A-(1-13)(1-5.6 micrograms, i.c.v.) or U-50,488H ((+/-)trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide, methanesulfonate hydrate) (0.1-1 mg/kg, i.p.) alone did not influence either spontaneous alternation performance or total arm entries, pirenzepine (3 micrograms, i.c.v.) impaired spontaneous alternation performance without producing any significant change in total arm entries. In contrast, dynorphin A-(1-13) (3 and 5.6 micrograms, i.c.v.) and U-50,488H (0.3 and 1 mg/kg, i.p.) ameliorated the pirenzepine (3 micrograms, i.c.v.)-induced impairment of spontaneous alternation performance. The ameliorating effects of dynorphin A-(1-13)(3 micrograms, i.c.v.) and U-50,488H (0.3 mg/kg, i.p.) were almost completely reversed by pretreatment with nor-binaltorphimine (4 micrograms, i.c.v.), a kappa-opioid receptor antagonist. These results suggest that the stimulation of kappa-opioid receptors improves memory dysfunctions resulting from the blockade of muscarinic M1 receptors.

Involvement of dopamine receptors in beneficial effects of tachykinins on scopolamine-induced impairment of alternation performance in mice.

The involvement of dopamine receptors in the beneficial effects of intracerebroventricular injection of substance P, neurokinin A and senktide on the scopolamine-induced impairment of spontaneous alternation performance was investigated in mice. Scopolamine (1 mg/kg) significantly impaired spontaneous alternation performance, while substance P (0.1 microg), neurokinin A (0.3 microg), senktide (0.003 microg) and S(-)-sulpiride (10 mg/kg), a dopamine D2 receptor antagonist, improved the scopolamine (1 mg/kg)-induced disturbance of spontaneous alternation performance. However, the dopamine D1 receptor antagonist SCH23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine maleate) did not influence the scopolamine-induced disturbance of spontaneous alternation performance. The dopamine D2 receptor agonist RU24213 (N-n-propyl-N-phenylethyl-p-(3-hydroxyphenyl)-ethylamine hydrochloride) (1 mg/kg) but not the dopamine D1 receptor agonist SKF38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepine hydrochloride) (3 and 10 mg/kg) reversed the beneficial effects of substance P (0.1 microg) and neurokinin A (0.3 microg) on the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance. In contrast, neither SKF38393 (3 and 10 mg/kg) nor RU24213 (0.3 and 1 mg/kg) significantly affected the beneficial effects of senktide (0.003 microg) on the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance. Although RU24213 (1 mg/kg) and SCH23390 (0.03 mg/kg) markedly decreased total arm entries, SKF38393 (10 mg/kg), RU24213 (1 mg/kg), SCH23390 (0.03 mg/kg) or S(-)-sulpiride (10 mg/kg) had no significant effects on spontaneous alternation performance. These results suggest that stimulation of dopamine D2 but not D1 receptors reverses the ameliorative effects of substance P and neurokinin A, whereas neither dopamine D1 nor D2 receptors play an important role in the beneficial effects of senktide on the scopolamine-induced impairment of spontaneous alternation performance associated with spatial working memory.

Dynorphin A-(1-13) potently improves scopolamine-induced impairment of passive avoidance response in mice.

The effects of intracerebroventricular administration of dynorphin A-(1-13) on scopolamine-induced amnesia were investigated in mice by using a step-down type passive avoidance task. The pre- or post-training, or pre-retention administration of dynorphin A-(1-13)(0.3-10 micrograms) alone failed to affect step-down latency of the passive avoidance response, while scopolamine (1 mg/kg) significantly shortened step-down latency. Dynorphin A-(1-13)(1 microgram) given 15 min before training and retention tests but not immediately after training significantly improved the scopolamine (1 mg/kg)-induced shortening of step-down latency of the passive avoidance response, indicating antiamnesic effects of dynorphin A-(1-13) (1 microgram). A lower dose (1 mg/kg) of the kappa-opioid receptor antagonist, (-)-(1R,5R,9R)-5,9-diethyl-2-(3-furyl-methyl)- 2'-hydroxy-6,7-benzomorphan, reversed the anti-amnesic effects of dynorphin A-(1-13) (1 microgram). These results suggest that the antiamnesic effects of dynorphin A-(1-13) depend on the timing of drug treatments.

Attenuation of memory with Tyr-D-Arg-Phe-beta-Ala-NH2, a novel dermorphin analog with high affinity for mu-opioid receptors.

The involvement of mu-opioid receptors in memory retrieval was examined in mice by using Tyr-D-Arg-Phe-beta-Ala-NH2 (TAPA), a novel dermorphin analog with high affinity for mu-opioid receptors, and passive avoidance learning. TAPA was intracerebroventricularly administered to mice before retention tests of passive avoidance learning. A 0.3-ng dose of TAPA markedly shortened step-down latency of passive avoidance learning, and the shortening of step-down latency was reversed by treatment with beta-funaltrexamine (5 micrograms), a mu-opioid receptor antagonist, indicating that TAPA (0.3 ng) attenuates memory retrieval. Although the attenuating dose (0.3 ng) of TAPA failed to affect horizontal or vertical locomotor activity, a 3-ng dose of TAPA showed a tendency to decrease vertical locomotor activity. A 30-ng dose of TAPA produced a significant increase in horizontal locomotor activity accompanied by a marked reduction of vertical locomotor activity. TAPA (3 ng) produced a significant increase in step-down latency of passive avoidance learning with lower intensity of electroshock or without electroshock during training. These results suggest that the activation of mu-opioid receptors impairs memory retrieval.

Tocolytic effects of a long-acting beta2-adrenoceptor agonist, formoterol, in rats.

We have assessed the tocolytic activity of formoterol, a novel long-acting and potent beta2-adrenoceptor agonist, through its production of cyclic adenosine monophosphate, in comparison with ritodrine, a beta2-adrenoceptor agonist used clinically to counter premature delivery. Formoterol and ritodrine inhibited the amplitude and frequency of rat uterine contraction, with IC50 values of 3.8 x 10(-10) and 4.7 x 10(-7) M, respectively. Intravenous administration of formoterol or ritodrine caused inhibition of uterine motility and increased heart rate in a dose-dependent manner. Inhibition of uterine motility by oral administration of formoterol (0.3 and 1 mg kg(-1)) continued for at least 60 min, whereas that with ritodrine (100 mg kg(-1)) persisted for 15 min with rapid recovery thereafter in pregnant rats. The beta-adrenoceptor binding of [125I]iodopindolol to the myometrium of pregnant rats was competitive with formoterol and ritodrine, with Ki values of 0.04 and 6.10 nM, respectively. Formoterol (10(-6)-10(-4) M) and ritodrine (10(-6)-10(-4) M) increased the level of cyclic adenosine monophosphate in lymphocytes in a dose-dependent manner. The results suggested that formoterol caused relaxation of uterine motility through production of cyclic adenosine monophosphate. Thus, formoterol may be useful as a treatment to counter premature delivery.

Tocolytic activity of formoterol against premature delivery in mice.

The tocolytic activity of formoterol (eformoterol), a long-acting potent beta(2)-adrenoceptor agonist, was assessed in pregnant mice, with determination of uterine effects on the 15th and 16th days of gestation. For examination in the lipopolysaccharide-induced premature delivery model, osmotic pumps filled with formoterol or saline solution were implanted subcutaneously under the back skin. The mice were sacrificed 18-20 h thereafter, and the numbers of fetuses in the uteri and the newborn were counted. The uteri, amniotic membranes and placenta were also rapidly removed for determination of IL-6 concentrations. Furthermore, the effect of formoterol on IL-6 secretion from mouse amnion cells was determined. Formoterol and ritodrine inhibited contraction responses of isolated mouse uteri and their intravenous administration resulted in lowered uterine motility. Lipopolysaccharide (30 microg mL(-1)/mouse) induced premature delivery, attributable to increased IL-6 secretion, and formoterol suppressed this. Doses of 5-500 microg/mouse thus reduced the number of prematurely delivered newborn, and 50 microg/mouse also depressed IL-6 secretion. On histopathologic analysis, the marked oedema and slight haemorrhage in the mouse cervix induced by lipopolysaccharide were reduced by administration of the beta(2)-adrenoceptor agonist. Neither formoterol (10(-7)-10(-5) M) nor ritodrine (10(-7)-10(-5) M) influenced spontaneous secretion of IL-6 in amnion cells. However, at 10(-7) and 10(-5) M, and 10(-6) and 10(-5) M, respectively, they inhibited lipopolysaccharide-induced IL-6 secretion and this inhibitory effect was competitively reversed by addition of ICI-118,551 (beta(2)-adrenoceptor antagonist), but not atenolol (beta(1)-adrenoceptor antagonist). These findings strongly suggest that formoterol can suppress premature delivery mediated by its actions on IL-6 secretion.

Ameliorative effects of tachykinins on scopolamine-induced impairment of spontaneous alternation performance in mice.

The present study was designed to clarify whether opioid neuronal systems are involved in the beneficial effects of tachykinins such as the neurokinin NK1 receptor agonist, substance P (SP), the neurokinin NK2 receptor agonist, neurokinin A (NKA), and the neurokinin NK3 receptor agonist, senktide, on the scopolamine-induced impairment of spontaneous alternation performance in mice. Intracerebroventricular injections of SP (0.1 microgram), NKA (0.3 microgram) and senktide (3 ng) inhibited the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance without influencing total arm entries, indicating the antiamnesic effects of tachykinins. Furthermore, the inhibitory effects of SP, but not those of NKA or senktide, were almost completely reversed by pretreatment with naloxone (1 mg/kg). However, the effects of SP on the scopolamine-induced impairment of spontaneous alternation performance were not influenced by pretreatment with the mu-opioid receptor antagonist, beta-funaltrexamine (5 micrograms), the delta-opioid receptor antagonist, naltrindole (4 ng), and the kappa-opioid receptor antagonist, nor-binaltorphimine (4 micrograms). These findings suggest that the effects of SP, unlike those of NKA or senktide, on the scopolamine-induced impairment of spontaneous alternation performance associated with spatial working memory are not mediated simply via a single type of opioid receptors, such as mu, delta or kappa.

[Clinical evaluation of imipenem/cilastatin sodium in gynecological infection].

The MK-0787/MK-0791 is a combination of imipenem (a carbapenem antibiotic) and cilastatin sodium (a dehydro peptidase-I inhibitor) in a 1 to 1 ratio, which produces a higher urinary recovery of imipenem than imipenem alone. The MK-0787/MK-0791 was used in 8 female patients with intrapelvic infections. Clinical efficacies were very good in all the patients. There were neither subjective nor objective side effects nor abnormal laboratory findings.

Neurokinin A and senktide attenuate scopolamine-induced impairment of spontaneous alternation performance in mice.

The effects of intracerebroventricular injections of the neurokinin-2 (NK-2) receptor agonist neurokinin A and the neurokinin-3 (NK-3) receptor agonist senktide on scopolamine (sc)-induced amnesia were investigated based on spontaneous alternation performance in mice. Spontaneous alternation performance is based on spatial working memory which produces a natural tendency to explore a less recently visited arm in a Y-maze. Neurokinin A (0.1-3 micrograms) or senktide (0.0003-0.03 microgram) alone did not influence either spontaneous alternation performance or total arm entries. However, neurokinin A (0.3 and 1 microgram) and senktide (0.003 and 0.03 microgram) inhibited the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance without affecting the scopolamine (1 mg/kg)-induced increase in total arm entries. Although the effects of neurokinin A (0.3 microgram) on the scopolamine-induced impairment of spontaneous alternation performance were almost completely antagonized by pretreatment with the NK-2 receptor antagonist cyclo (Gln-Trp-Phe-Gly-Leu-Met) (1 microgram), the inhibitory effects of senktide (0.003 microgram) were not influenced by pretreatment with the NK-3 receptor antagonist [Trp7, beta-Ala8]neurokinin A-(4-10). These findings suggest that neurokinin A inhibits the scopolamine-induced impairment of spontaneous alternation performance associated with working memory through the mediation of tachykinin NK-2 receptors, while senktide has some pharmacological action other than its effects on NK-3 receptors.

[Studies on HLA specificities in molar conceptions].

Complete mole is a form of natural allograft since it carries paternal genetic traits alone which differ antigenetically from those of the mother. Successful growth of mole is likely to be immunologically protected. Because the immune system is genetically controlled, the effect of HLA system on the development of androgenetic ova into moles is a subject of interest. In this study, HLA-A and -B specificities in the mole and its parent were compared with the ones of general population in Japan. Fifty-six molar tissues were used for absorption of HLA specificities determined by HLA typing of each patient and her husband. Results obtained were as follows. 1) HLA antigens were expressed on all molar tissues examined, and those antigen were derived selectively from paternal specificities, but not maternal one. 2) Fifty molar tissues had received the paternal haplotype and remaining six molar tissues had showed heterozygosity which were consistent with the paternal diplotype. Those suggested the fertilization of an empty egg by two spermatozoa. 3) A significant association was found with decreased frequency of HLA-Aw19 and HLA-Bw22 in the molar tissues (3.6% and 2.7%) compared with general population (16.4% and 11.5%). 4) The compatibility of HLA-A and -B types among moles with sequelae and the parents was higher(81%) than the estimated value(68%) in the control families. As a result, HLA analysis was useful for distinction of zygosity of molar tissues. Decreased frequencies of HLA-Aw19 and -Bw22 in the mole were assumed to be resulted from the wastage of androgenetic ova.(ABSTRACT TRUNCATED AT 250 WORDS)

[Establishment and characterization of the cell line derived from low differentiated adenocarcinoma of the endometrium].

A new human carcinoma cell line (HEC-1), which was derived from low differentiated adenocarcinoma of the endometrium, has been established. Cells from tumor tissues grown in athymic mice were cultured in minimal essential medium supplemented with 20% fetal calf serum. Contaminated mouse fibroblasts were removed from the culture by the absorption of anti-mouse serum. Continuous cell growth (doubling time: 51.6 hrs) could be observed during 64 passages. The cultured cells appeared monolayer and the cellular arrangement was a pavement-like pattern. The morphology of cells was analogous to the one of adenocarcinoma cells. The modal number of chromosomes of the original tumor cells were 46. The t. dic (1; 16)(p21; q24) marker which had been identified as the clonal abnormality in the original tumor cells, was also observed consistently in cultured cells, though the loss of chromosome 19 was disappeared during the passage. This suggested that the rearrangements of the long arm of chromosome 1 played an important role for the endometrial carcinogenesis.

[The age incidence of spontaneous abortion].

A series of studies on the age incidence of spontaneous abortion was conducted. The results of the studies is summarized as follows: A total of 16,179 deliveries accompanied by 1,537 cases of spontaneous abortion in 5 hospitals was investigated. The ratio (spontaneous abortion/deliveries) was 0.095 (1,537/16,179) in all age groups, 0.197 (15/76) in the under 20 years age group, 0.089 (215/2,422) in 20-24 years age group, 0.083 (705/8,478) in 25-29 years age group, 0.090 (404/4,496) in 30-34 years age group, 0.232 (149/641) in 35-39 years age group, 0.650 (39/60) in 40-44 years age group and 1.169 (7/6) in the over 45 years age group. The ratio in the under 20 years age group was higher than the ratio in 20-34 years age group (P less than 0.05). The ratio in the over 35 years age group was higher than the ratio in 20-24 years age group (P less than 0.001). This results indicated that spontaneous abortions depended on the maternal age. Deliveries in 20-34 years old occupied 95.2% of all 16,179 deliveries and the incidence of spontaneous abortions in 20-34 age group was stable. It is suggested, that the spontaneous abortion is natural selection in the mother's body and nature protects the older mother's body from deliveries and child-rearing.