Long-term outcomes of hemostatic therapy for variceal bleeding and the challenge pending in the post-direct-acting antivirals era.

Background and study aims: This study evaluated the longterm outcomes of mainly endoscopic hemostatic therapy for gastrointestinal variceal bleeding and of the transition of hemostatic therapy. Patients and methods: Among 1,163 patients treated for gastrointestinal varices between April 2006 and June 2020, a total of 125 patients who underwent emergency hemostatic therapy were enrolled. Survival rates and secondary evaluation points were analyzed. Additionally, patients were classified into two groups: the previous and latter term. Patients' background, therapeutic method, and treatment results were compared between the groups. Results: 94.4% had cirrhosis. The average Child-Pugh score was 8.90. Successful primary hemostasis rate was 98.4%, and 5.6% died within 2 weeks, all with a Child-Pugh score ≥9. The respective 1- and 5-year survival rates for Child-Pugh grade A/B were 81.3% and 55.4%, while those for Child-Pugh grade C were 58.1% and 17.8%. Child-Pugh grade C or hepatocellular carcinoma was significantly associated with poor prognosis. In total, 21.6% experienced variceal re-bleeding; 62.9% of these cases were triggered by continued alcohol consumption. There was no significant difference in survival between patients with and without variceal re-bleeding and in post-treatment survival between the previous and latter terms. In the latter term, the number of cases caused by continued alcohol consumption significantly increased. Conclusions: Multidisciplinary treatment and continuation of proper management after hemostatic therapy for variceal bleeding are crucial. Continued alcohol consumption leads to variceal bleeding and re-bleeding; its proper management, including alcohol abstinence, is one of the major challenges left in the post-directacting antivirals era.

Weight change after 20 years of age and the incidence of dyslipidemia: a cohort study of Japanese male workers.

BACKGROUND: While heavier weight is known to increase the incidence of dyslipidemia, limited data are available on the relationship between weight gain and its development. METHODS: A total of 2647 males were categorized into the following four groups according to the difference between their self-reported weight at 20 years of age and their measured weight in 1994-95: a loss of ≥5% (decrease), loss of <5% or gain of <5% (no change), gain of ≥5 to <15% (increase) and gain of ≥15% (sizable increase). They were followed up until their 2002-03 health examination. Using the 'no change' group as reference, the multivariable-adjusted odds ratio (adjusted for age, body mass index at 20 years of age, physical activity, smoking and alcohol intake) and 95% confidence interval (95% CI) for the incidence of dyslipidemia were determined using logistic regression models. RESULTS: A total of 1342 participants developed dyslipidemia during the follow-up period. The 'increase' and 'sizable increase' groups had odds ratios for the incidence of dyslipidemia of 1.97 (95% CI, 1.59-2.45) and 2.68 (2.15-3.34), respectively, demonstrating that there was a significant dose-response association between weight gain since 20 years of age and the incidence of dyslipidemia (P < 0.001 for trend). CONCLUSION: These results suggest that dyslipidemia could be prevented by avoiding weight gain in adulthood.

Impact of surgical menopause on lipid and bone metabolism.

OBJECTIVE: To clarify the effects of ovariectomy on lipid and bone metabolism. METHODS: This study was a prospective study with a longitudinal design within 1 year after surgery. Sixty-two premenopausal women were recruited and divided into two groups: group M (preservation of ovary, n=27) and group BSO (bilateral ovariectomy, n=35). Serum lipid levels, urinary N-telopeptide of type I collagen (NTx) and bone mineral density (BMD) were measured. We also examined the number of postoperative episodes requiring pharmacological intervention. RESULTS: There was a significant elevation in the level of low density lipoprotein cholesterol in group BSO from 6 to 12 months compared with the baseline level; the level did not change in group M. The NTx level significantly increased from 6 to 12 months, and the BMD was significantly decreased by as much as 6.7% at 12 months in group BSO; these variables did not change in group M. The effect of lipid and bone metabolism in group BSO was observed when the ages of the two groups were matched. Carbohydrate metabolism and arterial stiffness, measured by pulse wave velocity, did not change throughout the study period in either group. No subjects in group M required medication expect for two patients whose ovarian function was diminished by postoperative radiation and by natural menopause. Eleven women received medication in group BSO: nine for climacteric disorders using hormone therapy (25.7%), and two for dyslipidemia using statins (5.7%). CONCLUSIONS: Bilateral ovariectomy seems to cause dyslipidemia and serious loss of bone mineral density within only 1 year, and patients who lose ovarian function may require careful medical care.

One-year change in the second metacarpal bone mass associated with menopause nutrition and physical activity.

OBJECTIVES: To clarify the annual changes and effects of nutrition and physical activity on bone mass at the second metacarpal using computed X-ray densitometry. DESIGN: Population-based prospective follow-up study. MEASUREMENTS: Bone mass measurements and assessments of nutritional intake, exercise habits, and health status were conducted twice with a one-year interval. PARTICIPANT: 269 Japanese women aged 40 - to -80 - years old. RESULTS: The annual change rate among subjects who started menopause during the observation period was -4.2 +/- 4.9%. Bone mass subsequently continued to decrease 3% annually until 6 years after menopause. Subjects who consumed high levels of milk or calcium in the first year showed no substantial decrease in bone mass among the post-menopausal subjects. Premenopausal subjects who began or continued exercise evidenced increased bone mass, and peri-menopausal subjects who continued exercise or a high level of daily physical activity showed inhibited bone loss. CONCLUSION: Second metacarpal bone changed by menopause, nutrition and physical activity similar with other bone site presented in the previous studies.

Long-term forskolin stimulation induces AMPK activation and thereby enhances tight junction formation in human placental trophoblast BeWo cells.

BeWo cells, derived from human choriocarcinoma, have been known to respond to forskolin or cAMP analogues by differentiating into multinucleated cells- like syncytiotrophoblasts on the surfaces of chorionic villi of the human placenta. In this study, we demonstrated that long-term treatment with forskolin enhances the tight junction (TJ) formation in human placental BeWo cells. Interestingly, AMPK activation and phosphorylation of acetyl-CoA carboxylase (ACC), a molecule downstream from AMPK, were induced by long-term incubation (>12h) with forskolin, despite not being induced by acute stimulation with forskolin. In addition, co-incubation with an AMPK inhibitor, compound C, as well as overexpression of an AMPK dominant negative mutant inhibited forskolin-induced TJ formation. Thus, although the molecular mechanism underlying AMPK activation via the forskolin stimulation is unclear, the TJ formation induced by forskolin is likely to be mediated by the AMPK pathway. Taking into consideration that TJs are present in the normal human placenta, this mechanism may be important for forming the placental barrier system between the fetal and maternal circulations.

Physical activity level in healthy free-living Japanese estimated by doubly labelled water method and International Physical Activity Questionnaire.

OBJECTIVE: To measure total energy expenditure (TEE) for normal healthy Japanese by the doubly labelled water (DLW), and to compare the physical activity level (PAL) among categories classified by the categories used in daily reference intake (DRI), Japan and the International Physical Activity Questionnaire (IPAQ). SUBJECTS AND METHODS: A total of 150 healthy Japanese men and women aged 20- to 59-year-old living in four districts of Japan. TEE was measured by the DLW method, and the PAL was calculated from TEE divided by basal metabolic rate. Simultaneously with TEE measurement, the PAL was assessed employing the categories used in DRI, Japan and IPAQ. RESULTS: The average TEE and PAL were 10.78+/-1.67 MJ/day and 1.72+/-0.22 for males and 8.37+/-1.30 MJ/day and 1.72+/-0.27 for females, respectively. The subjects in the highly active categories assessed by both DRI and IPAQ showed significantly higher PAL compared with less active categories. However, PALs among light and moderate categories by DRI, and insufficient and sufficiently active by IPAQ were not significantly different. CONCLUSIONS: In developed countries, highly active subjects could be assessed by a simple questionnaire. However, the questionnaire should be improved to clarify the sedentary to moderately active subjects by assessing carefully very light to moderate physical activity.

Duodenal follicular lymphomas share common characteristics with mucosa-associated lymphoid tissue lymphomas.

BACKGROUND: Follicular lymphomas occasionally arise in the extra-nodal organs and are frequently found in the duodenum. They are often localised tumours with multiple polyps around the ampulla of Vater. AIMS: To examine a IgH/bcl-2 hybrid gene and VH gene to investigate the nature of the lymphoma cells and how they differ from nodal follicular lymphomas and MALT lymphomas. METHODS: Of 40 patients reported previously, 35 with duodenal follicular lymphoma were studied in detail with respect to clinicopathological characteristics. RESULTS: 37/40 patients were in clinical stage I (n = 30) or stage II (n = 7). Clonal immunoglobulin gene rearrangement was detected in 53.3% of examined cases, and rearrangement of IgH/bcl-2 gene at the major break point was detected in 27% of cases. Three of 8 examined cases were VH4 (38%); 2 out of them were VH4-34. As VH4 deviation is one of the common characteristics of MALT lymphomas and 2/3 were identical, duodenal follicular lymphomas have a similar aetiology to MALT lymphomas. Clinical course was also similar to that of MALT lymphomas. CONCLUSIONS: Results suggest that duodenal follicular lymphomas have intermediate characteristics of MALT lymphomas and nodal follicular lymphomas.

Relationship of lifestyle factors to bone mass in Japanese women.

BACKGROUND: Japanese women have a lower bone mass and smaller calcium intake than Caucasians. OBJECTIVE: To investigate the differences in the relationship between bone mass and lifestyle among Japanese women of different life stages. DESIGN: Cross-sectional and longitudinal investigations of the relationship between bone mass and lifestyle in Japanese women aged 15-69 years. RESULTS: In both cross-sectional and longitudinal investigations of high school students, exercise was shown to effectively increase bone mass. In the longitudinal investigation, bone mass was generally greater with high or increased milk consumption. In the cross-sectional investigation of nonparous women and women more than 36 months post partum, those who exercised had significantly higher bone mass. Twelve to 35 months post partum, bone mass was greater in women with higher calcium or milk intake. The effects of parity were not investigated longitudinally, but women who continuously exercised or started exercise had greater bone mass. Non-exercising women with a higher or increased frequency of intake of dairy products, small fish, and soy products had increased bone mass. The longitudinal investigations suggest that exercise increases bone mass in pre-menopausal women. In women just after menopause, it was shown cross-sectionally that bone mass was greater with a higher calcium intake, and longitudinally that exercise resulted in a slower decrease in bone mass. Among women more than 6-7 years past menopause, exercise inhibited the decrease in bone mass. CONCLUSION: The relationship between these lifestyle factors and bone mass differs according to pregnancy status and time since menopause.

Obesity, weight change and risks for hypertension, diabetes and hypercholesterolemia in Japanese men.

OBJECTIVE: To examine the effects of the degree of body mass index and weight gain as the risks for hypertension, hypercholesterolemia and diabetes in Japanese men, and to compare that to the corresponding effects in a Caucasian population. DESIGN: Prospective cohort study. SETTING: Cohort of all male employees at a company. SUBJECTS: A total of 4737 male employees followed until retirement or for 4 y (longest term 4 y). RESULTS: Increase of body mass index beyond 22 kg/m(2) related to an increased risk for hypertension even after being adjusted for possible confounding factors such as age, smoking status, alcohol intake, family history and baseline value of systolic blood pressure. The risks greatly increased in subjects with a body mass index above 27 kg/m(2) for hypertension, and 29 kg/m(2) for diabetes and hypercholesterolemia. Weight gain (more than 2 kg) was strongly related to an increased risk for hypertension and hypercholesterolemia after being adjusted for possible confounding factors. However, weight gain was not related to diabetes, and weight loss did not decrease the risks for any of the three diseases. CONCLUSIONS: Among Japanese, the degrees of body mass index associated with risks for hypertension, diabetes and hypercholesterolemia were lower than those in Caucasians. The risks for hypertension and hypercholesterolemia were strongly associated with weight gain in a Japanese male population who showed a low prevalence of severe obesity, and the risks were similar to or somewhat higher than those in a Caucasian population with a high prevalence of severe obesity. SPONSORSHIP: Health Science Research Grant by the Ministry of Health and Welfare of Japan.

N-methyl-D-aspartate receptor-dependent and -independent cytotoxic effects of Dictyostelium discoideum differentiation-inducing factor-1 on rat cortical neurons.

Differentiation-inducing factor-1 (DIF-1) is a chlorinated alkylphenone (small lipophilic hormone) that induces stalk cell formation in the cellular slime mold Dictyostelium discoideum. Recent studies have revealed that DIF-1 inhibits growth and induces the differentiation of mammalian tumor cells. The present study examines the effects of DIF-1 on rat cortical neurons in primary culture. We found that DIF-1 induced rapid neuronal cell death. The release of lactate dehydrogenase (LDH), as an indicator of cell death, increased dose-dependently with DIF-1. The release of LDH was inhibited by the N-methyl-D-aspartate (NMDA) receptor antagonists MK801 and AP5, suggesting that the NMDA receptor is involved in the induction of cell death by DIF-1. However, glutamate cytotoxicity could not explain the entire action of DIF-1 on neurons because the estimated concentration of glutamate around DIF-1-treated neurons was below 50 microM and DIF-1 caused more severe cell death than 500 microM glutamate. We discovered that another portion of DIF-1 cytotoxicity is independent of the NMDA receptor; that is, coaddition of DIF-1 and MK801 induced dendritic beading and increased expression of the immediate early genes c-fos and zif/268. These results indicate that DIF-1 induces rapid cell death via both NMDA receptor-dependent and -independent pathways in rat cortical neurons.

[Bowel perforation after extracorporeal shock wave lithotripsy: a case report].

A case of intestinal perforation caused by ESWL for left ureteral calculus is reported. A 69-year-old male underwent the graft replacement for bilateral iliac aneurysm in March, 1996. In February, 1999, there appeared left flank pain, and a diagnosis of left ureterolithiasis was made by radiological examination. On March 29 he was admitted to our department for ESWL. On March 30, ESWL for calculus in the pelvic region was performed with the patient in the prone position. The patient complained of the left lower abdominal pain immediately after ESWL, but no muscular defense was observed. Since the pain was not relieved, CT was performed on March 31, but no evident abnormal finding was found. Thereafter the pain continued and on April 2 muscular defense was also noted. On CT performed a second time, free air and evidence of ileus were found, so emergency operation was performed. Two perforations about 2 mm in size were found in the jejunum 130 cm from the Treitz' ligament, which led to diagnosis of intestinal perforation due to ESWL. The patient followed a satisfactory postoperative course and was discharged on April 23. There has been only one reported case of intestinal perforation due to ESWL. It is a very rare complication. However, this complication should be taken into consideration where the patient has the history of abdominal surgery and where ESWL was performed with the patient in the prone position.

Differential localization of prohormone convertases PC1 and PC2 in two distinct types of secretory granules in rat pituitary gonadotrophs.

Prohormone convertases PC1 and PC2 are endoproteases involved in prohormone cleavage at pairs of basic amino acids. There is a report that prohormone convertase exists in the rat anterior pituitary gonadotrophs, where it had previously been considered that proprotein processing does not take place. In addition to luteinizing hormone and follicle-stimulating hormone, rat pituitary gonadotrophs contain chromogranin A (CgA) and secretogranin II (SgII), two members of the family of granin proteins, which have proteolytic sites in their molecules. In the present study we examined whether there is a close correlation between subcellular localization of prohormone convertases and granin proteins. Ultrathin sections of rat anterior pituitary were immunolabeled with anti-PC1 or -PC2 antisera and then stained with immunogold. Immunogold particles for PC1 were exclusively found in large, lucent secretory granules, whereas those for PC2 were seen in both large, lucent and small, dense granules. The double-immunolabeling also demonstrated colocalization of PC2 and SgII in small, dense granules and of PC1, PC2, and CgA in large, lucent granules. These immunocytochemical results suggest that PC2 may be involved in the proteolytic processing of SgII and that both PC1 and PC2 may be necessary to process CgA.

Palmitoylation of the canine histamine H2 receptor occurs at Cys(305) and is important for cell surface targeting.

To determine the presence and functional role of the histamine H2 receptor (H2R) palmitoylation, a receptor with a Cys(305) to Ala (A(305) receptor) mutation was generated. Wild-type (WT) and A(305) receptors were tagged at their N-termini with a hemagglutinin (HA) epitope. WT, but not A(305), receptors incorporated [3H]palmitate by metabolic labeling, indicating that the H2R is palmitoylated at Cys(305). Immunocytochemistry of WT and A(305) receptors expressed in COS7 cells revealed WT receptors to be distributed at the plasma membrane, while the majority of A(305) receptors were localized intracellularly with only a small portion being at the plasma membrane. However, the affinity of the A(305) receptor for tiotidine was comparable to that of the WT receptor. In addition, when the amounts of cell surface receptors as determined by anti-HA antibody binding were equivalent, A(305) receptors mediated production of more cAMP than WT receptors. Preincubation of COS7 cells expressing each receptor with 10(-5) M histamine for 30 min reduced subsequent cAMP production in response to histamine via the receptors to similar extents, indicating that palmitoylation is not necessary for desensitization. In addition, cell surface A(305) receptors were capable of being internalized from the cell surface at a rate and extent similar to those of WT receptors. Finally, CHO cell lines stably expressing either WT or A(305) receptors were incubated with 10(-5) M histamine for 1, 6, 12 and 24 h. Total amounts of WT and A(305) receptors, as determined by tiotidine binding, were reduced by incubation, indicating downregulation. Downregulation of the A(305) receptor was more extensive than that of the WT receptor. Thus, palmitoylation of the H2R might be important for targeting to the cell surface and stability.

Release and aggregation of cytochrome c and alpha-synuclein are inhibited by the antiparkinsonian drugs, talipexole and pramipexole.

Recently, it has been shown that release of cytochrome c from the mitochondria to the cytosol is required for activation of the caspase-3-dependent cascade in apoptosis, and also for alpha-synuclein aggregation. In the present study, we examined the effects of talipexole and pramipexole on the release of cytochrome c and alpha-synuclein, their aggregations, and activation of caspases. Treatment of human neuroblastoma SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP(+), 1 mM) induced the first event, which was the release of cytochrome c from the organellar fraction to the cytosolic fraction, then came the DNA fragmentation, and caused the last event, which was the accumulation of alpha-synuclein protein in the cytosolic fraction. Talipexole and pramipexole at low concentration (0.1-1 mM) significantly inhibited the accumulation of cytochrome c or alpha-synuclein in the cytosolic fraction. These drugs at high concentration (3-10 mM) inhibited in vitro aggregation of cytochrome c by hydrogen peroxide or that of alpha-synuclein by cytochrome c and hydrogen peroxide. In addition, in vitro activation of caspase-3 induced by cytochrome c and/or dATP was also inhibited by drugs at high concentration (5-10 mM). These results suggest that talipexole and pramipexole may have protective effects against the neurodegeneration, which is induced by intracellular accumulation of cytochrome c and alpha-synuclein.

Molecular cloning and expression during development of the Drosophila gene for the catalytic subunit of DNA polymerase epsilon.

We have cloned the genomic DNA and cDNA of Drosophila DNA polymerase epsilon (pol-epsilon) catalytic subunit (GenBank No. AB035512). The gene is separated into four exons by three short introns, and the open reading frame consists of 6660 base pairs (bp) capable of encoding a polypeptide of 2220 amino acid residues. The calculated molecular mass is 255018, similar to that of mammalian and yeast homologues. The deduced amino acid sequence of the pol-epsilon catalytic subunit shares approximately 41% identity with human and mouse homologues as well as significant homology those of C. elegans, S. cerevisiae and S. pombe. Similar to the pol-epsilon catalytic subunits from other species, the pol-epsilon catalytic subunit contains domains for DNA polymerization and 3'-5' exonuclease in the N-terminal region, and two potential zinc-finger domains in the C-terminal regions. Interestingly, a 38 amino acid sequence in the C-terminal region from amino acid positions 1823 to 1861 is similar to the site for Mycoplasma ATP binding and/or ATPase domain (GenBank No. P47365). Northern hybridization analysis indicated that the gene is expressed at the highest levels in unfertilized eggs, followed by zero to 4h embryos and adult females, and then embryos at other embryonic stages, instar larva stages and adult males. Low levels of the mRNA were also detected at the pupa stage. This pattern of expression is similar to those of DNA replication-related enzymes such as DNA polymerase alpha and delta except for the high level of expression in adult males.

Increase of bcl-2 protein in neuronal dendritic processes of cerebral cortex and hippocampus by the antiparkinsonian drugs, talipexole and pramipexole.

Treatment of rats for 4 days with the antiparkinsonian drugs, talipexole and pramipexole, markedly increased Bcl-2 immunoreactivity in neuronal dendritic processes in both cerebral cortex and hippocampus, but treatment for 1 day with either of these drugs did not. Repeated administration of talipexole or pramipexole may have neuroprotective effect in neurodegenerative disorders.

Radiation-induced brain calcification: paradoxical high signal intensity in T1-weighted MR images.

BACKGROUND: Irradiation to the central nervous system (CNS) in childhood is known to induce cerebral calcification after a latent period. Calcification has been generally found to show nil or a reduction in signal intensity in magnetic resonance (MR) images. However, we have studied three patients with radiation-induced brain calcification, who manifested increased signal intensity on T1-weighted MR images. METHOD: Three girls had each been diagnosed as having a suprasellar germ cell tumour and were treated with conventional fractionated radiotherapy in their childhood. In one case, chemotherapy was given prior to the CNS irradiation. FINDINGS: All three patients survived their disease, and a follow-up CT scan revealed calcification in the brain, which has shown an increased signal intensity in the T1-weighted images of MR. INTERPRETATION: Cerebral calcification may be presented as a high signal intensity in the T1-weighted MR images. This may be explained by a surface-relaxation effect by the calcium salt particle, precipitated in the brain due to radiation-induced mineralising microangiopathy.

[A case report of skeletal muscle metastasis of renal cell carcinoma effectively treated with interferon-alpha].

The skeletal muscle is a very rare site of metastasis in renal cell carcinoma. We report the third case of skeletal muscle metastasis of renal cell carcinoma effectively treated with interferon-alpha. The patient was a 74-year-old woman who had undergone radical nephrectomy on the left side for renal cell carcinoma on April 23, 1990, and had been observed as an outpatient. In June 1997, she was admitted with a diagnosis of metastasis in the left great adductor muscle and right sixth rib, as well as multiple lung metastasis. The metastatic lesion in the great adductor muscle decreased in size by more than 50% following concomitant intramuscular administration of natural interferon-alpha (nIFN-alpha). In the other metastatic lesions, nIFN-alpha-sensitive and resistant metastatic foci were intermingled. Thus, the primary focus in the present study was presumably composed of several clones with different sensitivities to nIFN-alpha.

[Recurrent spontaneous rupture of the urinary bladder: a case report].

The patient was a 67-year-old woman who had undergone radical hysterectomy and postoperative radiotherapy for cervical cancer at the age of 46 years. Spontaneous rupture of the urinary bladder occurred twice in 1997, and conservative treatment was performed on each occasion. She was admitted to our hospital for the third time of spontaneous rupture of the urinary bladder. She underwent bilateral cutaneous ureterostomy because of panperitonitis and paralytic ileus. A review of 11 cases of recurrent rupture of the urinary bladder reported in Japan including the present case revealed that, patients who had been conservatively treated tended to be subject to recurrence. However, the risk of recurrence remains when a partial cystectomy is performed. Therefore, especially in recurrent cases, augmentation cystoplasty or urinary diversion should be considered as the treatment for spontaneous rupture of the urinary bladder due to radiation cystitis.

Ciliogenesis and ciliary abnormalities.

Cilia are motile processes extending from the basal bodies, playing important roles in the mucociliary clearance in the respiratory tract and the transport of the ovum from the ovary to the uterus in mammals. Ciliogenesis is divided into four stages: (1) duplication of centrioles; (2) migration of centrioles to the apical cell surface to become basal bodies; (3) elongation of cilia containing the axoneme; and (4) formation of accessory structures of basal bodies. The orderly course of ciliogenesis appears to be disturbed by various internal and external factors and, as a result, various unusual forms of the ciliary apparatus develop in the cell. Inhibition of basal body migration results in development of intracytoplasmic axonemes, cilia within periciliary sheaths, and intracellular ciliated cysts. Swollen cilia and the bulging type of compound cilia are formed during ciliary budding and elongation. This review also discusses the origin, composition, and function of the centriolar precursor structures.