A crucial role of uridine/cytidine kinase 2 in antitumor activity of 3'-ethynyl nucleosides.

The antitumor 3'-ethynyl nucleosides, 1-(3-C-ethynyl-beta-D-ribopentofuranosyl)cytosine (ECyd) and 1-(3-C-ethynyl-beta-D-ribopentofuranosyl)uridine (EUrd), are potent inhibitors of RNA polymerases and show excellent antitumor activity against various human solid tumors in xenograft models. ECyd is being investigated in phase I clinical trials as a novel anticancer drug possessing a unique antitumor action. ECyd and EUrd require the activity of uridine/cytidine kinase (UCK) to produce the corresponding active metabolite. The UCK family consists of two members, UCK1 and UCK2, and both UCKs are expressed in many tumor cells. It was unclear, however, whether UCK1 or UCK2 is responsible for the phosphorylation of the 3'-ethynyl nucleosides. We therefore established cell lines that are highly resistant to the 3'-ethynyl nucleosides from human fibrosarcoma HT-1080 and gastric carcinoma NUGC-3. All the resistant cell lines showed a high cross-resistance to ECyd and EUrd. As a result of cDNA sequence analysis, we found that UCK2 mRNA expressed in EUrd-resistant HT-1080 cells has a 98-base pair deletion of exon 5, whereas EUrd-resistant NUGC-3 cells were harboring the point mutation at nucleotide position 484 (C to T) within exon 4 of UCK2 mRNA. This mutation was confirmed by genome sequence analysis of the UCK2 gene. Moreover, the expression of UCK2 protein was decreased in these resistant cells. In contrast, no mutation in the mRNA or differences in protein expression levels of UCK1 were shown in the EUrd-resistant HT-1080 and NUGC-3 cells. These results suggest that UCK2 is responsible for the phosphorylation and activation of the antitumor 3'-ethynyl nucleosides.     

Inhibitory effect of murine kidney extracts on the proliferation of murine mast cells

We examined the effect of murine kidney extract (MKE) on the clonal growth of mast cells from murine peritoneal cells. Adding MKE resulted in a 40% inhibition of colony formation of mast cells in a methylcellulose culture, and a 90% decrease in mast cell numbers and histamine content in mast cells in a liquid culture containing stem cell factor and interleukin-3. The mast cell inhibitory factors in MKE were heat sensitive proteins of approximately 560 and 24 kDa. These results suggest that MKE contains regulators that suppress the growth of murine mast cells and histamine synthesis.     

Association between chronic pain with presarcopenia and central sensitization in Japanese community-dwelling older adults: A cross-sectional study

Older people with chronic pain are at higher risk of developing sarcopenia. Central sensitization (CS) has been implicated in chronic pain among community-dwelling older adults. However, a relationship between CS and chronic pain with sarcopenia has not been established. This cross-sectional study aimed to clarify the relationship between chronic pain with sarcopenia or presarcopenia and CS among community-dwelling older adults. We assessed chronic pain and sarcopenia in 104 older adults participating in community health checks. We defined sarcopenia using the Asian Working Group for Sarcopenia (AWGS) consensus recommendations based on the following outcomes: low muscle mass, low muscle strength, and slow gait speed. Pain-related assessments included pain intensity, the Pain Catastrophizing Scale, the CS Inventory-9, the pressure pain threshold, the Tampa Scale of Kinesiophobia-11, and the EuroQol 5-dimension 5-level (EQ5D-5L). Chronic pain was defined by related symptoms within the month prior to the health check that had continued for ≥ 3 months and corresponded to a numerical rating scale score of ≥ 1 at the site of maximum pain. The prevalence of chronic pain was 43.3%. In addition, the prevalence of chronic pain with sarcopenia or presarcopenia was 29.8%. A logistic regression analysis revealed that the pressure pain threshold (odds ratio: 0.82, 95% CI: 0.95–1.02) and the EQ5D-5L (odds ratio: 0.58, 95% CI: 0.36–0.76) were significantly associated with the presence of chronic pain with sarcopenia or presarcopenia. Chronic pain with sarcopenia or presarcopenia was affected by central sensitization. Therefore, CS should be evaluated in the elderly.     

Comparison of biochemical markers and cervical length for predicting preterm delivery

AIM: To examine the clinical utility of several prognostic factors for predicting preterm delivery. METHODS: One hundred and nineteen patients with a singleton pregnancy admitted to our hospital because of symptoms of preterm labor were included in this study. Maternal serum C-reactive protein (CRP), transvaginal sonographic measurement of cervical length (CL), granulocyte elastase (EL) in cervical secretions, fetal fibronectin (fFN), alpha-fetoprotein (AFP), and insulin-like growth factor binding protein-1 (IGFBP-1) in vaginal secretions were examined on admission. EL, fFN, AFP, and IGFBP-1 were measured by bed-side test kits. Correlation between each factor and the duration of pregnancy (from admission to delivery) was investigated. RESULTS: A significant correlation was found between the duration of pregnancy and CRP (r= -0.37, P<0.001), but not CL. The duration was significantly shorter in the fFN-positive group than in the negative group (P=0.0015). However, no significant difference was observed between the positive group and the negative group for each of CL, EL, AFP and IGFBP-1. CONCLUSION: Association between the duration of the pregnancy and two biochemical markers (CRP and fFN) was confirmed. As they can be examined quickly and easily, they are quite useful for estimating prognosis of preterm labor.     

Fractal analysis of the maternal surface of the placenta: preliminary report

AIMS: The objective of this study was to determine whether the maternal surface of the placenta is fractal, and whether the mean fractal dimension differs according to the gestational age and clinically or pathologically different conditions. METHODS: Using digitized images of the maternal surface of 75 placentas, fractal dimensions were measured with a fractal analysis software. RESULTS: The mean fractal dimension of the maternal surface of the placentas significantly exceeded the topological dimension of a surface (= 2). This means that the morphological pattern of the maternal surface fulfills the mathematical definition of fractal structures. Among the three different groups of gestational age, the mean fractal dimension in 22-29 weeks was significantly lower than that in 30-36 and 37-41 weeks (p = 0.022 and 0.014, respectively). Although not significantly different (p = 0.149), in 30-36 weeks the mean fractal dimension of the placentas complicated by pregnancy-induced hypertension (PIH) was greater than that without PIH. CONCLUSION: Fractal geometry, a vocabulary of irregular shapes, can be useful for describing quantitatively the architecture of the maternal surface of the placenta and become a useful tool for analyzing physiological and pathological placental formation mathematically.     

Combination therapy using tafamidis and neurohormonal blockers for cardiac amyloidosis and a reduced ejection fraction: a case report

Cardiac amyloidosis usually presents with diastolic dysfunction, but sometimes systolic dysfunction develops, particularly at its advanced stage. However, the therapeutic strategy for patients with cardiac amyloidosis and systolic dysfunction remains unknown. We report a 77-year-old man who was diagnosed with wild-type cardiac amyloidosis and systolic dysfunction with a left ventricular ejection fraction of 27%. Following 6-month medical therapy of tafamidis 80 mg and neurohormonal blockers (carvedilol 5.0 mg, enalapril 2.5 mg, and spironolactone 25 mg), the left ventricular ejection fraction improved to 55%. Tafamidis-incorporated neurohormonal blocker therapy might be a promising strategy to facilitate cardiac reverse remodeling in patients with cardiac amyloidosis and systolic dysfunction.     

Changes in muscarinic acetylcholine receptors in guinea-pig lung: Effects of aging,inhalation of an allergen,administration of drugs,and vagotomy

This study was undertaken to investigate the effects of aging; inhalation of Konjak-Maiko, a typical Japanese allergen; administration of various drugs; and unilateral cervical vagotomy on muscarinic acetylcholine receptors (MAchR) in guinea-pig lung. We assessed the characteristics of MAchR by determining the affinity and the density of MAchR using [³H]quinuclidinyl benzilate, a potent muscarinic antagonist. A significant decrease in the density of MAchR was observed at 6 months of age and this decrease became more prominent until 2 years of age. No significant change in the affinity of MAchR was noted through the experimental period. Inhalation of Konjak-Maiko (60 min/day, for 10 days) did not affect either the affinity or the density of the receptors. Administration of ipratropium bromide (0.1 mg/kg/day, for 10 days) or prednisolone acetate (2 mg/kg/day, for 7 days) did not affect the characteristics of the receptors. In contrast to these drugs, diisopropyl fluorophosphate, an irreversible acetylcholinesterase inhibitor, produced a 26% reduction in the density without affecting the affinity of the receptors. The right cervical vagotomy increased the density of MAchR in the right lung by 17% without affecting the affinity of MAchR. These results suggest that the density of MAchR in lung may be controlled by changes in the activity of the receptors.     

Some properties of calcium-induced contraction in the isolated human and guinea-pig tracheal smooth muscle

We studied the effects of the cyclooxygenase inhibitors, indomethacin and aspirin, the leukotriene antagonist, FPL 55712 and the Ca antagonist, verapamil on basal tone and Ca-induced contractions in the human and guinea-pig tracheal muscle. Indomethacin and aspirin usually increased spontaneous tone or Ca-induced contractions in human strips, while consistently decreased tension development in the guinea-pig muscle. FPL 55712 strongly reduced contractions in the human, whereas it had a very weak effect on the guinea-pig muscle. Verapamil had a small inhibitory effect in the human trachea, either at 5.9 or 40 mM K, but markedly suppressed Ca-induced contractions of guinea-pig trachea in 40 mM K and had little effect on contractions in 5.9 mM K in this tissue. It is concluded that active tone in the two different tracheal muscles were controlled by different processes; that different arachidonate by-products may exert an effect on basal tone in the two different muscles; and that different plasma membrane Ca channels may be operative under basal conditions in the different muscles.     

Three-dimensional computerized tomography angiography in patients with hyperacute intracerebral hemorrhage.

OBJECT: The authors confirm the usefulness of extravasation detected on three-dimensional computerized tomography (3D-CT) angiography in the diagnosis of continued hemorrhage and establishment of its cause in patients with acute intracerebral hemorrhage (ICH). METHODS: Thirty-one patients with acute ICH in whom noncontrast and 3D-CT angiography had been performed within 12 hours of the onset of hemorrhage and in whom conventional cerebral angiographic studies were obtained during the chronic stage were prospectively studied. Noncontrast CT scanning was repeated within 24 hours of the onset of ICH to evaluate hematoma enlargement. Findings indicating extravasation on 3D-CT angiography, including any abnormal area of high density on helical CT scanning, were observed in five patients; three of these demonstrated hematoma enlargement on follow-up CT studies. Thus, specificity was 60% (three correct predictions among five positives) and sensitivity was 100% (19 correct predictions among 19 negatives). Evidence of extravasation on 3D-CT angiography indicates that there is persistent hemorrhage and correlates with enlargement of the hematoma. Regarding the cause of hemorrhage, five cerebral aneurysms were visualized in four patients, and two diagnoses of moyamoya disease and one of unilateral moyamoya phenomenon were made with the aid of 3D-CT angiography. Emergency surgery was performed without conventional angiography in one patient who had an aneurysm, and it was clipped successfully. CONCLUSIONS: Overall, 3D-CT angiography was found to be valuable in the diagnosis of the cause of hemorrhage and in the detection of persistent hemorrhage in patients with acute ICH.