Placebo controlled evaluation of Xilei San,a herbal preparation in patients with intractable ulcerative proctitis

Background and Aim: Topical mesalamine or corticosteroid has shown efficacy in patients with ulcerative proctitis, but patients often become refractory to these interventions. Xilei San is a herbal preparation with evidence of anti‐inflammatory effects. We evaluated the efficacy of topical Xilei San in ulcerative proctitis patients. Methods: In a double blind setting, 30 patients with intractable ulcerative proctitis despite ≥ 4 weeks of topical mesalamine or corticosteroid were randomly assigned to True (n = 15) and placebo (n = 15). Patients in True received suppository Xilei San (0.1 g/dose per day of Xilei San), the other 15 received placebo suppository. The initial efficacy was evaluated on day 14. Primary endpoint of the trial was avoiding relapse during 180 days, relapse meant recurrence of active disease. Riley's index was applied for endoscopic and histological evaluations, while patients' quality of life was evaluated by an inflammatory bowel disease questionnaire. Results: On day 14, the number of patients who achieved remission, clinical activity index ≤ 4 in True was significantly higher versus placebo (P < 0.04). Likewise, at day 180, an 81.8% of patients in True were without relapse versus 16.7% in placebo (P < 0.001). Further, significant endoscopic (P < 0.01), histological (P < 0.02) and inflammatory bowel disease questionnaire (P < 0.04) improvements were observed in True, but not in placebo. Conclusions: This is the first controlled investigation showing significant clinical and endoscopic efficacy for Xilei San in patients with intractable ulcerative proctitis. Topical Xilei San was well tolerated, and was without safety concerns.     

An autopsy case of Ph1--positive acute lymphoblastic leukemia with disseminated infection of Fusarium solani

A 56-year-old woman with Ph1--Positive acute Lymphoblastic Leukemia was admitted to our hospital for induction chemotherapy in June 1999. The patient was presented with a central scotoma of left eye during treatment course and was given diagnosis of endophthalmitis. Thereafter she also developed skin induration and suffered from serious pneumonia. Amphotericin B administration was started because of high titer of beta-D-glucan, but soon discontinued due to its adverse effect. Blood cultures yielded colonies of fungus and it was identified Fusarium solani. Her general condition deteriorated with progression of pneumonia, and she died of respiratory insufficiency. Autopsy was performed, and its specimen revealed the disseminated infection of Fusarium solani (lung, eye, heart, kidney and skin). We should pay special attention to the fusariosis in Japan also.     

Endothelin-1(1-31) levels are increased in atherosclerotic lesions of the thoracic aorta of hypercholesterolemic hamsters

OBJECTIVE: The novel vaso-constricting 31-amino acid-length endothelin-1 [ET-1(1-31)] is selectively produced by human mast cell chymase via its action on big ET-1. However, the pathological role of ET-1(1-31) in atherosclerosis remains unclear. The aim of this study was to clarify vasoconstrictive response and expression of ET-1(1-31) in atherosclerotic aorta. METHODS AND RESULTS: Syrian golden hamster, was used for preparing the atherosclerotic models by the administration of a high cholesterol diet (HC), treatment with the nitric oxide synthase inhibitor (Nomega-nitro-L-arginine methylester, L-NAME) alone, or both (HC and L-NAME) for 40 weeks. Early atherosclerosis was observed in the case of HC or L-NAME alone treatments respectively and severe atherosclerosis was observed in the case of combined HC and L-NAME treatment. Vasoconstriction induced by ET-1(1-31) was not altered by the atherosclerotic changes, but the expression pattern of ET-1(1-31) was different at each stage of the atherosclerotic aorta. ET-1(1-31) was observed rarely in normal aortas or in early atherosclerotic lesions, but ET-1(1-31) expression was dramatically increased in aortic neointima and adventitia in a state of atherosclerosis with severe inflammation. CONCLUSION: ET-1(1-31) might play in a role of promoting atherosclerosis, and especially be involved in inflammatory mediation during the progression of atherosclerosis.     

CETP is a determinant of serum LDL-cholesterol but not HDL-cholesterol in healthy Japanese

Cholesteryl ester transfer protein (CETP) is one of the factors that regulate plasma levels of HDL-cholesterol. To identify the factors that may regulate CETP activity, and to determine to what extent CETP is correlated with physiologic concentrations of lipoprotein, we performed an epidemiologic study in 586 healthy volunteers (317 males and 269 females, mean age 52.2 ± 10.9 years). CETP activity in these subjects was 192.96 ± 48.73 (mean ± S.D.) nmol/ml/h and distributed to a wide range (60–450 nmol/ml/h). Using multiple regression analysis, we found significant positive correlations between CETP activity and LDL-cholesterol (P < 0.03), apolipoprotein (apo) E (P < 0.005) and LCAT activity (P < 0.001). CETP activities showed significant negative correlation with apo A-I (P < 0.03). However, CETP activity showed no significant correlation either with HDL cholesterol or with apo B. One-way layout analysis of variance showed that alcohol drinking and cigarette smoking significantly reduced CETP activity, but there was no significant association between CETP activity and body mass index. Although CETP activities were significantly higher in females than in males (P < 0.001), multiple regression analysis showed no correlation between CETP activity and age in either the males or the females. Our results suggest that CETP activity regulates the concentration of apo A-I and LDL-cholesterol, and that such activity may be influenced by gender, alcohol consumption and cigarette smoking.     

Behavioral intention to prevent cervical cancer and related factors among female high school students in Japan

Aim

This study aimed to examine female high school students’ behavioral intention to prevent cervical cancer and related factors.

Methods

The participants were 2158 female high school students at 16 high schools in A prefecture in the Tohoku region in Japan. A self‐administered questionnaire was carried out that was developed based on a conceptual framework comprising the Health Belief Model and Theory of Reasoned Action.

Results

The responses were obtained from 2072 students (96.0%). Of these, the answers of 2028 respondents were analyzed after excluding those participants who did not complete the behavioral intention item (effective response rate: 97.0%). A factor analysis and covariance structure analysis yielded a model with strong goodness‐of‐fit that explained the behavioral intentions based on an “Awareness of the importance and effectiveness of cervical cancer screening,” “Obstacles to cervical cancer prevention behavior,” “Subjective norms for adopting cervical cancer prevention behavior,” and “The behavior of someone close that encourages cervical cancer prevention behavior.”

Conclusion

The statistical analysis yielded a model with strong goodness‐of‐fit that explained female high school students’ behavioral intentions, which were related to four factors, including “the awareness of the importance and effectiveness of cervical cancer screening.”

     

Effect of age on the sensitivity of the rat thyroid gland to ionizing radiation

Exposure to ionizing radiation during childhood is a well-known risk factor for thyroid cancer. Our study evaluated the effect of age on the radiosensitivity of rat thyroid glands. Four-week-old (4W), 7 -week-old (7W), and 8-month-old (8M) male Wistar rats were exposed to 8 Gy of whole-body X-ray irradiation. Thyroids were removed 3–72 h after irradiation, and non-irradiated thyroids served as controls. Ki67-positivity and p53 binding protein 1 (53BP1) focus formation (a DNA damage response) were evaluated via immunohistochemistry. Amounts of proteins involved in DNA damage response (p53, p53 phosphorylated at serine 15, p21), apoptosis (cleaved caspase-3), and autophagy (LC3, p62) were determined via western blotting. mRNA levels of 84 key autophagy-related genes were quantified using polymerase chain reaction arrays. Ki67-positive cells in 4W (with high proliferative activity) and 7W thyroids significantly decreased in number post-irradiation. The number of 53BP1 foci and amount of p53 phosphorylated at serine 15 increased 3 h after irradiation, regardless of age. No increase in apoptosis or in the levels of p53, p21 or cleaved caspase-3 was detected for any ages. Levels of LC3-II and p62 increased in irradiated 4W but not 8M thyroids, whereas expression of several autophagy-related genes was higher in 4W than 8M irradiated thyroids. Irradiation increased the expression of genes encoding pro-apoptotic proteins in both 4W and 8M thyroids. In summary, no apoptosis or p53 accumulation was noted, despite the expression of some pro-apoptotic genes in immature and adult thyroids. Irradiation induced autophagy in immature, but not in adult, rat thyroids.     

Elderly-onset rheumatoid arthritis: ageing as an independent marker for better joint prognosis

To study the contribution of age to the outcome of rheumatoid arthritis (RA), 133 elderly-onset RA (ERA) patients (onset above 60-year-old) were selected out of 2164 out-patients with RA who (i) first visited the hospital within 2 years after onset of the disease, (ii) received no remission inducing drugs previously and (iii) who were treated in this hospital regularly without interruption for more than 2 years. The joint score of ERA patients between initial visit and final visit to the hospital was compared with that of matched 133 younger-onset RA (YRA) patients (onset below 60-year-old). Results indicated that, in ERA, the patients with no active joints requiring no remission inducing drugs were increased on final visit (P<0.001). Joint score at disease onset or on initial visit to the hospital was similar in the two groups, whereas joint score on final visit was significantly decreased in ERA (P=0.0001). In ERA, progression of the small joint disease and joint erosion was not accelerated, and the small joint disease was in fact decelerated as compared with YRA (P<0.0001) during initial visit and final visit. Discriminant function analysis of patients with or without no active joints on final visit reveals that joint erosion, in small joints on initial visit is a predictor of joint prognosis in ERA. The two groups were similar with regards to sex, disease duration, onset type and rheumatoid factor/antinuclear antibody positivity. Thus, older age is an independent marker of better joint prognosis of RA     

Serum total homocysteine concentrations and risk of mortality from stroke and coronary heart disease in Japanese: The JACC study

Evidence for association between serum total homocysteine (tHcy) level and cardiovascular disease is limited in Asian populations. We conducted a nested case-control study under JACC Study. A total of 39,242 subjects aged 40-79 years provided serum samples at baseline surveys between 1988 and 1990. Control subjects were selected by matching for sex, age, community and year of serum storage. Serum tHcy levels were measured by high-performance liquid chromatography. During the 10-year follow-up, there were 444 deaths due to total cardiovascular disease, including 310 total stroke (131 hemorrhage and 101 ischemic strokes) and 134 coronary heart diseases. The risks of mortality from ischemic stroke, coronary heart disease, and total cardiovascular disease were significantly higher in individuals with the highest serum tHcy quartile (>or=15.3micromol/L) than in those with the lowest quartile (<10.5micromol/L); the respective multivariable odds ratios (95% CI) were 4.35 (1.12-16.9), 3.40 (1.17-9.86), and 1.68 (1.02-2.77). The multivariable odds ratios associated with a 5-micromol/L increase in tHcy were 1.49 (1.01-2.18), 2.01 (1.21-3.35), and 1.15 (1.00-1.32), respectively. High serum tHcy levels were associated with increased mortality from ischemic stroke, coronary heart disease and total cardiovascular disease among Japanese.     

Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts

The mechanism responsible for cardiac depression in septic shock remains unknown. The present study examined whether nitric oxide (NO) overproduced by inducible NO synthase (iNOS) can inhibit aerobic energy metabolism and impair the myocardial function in endotoxin-treated rat hearts. Lipopolysaccharide (LPS) significantly decreased systolic blood pressure (BP) to 44% of control during the 48 h treatment. Hearts from control and LPS-treated rats were perfused in a Langendorff apparatus. After LPS injection, left ventricular (LV) developed pressure (LVDP) was significantly depressed, plasma NO2-/NO3- (NO(x)) concentration was markedly increased, and myocardial adenosine 5'-triphosphate (ATP), creatine phosphate (CrP), and the ratio of ATP/adenosine 5'-diphosphate were progressively decreased with time. Immunological examination showed a significant expression of iNOS protein in the LPS-treated myocytes. Aminoguanidine, an inhibitor of iNOS, significantly attenuated these LPS-induced functional and metabolic changes. Myocardial cyclic guanosine 3',5'-monophosphate (cGMP) content was significantly increased after LPS injection. Methylene blue, an inhibitor of soluble guanylate cyclase, blunted this increase in cGMP and significantly restored the LPS-induced contractile dysfunction 6 h after LPS injection. In addition, there was a significant negative correlation between LVDP and myocardial cGMP levels as well as a significant negative correlation between LVDP and plasma NO(x) levels. In contrast, 48 h after LPS injection, methylene blue no longer affected cardiac performance, and there was a significant positive correlation between LVDP and myocardial ATP content. Furthermore, the normalized activities (as a ratio of the citrate synthase activity) of mitochondrial NADH-CoQ reductase, succinate-CoQ reductase, and ATPase, were significantly inhibited, and the swelling or disruption of mitochondria cristae was seen in the 48 h LPS treatment. These LPS-induced functional and morphological disorders in the mitochondria were significantly improved by aminoguanidine. The findings suggest that sustained production of NO by iNOS leads to contractile dysfunction via cGMP in the early stage, but that it can directly impair the mitochondrial function, lower myocardial energy production, and contribute significantly to the myocardial dysfunction in the later stage of septic shock.