Rad9 modulates the P21WAF1 pathway by direct association with p53

<p>Abstract</p> <p>Background</p> <p>Previous studies suggest that human <it>RAD9 </it>(hRad9), encoding a DNA damage checkpoint molecule, which is frequently amplified in epithelial tumor cells of breast, lung, head and neck cancer, participates in regulation of the tumor suppressor p53-dependent transactivation of pro-survival <it>P21</it>^{<it>WAF1</it>}. This study examined the exact mechanism of the hRad9 function, especially through the phosphorylation of the C-terminus, in the transcription regulation of <it>P21</it>^{<it>WAF1</it>}.</p> <p>Results</p> <p>The transfection of phosphorylation-defective <it>hRAD9 </it>mutants of C-terminus resulted in reduction of the p53-dependent <it>P21</it>^{<it>WAF1 </it>}transactivation; the knockdown of total hRad9 elicited an increased <it>P21</it>^{<it>WAF1 </it>}mRNA expression. Immunoprecipitation and a ChIP assay showed that hRad9 and p53 formed a complex and both were associated with two p53-consensus DNA-binding sequences in the 5' region of <it>P21</it>^{<it>WAF1 </it>}gene. The association was reduced in the experiment of phosphorylation-defective <it>hRAD9 </it>mutants.</p> <p>Conclusion</p> <p>The present study indicates the direct involvement of hRad9 in the p53-dependent <it>P21</it>^{<it>WAF1 </it>}transcriptional mechanism, presumably via the phosphorylation sites, and alterations of the hRad9 pathway might therefore contribute to the perturbation of checkpoint activation in cancer cells.</p

Ischemic and Bleeding Risk After Percutaneous Coronary Intervention in Patients With Prior Ischemic and Hemorrhagic Stroke

Background: Prior stroke is regarded as risk factor for bleeding after percutaneous coronary intervention (PCI). However, there is a paucity of data on detailed bleeding risk of patients with prior hemorrhagic and ischemic strokes after PCI. Methods and Results: In a pooled cohort of 19 475 patients from 3 Japanese PCI studies, we assessed the influence of prior hemorrhagic (n=285) or ischemic stroke (n=1773) relative to no-prior stroke (n=17 417) on ischemic and bleeding outcomes after PCI. Cumulative 3-year incidences of the co-primary bleeding end points of intracranial hemorrhage, non-intracranial global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO) moderate/severe bleeding, and the primary ischemic end point of ischemic stroke/myocardial infarction were higher in the prior hemorrhagic and ischemic stroke groups than in the no-prior stroke group (6.8%, 2.5%, and 1.3%, P<0.0001, 8.8%, 8.0%, and 6.0%, P=0.001, and 12.7%, 13.4%, and 7.5%, P<0.0001). After adjusting confounders, the excess risks of both prior hemorrhagic and ischemic strokes relative to no-prior stroke remained significant for intracranial hemorrhage (hazard ratio (HR) 4.44, 95% CI 2.64-7.01, P<0.0001, and HR 1.52, 95% CI 1.06-2.12, P=0.02), but not for non-intracranial bleeding (HR 1.18, 95% CI 0.76-1.73, P=0.44, and HR 0.94, 95% CI 0.78-1.13, P=0.53). The excess risks of both prior hemorrhagic and ischemic strokes relative to no-prior stroke remained significant for ischemic events mainly driven by the higher risk for ischemic stroke (HR 1.46, 95% CI 1.02-2.01, P=0.04, and HR 1.49, 95% CI 1.29-1.72, P<0.0001). Conclusions: Patients with prior hemorrhagic or ischemic stroke as compared with those with no-prior stroke had higher risk for intracranial hemorrhage and ischemic events, but not for non-intracranial bleeding after PCI

Infective endocarditis caused by Salmonella enteritidis in a dialysis patient: a case report and literature review

BackgroundInfective endocarditis is significantly more common in haemodialysis patients as compared with the general population, the causative pathogen is generally Staphylococcus aureus; there have been no previously reported cases of infective endocarditis caused by a Salmonella species in haemodialysis patients.Case presentationWe report the case of a 68 year-old woman on haemodialysis who developed infective endocarditis as a result of Salmonella enteritidis. Although we treated the patient with ceftriaxone combined with ciprofloxacin, infective endocarditis was not detected early enough and unfortunately developed into cerebral septic emboli, which ultimately resulted in death.ConclusionAlthough there are several reports that Salmonella endocarditis without cardiac failure can be successfully treated with antibiotics alone, early surgical intervention is essential for some cases to prevent life-threatening complications. Transesophageal echocardiography should be performed in any patient with high clinical suspicion of infective endocarditis. To the best of our knowledge, this is the first case-report of Salmonella endocarditis in a haemodialysis patient

Two cases of Taeniasis Infection.

We report two cases of taeniasis caused by tapeworm infection. The first was a Japanese female, 23 years old, who had a history of eating raw meat during a visit to Thailand. She was referred to our hospital with a history of passing proglottids in feces. Taenia saginata or T. asiatica was suspected based on the proglottid morphologic features in addition to supportive information regarding her travel and dietary history. The patient was given praziquantel and the tapeworm was excreted. The second was a 35-year-old Thai male who had lived in Japan since 2000 and not left the country since that time. He had consumed beef cooked in the so-called yakiniku style and also sometimes raw, because of nostalgia for that Thai custom. The patient passed proglottids several times and then came to us. The proglottids were compatible with those of T. saginata. Praziquantel was prescribed and the tapeworm was excreted. In both cases, mitochondrial DNA analysis identified the worm species as T. saginata. Since morphological discrimination of three human-infecting Taenia species, T. saginata, T. solium, and T. asiatica, is not always possible, it is necessary to employ DNA analysis for diagnosis of taeniasis to confirm the worm species

Association of perceived stress and coping strategies with the renal function in middle-aged and older Japanese men and women

Elucidating the risk factors for chronic kidney disease is important for preventing end-stage renal disease and reducing mortality. However, little is known about the roles of psychosocial stress and stress coping behaviors in deterioration of the renal function, as measured by the estimated glomerular filtration rate (eGFR). This cross-sectional study of middle-aged and older Japanese men (n = 31,703) and women (n = 38,939) investigated whether perceived stress and coping strategies (emotional expression, emotional support seeking, positive reappraisal, problem solving, and disengagement) were related to the eGFR, with mutual interactions. In multiple linear regression analyses adjusted for age, area, lifestyle factors, and psychosocial variables, we found a significant inverse association between perceived stress and the eGFR in men (Ptrend = 0.02), but not women. This male-specific inverse association was slightly attenuated after adjustment for the history of hypertension and diabetes and was more evident in lower levels of emotional expression (Pinteraction = 0.003). Unexpectedly, problem solving in men (Ptrend < 0.001) and positive reappraisal in women (Ptrend = 0.002) also showed an inverse association with the eGFR. Perceived stress may affect the eGFR, partly through the development of hypertension and diabetes. The unexpected findings regarding coping strategies require the clarification of the underlying mechanisms, including the hormonal and immunological aspects

Effect of the interaction between physical activity and estimated macronutrient intake on HbA1c : population-based cross-sectional and longitudinal studies

Introduction Healthy diet and physical activity (PA) are essential for preventing type 2 diabetes, particularly, a combination of diet and PA. However, reports on interaction between PA and diet, especially from large epidemiological studies, are limited. We investigated the effect of interaction between PA and macronutrient intake on hemoglobin A1c (HbA1c) levels in the general population. Research design and methods We conducted a cross-sectional study of 55 469 men and women without diabetes who participated in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. A self-administered questionnaire ascertained PA and macronutrient intake (carbohydrate, fat, and protein). Multiple linear regression analyses were performed to adjust for confounding variables and examine the interactions. In addition, we conducted a longitudinal study during a 5-year period within a subcohort (n=6881) with accelerometer-assessed PA data. Results Overall, PA had a weak inverse association (β=−0.00033, p=0.049) and carbohydrate intake had a strong positive association (β=0.00393, p<0.001) with HbA1c. We observed a tendency of interactions between PA and carbohydrate or fat intake, but not protein intake, on HbA1c levels after adjusting for age, sex, study area, total energy intake, alcohol consumption, smoking, and medication for hypertension or hypercholesterolemia (Pinteraction=0.054, 0.006, and 0.156, respectively). The inverse associations between PA and HbA1c level were more evident in participants with high-carbohydrate (or low-fat) intake than in participants with low-carbohydrate (or high-fat) intake. Although further adjustment for body mass index slightly attenuated the above interactions (Pinteraction=0.098 for carbohydrate and 0.068 for fat), the associations between PA and HbA1c level in stratified analyses remained unchanged. Similar associations and interactions were reproduced in the longitudinal study. Conclusions The present results suggest that the effect of PA on HbA1c levels is modified by intake of macronutrient composition