Aim: Diabetic peripheral artery disease (PAD) is prone to be aggressive and recent reports have demonstrated that p53 accumulation may be responsible for impaired wound healing in diabetes. Statins has been demonstrated to facilitate p53 degradation by activating its specific ubiquitin ligase, MDM2. The aim of this study was to determine whether atorvastatin (ATR) improves the outcome of diabetic PAD through MDM2-mediated reduction of p53. Methods: Male KK/Ay mice (9 weeks old) were treated with ATR (2 mg/kg/day p.o.) or vehicle for 2 weeks and subjected to ischemic hindlimb operation to generate a diabetic PAD model. Incidences of amputation and changes of p53/MDM2 signaling in each ischemic limb were assessed 2 weeks after the operation (at 13 weeks of age). Effects of ATR on the insulin resistance of age-matched (13-weekold) and unoperated KK/Ay mice were assessed by the glucose tolerance test, circulating adiponectin concentration, and changes in insulin signaling (IRS-1/Akt phosphorylation). Results: In intact KK/Ay, ATR treatment mitigated insulin resistance without affecting cholesterol levels. All diabetic PAD models exhibited autoamputation (100%); however, ATR treatment partially restored the limb loss (41.7%). The p53 expression level in the ischemic limb of ATR-treated KK/Ay was significantly decreased and MDM2 phosphorylation level was markedly increased in tandem with the activation of Akt. Hypoxia mimetic iron chelator deferroxamine promoted p53 accumulation in H9c2 myoblast cells by suppressing the Akt/MDM2 pathway, which was restored by ATR. Conclusions: ATR was found to restore ischemic limb loss in diabetes by augmenting p53 degradation through direct activation of the Akt/MDM2 pathway in skeletal muscle.
SUMMARY:The age-group-specific incidence and etiological patterns of community-acquired pneumonia (CAP) have not been fully established in Japan. A 2-year prospective surveillance was conducted in Kochi city, Western Japan. All CAP patients aged AE15 years who visited a community-based hospital were enrolled in the study. Clinical samples were examined by conventional bacterial culture and urinary antigen tests, and 6 bacterial pathogens and 16 respiratory viruses were identified from sputum samples by multiplex polymerase chain reaction assays. The age-group-specific incidence of CAP was estimated using a population-based data set of the total number of outpatients in the whole city.
Summary Fibroblast growth factor 19 (FGF19) and FGF21 are members of a subfamily of the FGFs called endocrine FGFs. FGF19 regulates the bile acid synthetic pathway. FGF19 expression is induced by farnesoid X receptor (FXR), a nuclear hormone receptor activated by bile acids in the small intestine. FGF21 plays an important role in lipolysis that occurs in white adipose tissue. FGF21 expression is stimulated by the nuclear fatty acid receptor peroxisome proliferator-activated receptor a (PPARa) in the liver. FGF19 and FGF21 were recently identified as targets of activating transcription factor 4 (ATF4), which is activated in response to endoplasmic reticulum (ER) stress. ATF4 is also activated by oxidative stress and amino acid deprivation. In this study, we investigated FGF19 and FGF21 expression in response to oxidative stress and amino acid deprivation. We found that FGF19 mRNA is induced by oxidative stress inducers in Caco-2 cells, which are derived from the human intestinal epithelium, and rat intestinal epithelial IEC6 cells. In contrast, ileal FGF15 expression, the rodent ortholog of human FGF19, is not increased by oxidative stress. No notable changes in expression of FGF15/19 took place under amino acid deprivation either in vitro or in vivo. In contrast, FGF21 expression is induced by oxidative stress and amino acid deprivation both in vitro and in vivo. These results indicate distinctive patterns of regulation of FGF19 expression by ER stress, and FGF21 expression by ER stress, oxidative stress, and amino acid deprivation through ATF4 activation.
Acute immune thrombocytopenia (ITP) is a common benign bleeding disorder of variable etiology characterized by isolated thrombocytopenia. Intravenous immunoglobulin (IVIG) treatment is generally given as an initial treatment to pediatric patients with ITP, but markers predictive of the response to IVIG remain poorly defined. We retrospectively evaluated whether clinical and laboratory findings before treatment could predict response to IVIG and progression to chronic ITP in Japanese children with ITP. Between April 1997 and December 2011, a total of 49 children with newly diagnosed ITP were initially treated with IVIG. Their medical records were retrospectively reviewed. In multivariate analyses, lower white blood cell (WBC) count was the only unfavorable factor for response to IVIG and progression to chronic ITP. Patients with WBC count <7.0 × 10(9)/L had a lower probability of thrombocytopenia-free survival (41 vs. 77 %, P = 0.003) and a higher rate of progression to chronic ITP (29 vs. 6 %, P = 0.040) than those with WBC count ≥7.0 × 10(9)/L. These results suggest that ITP with lower WBC count may represent a distinct subgroup requiring initial treatment other than IVIG.
Background: In Japan, the school screening program for heart disease (SS) has been performed since 1973. However, little has been reported on the electrocardiogram (ECG) changes and long-term prognosis in patients with hypertrophic cardiomyopathy (HCM) detected by the SS. Methods: All 44 consecutive pediatric HCM patients (10.1 AE 3.0 years old), who had been originally consulted by the SS before the diagnosis of HCM from April 1981 to April 2017, were reviewed retrospectively. Results: At the SS, all patients showed mild or no symptoms. All patients showed ECG abnormalities, and 75 % had a high proposed ECG risk score (36). However, 30 % of them had no echocardiogram finding of myocardial hypertrophy. During the follow-up period (14.8 AE 10.0 years), life-threatening events (LTE) occurred in 11 (25 %) patients, and the first LTE occurred during exercise in 8 (18 %). The estimated LTE and heart failure death-free survival rate at 10 years was 64.9 %. The LTE-free survival rate was lower in patients without than in those with myocardial hypertrophy at the SS. Conclusions: The SS was useful in detecting patients with HCM with mild or no symptoms at the early stage. However, our study indicated that early detection of HCM is not associated with improvement in the prognosis of the patients. Further studies are needed.
Background
Many small for gestational age (SGA) infants have catch‐up growth during the first 2 years of life, but approximately 10% have no catch‐up growth, and short stature continues into adulthood. Identification of risk factors for absence of catch‐up growth at an early age may be useful for earlier diagnosis and earlier treatment.
Methods
This was a retrospective multicenter study. The subjects were SGA infants with very low‐birthweight (VLBW), who were followed up until the age of 3 years. The risk factors for absence of catch‐up growth were identified on statistical analysis.
Results
Of the 217 SGA infants in this study, 181 were in the catch‐up group and 36 were in the no catch‐up group. The catch‐up rate was 83%. On multivariate analysis adjusted for gestational age, birthweight, birth height, and birth head circumference, multipara, Z and ΔZ scores of length at 12 months of corrected age, and the Z score of height at 24 months of corrected age were risk factors for lack of catch‐up at 3 years.
Conclusions
The length Z and ΔZ scores at 12 months of corrected age may be useful for an earlier diagnosis and earlier initiation of growth hormone treatment in VLBW infants.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.