Characteristics of Type-2 Diabetics Who are Prone to High-Cost Medical Care Expenses by Bayesian Network.

Objective: This study aims to determine the characteristics of Type 2 diabetic patients who are more likely to cause high-cost medical expenses using the Bayesian network model. Methods: The 2011-2015 receipt data of Iwamizawa city, Japan were collected from the National Health Insurance Database. From the record, we identified patients with Type 2 diabetes with the following items: age, gender, area, number of days provided medical services, number of diseases, number of medical examinations, annual healthcare expenditures, and the presence or absence of hospitalization. The Bayesian network model was applied to identify the characteristics of the patients, and four observed values were changed using a model for patients who paid at least 3607 USD a year for medical expenses. The changes in the conditional probability of the annual healthcare expenditures and changes in the percentage of patients with high-cost medical expenses were analyzed. Results: After changing the observed value, the percentage of patients with high-cost medical expense reimbursement increased when the following four conditions were applied: the patient "has ever been hospitalized", "had been provided medical services at least 18 days a year", "had at least 14 diseases listed on medical insurance receipts", and "has not had specific health checkups in five years". Conclusions: To prevent an excessive rise in healthcare expenditures in Type 2 diabetic patients, measures against complications and promoting encouragement for them to undergo specific health checkups are considered as effective.

Identification of WWP1 as an obesity-associated E3 ubiquitin ligase with a protective role against oxidative stress in adipocytes.

White adipose tissue (WAT) is not only the main tissue for energy storage but also an endocrine organ that secretes adipokines. Obesity is the most common metabolic disorder and is related to alterations in WAT characteristics, such as chronic inflammation and increasing oxidative stress. WW domain containing E3 ubiquitin protein ligase 1 (WWP1) is a HECT-type ubiquitin E3 ligase that has been implicated in various pathologies. In the present study, we found that WWP1 was upregulated in obese WAT in a p53-dependent manner. To investigate the functions of WWP1 in adipocytes, a proteome analysis of WWP1 overexpression (OE) and knockdown (KD) 3T3-L1 cells was performed. This analysis showed a positive correlation between WWP1 expression and the abundance of several antioxidative proteins. Thus, we measured reactive oxygen species (ROS) in WWP1 OE and KD cells. Consistent with the proteome results, WWP1 OE reduced ROS levels, whereas KD increased them. These findings indicate that WWP1 is an obesity-inducible E3 ubiquitin ligase that can protect against obesity-associated oxidative stress in WAT.

Efficacy of mandibular manipulation technique for temporomandibular disorders patients with mouth opening limitation: a randomized controlled trial for comparison with improved multimodal therapy.

PURPOSE: Manual therapy has been used for the treatment of patients with temporomandibular disorders (TMD) with mouth-opening limitations. However, the curative effect of manipulation differs among researchers, and its necessity remains controversial. The purpose of this study was to confirm the efficacy of manipulation using a randomized controlled trial (RCT). METHODS: A total of 61 TMD patients who had mouth-opening limitation (upper and lower middle incisor distance ≤35mm) were selected. They were divided into two treatment groups: conventional treatment (n=30) and conventional treatment plus manipulation (n=31). The conventional treatment included two types of self-exercise: cognitive behavioral therapy for bruxism and education. Mouth-opening limitation, orofacial pain, and temporomandibular joint (TMJ) sounds were recorded from baseline to 18 weeks after baseline. These parameters were statistically compared between the two treatment groups by using analysis of variance (ANOVA) and Scheffe's test to assess mouth opening distance and pain; TMJ sounds were compared using Mann-Whitney U test. RESULTS: No statistical difference was observed between the two treatment groups except for mouth-opening limitation after treatment at the first visit. Subgroup analyses, stratified according to the pathological type of TMD, indicated a similar trend. CONCLUSIONS: The efficacy of manipulation seems to be limited, in contrast to our expectations, and improved execution of therapeutic exercises has a similar effect to that of manipulation during long-term observation. The advantage of manipulation was observed only during the first treatment session. The RCT was registered in the University Hospital Medical Information Network in Japan (UMIN-CTR: 000010437).

Two adult cases of Bland-White-Garland syndrome with lethal arrhythmia due to coronary steal phenomenon during physical or mental stress.

We experienced two adult cases of anomalous origin of the left coronary artery from the pulmonary artery, so-called Bland-White-Garland (BWG) syndrome, that presented with ventricular tachycardia (VT) and ventricular fibrillation during exertion in daily life. They presented to our hospital with syncope due to VT, and recovered following application of an automated external defibrillator with cardiopulmonary resuscitation. We diagnosed BWG syndrome by multi-detector computed tomography angiography and coronary angiography. We analyzed the mechanisms of lethal arrhythmias in relation to myocardial ischemia on exertion. Coronary flow modification and implantable cardioverter defibrillator implantation were performed in order to prevent future lethal arrhythmia due to myocardial ischemia. It is important to be aware of congenital heart disease in ordinary cases. .

Inhibitory effect of p53 on mitochondrial content and function during adipogenesis.

The p53 protein is known as a guardian of the genome and is involved in energy metabolism. Since the metabolic system is uniquely regulated in each tissue, we have anticipated that p53 also would play differential roles in each tissue. In this study, we focused on the functions of p53 in white adipose tissue (adipocytes) and skeletal muscle (myotubes), which are important peripheral tissues involved in energy metabolism. We found that in 3T3-L1 preadipocytes, but not in C2C12 myoblasts, p53 stabilization or overexpression downregulates the expression of Ppargc1a, a master regulator of mitochondrial biogenesis. Next, by using p53-knockdown C2C12 myotubes or 3T3-L1 preadipocytes, we further examined the relationship between p53 and mitochondrial regulation. In C2C12 myoblasts, p53 knockdown did not significantly affect Ppargc1a expression and mtDNA, but did suppress differentiation to myotubes, as previously reported. However, in 3T3-L1 preadipocytes and mouse embryonic fibroblasts, p53 downregulation enhanced both differentiation into adipocytes and mitochondrial DNA content. Furthermore, p53-depleted 3T3-L1 cells showed increase in mitochondrial proteins and enhancement of both Citrate Synthase and Complex IV activities during adipogenesis. These results show that p53 differentially regulates cell differentiation and mitochondrial biogenesis between adipocytes and myotubes, and provide evidence that p53 is an inhibitory factor of mitochondrial regulation in adipocyte lineage.

Autophagosomes accumulate in differentiated and hypertrophic adipocytes in a p53-independent manner.

Autophagy is induced by several kinds of stress, including oxidative, genotoxic, endoplasmic reticulum and nutrient stresses. The tumor suppressor p53, which is a stress sensor, plays a critical role in the regulation of autophagy. Although p53 is required for starvation (nutrient deficient stress)-induced autophagy, it is still not clear whether p53 is also required for the autophagy observed in differentiated and hypertrophic adipocytes, which accumulate excessive amounts of nutrients in the form of triglycerides. In this study, we demonstrated that starvation induces autophagy in p53-proficient adipocytes, but not in p53-deficient adipocytes as previously reported. On the other hand, autophagy was equally observed in both p53-deficient and -proficient differentiated and hypertrophic adipocytes. Similar results were obtained by in vivo analysis using white adipose tissue of high-fat diet-induced obese mice. Moreover, unexpectedly, the autophagy observed in the differentiated and hypertrophic adipocytes involved increased accumulation of autophagosomes and decreased autophagic flux. Thus, we concluded that in differentiated and hypertrophic adipocytes autophagosomes accumulate in a p53-independent manner, and this accumulation is caused by reduced autophagic flux.

Reversible induction of PARP1 degradation by p53-inducible cis-imidazoline compounds.

PARP1 is an important enzyme involved in various patho-physiological phenomena such as ischemia/reperfusion (I/R) injury, which occurs when blood flow is restored after cerebral infarction, myocardial infarction and transplantation of various organs. I/R-induced PARP1 over-activation is mediated by production of reactive oxygen species and is involved in NF-κB transactivation. For these reasons, PARP1 is an attractive target for strategies to protect against I/R injury. We previously reported that an MDM2 inhibitor Nutlin3a, a cis-imidazoline compound, induces PARP1 degradation in a p53 and proteasome-dependent manner. In this study, we evaluated the effect of Nutlin3a analogs, Nutlin3b and Caylin2, on PARP1 degradation. Like Nutlin3a, Caylin2, but not Nutlin3b, induced PARP1 degradation in both 3T3-L1 and 3T3-F442A. This result occurred almost in parallel with p53 accumulation. Furthermore Caylin2-induced PARP1 degradation was not observed in p53 deficient mouse embryonic fibroblasts or in the presence of the proteasome inhibitor MG132. These results suggest that Caylin2 induces PARP1 degradation by the same mechanism as Nutlin3a. Finally, we showed that Nutlin3a or Caylin2 treatment induces reversible PARP1 down-regulation without an inflammatory response. For protection against I/R injury, our results support the usability of the p53 inducible cis-imidazoline compounds, Nutlin3a and its analogs, as PARP1 inhibitors.

An Mdm2 antagonist, Nutlin-3a, induces p53-dependent and proteasome-mediated poly(ADP-ribose) polymerase1 degradation in mouse fibroblasts.

Nutlin-3a (Nutlin) is an Mdm2 inhibitor and is potent to stabilize p53, which is a tumor-suppressor involved in various biological processes such as cell cycle regulation, DNA repair, and apoptosis. Here we demonstrate that Nutlin treatment in mouse fibroblast cell lines reduces the protein levels of poly(ADP-ribose) polymerase1 (Parp1). Parp1 functions in DNA repair, replication, and transcription and has been regarded as a target molecule for anti-cancer therapy and protection from ischemia/reperfusion injury. In this study, first we found that Nutlin, but not DNA damaging agents such as camptothecin (Cpt), induced a decrease in the Parp1 protein levels. This reduction was not associated with cell death and not observed in p53 deficient cells. Next, because Nutlin treatment did not alter Parp1 mRNA levels, we expected that a protein degradation pathway might contribute to this phenomenon. Predictably, a proteasome inhibitor, MG132, inhibited the Nutlin-induced decrease in the levels of Parp1 protein. These results show that Nutlin induces the proteasomal degradation of Parp1 in a p53-dependent manner. Thus, this study demonstrates characterization of a novel regulatory mechanism of Parp1 protein. This novel regulatory mechanism of Parp1 protein level could contribute to development of inhibitors of the Parp1 signaling pathway.

Rupture of pseudoaneurysm of the pancreaticoduodenal arcade after acute aortic dissection in a patient on anticoagulant therapy.

An 81-year-old woman on anticoagulant therapy after mechanical heart valve replacement was admitted because of acute aortic dissection. Anticoagulant therapy had to be continued with heparin even after admission. Gastrointestinal hemorrhage occurred suddenly and she developed hemorrhagic shock. Computed tomography findings suggested that the bleeding was due to rupture of a pseudoaneurysm of the pancreaticoduodenal arcade. After the site of bleeding was identified by angiography, hemorrhage was successfully controlled by embolization with coils. With the aging of the population, vascular complications of arteriosclerosis are likely to increase. This case report provides important insights that could be helpful for treating such patients.