Preventive effect of aripiprazole once monthly on rehospitalization for bipolar disorder: A multicenter 1-year retrospective mirror image study.

AIM: We conducted a 1-year retrospective mirror-image study to investigate the effect of aripiprazole once monthly (AOM) on rehospitalization for bipolar disorder. METHODS: Participants were recruited from psychiatric emergency and acute care hospitals in western Japan. We included 39 participants with bipolar disorder who had been administered AOM for at least 1 year with no missing medical records during the observational period. The primary outcomes were rehospitalization rate, number of rehospitalizations, total hospitalization days, and time to rehospitalization in the context of overall psychiatric readmissions. The significance level was set at p < 0.05. RESULTS: AOM significantly reduced the rehospitalization rate from 23/39 (59%) to 7/39 (18%) (p = 0.001). The number of rehospitalizations decreased significantly from a mean of 0.85 per person-year to 0.41 per person-year (p = 0.048). The total hospitalization days significantly decreased from a mean of 34.9 days to 14.4 days (p = 0.008). AOM significantly prolonged the time to rehospitalization (p < 0.001). CONCLUSION: This study found that AOM reduces overall psychiatric rehospitalization for bipolar disorder based on data from 1 year before and after AOM administration in the real-world setting. Future studies should examine the robustness and persistence of the rehospitalization preventive effect of AOM with larger sample sizes and longer observation periods beyond 1 year.

The trajectory of non-depressed suicidal ideation in community-dwelling older people in a rural area in Japan: a prospective longitudinal study with a 3-year follow-up.

BACKGROUND: Suicidal ideation is closely related to severe suicidal behaviour and is an important predictor of suicide attempt and completion, including in older people. Older people tend to have many opportunities to be conscious of death, and may have vague suicidal ideation because of various loss experiences, even if they are not depressed. We hypothesised that suicidal ideation among older people might be a risk factor for later transition to depression. The present study aimed to clarify risk factors that predict the incidence of depression in older people 3 years post-baseline in a rural area of Japan, and to examine the subsequent course of depression among non-depressed older people with suicidal ideation. METHODS: In 2015 and 2018, survey questionnaires were mailed to residents aged 65 years and over living in a rural area in Japan. Participants were divided into a depression group and a non-depression group using 15-item Geriatric Depression Scale scores 3 years post-baseline. Logistic regression analysis was used to identify predictive factors of late-life depression 3 years post-baseline. RESULTS: We received 597 valid responses, with a 3-year follow-up rate of 78.8%. Regarding suicidal ideation, 6.7% of non-depressed older people exhibited suicidal ideation at baseline. Of these, 9.8% exhibited depression after 3 years post-baseline. Logistic regression analysis indicated that development of late-life depression is significantly associated with suicidal ideation, being female, and poor health-related quality of life (HRQOL). CONCLUSIONS: The results revealed that suicidal ideation, being female, and poor HRQOL were predictive factors of the development of late-life depression 3 years post-baseline in a rural area of Japan. These findings provide novel information regarding the transition to depression among community-dwelling older people who are not depressed but have suicidal ideation. Whereas suicidal ideation is considered to be a symptom of depression, the current results suggest that suicidal ideation may precede depression in some older people.

Intravoxel Incoherent Motion Factors Affecting Collapse and Nonunion of Osteoporotic Vertebral Fracture.

STUDY DESIGN: Longitudinal study. OBJECTIVES: Intravoxel incoherent motion (IVIM), a magnetic resonance imaging (MRI) scanning technique that applies diffusion-weighted imaging (DWI), is effective for the quantitative assessment of malignant tumors of the vertebral bone. We hypothesized that IVIM parameters of vertebral bodies are associated with the prognosis of osteoporotic vertebral fracture (OVF). We aimed to explore the relationships between IVIM parameters for vertebral collapse and non-union after OVF and calculate the cut-off values of these parameters for vertebral collapse and non-union. METHODS: A total of 150 patients with acute OVF (150 women; mean age: 79.1 ± 7.4 years) were included and treated conservatively with bracing. MRI was performed at the time of injury. IVIM parameters, such as apparent diffusion coefficient (ADC), molecular diffusion coefficient (D), and perfusion-related diffusion (D*) were recorded. The patients were classified into 3 groups: low-collapse (height loss of ≤50%), high-collapse (height loss of >50%), and non-union. We compared ADC, D, and D* among the low-collapse, high-collapse, and non-union groups and performed a receiver operating characteristic (ROC) curve analysis to determine the boundary values of the high-collapse and non-union groups. RESULTS: The low-collapse, high-collapse, and non-union groups had no significant differences in ADC and D. However, D* differed significantly among the 3 groups. ROC analysis revealed cut-off values of 19.0 × 10-3 mm2/s and 12.3 × 10-3 mm2/s for the high-collapse and non-union groups, respectively. CONCLUSIONS: D* is a significant prognostic indicator for high-collapse and non-union groups with OVF. This suggests that D* should be considered when assessing OVF.

Inconsistent Control Status of Office, Home, and Ambulatory Blood Pressure All Taken Using the Same Device: The HI-JAMP Study Baseline Data.

BACKGROUND: Inconsistencies between the office and out-of-office blood pressure (BP) values (described as white-coat hypertension or masked hypertension) may be attributable in part to differences in the BP monitoring devices used. METHODS: We studied consistency in the classification of BP control (well-controlled BP vs. uncontrolled BP) among office, home, and ambulatory BPs by using a validated "all-in-one" BP monitoring device. In the nationwide, general practitioner-based multicenter HI-JAMP study, 2,322 hypertensive patients treated with antihypertensive drugs underwent office BP measurements and 24-hour ambulatory BP monitoring (ABPM), consecutively followed by 5-day home BP monitoring (HBPM), for a total of seven BP measurement days. RESULTS: Using the thresholds of the JSH2019 and ESC2018 guidelines, the patients with consistent classification of well-controlled status in the office (<140 mmHg) and home systolic BP (SBP) (<135 mmHg) (n = 970) also tended to have well-controlled 24-hour SBP (<130 mmHg) (n = 808, 83.3%). The patients with the consistent classification of uncontrolled status in office and home SBP (n = 579) also tended to have uncontrolled 24-hour SBP (n = 444, 80.9%). Among the patients with inconsistent classifications of office and home BP control (n = 803), 46.1% had inconsistent ABPM-vs.-HBPM out-of-office BP control status. When the 2017 ACC/AHA thresholds were applied as an alternative, the results were essentially the same. CONCLUSIONS: The combined assessment of the office and home BP is useful in clinical practice. Especially for patients whose office BP classification and home BP classification conflict, the complementary clinical use of both HBPM and ABPM might be recommended.

Comparative effects of topiroxostat and febuxostat on arterial properties in hypertensive patients with hyperuricemia.

Elevated serum uric acid is a cardiovascular risk factor in patients with hypertension, even when blood pressure (BP) is well controlled. Xanthine oxidoreductase inhibitors (XORi) reduce serum uric acid levels and have several other potential effects. This multicenter, randomized, open-label study compared the effects of two XORi, topiroxostat and febuxostat, on arterial stiffness, uric acid levels, and BP in hypertensive patients with hyperuricemia. Patients received topiroxostat 40-160 mg/day or febuxostat 10-60 mg/day, titrated to maintain serum uric acid <6 mg/dl, for 24 weeks. The primary endpoint was change in the cardio-ankle vascular index (CAVI) from baseline to 24 weeks. There were no significant changes in CAVI from baseline to 24 weeks (from 9.13 to 9.16 [feboxustat] and 8.98 to 9.01 [topiroxostat]). Compared with baseline, there were significant reductions in serum uric acid (-2.9 and -2.5 mg/dl; both p < 0.001) and morning home systolic BP (-3.6 and -5.1 mm Hg; both p < 0.01) after 24 weeks' treatment with febuxostat and topiroxostat. BP decreased to the greatest extent in the subgroup of patients with uncontrolled blood pressure at baseline. Topiroxostat, but not febuxostat, significantly decreased plasma xanthine oxidoreductase activity versus baseline. The urinary albumin-creatinine ratio (UACR) decreased significantly from baseline to 24 weeks with topiroxostat (-20.8%; p = 0.021), but not febuxostat (-8.8%; p = 0.362). In conclusion, neither topiroxostat nor febuxostat had any significant effects on arterial stiffness over 24 weeks' treatment.

Effects of luseogliflozin on arterial properties in patients with type 2 diabetes mellitus: The multicenter, exploratory LUSCAR study.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the occurrence of cardiovascular and renal complications in patients with type 2 diabetes mellitus (T2DM) and represent guideline-recommended therapy in this indication. However, precise mechanisms underlying the beneficial cardiovascular effects of SGLT2 inhibitors are not fully understood. This study investigated the effects of the SGLT2 inhibitor, luseogliflozin, on arterial properties and home blood pressure (BP) in patients with T2DM. This multicenter, single-arm study enrolled adults with T2DM, glycosylated hemoglobin (HbA1c) 6.5%-8.9% in the previous 4 weeks, and an indication for new/additional antidiabetic therapy. Luseogliflozin 2.5 mg/d was given for 12 weeks. Primary outcome was change in cardio-ankle vascular index (CAVI) from baseline to Week 4 and Week 12. Home and office BP, BP variability, and metabolic parameters were secondary endpoints. Forty-seven patients (mean age 63.5 ± 10.7 years) treated with luseogliflozin were included in the full analysis set. CAVI did not change significantly from baseline (mean [95% confidence interval] 8.67 [8.37-8.97]) to Week 12 (8.64 [8.38-8.91]; P = .750), but there were significant reductions from baseline in morning home BP, HbA1c, body weight, body mass index, and serum uric acid levels during luseogliflozin therapy. The reduction in morning home systolic BP was ≥ 5 mm Hg and was independent of baseline BP and BP control status. In conclusion, there was no change in arterial stiffness (based on CAVI) during treatment with luseogliflozin, but changes in BP and metabolic parameters were consistent with the known beneficial effects of SGLT2 inhibitors in T2DM.

Age-related difference of the association of cardiovascular risk factors with the cardio-ankle vascular index in the Cardiovascular Prognostic Coupling Study in Japan (the Coupling Registry).

The value of the cardio-ankle vascular index (CAVI) increases with age. All large-scale studies of the CAVI have investigated patients <80 years old. Thus, the clinical characteristics of high CAVI in patients aged 80 or more remain unclear. Therefore, we investigated (1) the CAVI in very elderly patients and (2) the determinants of a high CAVI in high-risk patients, including very elderly patients. The Cardiovascular Prognostic Coupling Study in Japan (Coupling Registry) is a prospective observational study of Japanese outpatients with any cardiovascular risk factors. We enrolled 5109 patients from 30 institutions (average age 68.7 ± 11.4 years, 52.4% males). We investigated the determinants of the CAVI by separating the patients into three groups: 970 middle-aged (<60 years), 3252 elderly (60-79 years), and 887 very elderly (≥80 years) patients. The CAVI values of the males were significantly higher those of the females in all age groups (<60 years: 7.81 ± 1.11 vs. 7.38 ± 0.99, P < .001; 60-79 years: 9.20 ± 1.29 vs. 8.66 ± 1.07, P < .001; ≥80 years: 10.26 ± 1.39 vs. 9.51 ± 1.12, P < .001). In all age groups, the CAVI of the patients with diabetes/glucose tolerance disorder was higher than that of the patients without diabetes/glucose tolerance disorder (<60 years: 7.82 ± 1.22 vs 7.58 ± 1.03, P = .002; 60-79 years: 9.23 ± 1.20 vs 8.78 ± 1.19, P < .001; ≥80 years: 10.04 ± 1.24 vs 9.75 ± 1.32, P = .002). The determinants of the CAVI in these very elderly patients were age, male sex, low BMI, and mean blood pressure. Diabetes/glucose tolerance disorder and glucose were independently associated with the CAVI in the patients aged <60 years and 60-79 years, but not in those aged ≥80 years after adjusting for other covariates.

Rationale, design, and baseline characteristics of the Cardiovascular Prognostic COUPLING Study in Japan (the COUPLING Registry).

Vascular biomarkers, including the cardio-ankle vascular index (CAVI), are increasingly being recognized as important indicators of cardiovascular risk. CAVI has been shown to have good discriminative ability for detecting new-onset hypertension, but results of studies investigating cardiovascular risk prediction are inconsistent. Furthermore, there is a lack of data on the prognostic value of changes in CAVI over time. The Cardiovascular Prognostic Coupling study was designed to determine the impact of baseline CAVI and changes in CAVI on cardiovascular events in a Japanese cohort. The design of the ongoing, multicenter, prospective, observational registry and baseline characteristics of the enrolled population are reported. Eligible consecutive patients were aged ≥30 years, had ≥1 cardiovascular risk factor, and were being treated according to relevant Japanese guidelines. The primary outcome is time to onset of a major cardiovascular event (a composite of cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, stroke of unknown etiology, myocardial infarction, cardiovascular intervention for angina pectoris, and sudden death). Screening and enrollment occurred over a period of 3 years, followed by ≥7 years of follow-up, with CAVI determined annually. A total of 5279 patients were registered, of whom 5109 had baseline data available and will be included in future analyses. Mean CAVI at baseline was 8.8 ± 1.4. The proportion of patients with CAVI of <8, 8-10 or >10 was 25.3%, 57.0%, and 17.7%, respectively. Data from this registry should provide information on the significance of baseline CAVI and change in CAVI as indicators of cardiovascular prognosis in a representative patient population.

Long-term efficacy of comprehensive multidisciplinary antibiotic stewardship programs centered on weekly prospective audit and feedback.

OBJECTIVE: To evaluate the long-term effects of comprehensive antibiotic stewardship programs (ASPs) on antibiotic use, antimicrobial-resistant bacteria, and clinical outcomes. DESIGN: Before-after study. SETTING: National university hospital with 934 beds. INTERVENTION: Implementation in March 2010 of a comprehensive ASPs including, among other strategies, weekly prospective audit and feedback with multidisciplinary collaboration. METHODS: The primary outcome was the use of antipseudomonal antibiotics as measured by the monthly mean days of therapy per 1000 patient days each year. Secondary outcomes included overall antibiotic use and that of each antibiotic class, susceptibility of Pseudomonas aeruginosa, the proportion of patients isolated methicillin-resistant Staphylococcus aureus (MRSA) among all patients isolated S. aureus, the incidence of MRSA, and the 30-day mortality attributable to bacteremia. RESULTS: The mean monthly use of antipseudomonal antibiotics significantly decreased in 2011 and after as compared with 2009. Susceptibility to levofloxacin was significantly increased from 2009 to 2016 (P = 0.01 for trend). Its susceptibility to other antibiotics remained over 84% and did not change significantly during the study period. The proportion of patients isolated MRSA and the incidence of MRSA decreased significantly from 2009 to 2016 (P < 0.001 and = 0.02 for trend, respectively). There were no significant changes in the 30-day mortality attributable to bacteremia during the study period (P = 0.57 for trend). CONCLUSION: The comprehensive ASPs had long-term efficacy for reducing the use of the targeted broad-spectrum antibiotics, maintaining the antibiotic susceptibility of P. aeruginosa, and decreasing the prevalence of MRSA, without adversely affecting clinical outcome.

The Presence of Venous Gas Does Not Affect the Prognosis in Emphysematous Cystitis.

Objective Emphysematous cystitis (EC) has a high mortality rate compared with urinary tract infection without emphysema. However, its prognostic factors have yet to be determined. The presence of venous gas is suspected to be a rare, adverse prognostic factor of EC. However, all four previously reported cases improved. We hypothesized that venous gas is not an adverse prognostic factor of EC and aimed to assess the effect of venous gas on the EC prognosis. Methods Medical records were reviewed retrospectively. Patients The patients diagnosed with EC at Yodogawa Christian Hospital between April 2004 and September 2014 were included. Results Venous gas was present in 15 of 23 patients with EC. There was no significant difference in the background or clinical presentation between patients with or without venous gas. All patients with venous gas survived without invasive measures, whereas 50% of patients without venous gas died. Conclusion There was no marked difference in the mortality rate due to EC between the patients with and without venous gas. Venous gas may be a more common and less worrying finding in EC than assumed. It does not reflect the severity of infection, and air embolisms have not been reported so far. Venous gas may not affect the prognosis. This may be due to the differences in the mechanism of venous gas production. Gas in EC may develop due to glucose fermentation and intravesical pressurization, in contrast to the necrotizing infection seen in other emphysematous infections. This is the first study to assess the effect of venous gas on EC prognosis.

Regional osteoporosis due to osteoclast activation as a trigger for the pain-like behaviors in tail-suspended mice.

Pathological conditions with refractory skeletal pain are often characterized by regional osteoporotic changes such as transient osteoporosis of the hip, regional migratory osteoporosis, or complex regional pain syndrome (CRPS). Our previous study demonstrated that the acidic microenvironment created by osteoclast activation under high bone turnover conditions induced pain-like behaviors in ovariectomized mice through the stimulation of acid-sensing nociceptors. The aim of the present study was to examine whether regional transient osteoporotic changes are related to pain-like behaviors in the hind limb using tail-suspended model mice. The hind limbs of tail-suspended mice were unloaded for 2 weeks, during which time the mice revealed significant regional osteoporotic changes in their hind limbs accompanied by osteoclast activation. In addition, these changes were significantly recovered by the resumption of weight bearing on the hind limbs for 4 weeks. Consistent with the pathological changes in the hind limbs, pain-like behaviors in the mice were induced by tail suspension and recovered by the resumption of weight bearing. Moreover, treatment with bisphosphonate significantly prevented the triggering of the regional osteoporosis and pain-like behaviors, and antagonists of the acid-sensing nociceptors, such as transient receptor potential channel vanilloid subfamily member 1 and acid-sensing ion channels, significantly improved the pain-like behaviors in the tail-suspended mice. We, therefore, believe that regional transient osteoporosis due to osteoclast activation might be a trigger for the pain-like behaviors in tail-suspended model mice. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1226-1236, 2017.

Comparisons of prevalence and related factors of depression in middle-aged adults between urban and rural populations in Japan.

BACKGROUND: Findings of urban-rural differences in the prevalence of depression have been controversial, and few reports have directly compared the related factors of depression between urban and rural areas. The present study aimed to investigate differences between urban and rural areas in Japan with regards to the prevalence of and related factors of depression in middle-aged adults, in order to further understanding of the features of depression in this demographic. METHODS: We used a multistage, random sampling procedure and mailing method. In total, 5000 participants were recruited from urban and rural areas in Kumamoto Prefecture (2500 in each area). Participants were aged from 40 to 64 years. Depression was assessed using the Center for Epidemiologic Studies Depression scale (CES-D). RESULTS: The prevalence of middle-aged depression was not different between the urban and rural areas. Logistic regression analysis found that being female, living alone, and having a chronic illness were significantly associated with depression in urban-dwelling middle-aged adults. Younger age, sleep disturbance, and financial strain were significantly associated with depression in both urban and rural areas. LIMITATIONS: The definition of depression was based on CES-D scores, without corroborating clinical evaluation. CONCLUSIONS: We found no marked differences in the prevalence of middle-aged depression between the urban and rural areas. Some related factors of depression in middle-aged adults differed between urban and rural areas in Japan. Effective intervention programs for middle-aged adults with depression should consider regional differences.

Acid-sensing ion channel 3 or P2X2/3 is involved in the pain-like behavior under a high bone turnover state in ovariectomized mice.

We have recently demonstrated that pathological changes leading to increased bone resorption by osteoclast activation are related to the induction of pain-like behavior in ovariectomized (OVX) mice. In addition, bisphosphonate and the antagonist of transient receptor potential vanilloid type 1 (TRPV1), an acid-sensing nociceptor, improved the threshold value of pain-like behaviors accompanying an improvement in the acidic environment in the bone tissue based on osteoclast inactivation. The aim of this study was to evaluate the effect of (i) an inhibitor of vacuolar H(+) -ATPase, known as an proton pump, (ii) an antagonist of acid-sensing ion channel (ASIC) 3, as another acid-sensing nociceptor, and (iii) the P2X2/3 receptor, as an ATP-ligand nociceptor, on pain-like behavior in OVX mice. This inhibitor and antagonists were found to improve the threshold value of pain-like behavior in OVX mice. These results indicated that the skeletal pain accompanying osteoporosis is possibly associated with the acidic microenvironment and increased ATP level caused by osteoclast activation under a high bone turnover state.

Inhibitory effect of bisphosphonate on osteoclast function contributes to improved skeletal pain in ovariectomized mice.

The aim of this study was to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effect of bisphosphonate (BP) on pain in an ovariectomized (OVX) mouse model. We evaluated skeletal pain in OVX mice through an examination of pain-like behavior as well as immunohistochemical findings. In addition, we assessed the effects of alendronate (ALN), a potent osteoclast inhibitor, on those parameters. The OVX mice showed a decrease in the pain threshold value, and an increase in the number of c-Fos immunoreactive neurons in laminae I-II of the dorsal horn of the spinal cord. Alendronate caused an increase in the pain threshold value and inhibited c-Fos expression. The serum level of tartrate-resistant acid phosphatase 5b, a marker of osteoclast activity, was significantly negatively correlated with the pain threshold value. Furthermore, we found that an antagonist of the transient receptor potential channel vanilloid subfamily member 1, which is an acid-sensing nociceptor, improved pain-like behavior in OVX mice. These results indicated that the inhibitory effect of BP on osteoclast function might contribute to an improvement in skeletal pain in osteoporosis patients.

Item non-response on self-reported depression screening questionnaire among community-dwelling elderly.

BACKGROUND: In responses to self-reported depression screening questionnaires, item non-response, which refers to the absence of answers to specific questions, is problematic. The objective of this study were (1) to clarify the features of respondents with item non-response on a self-reported elderly depression screening questionnaire (15-item geriatric depression scale; GDS-15) as compared to respondents with full responses, and (2) to compare positive depression screening rates calculated using two methods: excluding respondents with item non-response (complete case analysis; CCA) and estimating by multiplying mean scores from valid responses by the total number of GDS-15 items for respondents with item non-response. METHODS: This was a cross-sectional study conducted from 2010 to 2012. Of 4794 elderly subjects (65 years and older) living in one town in Japan 2836 community-dwelling elderly people (59.2%) were included in the analysis. RESULTS: Item non-response was observed in 25.0% of respondents. Respondents with item non-response had a higher rate of depression and mental and physical problems. Respondents with depression (estimated GDS-15 score ≥6) and suicidal ideation both had a 1.6-times higher risk of item non-response on the GDS-15. The positive depression screening rate on GDS-15 by CCA was 16.5%, compared with 18.9% when calculated by the estimated GDS-15 score. LIMITATIONS: Our survey was conducted in one rural area and targeted only elderly people. CONCLUSION: The incidence of item non-response among community-dwelling elderly people was associated with depression of the respondent. Excluding subjects with item non-response when calculating positive depression screening rates in elderly individuals causes the rate to be underestimated.

A case of nosocomial Legionella pneumonia associated with a contaminated hospital cooling tower.

We report the epidemiological investigation of a nosocomial pneumonia case due to Legionella pneumophila linked to a contaminated hospital cooling tower in an immune-compromised patient. A 73-year-old female patient was diagnosed with nosocomial Legionella pneumonia proven by a culture of L. pneumophila serogroup 1 from bronchoalveolar lavage fluid. Two strains isolated from the patient and two strains isolated from two cooling towers were found to be identical using repetitive-sequence-based-PCR with a 95% probability. This Legionella pneumonia case might be caused by aerosol from cooling towers on the roof of the hospital building which was contaminated by L. pneumophila. We increased up the temperature of hot water supply appropriately for prevention of Legionella breeding in an environment of patients' living. On the other hand, as the maintenance of cooling tower, we increased the frequency of Legionella culture tests from twice a year to three times a year. In addition, we introduced an automated disinfectants insertion machine and added one antiseptic reagent (BALSTER ST-40 N, Tohzai Chemical Industry Co., Ltd., Kawasaki, Japan) after this Legionella disease, and thereafter, we have no additional cases of Legionella disease or detection of Legionella spp. from the cooling tower or hot water supply. This case demonstrates the importance of detecting the infection source and carrying out environmental maintenance in cooperation with the infection control team.

Valproate as a risk factor for lamotrigine discontinuation.

BACKGROUND: Although lamotrigine may be useful for treating bipolar depressive patients, some lamotrigine-associated adverse effects may prevent the continuation of treatment. The purpose of the present study was to identify risk factors for lamotrigine discontinuation after adjustment for several potential interactive factors. METHODS: We examined tolerability in those who discontinued lamotrigine within 2 months of treatment and those who maintained lamotrigine for more than 2 months. Groups were examined separately because 6-8 weeks are necessary to titrate dose and drug eruptions can often occur within 2 months of treatment commencement. RESULTS: Multiple regression analysis revealed that valproate combination was positively and significantly associated with lamotrigine discontinuation after adjustment for other factors. LIMITATIONS: The limitations of the present study were retrospective observation and a relatively small number of subjects. CONCLUSIONS: The present findings reconfirm that lamotrigine and valproate combination treatment may prevent the continuation of lamotrigine in some patients.

Delayed fracture healing in tetranectin-deficient mice.

Tetranectin is a plasminogen-binding protein that enhances plasminogen activation, which has been suggested to play a role in tissue remodeling. Recently, we showed that tetranectin has a role in the wound-healing process. In this study, we investigated whether tetranectin plays a role in fracture healing. The fracture-healing process was studied using a femoral osteotomy model in tetranectin-null mice, previously generated by the authors. Radiographic imaging, micro-computed tomography (µCT), and histological analysis were used to evaluate osteotomy healing. In wild-type mice, a callus was apparent from 7 days, and most samples showed marked callus formation and rebridging of the cortices at the osteotomy site at 21 days. In contrast, in the tetranectin-null mice there was no callus formation at 7 days and much less callus formation and no bridging of cortices were observed at 21 days. At 35 days, all osteotomy sites showed clear rebridging, and secondary bone formation was achieved in wild-type mice by 42 days. In contrast, no clear rebridging or secondary bone formation was observed at 42 days in the tetranectin-null mice. Analysis using µCT at 21 days after osteotomy revealed that the callus area in tetranectin-null mice was smaller than that in wild-type mice. Histological analysis also showed that soft tissue and callus formation were smaller in the tetranectin-null mice at the early stage of the healing process after drill-hole injury. These results suggested that tetranectin could have a role in the positive regulation at the early stage of the fracture-healing process, which was reflected in the delayed fracture healing in tetranectin-deficient mice.

Possibility of ex vivo animal training model for colorectal endoscopic submucosal dissection.

PURPOSE: Colorectal endoscopic submucosal dissection (ESD) has not been standardized due to technical difficulties and requires extensive training for reliability. Ex vivo animal model is convenient, but has no blood flow. The objective of this study is to evaluate the characteristics of various ex vivo animal models including a blood flow model for colorectal ESD training and the usefulness of practicing endoscopic hemostasis and closure using an animal model. METHODS: Harvested porcine cecum, rectum, and stomach and bovine cecum and rectum were analyzed regarding ease of mucosal injection, degree of submucosal elevation, and status of the proper muscle layer. Ex vivo animal model with blood flow was made using the bovine cecum. The vessel around the cecum was detached, and red ink was injected. Endoscopic hemostasis for perioperative hemorrhage and endoscopic closure for perforation were performed in this model. RESULTS: Mucosal injection was easily performed in the bovine cecum and rectum. Submucosal elevation was low in the bovine cecum, while the proper muscle layer was not tight in the porcine rectum and bovine cecum. Endoscopic hemostasis were accomplished in six (60 %) out of ten procedures of the ex vivo blood flow model. In two non-experts, the completion rates of endoscopic closure were 40 and 60 % in the first five procedures. These rates became 100 % in the last five procedures. CONCLUSIONS: We have evaluated the characteristics of various ex vivo animal models and shown the possibility of training for endoscopic hemostasis and endoscopic closure in the ex vivo animal model.

Emergence of HA mutants during influenza virus pneumonia.

During the influenza pandemic of 2009, the number of viral pneumonia cases showed a marked increase in comparison with seasonal influenza viruses. Mutations at amino acid 222 (D222G mutations) in the virus hemagglutinin (HA) molecule, known to alter the receptor-recognition properties of the virus, were detected in a number of the more severely-affected patients in the early phases of the pandemic. To understand the background for the emergence of the mutant amino acid D222G in human lungs, we conducted histological examinations on lung specimens of patients from Mexico who had succumbed in the pandemic. Prominent regenerative and hyperplastic changes in the alveolar type II pneumocytes, which express avian-type sialoglycan receptors in the respiratory tract of severely affected individuals, were observed in the Mexican patients. An infection model utilizing guinea pigs, which was chosen in order to best simulate the sialic acid distribution of severe pneumonia in human patients, demonstrated an increase of D222G mutants and a delay in the diminution of mutants in the lower respiratory tract in comparison to the upper respiratory tract. Our data suggests that the predominance of avian-type sialoglycan receptors in the pneumonic lungs may contribute to the emergence of viral HA mutants. This data comprehensively illustrates the mechanisms for the emergence of mutants in the clinical samples.