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Purpose: Deep white matter lesions (DWMLs), T2 high-intensity areas in the subcortical white matter on magnetic resonance imaging (MRI), are a clinical phenotype of cerebral small vessel disease. Factors such as age and hypertension have been reported to significantly contribute to the presence and severity of DWMLs in cross-sectional studies. We herein report a 10-year longitudinal study on DWMLs in elderly Japanese subjects to reveal the clinical variables contributing to the progression of DWMLs. Methods: A total of 469 Japanese subjects were invited to participate in the study. Of the participants at baseline, 259 subjects completed the revisit MRI study 10 years later. In those 259 subjects, we evaluated the correlation between the progression of DWMLs and clinical variables, such as the gender, age, and overt vascular risk factors. To clarify the role of hypertension, 200 subjects with grade 1 DWMLs at baseline were categorized into three groups according to their status of hypertension and its treatment. Results: Of the 200 subjects with grade 1 DWMLs, 47 subjects (23.5%) showed progression of DWMLs (progression group). In the progression group, the percentage of subjects with hypertension and the systolic blood pressure values were higher than in the non-progression group. In addition, subjects ≥ 60 years old at baseline tended to show deterioration of DWMLs in the group with hypertension without antihypertensive treatment. Conclusion: The results of this 10-year longitudinal study imply a positive correlation between long-standing hypertension and the progression of DWMLs. [ABSTRACT FROM AUTHOR]

Objectives: To examine the effect of a dietary supplement containing bilberry extract (BE) on eye fatigue induced by acute video display terminal (VDT) loads. Design and setting: A prospective, randomized, double-blind, placebo-controlled study was performed from August 2012 to February 2013 in the Medical Corporation Jico-kai Yagi Hospital, and the Shinyokohama Shinoharaguchi Orthopedic Surgery and Dermatology Clinic, in Japan. Participants: Two hundred eighty-one office workers aged 20-40 years that used VDTs were screened by critical flicker fusion (CFF) and near point accommodation (NPA). Intervention: The participants were randomized to either a BE (480 mg/day) or placebo (vehicle) group, and took allocated capsule, daily, for 8 weeks. Measurements: The CFF, NPA, contrast visual acuity, functional visual acuity, keratoconjunctival epithelial damage, and fluorescein tear film break-up time were examined, and 18 subjective symptoms of eye fatigue were evaluated by questionnaire. Adverse events were reported via medical interviews. Data were collected both before and after VDT load at baseline, and 4, and 8 weeks after daily supplementation with either BE or placebo. Results: Of 281 participants screened, 88 having relatively lower levels of CFF and NPA were enrolled in the study. Of these, 37 control and 43 BE group subjects completed the study. The VDT load-induced reduction in CFF was alleviated after 8 weeks of BE supplementation (95% confidence interval, 0.10-1.60; p=0.023), in contrast to placebo supplementation, while NPA variation was not. Of the subjective symptoms of eye fatigue, VDT load-induced ocular fatigue sensation, ocular pain, eye heaviness, uncomfortable sensation, and foreign body sensation were mitigated more in the BE group than in the control group, at week 8 (p<0.05). There were no severe adverse events in either group. Conclusions: BE supplementation improved some of the objective and subjective parameters of eye fatigue induced by VDT loads. [ABSTRACT FROM AUTHOR]

Summary: A 12-month extension phase of DIRECT in Japanese subjects with osteoporosis showed that total 3 years of denosumab treatment in Japanese postmenopausal women and men with osteoporosis was associated with low fracture rates, persistent bone turnover marker (BTM) reductions, continuous bone mineral density (BMD) increases, and a favorable overall benefit/risk profile. Introduction: The DIRECT trial demonstrated that 2 years of treatment with denosumab 60 mg subcutaneously every 6 months significantly reduced the incidence of vertebral fracture compared to placebo in Japanese postmenopausal women and men with osteoporosis. The purpose of this study is to evaluate the efficacy and safety of denosumab treatment for up to 3 years. Methods: This study includes a 2-year randomized, double-blind, placebo-controlled phase and a 1-year open-label extension phase in which all subjects received denosumab. The data correspond to 3 years of denosumab treatment in subjects who received denosumab (long-term group) and 1 year of denosumab treatment in subjects who received placebo (cross-over group) in the double-blind phase. Results: Eight hundred and ten subjects who completed the double-blind phase enrolled into the extension phase, and 775 subjects completed the study. All subjects received denosumab with daily supplements of calcium and vitamin D. The cumulative 36-month incidences of new or worsening vertebral fractures and new vertebral fractures were 3.8 and 2.5 %, respectively, in the long-term group. In this group, the BMD continued to increase, and the reduction in BTMs was maintained. In the cross-over group, comparable BMD increases and BTMs reductions to those of in their first year of the long-term group were confirmed. Adverse events did not show a notable increase with long-term denosumab administration. One event of osteonecrosis of the jaw occurred in the cross-over group. Conclusions: Three-year denosumab treatment in Japanese subjects with osteoporosis showed a favorable benefit/risk profile. [ABSTRACT FROM AUTHOR]

Summary: This multi-center, prospective, open-label, observational study evaluated the effects of once-monthly minodronate (50 mg) on treatment persistence, bone turnover markers, bone mineral density, low back pain, and upper gastrointestinal symptoms in outpatients with osteoporosis previously treated with daily or weekly bisphosphonate products. Introduction: The purposes of this study were to investigate the effects of once-monthly oral minodronate (MIN 50 mg) on bone turnover markers and bone mineral density, low back pain, and upper gastrointestinal symptoms, as well as preference for and treatment persistence of MIN 50 mg among Japanese osteoporosis patients currently treated with daily or weekly bisphosphonates. Methods: Study patients were allocated based on their preference to either the Switch group (patients willing to switch over to MIN 50 mg) or the Continue group (patients wanting to continue their current therapies). Patients' treatment persistence and satisfaction levels with the therapies were assessed using a self-administered questionnaire. The study endpoints were serum TRACP-5b, serum P1NP, bone mineral density, upper gastrointestinal symptoms, and low back pain. Results: In total, 264 and 133 patients were allocated into the Switch and Continue groups, respectively. Approximately, 65 % of patients were willing to switch to MIN 50 mg, with the predominant reason being 'less frequent dosing more convenient.' Treatment persistence was significantly higher in the Switch group (MIN 50 mg) than the Continue group. Almost all patients with abnormal bone metabolism markers demonstrated normalization after switchover. MIN 50 mg alleviated low back pain and upper gastrointestinal symptoms induced by prior bisphosphonate use. Conclusions: MIN 50 mg alleviates low back pain, reduces bone turnover markers and increases bone density, and induces fewer upper gastrointestinal symptoms after switchover from prior bisphosphonate products, and therefore, it may provide patients with a more convenient treatment option and enhance long-term treatment persistence. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate the interactions of itraconazole (ITCZ) with orally administered calcineurin inhibitors (CNIs) in Japanese allogeneic hematopoietic stem cell transplant (HSCT) recipients. Methods: Sixteen HSCT patients (8 patients each receiving tacrolimus or cyclosporine) were enrolled. An ITCZ oral solution was administered from day 30 after the initiation of ITCZ administration as a loading dose. Before the co-administration of ITCZ and CNI and 1 week daily thereafter, whole blood ITCZ and CNI (tacrolimus or cyclosporine) concentrations were measured in samples taken just before (C) and 2 h (C) after CNI administration. Results: The median dose-adjusted C values of tacrolimus and cyclosporine on day 7 after the start of ITCZ co-administration were 5.6- and 2.7-fold higher, respectively, than the corresponding values obtained before the initiation of ITCZ treatment. On day 7 after ITCZ treatment, the mean single dosages of tacrolimus and cyclosporine were reduced to 33.7 and 66.5 % of the dosages before ITCZ co-administration, respectively, to adjust the CNI target concentration. Although ITCZ co-administration did not alter the dose-adjusted C values of tacrolimus in a patient with a CYP3A5*1/*1 allele, it did change this value of tacrolimus in patients with CYP3A5*3 alleles. However, in patients receiving cyclosporine, no such tendency was observed. Conclusion: The magnitude of the interaction between orally administered tacrolimus and ITCZ was significantly greater than that between cyclosporine and ITCZ. Prospective analysis of the CYP3A5 polymorphism may be important to ensure safe and reliable immunosuppressive therapy with tacrolimus in patients treated with ITCZ. [ABSTRACT FROM AUTHOR]

Purpose: Congestive heart failure (CHF) alters the pharmacokinetics of various drugs, including cardiovascular agents, due to decreased cardiac output and decreased renal blood flow. The purpose of this study was to evaluate the influence of CHF on the clearance of vancomycin, a glycopeptide antibacterial agent. Methods: After reviewing more than 1,500 clinical charts of patients who received vancomycin therapy and whose serum vancomycin level was monitored, we identified 101 patients who also had the left ventricular ejection fraction (LVEF) assessed at that time. The fluorescence polarization immunoassay method was used to measure vancomycin serum concentrations in these patients 1 h after the end of vancomycin infusion and just before the next administration. Using these two measurements, we calculated the pharmacokinetic parameters using the Bayesian estimator. Results: Patients with an LVEF of <40 % (16 patients) or those with an LVEF of ≥ 40 % and <60 % (40 % ≤ LVEF < 60 % ; 32 patients) had a significantly lower vancomycin clearance than patients with LVEF of ≥60 % (53 patients) (2.29 ± 0.95 or 2.79 ± 0.99 vs. 3.50 ± 1.04 L/h; p < 0.001 or p < 0.01, respectively). Vancomycin clearance was strongly correlated not only with estimated creatinine clearance (CLcr) in patients with an LVEF of <40 % ( r = 0.828) and 40 % ≤ LVEF < 60 % ( r = 0.773), but also with an LVEF in patients with a CLcr of <60 mL/min ( r = 0.646). Consistent with these findings, multiple regression analysis revealed that CLcr, LVEF and body weight were important independent variables for vancomycin clearance ( r = 0.649). Conclusions: Vancomycin clearance decreased with decreasing cardiac function (LVEF) and decreasing CLcr. This finding suggests that vancomycin clearance is affected by cardiac function and would be predicted not only CLcr but also by LVEF. [ABSTRACT FROM AUTHOR]

Background: The change (Δ) in the low-density lipoprotein cholesterol (LDL-C) / high-density lipoprotein cholesterol (HDL-C) ratio ( ΔLDL-C/HDL-C) and obesity are known to play important roles in the progression of coronary atherosclerosis. We hypothesized that a reasonable predictive model of coronary plaque regression could be constructed using ΔLDL-C/HDL-C and the body mass index (BMI). Objective: The purpose of this study was to establish a predictive model of coronary plaque regression using ΔLDL-C/HDL-C and BMI. Methods and Results: A 6-month prospective observational study was conducted among 114 patients with coronary artery disease (CAD) who were treated with pravastatin. The plaque volume, as assessed using volumetric intravascular ultrasound, decreased significantly by 9.9 % (p < 0.0001 vs baseline). In a multi-variate regression analysis with traditional risk factors, ΔLDL-C/HDL-C (β: 0.473, p = 0.0001) and the baseline BMI (β : 0.249, p= 0.004) were identified as independent predictors of the Δplaque volume. The patients were divided using the 50th percentile of the baseline BMI and the 50th percentile of the ΔLDL-C/HDL-C ratio as cutoffs, and a model for predicting coronary atherosclerotic regression was prepared using a combination of the two variables. The Δplaque volumes were -18.3 %, -14.1 %, -4.8%, and - 2.2% for the groups with ΔLDL-C/HDL-C≤-22.2 % and a BMI ≤ 24.1 kg /m², ΔLDL-C/HDL-C≤-22.2 % and ΔBMI >24.1 kg /m², ΔLDL-C/HDL-C>-22.2 % and BMI ≤ 24.1 kg /m² and ΔLDL-C/HDL-C>-22.2 % and BMI >24.1 kg /m², respectively (p = 0.003). Conclusion: A predictive model for coronary plaque regression based on a combination of ΔLDL-C/HDL-C and the baseline BMI may be a useful clinical tool in patients with CAD. [ABSTRACT FROM AUTHOR]

Study design:A prospective clinical cohort study.Objectives:To test if maximum voluntary ventilation (MVV), which is currently underutilized in diseases, serves for assessing subclinical ventilatory impairment in cervical spondylotic myelopathy (CSM).Setting:Kochi Medical School, Japan.Methods:We studied ventilatory function in 49 CSM patients and 20 age- and sex-matched control patients with either lumbar stenosis or lower limb osteoarthritis. All patients underwent ventilatory function studies consisting of flow volume curves, vital capacity (VC) and the MVV in 12 s before and after surgery. Tetraparesis was assessed by the functional scale of the Japanese Orthopaedic Association (JOA).Results:The CSM group had significantly smaller %forced VC , %peak expiratory flow rate (%PEFR) and %MVV than the control group preoperatively. In contrast to the control group, the CSM group showed a significant increase in %MVV from 74.9±18.7% preoperatively to 80.3±19.0% postoperatively (P<0.005), but not in any other ventilatory measures. This postoperative increase in %MVV significantly correlated with the JOA score (r=0.493; P<0.001). As a possible effect of diaphragmatic recovery, the %PEFR significantly increased postoperatively only in patients with the primary site of involvement at or rostral to C3-4.Conclusion:Of the various ventilatory measurements, MVV was most sensitive to changes in tetraparesis in CSM, presumably because MVV, unlike the other ventilatory measures, reflects the coordination in addition to the strength of respiratory muscles. [ABSTRACT FROM AUTHOR]

Objectives: To determine the presence or extent of arginine deficiency in pressure ulcer (PU) patients on percutaneous endoscopic gastrostomy (PEG) feeding and to examine the effects of arginine supplementation on PU healing. Design: All eligible PEG patients, with and without PU, were cross-sectionally assessed for plasma arginine. Three-month supplementation with arginine-enriched water (Arginaid Water) was performed on a subset of patients with PU. This intervention study was a prospective, non-controlled trial with 5 PU patients. Setting: Geriatric ward of a rural clinical hospital in Japan. Participants: Thirty-nine inpatients with PEG feeding were assessed for plasma arginine. Five of the 13 patients with PU and five of 26 patients without PU underwent amino acid profiling. Intervention: Five of the patients with PU received Arginaid Water supplementation. Measurements: Plasma amino acid measurements and biochemical analyses were performed. For those with PU on Arginaid Water supplementation, plasma arginine concentration and PU status were monitored every month. Results: Patients with PU showed significantly lower plasma arginine concentration compared to those without PU (control vs. PU; 80.2±21.3 vs 62.8±14.7 nmol/ml, p<0.01). After the addition of Arginaid Water, plasma arginine concentration increased (before vs 3 months later; 57.9±1.8 vs 83.1±8.5, p<0.01), and PU area, perimeter, DESIGN-R and PUSH scores significantly improved. Conclusion: Plasma arginine was lower in PEG patients with PU. The healing rate of PU is improved with Arginaid Water supplementation. The findings from this study support the use of arginine supplementation in PEG patients with PU. [ABSTRACT FROM AUTHOR]