The effects of switching daily teriparatide to oral bisphosphonates or denosumab in patients with primary osteoporosis

The aim of this 12-month, observational study was to compare the effects of switching daily teriparatide (TPTD) to oral bisphosphonates (BP) therapy or denosumab (DMAb) therapy in patients with primary osteoporosis. Patients [n = 78; 71 postmenopausal women and seven men; mean age 76.3 (64–94) years; mean duration of prior daily TPTD therapy 20.1 (6–24) months] were allocated to either the (1) “switch-to-BP” group [n = 36; weekly alendronate 35 mg (n = 19), weekly risedronate 17.5 mg (n = 12), monthly minodronate 50 mg (n = 5)]; or (2) “switch-to-DMAb” group (n = 42; 60 mg sc every 6 months) based on each physicians’ decision. Changes in bone mineral density (BMD) and serum bone turnover markers were monitored every 6 months. No significant difference was observed in baseline clinical characteristics between the groups. After 12 months, the increase in BMD was significantly greater in the switch-to-DMAb group compared to the switch-to-BP group: lumbar spine (6.2 vs. 2.6 %; P < 0.01), total hip (4.2 vs. 1.1 %; P < 0.05), and femoral neck (3.5 vs. 1.4 %; P < 0.05). In addition, the patients in the switch-to-DMAb group showed a significant decrease compared to those in the switch-to-BP group in TRACP-5b (−55.8 vs. −32.8 %; P < 0.01) and ucOC (−85.5 vs. −65.0 %; P < 0.001), while no significant difference was observed in PINP (−67.5 vs. −62.1 %). Switching daily TPTD to DMAb significantly increased BMD and decreased bone resorption marker compared to switching to oral BP at 12 months, and thus may provide an effective sequential treatment option after daily TPTD treatment.This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s00774-015-0731-xEbina K., Hashimoto J., Kashii M., et al. The effects of switching daily teriparatide to oral bisphosphonates or denosumab in patients with primary osteoporosis. Journal of Bone and Mineral Metabolism 35, 91 (2017); https://doi.org/10.1007/s00774-015-0731-x

Natural polyphenols convert proteins into histone-binding ligands

peer reviewedAntioxidants are sensitive to oxidation and are immediately converted into their oxidized forms that can react with proteins. We have recently found that proteins incubated with oxidized vitamin C (dehydroascorbate) gain a new function as a histone-binding ligand. This finding led us to predict that antioxidants, through conversion to their oxidized forms, may generally have similar functions. In the present study, we identified several natural polyphenols as a source of histone ligands and characterized the mechanism for the interaction of protein-bound polyphenols with histone. Through screening of 25 plant-derived polyphenols by assessing their ability to convert bovine serum albumin into histone ligands, we identified seven polyphenols, including (-)-epigallocatechin-3-O-gallate (EGCG). Additionally, we found that the histone tail domain, which is a highly charged and conformationally flexible region, is involved in the interaction with the polyphenol-modified proteins. Further mechanistic studies showed the involvement of a complex heterogeneous group of the polyphenol-derived compounds bound to proteins as histone-binding elements. We also determined that the interaction of polyphenol-modified proteins with histones formed aggregates and exerted a protective effect against histone-mediated cytotoxicity toward endothelial cells. These findings demonstrated that histones are one of the major targets of polyphenol-modified proteins and provide important insights into the chemoprotective functions of dietary polyphenols

Comparison of the effects of denosumab between a native vitamin D combination and an active vitamin D combination in patients with postmenopausal osteoporosis

The aim of this 12-month, retrospective study was to compare the effects of denosumab (DMAb; 60 mg subcutaneously every 6 months) plus native vitamin D (VD) (cholecalciferol) combination therapy with DMAb plus active VD analog (alfacalcidol) combination therapy in patients with postmenopausal osteoporosis. Patients [N = 127; mean age 75.6 years (range 58–93 years); 28 treatment-naïve patients, 59 patients treated with oral bisphosphonate therapy, 40 patients treated with teriparatide daily] were allocated to either (1) the DMAb plus native VD group (n = 60; cholecalciferol, 10 μg, plus calcium, 610 mg/day; 13 treatment-naïve patients, 28 patients treated with oral bisphosphonate therapy, and 19 patients treated with teriparatide daily) or (2) the DMAb plus active VD group [n = 67; alfacalcidol, 0.8 ± 0.0 μg, plus calcium, 99.2 ± 8.5 mg/day; 15 treatment-naïve patients, 31 patients treated with oral bisphosphonate therapy, and 21 patients treated with teriparatide daily) on the basis of each physician’s decision. Changes in bone mineral density (BMD), serum bone turnover marker levels, and fracture incidence were monitored every 6 months. There were no significant differences in baseline age, BMD, bone turnover marker levels, and prior treatments between the two groups. After 12 months, compared with the DMAb plus native VD group, the DMAb plus active VD group showed similar increases in the BMD of the lumbar spine (6.4% vs 6.5%) and total hip (3.3% vs 3.4%), but significantly greater increases in the BMD of the femoral neck (1.0% vs 4.9%, P < 0.001) and the distal part of the forearm (third of radius) (−0.8% vs 3.9%, P < 0.01). These tendencies were similar regardless of the differences in the prior treatments. The rates of decrease of bone turnover marker levels were similar for tartrate-resistant acid phosphatase isoform 5b (−49.0% vs −49.0%), procollagen type I N-terminal propeptide (−45.9% vs −49.3%), and undercarboxylated osteocalcin (−56.0 vs −66.5%), whereas serum intact parathyroid hormone levels were significantly lower in the DMAb plus active VD group (47.6 pg/mL vs 30.4 pg/mL, P < 0.001). The rate of hypocalcemia was 1.7% in the DMAb plus native VD group and 1.5% in the DMAb plus active VD group, and the rate of clinical fracture incidence was 8.3% in the DMAb plus native VD group and 4.5% in the DMAb plus active VD group, with no significant difference between the groups. DMAb with active VD combination therapy may be a more effective treatment option than DMAb with native VD combination therapy in terms of increasing BMD of the femoral neck and distal part of the forearm and also maintaining serum intact parathyroid hormone at lower levels.This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s00774-016-0792-5Ebina K., Kashii M., Hirao M., et al. Comparison of the effects of denosumab between a native vitamin D combination and an active vitamin D combination in patients with postmenopausal osteoporosis. Journal of Bone and Mineral Metabolism 35, 571 (2017); https://doi.org/10.1007/s00774-016-0792-5

Impact of Native Coronary Artery Calcification on Lesion Outcome Following Drug-Coated Balloon Angioplasty for Treatment of In-Stent Restenosis

This study aimed to clarify whether native coronary artery（CA） calcification before index percutaneous coronary intervention（PCI） has an impact on the effectiveness of drug-coated balloon（DCB） angioplasty for the treatment of in-stent restenosis（ISR）. 100consecutive patients with 166ISR lesions underwent quantitative coronary angiography（QCA） before and after index PCI and before and after DCB angioplasty for ISR. CA calcification before index PCI was assessed by angiography and results were analyzed to reveal the predictive values for target lesion revascularization（TLR） and major adverse cardiac events（MACE）. During 1.03±1.03years of follow-up, TLR occurred in 44lesions（26.5%） and MACE in 33 patients（33%）. On multivariate analysis, CA calcification before index PCI（p=0.016）, and % diameter of stenosis（%DS）≥73%（p=0.023） and minimal lumen diameter（MLD）<0.65mm（p=0.001） before DCB angioplasty were independent predictors for TLR after DCB angioplasty. MACE was also associated with CA calcification before index PCI（p=0.01）, and %DS≥73%（p=0.001） and MLD<0.65mm（p=0.01） before DCB angioplasty, but only %DS≥73% before DCB angioplasty was an independent predictor for MACE after DCB angioplasty（p=0.039）. The combination of CA calcification before index PCI and these QCA factors before DCB angioplasty was an independent and more powerful predictor for MACE than the QCA factors alone（p<0.001）. Thereafter, the combination of CA calcification and %DS≥73% before DCB angioplasty stratified the risk of MACE after DCB angioplasty（p<0.05）. CA calcification before index PCI, as well as anatomical information at ISR, have an impact on outcome after DCB angioplasty for ISR

Efficacy of Combination Therapy with Oseltamivir Phosphate and Azithromycin for Influenza: A Multicenter, Open-Label, Randomized Study

Background: Macrolides have antibiotic and immunomodulatory activities, which may have a favorable effect on the clinical outcome of patients with infections, including influenza. This study aimed to evaluate the effects of combination therapy with an anti-influenza agent, oseltamivir, and a single-dose formulation of azithromycin (AZM), which has been used for influenza-related secondary pneumonia, on influenza patients. The primary endpoint was a change in the expression levels of inflammatory cytokines. Secondary endpoints were the time required for resolution of influenza-related symptoms, incidence of complications, and adverse reactions. Methods: Patients with seasonal influenza were enrolled in this multicenter, open-label, randomized study. Patients were stratified according to the presence of a high risk factor and were randomized to receive combination therapy with oseltamivir plus an extended-release formulation of AZM (combo-group) or oseltamivir monotherapy (mono-group). Results: We enrolled 107 patients and randomized them into the mono-group (56 patients) or the combo-group (51 patients). All patients were diagnosed with influenza A infection, and none of the patients had comorbid pneumonia. Statistically significant differences were not observed in the expression levels of inflammatory cytokines and chemokines between the 2 groups. The maximum temperature in the combo-group was lower than that in the mono-group on day 3 through day 5 (p = 0.048), particularly on day 4 (p = 0.037). Conclusion: To our knowledge, this is the first prospective, randomized, clinical trial of oseltamivir and AZM combination therapy for influenza. Although the difference in inflammatory cytokine expression level was not statistically significant, combination therapy showed an early resolution of some symptoms. Name of registry: University hospital Medical Information Network (UMIN). Trial Registration no.: UMIN000005371

Clinical features, risk factors and treatment of fulminant Mycoplasma pneumoniae pneumonia: A review of the Japanese literature

Mycoplasma pneumoniae (MP) is one of the most common causes of community-acquired pneumonia in children and young adults. Although MP sometimes causes self-limiting pneumonia, severe and fulminant cases with hypoxia occur, but their clinical features have rarely been reported. This study aimed to reveal the clinical manifestations, risk factors, and treatment of fulminant MP pneumonia (MPP). Using PubMed and abstracts from the proceedings of several domestic Japanese academic societies, we reviewed the Japanese and English literature for cases of fulminant or severe MPP reported in Japan. All clinical information such as sex, age, underlying diseases, clinical symptoms, clinical course, laboratory and radiological findings, and treatment was collected and analyzed. In total, 52 fulminant MPP cases were reported between September, 1979 and February, 2010. The dominant population of fulminant MPP was young adults without severe underlying diseases. Cough (97.3%), fever (100.0%), and dyspnea (83.3%) with diffuse abnormal findings in radiological examinations were noted. Antibiotics without antimycoplasmal activity were used in 32 cases (61.5%) as initial treatment prior to the onset of hypoxia. Anti-mycoplasmal drugs were appropriately used in 41 cases (78.8%) after onset of respiratory failure with steroids (23 cases, 45.1%) and effective. The majority of patients improved within 3-5 days after steroid administration. There were only 2 fatal cases. Although this small retrospective study did not reveal the apparent risk factors of fulminant MPP, initial inappropriate use of antibiotics may be a risk factor, and early administration of appropriate anti-mycoplasmal drugs with steroids as a cellular immune suppressor is required

Pathogenesis and clinical features of chronic pulmonary aspergillosis ? Is it possible to distinguish CNPA and CCPA clinically?

Background: The pathogenesis of chronic pulmonary aspergillosis (CPA) including chronic necrotizing pulmonary aspergillosis (CNPA), chronic cavitary pulmonary aspergillosis (CCPA), and simple aspergilloma (SA) has been poorly investigated. We examined all types of CPA cases with histopathological evidence to clarify the differences in pathogenesis and clinical features. Method: We searched for cases diagnosed as pulmonary aspergillosis by histopathological examination in Nagasaki University Hospital between 1964 and September 2010. All available clinical information including radiological findings were collected and analyzed. Result: We found 7, 5, 8, and 7 cases of proven CNPA, probable CNPA, CCPA, and SA, respectively. The radiograph of proven and probable CNPA was initially infiltrates or nodules that progress to form cavities with or without aspergilloma, whereas the radiograph of CCPA showed pre-existed cavities and pericavitary infiltrates with or without aspergilloma. The patients with proven and probable CNPA exhibited not only respiratory symptoms but also systemic symptoms and malnutrition. Aspergillus fumigatus was the most frequently isolated Aspergillus species (n = 14), however, Aspergillus niger was the predominant isolated species in proven CNPA cases (n = 4). Conclusion: Our data indicate that the cases with chronic infiltration, progressive cavitation, and subsequent aspergilloma formation should be diagnosed as CNPA, and the cases with pre-existed cavities showing peri-cavitary infiltrates with or without aspergilloma would mean CCPA. However, it may be difficult to distinguish the two subtypes if a series of adequate radiography films are not available. We propose the term "chronic progressive pulmonary aspergillosis (CPPA)" for the clinical syndrome including both CNPA and CCPA

Review Article : Feudalism or Absolute Monarchism?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68809/2/10.1177_009770049001600304.pd

Efficacy of aerosolized liposomal amphotericin B against murine invasive pulmonary mucormycosis

Invasive pulmonary mucormycosis is a life-threatening fungal infection encountered in immunocompromised patients. An intravenous high-dose lipid formulation of amphotericin B, such as liposomal amphotericin B (L-AMB), is the recommended treatment. The efficacy of inhaled L-AMB against mucormycosis has not been evaluated. We evaluated the efficacy of inhaled aerosolized L-AMB in murine invasive pulmonary mucormycosis. ICR female mice were immunosuppressed with cortisone acetate and cyclophosphamide and challenged on day 0 with 1 × 106 conidia of Rhizopus oryzae (TIMM 1327) intratracheally. Infected mice were assigned to one of the following 3 treatment groups: (i) control, (ii) treatment only (aerosolized L-AMB from day 1-5 after challenge), and (iii) prophylaxis followed by treatment (aerosolized L-AMB from day -2 to 5 before and after challenge). Survival was monitored until 12 days after challenge. For fungalburden and histopathological examination, mice were sacrificed 4 h after treatment on day 3. Numbers of colony-forming units per lung were calculated. To study the distribution of AMB after inhalation of L-AMB, immunohistochemical studies using AMB antibody were performed. Aerosolized L-AMB significantly improved survival rate and decreased fungal burden compared with control group, and histopathology findings were superior to those of control group. However, no significant differences were detected between the treatment-only and prophylaxis followed by treatment groups. Immunohistochemical analysis showed that L-AMB was promptly distributed in lung tissue after inhalation therapy. Aerosolized L-AMB showed modest efficacy against R. oryzae infection in mice treated after fungal challenge. Prophylaxis with aerosolized L-AMB was not effective in this animal model

Challenges in Using Cultured Primary Rodent Hepatocytes or Cell Lines to Study Hepatic HDL Receptor SR-BI Regulation by Its Cytoplasmic Adaptor PDZK1

Background: PDZK1 is a four PDZ-domain containing cytoplasmic protein that binds to a variety of membrane proteins via their C-termini and can influence the abundance, localization and/or function of its target proteins. One of these targets in hepatocytes in vivo is the HDL receptor SR-BI. Normal hepatic expression of SR-BI protein requires PDZK1 - <5% of normal hepatic SR-BI is seen in the livers of PDZK1 knockout mice. Progress has been made in identifying features of PDZK1 required to control hepatic SR-BI in vivo using hepatic expression of wild-type and mutant forms of PDZK1 in wild-type and PDZK1 KO transgenic mice. Such in vivo studies are time consuming and expensive, and cannot readily be used to explore many features of the underlying molecular and cellular mechanisms. Methodology/Principal Findings: Here we have explored the potential to use either primary rodent hepatocytes in culture using 2D collagen gels with newly developed optimized conditions or PDZK1/SR-BI co-transfected cultured cell lines (COS, HEK293) for such studies. SR-BI and PDZK1 protein and mRNA expression levels fell rapidly in primary hepatocyte cultures, indicating this system does not adequately mimic hepatocytes in vivo for analysis of the PDZK1 dependence of SR-BI. Although PDZK1 did alter SR-BI protein expression in the cell lines, its influence was independent of SR-BI’s C-terminus, and thus is not likely to occur via the same mechanism as that which occurs in hepatocytes in vivo. Conclusions/Significance: Caution must be exercised in using primary hepatocytes or cultured cell lines when studying the mechanism underlying the regulation of hepatic SR-BI by PDZK1. It may be possible to use SR-BI and PDZK1 expression as sensitive markers for the in vivo-like state of hepatocytes to further improve primary hepatocyte cell culture conditions.National Institutes of Health (U.S.) (Grant HL052212)National Institutes of Health (U.S.) (Grant HL066105)National Institutes of Health (U.S.) (Grant ES015241)National Institutes of Health (U.S.) (Grant GM068762