Fact-finding survey on the competencies and literacy of radiological technologists regarding radiation disasters.

BACKGROUND: Radiological technologists serve as risk communicators who aim to lessen patients' anxiety about radiation exposure, in addition to performing radiological examinations. OBJECTIVE: We conducted a fact-finding survey on knowledge and awareness of radiation disasters among the radiological technologists to reveal their literacy and competencies regarding radiation disasters. METHODS: A paper questionnaire was distributed to 1,835 radiological technologists at 166 National Hospital Organization facilities in Japan. The 28-item questionnaire covered knowledge and awareness of radiation protection and radiation disasters. Radiological technologists were divided into 2 groups by regionality: areas where a nuclear power station was present/nearby (NPS areas) and non-NPS areas. RESULTS: Completed questionnaires were returned from 148 facilities with a facility response rate of 89.2% and from 1,391 radiological technologists with a response rate of 75.8%. There were 1,290 valid responses with a valid response rate of 70.3%. The correct answer rate for knowledge of radiation protection and radiation disasters was high in the 24 NPS areas. There were no differences in awareness of radiation disasters between NPS and non-NPS areas. CONCLUSIONS: Establishing a nationwide, region-independent training system can be expected to improve literacy regarding radiation disasters among radiological technologists. Willingness to assist during disasters was high among radiological technologists irrespective of area, indicating that the competencies of radiological technologists represent a competency model for radiation disaster assistance.

Vaginal delivery after improvement in COVID-19 by monoclonal antibody treatment: A case report and literature review.

As the COVID-19 pandemic persists, pregnant women have been increasingly affected worldwide. Women during the last trimester of pregnancy are susceptible to severe COVID-19, and there are many challenges towards its treatment. Monoclonal antibody treatment (MAT) is approved for COVID-19 patients to reduce disease severity. However, there are few reports on the MAT in perinatal women. Herein, we report a 39-year-old pregnant female (36 weeks and 6 days of gestation) with improvement in COVID-19 pneumonia after treatment with casiribimab/imdevimab, resulting in successful vaginal delivery (a 2.868 kg male newborn), along with a literature review. Early diagnosis and treatment of pregnant women with COVID-19 are important. Infectious diseases doctors and/or obstetricians should be aware of the MAT option administered to perinatal COVID-19 women to reduce disease severity.

Study of factors related to recurrence within 30 days after pneumonia treatment for community-onset pneumonia.

INTRODUCTION: It is not uncommon for patients hospitalized with pneumonia to experience an early relapse. Here, we investigated the factors related to pneumonia recurrence in Japan. PURPOSE: We aimed to elucidate the factors related to early recurrence after completion of pneumonia treatment. METHODS: We examined 696 patients with community-acquired pneumonia (CAP) and nursing and healthcare-associated pneumonia (NHCAP) who were admitted to our hospital between October 2010 and February 2018, excluding those who died during hospitalization. Logistic regression analysis was used to assess the endpoint of recurrence within 30 days after the end of antibiotic treatment. RESULTS: NHCAP, chronic lung disease and duration of antibiotic treatment were significant risk factors for recurrence of pneumonia within 30 days after antibiotic discontinuation. Aspiration pneumonia was not be a significant factor in the early recurrence of pneumonia. CONCLUSIONS: Long-term use of antimicrobials may be a risk factor in early recurrence of pneumonia.

Association between oral candidiasis and bacterial pneumonia: A retrospective study.

OBJECTIVE: To investigate associated risk factors for oral candidiasis in elderly patients hospitalized in a community-based acute-care hospital with no dental units. METHODS: Two hundred and twenty-eight elderly patients (male: 105, female: 123), who were hospitalized with several systemic diseases in a community-based acute-care hospital from May 2014 to October 2016, were retrospectively analysed by multiple logistic regression. RESULTS: Multiple logistic regression analysis shows that bacterial pneumonia has a statistically strong relationship with oral candidiasis (p = 0.000, OR: 5.173, 95% CI: 2.368-11.298). The order followed is poor oral hygiene (p = 0.001, OR: 6.095, 95% CI: 2.003-18.545) and severe dry mouth (p = 0.043, OR: 2.507, 95% CI: 1.031-6.098). Other correlated factors including diabetes mellitus, denture wearer, dysphagia, malnutrition, requiring care and use of inhalation steroids, were not statistically significant in this study. CONCLUSIONS: Bacterial pneumonia correlates with oral candidiasis.

Sequential Treatment with Eldecalcitol After PTH Improves Bone Mechanical Properties of Lumbar Spine and Femur in Aged Ovariectomized Rats.

Parathyroid hormone (PTH) analogs have a powerful anabolic effect on bone and are used in the treatment of patients with severe osteoporosis. However, there are limitations to how long they can be safely administered. Withdrawal of PTH results in the cancelation of its effects, necessitating subsequent treatment to maintain the bone quantity and quality. This study assessed the effects of Eldecalcitol (ELD), an active vitamin D3 derivative, after PTH in estrogen-deficient osteoporotic rats. Six-month-old female rats were ovariectomized, and PTH administration was started 7 weeks later. After 4 weeks of PTH treatment, the animals were divided into three groups and either continued to receive PTH (PTH-PTH), or were switched to ELD (PTH-ELD) or vehicle (PTH-Veh) for an additional 4 weeks. In the femur, increased BMD by 4 weeks treatment of PTH was significantly reduced in PTH-Veh but not in PTH-PTH and PTH-ELD. The same tendency was observed in the lumbar vertebrae. MicroCT imaging and histomorphometry analysis revealed that the favorable bone structure changes by PTH administration were also maintained in the femurs and tibias of the PTH-PTH and PTH-ELD groups. Increased bone strength by 4-week treatment of PTH in lumber also maintained in PTH-ELD. Furthermore, minimodeling was observed in the PTH-ELD group. These results demonstrate that treatment with ELD sequentially following PTH prevented the bone quantity and strength reduction that accompanies PTH withdrawal in estrogen-deficient rats.

Procalcitonin is not an independent predictor of 30-day mortality, albeit predicts pneumonia severity in patients with pneumonia acquired outside the hospital.

BACKGROUND: Procalcitonin (PCT) is a useful marker for pneumonia. However, its clinical usefulness in elderly patients has not been studied extensively. This study aimed to assess the relationship between PCT and prognosis and pneumonia severity in elderly patients with pneumonia acquired outside the hospital. METHODS: Data considered relevant to pneumonia severity and prognosis were retrospectively obtained from clinical charts of all patients with pneumonia who were admitted to our hospital from 2010 to 2017. The primary outcome was 30-day mortality in elderly patients (aged ≥75 years), and the relationship between PCT levels and pneumonia severity, as determined by the pneumonia severity index (PSI) was also examined. RESULTS: Data were collected from 667 patients, of which 436 were elderly patients. Multivariate and receiver operating characteristic curve analysis revealed that albumin, body mass index, and PSI class rather than PCT are important factors related to 30-day mortality in elderly patients. PCT was also not an independent prognostic factor in younger patients. PCT levels significantly differed by pneumonia severity (mild, moderate, and severe) in both younger (p < 0.001) and elderly (p < 0.0001) patients, with levels increasing as severity increased. In contrast, C-reactive protein (CRP) levels and white blood cell counts did not significantly differ by pneumonia severity in younger and elderly patients. A subgroup analysis focused on Streptococcus pneumoniae pneumonia revealed that PCT levels differed by severity in elderly patients (p = 0.03), with levels increasing as severity increased. CONCLUSION: PCT was not an independent predictor of 30-day mortality in both of elderly and younger patients. PCT levels, but not CRP levels, significantly increased with increasing pneumonia severity in younger and elderly patients, although the degree of increase tended to be lower in elderly patients compared to younger patients for the same severity. PCT levels also significantly increased with increasing pneumonia severity in elderly patients with Streptococcus pneumoniae pneumonia.

Simian Immunodeficiency Virus Targeting of CXCR3+ CD4+ T Cells in Secondary Lymphoid Organs Is Associated with Robust CXCL10 Expression in Monocyte/Macrophage Subsets.

Glycosylation of Env defines pathogenic properties of simian immunodeficiency virus (SIV). We previously demonstrated that pathogenic SIVmac239 and a live-attenuated, quintuple deglycosylated Env mutant (Δ5G) virus target CD4+ T cells residing in different tissues during acute infection. SIVmac239 and Δ5G preferentially infected distinct CD4+ T cells in secondary lymphoid organs (SLOs) and within the lamina propria of the small intestine, respectively (C. Sugimoto et al., J Virol 86:9323-9336, 2012, https://doi.org/10.1128/JVI.00948-12). Here, we studied the host responses relevant to SIV targeting of CXCR3+ CCR5+ CD4+ T cells in SLOs. Genome-wide transcriptome analyses revealed that Th1-polarized inflammatory responses, defined by expression of CXCR3 chemokines, were distinctly induced in the SIVmac239-infected animals. Consistent with robust expression of CXCL10, CXCR3+ T cells were depleted from blood in the SIVmac239-infected animals. We also discovered that elevation of CXCL10 expression in blood and SLOs was secondary to the induction of CD14+ CD16+ monocytes and MAC387+ macrophages, respectively. Since the significantly higher levels of SIV infection in SLOs occurred with a massive accumulation of infiltrated MAC387+ macrophages, T cells, dendritic cells (DCs), and residential macrophages near high endothelial venules, the results highlight critical roles of innate/inflammatory responses in SIVmac239 infection. Restricted infection in SLOs by Δ5G also suggests that glycosylation of Env modulates innate/inflammatory responses elicited by cells of monocyte/macrophage/DC lineages.IMPORTANCE We previously demonstrated that a pathogenic SIVmac239 virus and a live-attenuated, deglycosylated mutant Δ5G virus infected distinct CD4+ T cell subsets in SLOs and the small intestine, respectively (C. Sugimoto et al., J Virol 86:9323-9336, 2012, https://doi.org/10.1128/JVI.00948-12). Accordingly, infections with SIVmac239, but not with Δ5G, deplete CXCR3+ CCR5+ CD4+ T (Th1) cells during the primary infection, thereby compromising the cellular immune response. Thus, we hypothesized that distinct host responses are elicited by the infections with two different viruses. We found that SIVmac239 induced distinctly higher levels of inflammatory Th1 responses than Δ5G. In particular, SIVmac239 infection elicited robust expression of CXCL10, a chemokine for CXCR3+ cells, in CD14+ CD16+ monocytes and MAC387+ macrophages recently infiltrated in SLOs. In contrast, Δ5G infection elicited only modest inflammatory responses. These results suggest that the glycosylation of Env modulates the inflammatory/Th1 responses through the monocyte/macrophage subsets and elicits marked differences in SIV infection and clinical outcomes.

Comprehensive analysis of prognostic factors in hospitalized patients with pneumonia occurring outside hospital: Serum albumin is not less important than pneumonia severity assessment scale.

PURPOSE: This study aimed to elucidate factors related to 30-day mortality of pneumonia occurring outside hospital by comprehensively analyzing data considered relevant to prognosis. METHODS: Data considered relevant to prognosis were retrospectively examined from clinical charts and chest X-ray images of all patients with pneumonia occurring outside hospital admitted to our hospital from 2010 to 2016. The primary outcome was 30-day mortality. RESULTS: Data were collected from 534 patients (317 community-acquired pneumonia and 217 nursing- and healthcare associated pneumonia patients; 338 men (63.3%); mean age, 76.2 years-old). Eighty-three patients (9.9%) died from pneumonia within 30 days from the date of admission. The numbers of patients with pneumonia severity index (PSI) classes of I/II/III/IV/V and age, dehydration, respiratory failure, orientation disturbance, pressure (A-DROP) scores of 0/1/2/3/4/5 were 29/66/127/229/83, and 71/107/187/132/30/7, respectively. Mean (standard deviation) body mass index (BMI), serum albumin, blood procalcitonin, white blood cell and C-reactive protein were 20.00 (4.12) kg/m2, 3.16 (0.60) g/dL, 3.69 (13.15) ng/mL, 11559.4 (5656.9)/mm3, and 10.92 (8.75) mg/dL, respectively. Chest X-ray images from 152 patients exhibited a pneumonia shadow over a quarter of total lung field. Logistic regression analysis revealed that PSI class or A-DROP score, BMI, serum albumin, and extent of pneumonia shadow were related to 30-day mortality. Receiver operating characteristics curve analysis revealed that serum albumin was superior to PSI class or A-DROP score for predicting 30-day mortality. CONCLUSION: Serum albumin is not less important than PSI class or A-DROP score for predicting 30-day mortality in hospitalized patients with pneumonia occurring outside hospital.

Antiviral activity of acid beta-glucosidase 1 on enterovirus 71, a causative agent of hand, foot and mouth disease.

Enterovirus 71 (EV71) is a causative agent of hand, foot and mouth disease (HFMD). EV71 causes fever, rash, diarrhoea and, in some cases, acute encephalopathy/encephalitis, which can be fatal. No specific treatment is currently available for EV71 infection. Here, we conducted a cDNA library screen and identified acid ß-glucosidase 1 (GBA1; also known as ß-glucocerebrosidase) as an EV71 resistance factor. The anti-EV71 function of GBA1 was verified by gene transduction and knockdown experiments. Cerezyme, a molecular drug used to treat Gaucher's disease and having recombinant human GBA1 as the active ingredient, protected against EV71 infection. The anti-EV71 activity of GBA1 was bimodal: endogenous GBA1 restricted cell surface expression levels of scavenger receptor class B, member 2 (SCARB2), also known as lysosomal integral membrane protein 2 (LIMP-2), and exogenous recombinant GBA1 interfered with EV71 to interact with SCARB2 outside the cell. Thus, our findings suggest that GBA1 may represent a novel molecular target for the treatment of EV71 infection.

Eldecalcitol, an Active Vitamin D3 Derivative, Prevents Trabecular Bone Loss and Bone Fragility in Type I Diabetic Model Rats.

Diabetes mellitus is known to adversely affect the bones and be associated with increased fracture risk. We examined whether eldecalcitol (ELD), an active vitamin D3 derivative, could inhibit the diabetic bone loss in streptozotocin-induced type I diabetic rats. ELD (10, 20, or 40 ng/kg), alfacalcidol (ALF; 25, 50, or 100 ng/kg), or vehicle was administered 5 times per week for 12 weeks from 1 week after diabetes induction. Normal control rats received the vehicle. Bone turnover markers, bone mineral density (BMD), and biomechanical strength of the lumbar spine and femur were measured, and bone histomorphometry was performed. Content of advanced glycation end products (AGEs) in the femoral shaft was also determined. In diabetic rats, serum osteocalcin (OC) concentration was lower and urinary excretion of deoxypyridinoline (DPD) tended to be higher than in normal rats. Areal BMD and maximum load of the lumbar vertebrae and femoral shaft were lower in diabetic rats than in normal rats. All doses of ELD and the highest dose of ALF reduced urinary DPD excretion, but had no effect on serum OC. The 20 and 40 ng/kg doses of ELD prevented decreases in BMD and the highest dose of ELD prevented the reduction in maximum load of the lumbar vertebrae, while ALF did not change these parameters. ELD and ALF did not affect areal BMD or biomechanical strength of the femoral shaft. In diabetic rats, bone volume and trabecular thickness in the trabecular bone of the lumbar vertebrae decreased and trabecular separation increased compared to normal rats. ELD and ALF prevented diabetes-induced deterioration of trabecular microstructure. AGE content in the femoral cortical bone increased in the diabetic rats, and ELD and ALF did not change AGE content compared to the diabetic rats. These results indicated that ELD suppressed bone resorption and prevented trabecular bone loss and deterioration of trabecular microstructure, resulting in prevention of reduction in biomechanical strength in type I diabetic rats.

Intermittent Ibandronate Maintains Bone Mass, Bone Structure, and Biomechanical Strength of Trabecular and Cortical Bone After Discontinuation of Parathyroid Hormone Treatment in Ovariectomized Rats.

Although parathyroid hormone (PTH) expresses an anabolic effect on bone mass, the increased bone mass disappears once PTH treatment is withdrawn. Therefore, sequential treatment with anti-bone-resorptive agents is required to maintain bone mass after PTH treatment. We examined the effect of sequential treatment with ibandronate (IBN), a nitrogen-containing bisphosphonate, following PTH in ovariectomized (OVX) rats. Wistar-Imamichi rats (27 weeks old) were ovariectomized and treated with PTH (10 µg/kg, s.c.; 5 times/week; PTH group) for 8 weeks from 8 weeks after OVX. Thereafter, PTH was withdrawn and rats were administered IBN (10 µg/kg, s.c.; every 4 weeks; PTH-IBN group) or vehicle (PTH-Veh group) for another 8 weeks. PTH increased bone mineral density (BMD) measured by dual-energy X-ray absorptiometry and biomechanical strength in the lumbar spine and femur as compared to the disease control rats. BMD and biomechanical strength in the PTH-Veh group were lower than in the PTH group, whereas in the PTH-IBN group they were maintained at the level of the PTH group. Microstructure of the trabecular and cortical bone in the PTH-IBN group was not significantly different from that in the PTH group. In histomorphometric analysis of the lumbar vertebra, eroded surface and osteoclast surface in the PTH-Veh group were no different from those in the PTH group, whereas they were lower in the PTH-IBN group. Osteoid surface, osteoblast surface, and mineralize surface decreased in both PTH-IBN and PTH-Veh groups compared to the PTH group, and these parameters in the PTH-IBN group were lower than in the PTH-Veh group. These results indicated that intermittent IBN after PTH treatment suppressed bone turnover and maintained BMD, biomechanical strength, and microstructure in the lumbar spine and femur of OVX rats.

Conformational properties of the third variable loop of HIV-1AD8 envelope glycoprotein in the liganded conditions.

The conformational dynamics of the HIV-1 envelope glycoprotein gp120 and gp41 (Env) remains poorly understood. Here we examined how the V3 loop conformation is regulated in the liganded state using a panel of recombinant HIV-1NL4-3 clones bearing HIV-1AD8 Env by two experimental approaches, one adopting a monoclonal neutralizing antibody KD-247 (suvizumab) that recognizes the tip of the V3 loop, and the other assessing the function of the V3 loop. A significant positive correlation of the Env-KD-247 binding was detected between the liganded and unliganded conditions. Namely, the mutation D163G located in the V2 loop, which enhances viral susceptibility to KD-247 by 59.4-fold, had little effect on the sCD4-induced increment of the virus-KD-247 binding. By contrast, a virus with the S370N mutation in the C3 region increased the virus-KD-247 binding by 91.4-fold, although it did not influence the KD-247-mediated neutralization. Co-receptor usage and the susceptibility to CCR5 inhibitor Maraviroc were unaffected by D163G and S370N mutations. Collectively, these data suggest that the conformation of the liganded V3-loop of HIV-1AD8 Env is still under regulation of other Env domains aside from the V3 loop, including V2 and C3. Our results give an insight into the structural properties of HIV-1 Env and viral resistance to entry inhibitors by non-V3 loop mutations.

Ibandronate concomitantly blocks immobilization-induced bone and muscle atrophy.

Both bone and muscle volume is concomitantly reduced under immobilization conditions; however, no single drug is currently available to block these outcomes simultaneously. Bisphosphonates are utilized clinically to inhibit osteoclast-dependent bone resorption, but their effects on muscle are largely unknown. Here we show that skeletal muscle is a direct target of the bisphosphonate ibandronate (IBN) and that reduced muscle volume and induction of Atrogin-1 and MuRF1, both atrogenes, are significantly inhibited by IBN administration in vivo using a mouse model of muscle atrophy. IBN treatment also significantly blocked immobilization-induced bone loss in vivo. We also report that expression of Atrogin-1 and MuRF1 and accumulation of Smad2/3 proteins, which are upstream of atrogines, occurred following serum starvation of myogenic C2C12 cells in vitro, effects significantly inhibited by IBN treatment. Interestingly, IBN effects on C2C12 cells were abrogated by MG132, an ubiquitin/proteasome inhibitor, suggesting that IBN functions via the ubiquitin-proteasome system. Our findings lend new insight into the role of IBN in preventing muscle atrophy.

Long-term treatment with eldecalcitol (1α, 25-dihydroxy-2ß- (3-hydroxypropyloxy) vitamin D3) suppresses bone turnover and leads to prevention of bone loss and bone fragility in ovariectomized rats.

The purpose of this study is to estimate the efficacy of eldecalcitol (1α, 25-Dihydroxy-2ß- (3-hydroxypropyloxy) vitamin D3; ELD) on bone metabolism after long-term administration. Six-month-old Wistar-Imamichi rats were ovariectomized (OVX) and administered ELD orally at doses of 7.5, 15, or 30 ng/kg daily. Bone mineral density (BMD), urinary excretion of deoxypyridinoline (DPD), a bone resorption marker, and serum total alkaline phosphatase (ALP), a surrogate marker of bone formation, were assessed after 3, 6, and 12 months of treatment. After 12 months of treatment, the biomechanical strength of the L4 lumbar vertebra and femoral shaft was measured, and bone histomorphometry was performed on the L3 lumbar vertebra and the tibia diaphysis. ELD prevented OVX-induced decreases in BMD of the lumbar vertebrae and femur throughout the treatment period. ELD significantly suppressed OVX-induced increases in urinary DPD excretion throughout the treatment period with minimal effects on ALP. OVX resulted in significant decreases in ultimate load and stiffness of the L4 lumbar vertebra and femoral shaft, and ELD significantly prevented the reduction in these biomechanical parameters. Bone histomorphometry at the L3 lumbar vertebra revealed that OVX induced increases in bone resorption parameters (osteoclast surface and osteoclast number) and bone formation parameters (osteoblast surface, osteoid surface, and bone formation rate), and ELD suppressed these parameters after 12 months treatment. Activation frequency, which was elevated in the OVX/vehicle group, was significantly suppressed to baseline levels in ELD-treated groups, indicating that ELD maintained bone turnover at a normal level. ELD also prevented OVX-induced deterioration of microstructure in trabecular and cortical bone. These results indicated that long-term treatment of OVX rats with ELD suppressed bone turnover, and prevented OVX-induced bone loss, deterioration of bone microstructure, and reduction in bone biomechanical strength.

Influenza vaccination during pregnancy and its usefulness to mothers and their young infants.

The current approach to protecting pregnant women from influenza infection and serious influenza-related complications is vaccination. It is, therefore, critical to evaluate the vaccine's safety, immunogenicity, and protection efficacy during pregnancy. However, because it is affected by previous influenza vaccination or infection, the efficacy of the seasonal trivalent inactivated influenza vaccine is difficult to evaluate in pregnant women. The A/H1N1pdm pandemic in 2009 provided us with the opportunity to evaluate the immunogenicity of the influenza vaccine unaffected by previous vaccinations or infections. Vaccination with inactivated influenza virus during pregnancy elicited neutralizing antibody titers that were sufficient and comparable to those of naturally infected individuals. Furthermore, post-pandemic surveys provided a wealth of definitive information on vaccine efficacy and safety. In addition, transplacental transfer of antibodies following vaccination protected newborn infants against influenza infection. With reports showing the effectiveness of influenza vaccine during pregnancy, it is suggested that influenza vaccination benefits both mothers and their young infants.

Enhanced susceptibility of B lymphoma cells to measles virus by Epstein-Barr virus type III latency that upregulates CD150/signaling lymphocytic activation molecule.

Measles virus (MV) is one of the candidates for the application of oncolytic virotherapy (OVT). Although an advanced clinical study has been reported on a T-cell lymphoma, the potential of MV OVT against B-cell lymphomas remains to be clarified. We found that an EBV-transformed B lymphoblastoid cell line, a model for diffuse large B-cell lymphoma, and EBV-positive Burkitt's lymphoma cells bearing type III latency were highly susceptible to the cytolysis induced by an MV vaccine strain CAM-70. As analyzed by EBV-positive and -negative counterparts of the same cytogenetic background, type III EBV latency, not type I, was shown to augment the susceptibility of B lymphoma cells to MV-induced cytolysis. Cell surface levels of CD150/signaling lymphocytic activation molecule, a receptor of MV, were upregulated in B lymphoma cell lines with type III EBV latency by 3.8-fold, on average. The cytolytic activity of CD150-tropic WT MV was akin to that of CD46- and CD150-tropic CAM-70, suggesting that CD150 is critical for the susceptibility to MV-induced cytolysis. Among EBV-encoded genes, latent membrane protein 1 was responsible for the CD150 upregulation. It was notable that the majority of B lymphoma cell lines of type III EBV latency showed higher susceptibility to the non-Edmonston-derived CAM-70 than to the Edmonston-derived Schwarz strain. This is the first report indicating the potential of non-Edmonston MV strain for the application of OVT. Furthermore, a cellular regulator of MV replication was implicated that functions in a vaccine strain-specific fashion. Altogether, the MV OVT should serve as an alternative therapy against EBV-positive diffuse large B-cell lymphoma with type III EBV latency.

22-Oxacalcitriol prevents progression of endothelial dysfunction through antioxidative effects in rats with type 2 diabetes and early-stage nephropathy.

BACKGROUND: Vitamin D deficiency is associated with endothelial dysfunction in type 2 diabetes patients, but the effectiveness of vitamin D supplementation remains controversial. We assessed whether 22-oxacalcitriol (OCT) could prevent endothelial dysfunction in type 2 diabetes mellitus (DM) rats. METHODS: DM rats with early-stage nephropathy were treated for 10 weeks with OCT (0.2 µg/kg) three times per week or by an implanted insulin pellet. Endothelial dysfunction was assessed by femoral flow-mediated dilation (FMD). RESULTS: Insulin significantly improved FMD as blood glucose levels normalized. OCT also improved FMD without hypercalcemia or hyperphosphatemia and without affecting blood glucose or blood pressure. In femoral arteries, OCT significantly suppressed the elevated expression of p22(phox), a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit, and improved the endothelial nitric oxide synthase (eNOS) dimer-to-monomer ratio. In cultured endothelial cells, OCT significantly inhibited high-glucose (HG)-induced reactive oxygen species (ROS) production. Simultaneously, OCT significantly suppressed HG-induced p22(phox) expression and improved eNOS uncoupling as was observed in the in vivo study. CONCLUSION: In DM rats, OCT improved endothelial dysfunction, at least in part, by suppressing ROS generation through p22(phox) expression, which might contribute to improving eNOS uncoupling.

A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy.

In an extension of our study on gamma hydroxy carboxylic acid analogs, we explored a series of nonsecosteroidal vitamin D receptor (VDR) agonists in which 1,3-diol of 1,25(OH)2D3 had been replaced by aryl acetic acid. These analogs showed very potent activity in vitro compared with 1,25(OH)2D3. An X-ray analysis of 8d showed that the inserted phenyl ring well mimicked the folded methylene linker of the gamma hydroxy carboxylic acid moiety but the carboxylic acid of 8d interacted with VDR in a different manner from gamma hydroxy carboxylic acids. Through our in vivo screening in an osteoporosis rat model using immature rats, we identified a potent active vitamin D3 analog, compound 7e. In mature rats of the same model, compound 7e also showed good PK profiling and excellent ability to prevent bone mineral density loss without severe hypercalcemia. Our nonsecosteroidal VDR agonist 7e (CH5036249) could be a possible new drug candidate for treating osteoporosis in human.

Mechanisms of the beneficial effects of vitamin B6 and pyridoxal 5-phosphate on cardiac performance in ischemic heart disease.

Although vitamin B6 and its metabolite, pyridoxal 5'-phosphate (PLP), have been shown to exert beneficial effects in ischemic heart disease, the mechanisms of their action are not fully understood. Some studies have shown that ventricular arrhythmias and mortality upon the occlusion of coronary artery were attenuated by pretreatment of animals with PLP. Furthermore, ischemia-reperfusion-induced abnormalities in cardiac performance and defects in sarcoplasmic reticular Ca2+-transport activities were decreased by PLP. The increase in cardiac contractile activity of isolated heart by ATP was reduced by PLP, unlike propranolol, whereas that by isoproterenol was not depressed by PLP. ATP-induced increase in [Ca2+]i, unlike KCl-induced increase in [Ca2+]i in cardiomyocytes was depressed by PLP. Both high- and low-affinity sites for ATP binding in sarcolemmal membranes were also decreased by PLP. These observations support the view that PLP may produce cardioprotective effects in ischemic heart disease by attenuating the occurrence of intracellular Ca2+ overload due to the blockade of purinergic receptors.

Elevation of serum C-reactive protein predicts failure of the initial antimicrobial treatment for febrile neutropenia with lung cancer.

Febrile neutropenia frequently develops after chemotherapy, and the prompt administration of antimicrobial agents is required for treatment. In the present study, we searched for predictive factors for the failure of the initial antimicrobial agents used for febrile neutropenia (FN) in patients with lung cancer. Sixty FN patients treated in our ward from June 2005 to May 2011 were retrospectively analyzed. The definition of FN and the response to antimicrobial agents were determined by the Japanese guidelines. We divided the FN patients into two groups by their response to the initial antimicrobial agents. Next, the characteristics of the two groups were compared. The Multinational Association of Supportive Care in Cancer (MASCC) score did not differ between the two groups. The non-responder group demonstrated significant elevation of serum C-reactive protein (CRP) level. A multivariate analysis demonstrated that a CRP level higher than 10 mg/dl is an independent risk factor for the failure of initial antimicrobial agents for FN with lung cancer (OR 11.0, 95 % CI 1.635-74.5). When the CRP score was added to the MASCC score, the scoring system could more precisely predict the failure of initial antimicrobial agents in patients with lung cancer who developed febrile neutropenia.