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Reduced GFR in patients with CKD causes systemic accumulation of uremic toxins, which has been correlated with disease progression and increased morbidity. The orally administered spherical carbon adsorbent AST-120 reduces systemic toxin absorption through gastrointestinal sequestration, which may slow disease progression in these patients. The multinational, randomized, double-blind, placebo-controlled Evaluating Prevention of Progression in CKD (EPPIC)-1 and EPPIC-2 trials evaluated the effects of AST-120 on the progression of CKD when added to standard therapy. We randomly assigned 2035 adults with moderate to severe disease (serum creatinine at screening, 2.0-5.0 mg/dl for men and 1.5-5.0 mg/dl for women) to receive either placebo or AST-120 (9 g/d). The primary end point was a composite of dialysis initiation, kidney transplantation, and serum creatinine doubling. Each trial continued until accrual of 291 primary end points. The time to primary end point was similar between the AST-120 and the placebo groups in both trials (EPPIC-1: hazard ratio, 1.03; 95% confidence interval, 0.84 to 1.27; P=0.78) (EPPIC-2: hazard ratio, 0.91; 95% confidence interval, 0.74 to 1.12; P=0.37); a pooled analysis of both trials showed similar results. The estimated median time to primary end points for the placebo groups was 124 weeks for power calculations, but actual times were 189.0 and 170.3 weeks for EPPIC-1 and EPPIC-2, respectively. Thus, disease progression was more gradual than expected in the trial populations. In conclusion, the benefit of adding AST-120 to standard therapy in patients with moderate to severe CKD is not supported by these data.

BACKGROUND: Aneurysmal bone cyst is a benign, locally destructive lesion of bone. The rates of local recurrence after curettage have varied widely. Therefore, we performed a retrospective study of patients who had had an aneurysmal bone cyst in order to identify the rate of local recurrence and the prognostic factors related to local recurrence after use of contemporary methods of curettage with a high-speed burr. METHODS: We reviewed the cases of forty patients who had been managed by the same surgeon for an aneurysmal bone cyst, as diagnosed on the basis of the latest pathological review, between January 1, 1976, and December 31, 1993. The patients were evaluated with regard to age, gender, the duration and type of symptoms, the presence or absence of pathological fracture, the status of the growth plate, the bone and part of the bone that were involved, the type of operative procedure, the outcome, the radiographic stage, the findings on magnetic resonance imaging and computerized tomography (when it became available) and on bone scintigraphy, and histological parameters. The median duration of follow-up was eighty-seven months (range, fifteen to 267 months). According to the criteria of Enneking, no patient had a stage-1 lesion (one with a surrounding rim of cortical bone), twenty-four had a stage-2 lesion (one with a clearly defined border but no cortical bone), and sixteen had a stage-3 lesion (one with no clearly defined border). RESULTS: Of the forty patients, thirty-four had curettage with use of a high-speed burr. Of these thirty-four, twenty-two had filling of the defect with a cancellous autogenous graft; four, with a cancellous allograft; and three, with polymethylmethacrylate. In five patients, no material was put into the defect. The remaining six patients had resection through the margin of the lesion. Four (12 percent) of the thirty-four patients who had curettage had a local recurrence. No patient who had an excision through the margin of the lesion had a local recurrence. All local recurrences were in skeletally immature girls who were three, four, ten, and eleven years old. Univariate analysis with use of the chi-square, Fisher exact, and Wilcoxon log-rank tests showed that local recurrence was associated only with a young age (p = 0.0036) and open growth plates (p = 0.039). All local recurrences occurred within two years postoperatively, at two, seven, nine, and twenty-four months, and all were treated successfully with a second operation. CONCLUSIONS: Rates of local control of almost 90 percent can be achieved with thorough curettage with use of a mechanical burr and without use of liquid nitrogen, phenol, or other adjuvants in patients who have an aneurysmal bone cyst of an extremity. A young age and open growth plates are associated with an increased risk of local recurrence.

Age determination is undertaken for nearby early type (BAF) stars, which constitute attractive targets for high-contrast debris disk and planet imaging surveys. Our analysis sequence consists of acquisition of uvbyβ photometry from catalogs, correction for the effects of extinction, interpolation of the photometry onto model atmosphere grids from which atmospheric parameters are determined, and finally, comparison to the theoretical isochrones from pre-main sequence through post-main sequence stellar evolution models, accounting for the effects of stellar rotation. We calibrate and validate our methods at the atmospheric parameter stage by comparing our results to fundamentally determined T_(eff) and log g values. We validate and test our methods at the evolutionary model stage by comparing our results on ages to the accepted ages of several benchmark open clusters (IC 2602, α Persei, Pleiades, Hyades). Finally, we apply our methods to estimate stellar ages for 3493 field stars, including several with directly imaged exoplanet candidates.

Canine distemper of domestic dogs is caused by canine distemper virus (CDV), a member of the morbilliviruses. It has been a highly contagious disease of great veterinary importance for centuries, but for the last several decades it has been controlled satisfactorily by modified live vaccines. In the 1990s, however, it was described that CDV strains genetically different from vaccine strains may have caused the disease in vaccinated dogs. The highest antigenic variation is found in the H protein. Therefore, in the present study, hemagglutinin (H) genes obtained from current vaccines and field isolates and amplified directly from clinical specimens were genetically analyzed by restriction fragment length polymorphism assay and sequencing. Phylogenetic analysis of the H-gene amino acid sequences revealed that at least two CDV genotypes are circulating among dogs in Japan; one is a genotype to which almost all Japanese CDV isolates belong and the other has not been previously described. Both are separate and independent from the other lineages or genotypes of vaccine strains, as well as European and U.S. CDV isolates. The results suggest that CDV has also evolved in Japan, and further studies will be needed for an evaluation and possible improvement of the efficacies of current CDV vaccines.

OBJECTIVE: Treatment of autoimmune diseases with therapies that tolerize pathogenic lymphocytes may obviate the need for longterm global immunosuppression. In vitro, non-Fc receptor binding derivatives of anti-murine CD3 monoclonal antibodies tolerize type 1 T cells and stimulate type 2 T cells. Recently, a humanized non-FcR binding derivative of the anti-human CD3 Mab OKT3, huOKT3gamma1(ala-ala), has been described. We hypothesized that this Mab may be safe and efficacious in the treatment of type 1 T lymphocyte mediated chronic autoimmune diseases such as psoriatic arthritis (PsA). METHODS: In a Phase I/II trial, 7 patients with PsA were treated with escalating daily doses of huOKT3gamma1(ala-ala) for 12 to 14 days. Number of tender and swollen joints and a visual analog pain scale were used to rate disease activity at entry and Day 30 and Day 90 after treatment. RESULTS: At Day 30, 6 of 7 patients had > or = 75% improvement in the number of inflamed joints and an average 63% improvement on the patient pain scale. Two of 6 responders had sustained improvement at Day 90. No patient treated with an initial dose < or = 1 mg had significant side effects, nor did they have detectable increases in serum cytokines. One patient treated with 4 mg without escalation developed mild cytokine release symptoms associated with elevation of interleukin 10. Transient T cell depletion occurred following treatment with the maximum dose of 4 mg, which resolved by Day 30. Antiidiotypic antibodies developed in 2 patients; however, there was no concurrent decrease in efficacy. CONCLUSION: These data indicate that huOKT3gamma1(ala-ala) may be useful in treating PsA.

One-third of the lipid A found in the Escherichia coli outer membrane contains an unsubstituted diphosphate unit at position 1 (lipid A 1-diphosphate). We now report an inner membrane enzyme, LpxT (YeiU), which specifically transfers a phosphate group to lipid A, forming the 1-diphosphate species. (32)P-labelled lipid A obtained from lpxT mutants do not produce lipid A 1-diphosphate. In vitro assays with Kdo(2)-[4'-(32)P]lipid A as the acceptor shows that LpxT uses undecaprenyl pyrophosphate as the substrate donor. Inhibition of lipid A 1-diphosphate formation in wild-type bacteria was demonstrated by sequestering undecaprenyl pyrophosphate with the cyclic polypeptide antibiotic bacitracin, providing evidence that undecaprenyl pyrophosphate serves as the donor substrate within whole bacteria. LpxT-catalysed phosphorylation is dependent upon transport of lipid A across the inner membrane by MsbA, a lipid A flippase, indicating a periplasmic active site. In conclusion, we demonstrate a novel pathway in the periplasmic modification of lipid A that is directly linked to the synthesis of undecaprenyl phosphate, an essential carrier lipid required for the synthesis of various bacterial polymers, such as peptidoglycan.

The suprachiasmatic nucleus (SCN) of the hypothalamus is the neural locus of the circadian clock. To explore the organization of the SCN, two strains of transgenic mice, each bearing a jellyfish green fluorescent protein (GFP) reporter, were used. In one, GFP was driven by the promoter region of the mouse Period1 gene (mPer1) (Per1::GFP mouse), whereas in the other, GFP was inserted in the promoter region of calbindin-D(28K)-bacterial artificial chromosome (CalB::GFP mouse). In the latter mouse, GFP-containing SCN cells are immunopositive for gastrin-releasing peptide. In both mouse lines, light-induced Per1 mRNA and Fos are localized to the SCN subregion containing gastrin-releasing peptide. Double-label immunohistochemistry reveals that most gastrin-releasing peptide cells (approximately 70%) contain Fos after a brief light pulse. To determine the properties of SCN cells in this light-responsive region, we examined the expression of rhythmic Period genes and proteins. Gastrin-releasing peptide-containing cells do not express detectable rhythms in these key components of the molecular circadian clock. The results support the view that the mammalian SCN is composed of functionally distinct cell groups, of which some are light induced and others are rhythmic with respect to clock gene expression. Furthermore, the findings suggest that gastrin-releasing peptide is a potential mediator of intercellular communication between light-induced and oscillator cells within the SCN.

Since the emergence of Canine parvovirus (CPV-2) in the late 1970s, CPV-2 has evolved consecutively new antigenic types, CPV-2a and 2b. Although CPV-2 did not have a feline host range, CPV-2a and 2b appear to have gained the ability to replicate in cats. Recent investigations demonstrate the prevalence of CPV-2a and 2b infection in a wide range of cat populations. We illustrate the pathogenic potential of CPV in cats and assess the risk caused by CPV variants.

Preclinical studies have revealed that the elevation of nicotinamide adenine dinucleotide (NAD + ) upon the administration of nicotinamide mononucleotide (NMN), an NAD + precursor, can mitigate aging-related disorders; however, human data on this are limited. We investigated whether the chronic oral supplementation of NMN can elevate blood NAD + levels and alter physiological dysfunctions in healthy older participants. We administered 250 mg NMN per day to aged men for 6 or 12 weeks in a placebo-controlled, randomized, double-blind, parallel-group trial. Chronic NMN supplementation was well tolerated and caused no significant deleterious effect. Metabolomic analysis of whole blood samples demonstrated that oral NMN supplementation significantly increased the NAD + and NAD + metabolite concentrations. There were nominally significant improvements in gait speed and performance in the left grip test, which should be validated in larger studies; however, NMN exerted no significant effect on body composition. Therefore, chronic oral NMN supplementation can be an efficient NAD + booster for preventing aging-related muscle dysfunctions in humans.

Nicotinamide mononucleotide (NNM) is an orally bioavailable NAD + precursor that has demonstrated beneficial effects against aging and aging-associated diseases in animal models. NMN is ultimately converted to NAD + , a redox cofactor that mediates many metabolic enzymes. NAD + also serves as the substrate for poly(ADP-ribose) polymerase (PARP) and sirtuins, and regulates various biological processes, such as metabolism, DNA repair, gene expression, and stress responses. Previous mouse models showed that NMN administration can increase NAD + in various organs and ameliorate aging-related diseases, such as obesity, diabetes, heart failure, stroke, kidney failure, and Alzheimer’s disease through NAD + -mediated pathways. However, evidence of its effect on humans is still scarce. In this study, we conducted a placebo-controlled, randomized, double blind, parallel-group trial to investigate the safety of orally administered NMN and its efficacy to increase NAD + levels in thirty healthy subjects. Healthy volunteers received 250 mg/day of NMN ( n = 15) or placebo ( n = 15) for 12 weeks, and physiological and laboratory tests were performed during this period. In addition, NAD + and its related metabolites in whole blood were examined. Oral supplementation of NMN for 12 weeks caused no abnormalities in physiological and laboratory tests, and no obvious adverse effects were observed. NAD + levels in whole blood were significantly increased after NMN administration. We also observed the significant rise in nicotinic acid mononucleotide (NAMN) levels, but not in NMN. We also found that the increased amount of NAD + was strongly correlated with pulse rate before the administration of NMN. These results suggest that oral administration of NMN is a safe and practical strategy to boost NAD + levels in humans. Clinical Trial Registration: JRCT [ https://jrct.niph.go.jp/ ], identifier: [jRCTs041200034].

We studied the effect of Age-Adjusted Comorbidity Index Score in colorectal cancer patients who underwent similarly aggressive treatment. Using the National Health Insurance Research Database of Taiwan, we identified 5643 patients with colorectal cancer who underwent surgical resection and chemoradiation from 2007 through 2011. We estimated survival according to Age-Adjusted Comorbidity Index Scores and 5-year survival using Cox proportional hazard regression analysis, adjusting for sex, oxaliplatin-based chemotherapy, socioeconomic status, geographic region, and hospital characteristics. In the cohort were 3230 patients with colonic cancer and 2413 patients with rectal cancer, who had undergone combined surgical resection and either neoadjuvant or adjuvant chemoradiation. After adjusting for patient characteristics (sex, oxaliplatin-based chemotherapy, socioeconomic status, geographic region, and hospital-characteristics), colonic cancer patients with age-adjusted Charlson (AAC) ≥ 6 had a 106% greater risk of death within 5 years (adjusted HR = 2.06; 95% CI, 1.66-2.56). In rectal cancer patients, patients with an AAC score of 4-5 had a 28% greater risk of death within 5 years (adjusted HR = 1.28; 95% CI, 1.02-1.61), and those with AAC ≥ 6 had a 47% greater risk (adjusted HR = 1.47; 95% CI, 1.15-1.90). Age and burden of comorbidities influence survival of patients with colonic or rectal cancer. Age-Adjusted Comorbidity Score remains an independent prognostic factor even after adjusting for the aggressiveness of treatment.

OBJECTIVE: Studies have shown the roles of oxidative stress in the pathogenesis of osteoarthritis (OA) and induction of chondrocyte senescence during OA progression. The aim of this study was to examine the potential of a strong free-radical scavenger, water-soluble fullerene (C60), as a protective agent against catabolic stress-induced degeneration of articular cartilage in OA, both in vitro and in vivo. METHODS: In the presence or absence of C60 (100 microM), human chondrocytes were incubated with interleukin-1beta (10 ng/ml) or H2O2 (100 microM), and chondrocyte activity was analyzed. An animal model of OA was produced in rabbits by resection of the medial meniscus and medial collateral ligament. Rabbits were divided into 5 subgroups: sham operation or treatment with C60 at 0.1 microM, 1 microM, 10 microM, or 40 microM. The left knee joint was injected intraarticularly with water-soluble C60 (2 ml), while, as a control, the right knee joint received 50% polyethylene glycol (2 ml), once weekly for 4 weeks or 8 weeks. Knee bone and cartilage tissue were prepared for histologic analysis. In addition, in the OA rabbit model, the effect of C60 (10 microM) on degeneration of articular cartilage was compared with that of sodium hyaluronate (HA) (5 mg/ml). RESULTS: C60 (100 microM) inhibited the catabolic stress-induced production of matrix-degrading enzymes (matrix metalloproteinases 1, 3, and 13), down-regulation of matrix production, and apoptosis and premature senescence in human chondrocytes in vitro. In rabbits with OA, treatment with water-soluble C60 significantly reduced articular cartilage degeneration, whereas control knee joints showed progression of cartilage degeneration with time. This inhibitory effect was dose dependent, and was superior to that of HA. Combined treatment with C60 and HA yielded a significant reduction in cartilage degeneration compared with either treatment alone. CONCLUSION: The results indicate that C60 fullerene is a potential therapeutic agent for the protection of articular cartilage against progression of OA.

AIM: To assess the efficacy, safety and dose-response relationship of once-daily teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with diet and exercise. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study, patients (n = 324) were randomized to receive teneligliptin 10, 20 or 40 mg, or placebo, once daily before breakfast for 12 weeks. The primary endpoint was the change in haemoglobin (Hb)A1c from baseline to week 12. RESULTS: All teneligliptin-treated groups showed significantly greater reductions in HbA1c and fasting plasma glucose (FPG) than did the placebo group. The differences between the teneligliptin 10, 20 or 40 mg groups and the placebo group for the change in HbA1c were -0.9 [least-squares (LS) mean; 95% confidence interval: -1.0, -0.7], -0.9 (-1.1, -0.7) and -1.0 (-1.2, -0.9)%, respectively (all, p < 0.001). The respective LS means for FPG were -17.8 (-23.4, -12.1), -16.9 (-22.6, -11.2) and -20.0 (-25.7, -14.3) mg/dl (all, p < 0.001). There were no significant differences in HbA1c among the three doses of teneligliptin. The incidence of adverse events and adverse drug reactions was similar in each group. The incidence of hypoglycaemia was not significantly different among the four groups. CONCLUSIONS: Treatment with teneligliptin for 12 weeks provided significant and clinically meaningful reductions in HbA1c and FPG across the dose range studied and was generally well tolerated in Japanese patients with T2DM.

Rotavirus is the most common cause of severe gastroenteritis in infants and children worldwide. The cell attachment of most animal rotaviruses, which belong to the neuraminidase-sensitive strains, requires sialic acid residues on the host cell membranes. On the other hand, most human rotaviruses are classified as neuraminidase-insensitive strains. The involvement of gangliosides on the host cell surface in human rotavirus infection was investigated by immunostaining analysis of target cells, and by assaying the neutralization of infection by rotavirus and the blocking of target cellular receptors. In host cells (MA104 cells) pretreated with Arthrobacter ureafaciens neuraminidase, which were still infected by human rotaviruses (KUN and MO strains), GM(3) was hydrolyzed markedly by the neuraminidase, while GM(1a) was not hydrolyzed at all. Infection by the rotaviruses was strongly inhibited by exogenous ganglioside GM(1a), but not GA(1). Infection was also inhibited by pretreatment of the MA104 cells with cholera toxin B-subunit, which specifically blocked ganglioside GM(1a) on the plasma membrane. The treatment of MA104 cells with the endoglycoceramidase attenuated human rotavirus infection. From these findings, we concluded that GM(1a) on the plasma membrane of the host cells was involved in the infection by human rotavirus KUN and MO strains.

Background and Purpose We conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT‐1303), a second‐generation sphingosine 1‐phosphate (S1P) receptor modulator, designed to reduce the bradycardia associated with fingolimod and other S1P receptor modulators. Experimental Approach The selectivity of the active metabolite amiselimod phosphate (amiselimod‐P) for human S1P receptors and activation of G‐protein‐coupled inwardly rectifying K + (GIRK) channels in human atrial myocytes were assessed. Its cardiac distribution was determined in rats, and cardiovascular telemetry was assessed in monkeys. We also examined the pharmacokinetics, pharmacodynamics and safety of amiselimod in healthy humans. Key Results Amiselimod‐P showed potent selectivity for S1P 1 and high selectivity for S1P 5 receptors, with minimal agonist activity for S1P 4 and no distinct agonist activity for S1P 2 or S1P 3 receptors and approximately five‐fold weaker GIRK activation than fingolimod‐P. After oral administration of amiselimod or fingolimod at 1 mg·kg −1 , the concentration of amiselimod‐P in rat heart tissue was lower than that of fingolimod‐P, potentially contributing to the minimal cardiac effects of amiselimod. A telemetry study in monkeys confirmed that amiselimod did not affect heart rate or ECG parameters. In healthy human subjects, peripheral blood lymphocyte counts gradually reduced over the 21 day dosing period, with similar lymphocyte count profiles with the highest doses by day 21, and no clinically significant bradycardia observed on day 1 or during the study. Conclusions and Implications Amiselimod exhibited potent therapeutic efficacy with minimal cardiac effects at the anticipated clinical dose and is unlikely to require dose titration.

Stress-induced hyperglycemia (SIH) has been independently associated with an increased risk of mortality in critically ill patients without diabetes. However, it is also necessary to consider preexisting hyperglycemia when investigating the relationship between SIH and mortality in patients with diabetes. We therefore assessed whether the gap between admission glucose and A1C-derived average glucose (ADAG) levels could be a predictor of mortality in critically ill patients with diabetes.We retrospectively reviewed the Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores and clinical outcomes of patients with diabetes admitted to our medical intensive care unit (ICU) between 2011 and 2014. The glycosylated hemoglobin (HbA1c) levels were converted to the ADAG by the equation, ADAG = [(28.7 × HbA1c) - 46.7]. We also used receiver operating characteristic (ROC) curves to determine the optimal cut-off value for the glycemic gap when predicting ICU mortality and used the net reclassification improvement (NRI) to measure the improvement in prediction performance gained by adding the glycemic gap to the APACHE-II score.We enrolled 518 patients, of which 87 (17.0%) died during their ICU stay. Nonsurvivors had significantly higher APACHE-II scores and glycemic gaps than survivors (P < 0.001). Critically ill patients with diabetes and a glycemic gap ≥80 mg/dL had significantly higher ICU mortality and adverse outcomes than those with a glycemic gap <80 mg/dL (P < 0.001). Incorporation of the glycemic gap into the APACHE-II score increased the discriminative performance for predicting ICU mortality by increasing the area under the ROC curve from 0.755 to 0.794 (NRI = 13.6%, P = 0.0013).The glycemic gap can be used to assess the severity and prognosis of critically ill patients with diabetes. The addition of the glycemic gap to the APACHE-II score significantly improved its ability to predict ICU mortality.

Type I interferons (IFNs) are important in innate and adaptive immunity. They are used to treat virus infections, cancer, and multiple sclerosis (MS). There are 5 type I IFN families in humans-IFN-α with 13 subtypes, plus IFN-β, ɛ, κ, and ω. Because their receptor binding affinities vary, these IFNs have different gene induction profiles and quite variable therapeutic effects. IFN-α subtypes may each be specific for certain viruses, but can be neurotoxic. IFN-β induces IFN-α, plus has additional direct effects on target cells. IFN-β was the first therapy approved that could change the course of MS. It has broader specificity than IFN-α, enhances cognition in MS, and may be neuroprotective and can potentially enhance fertility in women. Priming the IFN signaling system with an injection of IFN-β can enhance subnormal type I IFN signals in MS. Many other commonly used drugs and vitamins may potentiate clinical benefits of IFN-β.

Deteriorating sleep quality and physical or mental fatigue in older adults leads to decreased quality of life and increased mortality rates. This study investigated the effects of the time-dependent intake of nicotinamide mononucleotide (NMN) on sleep quality, fatigue, and physical performance in older adults. This randomized, double-blind placebo-controlled study evaluated 108 participants divided into four groups (NMN_AM; antemeridian, NMN_PM; post meridian, Placebo_AM, Placebo_PM). NMN (250 mg) or placebo was administered once a day for 12 weeks. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index. Fatigue was evaluated using the "Jikaku-sho shirabe" questionnaire. Grip strength, 5-times sit-to-stand (5-STS), timed up and go, and 5-m habitual walk were evaluated to assess the physical performance. Significant interactions were observed between 5-STS and drowsiness. 5-STS of all groups on post-intervention and drowsiness of the NMN_PM and Placebo_PM groups on mid- and post-intervention showed significant improvement compared with those in pre-intervention. The NMN_PM group demonstrated the largest effect size for 5-STS (d = 0.72) and drowsiness (d = 0.64). Overall, NMN intake in the afternoon effectively improved lower limb function and reduced drowsiness in older adults. These findings suggest the potential of NMN in preventing loss of physical performance and improving fatigue in older adults.