Risk factors for thrombocytopenia and analysis of time to platelet transfusion after azacitidine treatment.

The use of azacitidine (AZA) has been known to lead to a high incidence of hematotoxic adverse events. The aims of this study were to identify the risk factors for thrombocytopenia after the administration of AZA and to analyze time to the initial platelet transfusion. Sixty-two patients with myelodysplastic syndrome (MDS), who were treated with AZA in Gifu Municipal Hospital between March 2012 and June 2020, were included in this study. The risk factors for thrombocytopenia were identified using univariate analysis of patient characteristics, disease type, and laboratory values immediately before the start of treatment. Variables with p<0.2 identified in the univariate analysis were used as independent variables in the multivariate analysis. This analysis identified "creatinine clearance (CCr) <60 mL/min" as a significant factor (odds ratio, 4.790; 95% confidence interval [CI], 1.380-16.70; p=0.014). Subsequently, time in days to the initial platelet transfusion after the initial administration of AZA was analyzed using the log-rank test. The overall median time in days to platelet transfusion was 370 days. The log-rank test was used to determine the influence of patient characteristics, disease type, and laboratory values immediately before the start of treatment. The subsequent Cox proportional hazard regression analysis using variables with p<0.2 as independent variables identified "hemoglobin (Hb) <8.0 g/dL" as a significant factor (hazard ratio, 2.143; 95% CI, 1.001-4.573; p=0.048). The results of this study led to the following clinical implications: first, patients with CCr of <60 mL/min at the start of treatment should be treated with caution due to the risk of thrombocytopenia. Second, patients with Hb of <8.0 g/dL at the start of treatment may require platelet transfusion in the early stage of treatment.

Effects of polypharmacy on the prevalence of adverse drug events resulting in outpatient visits and hospitalization.

A high proportion of hospitalizations is attributable to the prevalence of adverse drug events. This retrospective study included outpatients and inpatients to determine the prevalence of adverse drug events and if polypharmacy increases it. The prevalence, classification, and causality of adverse drug events were assessed based on medical records, laboratory values, and other data. Multivariate analysis (multiple logistic regression analysis) was performed with the presence or absence of adverse drug events at the time of the visit as the dependent variable and items for which the P-value was <0.25 in the univariate analysis as independent variables. The prevalence of adverse drug events was 13.0%, 10.9%, and 16.0% among all patients, the outpatient group, and the inpatient group, respectively. Multivariate analysis showed that polypharmacy (≥5 drugs) significantly increased the risk of adverse drug events in all patients. The prevalence of adverse drug events significantly increased with each additional drug used. We expect that minimizing the number of medications through moderation of the number of prescription drugs and elimination of polypharmacy will reduce the number of outpatient visits and hospitalizations due to adverse drug events.

Relationship Between Initial Renal Function and the Inhibitory Effect of Dipeptidyl Peptidase-4 Inhibitor Treatment on Renal Function Decline.

We retrospectively investigated the renal function index of patients with type 2 diabetes mellitus (T2DM) to examine the influence of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal function between patients up to early nephropathy and after overt nephropathy. Patients with T2DM (>18 years old) who had been prescribed hypoglycemic agents for ≥3 months at Gifu Municipal Hospital between March 2010 and April 2014 were included in the study. Renal function was evaluated as the estimated glomerular filtration rate (eGFR) decline from baseline at 12 months. Patients in the DPP-4 inhibitor-treated and untreated groups with an eGFR ≥60 (358 [58.2 %] and 257 [41.8 %], respectively) and eGFR <60 (115 [60.2 %] and 76 [39.8 %], respectively) were subjected to multiple logistic regression analysis. Among patients with an eGFR ≥60, no significant differences were observed in eGFR decline rates over time. However, among patients with an eGFR <60, significant decreases were observed in eGFR decline rates >10 % (6 months; odds ratio, 0.476; P = 0.043, 12 months; odds ratio, 0.413; P = 0.010). Similar results were obtained for an eGFR decline rate >20 % (12 months; odds ratio, 0.369; P = 0.049). DPP-4 inhibitors are renoprotective in patients with T2DM and an eGFR <60.

Risk factors for Clostridium difficile-associated diarrhea and the effectiveness of prophylactic probiotic therapy.

Measures for prevention of Clostridium difficile-associated diarrhea, a common nosocomial infection, in hospital settings are urgently needed. This study was conducted to identify the risk factors contributing to C. difficile-associated diarrhea and to evaluate the clinical benefit of probiotics in its prevention. The study included 2716 patients at least 20 years old who received an injected antibiotic at any time between February 2010 and February 2011; a total of 2687 patients (98.9%) were assigned to the non-C. difficile-associated diarrhea group, and 29 patients (1.1%) were assigned to the C. difficile-associated diarrhea group. Univariate analysis revealed a significant difference between the two groups for the following factors: antibiotic therapy for > or = 8 days; enteral nutrition; intravenous hyperalimentation; fasting; proton pump inhibitor use; H2 blocker use; and serum albumin < or = 2.9g/dL (p<0.05). Multivariate logistic regression analysis revealed a significant difference between the two groups for several factors. Antibiotic therapy for > or = 8 days, intravenous hyperalimentation, proton pump inhibitor use, and H2 blocker use were therefore shown to be risk factors for C. difficile-associated diarrhea. Prophylactic probiotic therapy was not shown to suppress the occurrence of C. difficile-associated diarrhea.

Opposing functions of Fbxw7 in keratinocyte growth, differentiation and skin tumorigenesis mediated through negative regulation of c-Myc and Notch.

The tumor suppressor Fbxw7 (also known as Sel-10, hCdc4, hAgo, or Fbw7) is an F-box protein that functions as the substrate-recognition subunit of an SCF ubiquitin ligase complex and targets a group of oncoproteins for degradation. We now show that Fbxw7 regulates the proliferation and differentiation of keratinocytes by mediating the degradation of c-Myc and Notch proteins. Fbxw7-deficient keratinocytes showed an increased proliferative capacity that was dependent on the accumulation of c-Myc but not on that of Notch. Fbxw7 deficiency also resulted in the premature differentiation of keratinocytes in a manner dependent on both c-Myc and Notch. Although Fbxw7-deficient keratinocytes proliferated excessively in vitro, loss of Fbxw7 did not predispose keratinocytes to the formation of squamous cell carcinoma in vivo induced by the expression of oncogenic Ras, possibly because the stem cell population of keratinocytes becomes exhausted as a result of enhanced Notch activity. Indeed, suppression of Notch signaling by additional ablation of RBP-J in Fbxw7-deficient keratinocytes conferred a more aggressive tumorigenic capacity. Collectively, these results indicate that Fbxw7 controls the proliferation and differentiation of keratinocytes, and that it exerts both inhibitory and stimulatory actions in skin carcinogenesis by counteracting the proliferation-promoting effect of c-Myc and the tumor-suppressive effect of Notch, respectively.

Impact of levofloxacin dose adjustments by dispensing pharmacists on adverse reactions and costs in the treatment of elderly patients.

Ensuring an appropriate dosage of renally eliminated drugs for patients with renal insufficiency is important for preventing adverse drug reactions. We investigated the effectiveness of interventions by pharmacists in a hospital pharmaceutical department. The comparative study was performed at Gifu Municipal Hospital in Japan from March to August 2011, and included an intervention (142 patients) and a control group (98 patients). Upon receiving a prescription of levofloxacin for patients aged > or = 75 years, pharmacists evaluated the patients' kidney function and adjusted the appropriate dosage at the time of dispensation. In the intervention and control groups, levofloxacin-induced adverse reactions developed in 6 of 142 (4.2%) and 13 of 98 (13.3%) patients, respectively (p < 0.05). The cost of reducing levofloxacin per patient was yen 191.1 and yen 0 in the intervention and control groups, respectively. The cost per patient for adverse reaction treatments and examinations was yen 15.5 and yen 290.0 in the intervention and control groups, respectively. The intergroup difference in the total cost per patient was yen 465.6. Dose adjustment of levofloxacin at the time of dispensation by the pharmacist for patients aged > or = 75 years resulted in a decrease in the incidence of adverse reactions and cost. These findings can be applied not only to hospitals, but also to community pharmacies, because the intervention, which is a manual system, is simply performed when pharmacists are dispensing drugs.

Hemodynamic stabilizing effects of L-carnitine in chronic hemodialysis patients.

BACKGROUND: The effects of L-carnitine on the hemodynamic state of chronic hemodialysis patients have been debated. In order to clarify the effect of administered L-carnitine on cardiac function and hypotensive episodes during the hemodialysis procedure, a randomized double-blind placebo-controlled study was performed for 3 months. METHODS AND RESULTS: TWENTY STABLE OUTPATIENTS UNDERGOING HEMODIALYSIS TREATMENT WERE DIVIDED INTO TWO GROUPS: controls (placebo) and treated patients (L-carnitine 900 mg p.o. daily). After 3 months, cardiac function was reevaluated by echocardiography, and hypotensive episodes during hemodialysis were assessed. Free and acyl carnitine levels increased significantly from 22.3 ± 7.1 to 140.3 ± 57.5 µmol/l and from 15.8 ± 2.8 to 94.8 ± 50.4 µmol/l, respectively, in the treated group. The ejection fraction significantly increased from 61.8 ± 16.0 to 64.4 ± 13.8% (p < 0.05) in the treated group. However, there was no difference in other echocardiographic parameters between the two groups. Hypotensive episodes significantly decreased from 4.0 ± 1.7 to 1.3 ± 0.9 times per month (p < 0.05), although patients' body weight did not change significantly. CONCLUSIONS: Beneficial effects of L-carnitine on the hemodynamic state of chronic hemodialysis patients were observed. L-Carnitine supplementation might be considered especially for chronic hemodialysis patients with unstable hemodynamic conditions.

Tensor force manifestations in ab initio study of the 2H(d,γ)4He, 2H(d,p)3H, and 2H(d,n)3He reactions.

The (2)H(d,p)(3)H, (2)H(d,n)(3)He, and (2)H(d,γ)(4)He reactions are studied at low energies in a multichannel ab initio model that takes into account the distortions of the nuclei. The internal wave functions of these nuclei are given by the stochastic variational method with the AV8' realistic interaction and a phenomenological three-body force included to reproduce the two-body thresholds. The obtained astrophysical S factors are all in very good agreement with the experiment. The most important channels for both transfer and radiative capture are identified by comparing to calculations with an effective central force. They are all found to dominate thanks to the tensor force.

Frontal cerebral blood flow change associated with infant-directed speech.

OBJECTIVE: To examine the auditory perception of maternal utterances by neonates using near-infrared spectroscopy (NIRS). METHODS: Twenty full-term, healthy neonates were included in this study. The neonates were tested in their cribs while they slept in a silent room. First, two probe holders were placed on the left and right sides of the forehead over the eyebrows using double-sided adhesive tape. The neonates were then exposed to auditory stimuli in the form of infant-directed speech (IDS) or adult-directed speech (ADS), sampled from each of the mothers, through an external auditory speaker. RESULTS: A 2 (stimulus: IDS and ADS) x 2 (recording site: channel 1 (right side) and channel 2 (left side)) analysis of variance for these relative oxygenated haemoglobin values showed that IDS (Mean = 0.25) increased brain function significantly (F = 3.51) more than ADS (Mean = -0.26). CONCLUSIONS: IDS significantly increased brain function compared with ADS. These results suggest that the emotional tone of maternal utterances could have a role in activating the brains of neonates to attend to the utterances, even while sleeping.

Pigmented villonodular synovitis of the temporomandibular joint: differential diagnosis and case report.

Pigmented villonodular synovitis of the temporomandibular joint (TMJ) is rare. We present a patient in whom the lesion had invaded the infratemporal fossa and destroyed the mandibular condyle.

Expression of Dmrt1 protein in developing and in sex-reversed gonads of amphibians.

Many genes are known to be involved in gonadal differentiation in vertebrates. Dmrt1, a gene that encodes a transcription factor with a DM-domain, is considered to be one of the essential genes controlling testicular differentiation in mammals, birds, reptiles, amphibians and fish. However, it still remains unknown which testicular cells of animals other than mice and chicks express Dmrt1 protein. For an explanation of its role(s) in testicular differentiation in vertebrates, the expression of the Dmrt1 protein needs to be studied. For this purpose, we conducted an immunohistochemical study of this protein in an amphibian by using an antibody specific for Dmrt1. No positive signal was found in the indifferent gonad of tadpoles of Rana rugosa at early stages. However, in the testis of tadpoles at later stages (XV-XXV) and in frogs one month after metamorphosis, this protein was expressed in interstitial cells and Sertoli cells. In the testis of adult frogs, germ cells also expressed Dmrt1 protein. RT-PCR analysis revealed that the gene for this protein was not transcribed at any time during ovarian development, but was expressed in the female to male sex-reversed gonad. This was true when immunohistological studies were performed. In addition, Southern blot analysis showed DMRT1 to be an autosomal gene. Taken together, our findings indicate that Dmrt1 protein is expressed by interstitial cells, Seroli cells and germ cells in the testis of R. rugosa. Dmrt1 may thus be very involved in the testicular differentiation of amphibians.

Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's disease.

Research and development of the adenosine A2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson's disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A2A receptors in the "dual" modulation of GABAergic synaptic transmission. Experiments with dopamine D2 receptor knockout mice showed that A2A receptors can function and anti-PD activities of A2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with L-dopa-related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A2A biologic research has been applied successfully to "proof of concept" clinical studies. The selective A2A antagonist should provide a novel nondopaminergic approach to PD therapy.

Targeting oncogenesis by introduction of a 5.2-kbp segment of the 5' regulatory region of the human thyrotropin beta-subunit gene.

We produced transgenic mice carrying a fusion gene (TTP-5) consisting of a 5.2-kbp segment of the 5' flanking sequence of the human thyrotropin beta-subunit (TSH beta) gene linked to the simian virus 40 large T antigen (SVT) gene. These mice developed pituitary tumors 6 months after birth and wasted away. With the 5.2-kbp TSH beta 5' flanking region governing SVT expression, SVT mRNA was present in the pituitary and testis but not in other tissues, as detected by the reverse transcriptase-polymerase chain reaction. Histological and immunohistochemical analyses showed that the pituitary tumors of the transgenic mice were composed of moderately differentiated pituitary cells that expressed TSH, growth hormone, and prolactin. These results indicate that the 5.2-kbp segment of the human TSH beta 5' regulatory region is sufficient to drive expression of SVT and induce tumorigenesis of hormone-producing pituitary cells in transgenic mice.

Differential diagnosis of calcium pyrophosphate dihydrate deposition of the temporomandibular joint.

Calcium pyrophosphate dihydrate (CPPD) deposition disease (pseudogout) of the temporomandibular joint (TMJ) is rare. It is characterized by the presence of crystal deposits that are birefringent under polarized light. Although these crystals are characteristically weakly birefringent, some other crystals such as those of calcium oxalate, synthetic steroids, and ethylenediaminetetraacetic acid are also birefringent. The differential diagnosis should therefore be based on a quantitative analysis of crystals or observation of the crystal structure in calcified sections. We present a case of CPPD deposition disease of the TMJ and report on the value of such an analysis to substantiate the diagnosis.

Reactions of a series of 1-aminobenzimidazoles and 1-amino-3-methylbenzimidazolium chlorides with 2,4-pentanedione.

Reactions of a series of 1-aminobenzimidazoles and 1-amino-3-methylbenzimidazolium chlorides with 2,4-pentanedione were carried out and pyridazino[1,6-a]benzimidazoles and 2-pyrazolylanilines were generated. The product ratios of these compounds remarkably depended on the reaction conditions and on the electronic character of the substituent at the benzene moiety. The possible mechanisms involved in these reactions are discussed.

Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist.

In Parkinson's disease a degeneration of dopaminergic neurons of the nigrostriatal pathway is observed. Loss of dopaminergic regulation of striatal neuron activity results in altered motor functions. Adenosine A2A (A2AR) and dopamine D2 (D2R) receptors are colocalized in striatal medium spiny neurons. It has been proposed that adenosine binding to A2AR lowers the affinity of dopamine for D2R, thus modulating the function of this receptor. Absence of D2R in knockout mice (D2R-/-) results in impaired locomotion and coordinated movements. This indicates that absence of dopamine in Parkinson's disease might principally affect D2R-mediated effects with regard to locomotor functions. A2AR-selective antagonists have been demonstrated to have anti- parkinsonian activities in various models of Parkinson's disease in rodents and nonhuman primates. In this article, D2R-/- mice were used to explore the possibility that an A2AR antagonist might reestablish their motor impairment. Interestingly, blockade of A2AR rescues the behavioral parameters altered in D2R-/- mice. In addition, the level of expression of enkephalin and substance P, which were altered in D2R-/-, were also reestablished to normal levels after A2AR antagonist treatment. These results show that A2AR and D2R have antagonistic and independent activities in controlling neuronal and motor functions in the basal ganglia. They also provide evidence that selective A2AR antagonists can exhibit their anti-parkinsonian activities through a nondopaminergic mechanism.

Reactions of chloride salts of 7-amino-9-ethylguanine and 1-amino-3-methylbenzimidazoles with lead(IV) acetate: formation of 8-aza-9-ethylguanine and 1-methyl-1H-benzotriazoles.

Reaction of 7-amino-9-ethylguaninium chloride with lead(IV) acetate (LTA) in MeOH yielded 8-aza-9-ethylguanine. Similarly, the reaction of 1-amino-3-methylbenzimidazolium chloride or its substituted derivatives (6-methyl, 5,6-dimethyl and 5-nitro) with LTA gave the corresponding 1-methyl-1H-benzotriazole (or 1-methyl-2-azabenzimidazole) derivatives along with N-methylformananilide derivatives.

Cytotoxicity of 1-amino-4-phenyl-1,2,3,6-tetrahydropyridine and 1-amino-4-phenylpyridinium ion, 1-amino analogues of MPTP and MPP+, to clonal pheochromocytoma PC12 cells.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces parkinsonism in humans after its oxidation into 1-methyl-4-phenylpyridinium ion (MPP+) by type B monoamine oxidase. The 1-amino analogues of MPTP and MPP+, 1-amino-4-phenyl-1,2,3, 6-tetrahydropyridine (APTP) and 1-amino-4-phenylpyridinium ion (APP+), were synthesized, and their cytotoxicity to clonal pheochromocytoma PC12 cells was examined using a tetrazolium formazan assay. After incubation for 48 and 72 h, both APP+ and APTP were found to be cytotoxic to PC12 cells, whereas with the N-methyl analogues, only MPP+, but not MPTP, was cytotoxic. The cytotoxicity of APTP increased with incubation time and equaled that of MPP+ after 72 h. It was found that APTP was oxidized to APP+ by type A monoamine oxidase in PC12 cells, suggesting that APP+ itself may damage the cells. In addition to APTP and APP+, N-amino analogues of N-methylisoquinolines and related derivatives were also synthesized and examined for their cytotoxicity to PC12 cells.

Hepatic veno-occlusive disease in a case of polymyositis associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome.

A 50-year-old woman was treated with prednisolone for polymyositis. During the therapy, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) occurred. Neither plasma infusion nor plasma exchange could relieve the clinical manifestations of TTP/HUS. Moreover, massive ascites appeared and worsened her condition. She died approximately one year after the diagnosis of polymyositis. The autopsy revealed centri-lobular hepatic necrosis and nonthrombotic obliteration of hepatic small veins. The diagnosis of hepatic veno-occlusive disease (VOD) was made. It was suspected that common factors other than cytoreductive therapy had damaged the endothelium and caused TTP/HUS and VOD in a case of polymyositis.