Pretransplant HbA1c Is a Useful Predictor for the Development of New-Onset Diabetes in Renal Transplant Recipients Receiving No or Low-Dose Erythropoietin

Aims. To evaluate the predictive power of pretransplant HbA1c for new-onset diabetes after transplantation (NODAT) in kidney transplant candidates, who had several predispositions for fluctuated HbA1c levels. Methods. We performed a retrospective study of 119 patients without diabetes who received kidney transplantation between March 2000 and January 2012. Univariate and multivariate logistic regression analyses were used to investigate the association of several parameters with NODAT. Predictive discrimination of HbA1c was assessed using a receiver-operating characteristic curve. Results. Seventeen patients (14.3%) developed NODAT within 1 year of transplantation. Univariate logistic regression analysis revealed that recipient age, gender, and HbA1c were predictors of NODAT. In the multivariate analysis, the association between pretransplant HbA1c and NODAT development did not reach statistical significance ( = 0.07). To avoid the strong influence of high-dose erythropoietin on HbA1c levels, we performed subgroup analyses on 85 patients receiving no or low-dose (≤6000 IU/week) erythropoietin. HbA1c was again an independent predictor for NODAT. Receiver-operating characteristic analysis revealed a cut-off value of 5.2% with an optimal sensitivity of 64% and specificity of 78% for predicting NODAT. Conclusions. Our results reveal that the pretransplant HbA1c level is a useful predictor for NODAT in patients receiving no or low-dose erythropoietin

Brexpiprazole II: Antipsychotic-Like and Procognitive Effects of a Novel Serotonin-Dopamine Activity Modulator

ABSTRACT Brexpiprazole piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT 1A ) and D 2/3 receptors, combined with potent antagonist effects on 5-HT 2A , a 1B -, and a 2C -adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED 50 = 6.0 mg/kg), apomorphine-or D-amphetamine-induced hyperactivity (ED 50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED 50 = 2.9) in rats at clinically relevant D 2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED 50 = 20) well above clinically relevant D 2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D 2 occupancies. In the NOR test

A low mortality, high morbidity Reduced Intensity Status Epilepticus (RISE) model of epilepsy and epileptogenesis in the rat

Animal models of acquired epilepsies aim to provide researchers with tools for use in understanding the processes underlying the acquisition, development and establishment of the disorder. Typically, following a systemic or local insult, vulnerable brain regions undergo a process leading to the development, over time, of spontaneous recurrent seizures. Many such models make use of a period of intense seizure activity or status epilepticus, and this may be associated with high mortality and/or global damage to large areas of the brain. These undesirable elements have driven improvements in the design of chronic epilepsy models, for example the lithium-pilocarpine epileptogenesis model. Here, we present an optimised model of chronic epilepsy that reduces mortality to 1% whilst retaining features of high epileptogenicity and development of spontaneous seizures. Using local field potential recordings from hippocampus in vitro as a probe, we show that the model does not result in significant loss of neuronal network function in area CA3 and, instead, subtle alterations in network dynamics appear during a process of epileptogenesis, which eventually leads to a chronic seizure state. The model’s features of very low mortality and high morbidity in the absence of global neuronal damage offer the chance to explore the processes underlying epileptogenesis in detail, in a population of animals not defined by their resistance to seizures, whilst acknowledging and being driven by the 3Rs (Replacement, Refinement and Reduction of animal use in scientific procedures) principles

Limited utility of blood cultures in the management of febrile outpatient kidney transplant recipients

Background/Purpose: Blood cultures for patients suspected of having bacteremia are standard practice, although several studies demonstrate that blood cultures have limited utility because of a low true-positive rate and infrequent resultant changes in antibiotic treatment. However, most reports exclude immunocompromised patients such as transplant recipients. We assessed the utility of blood cultures in transplant recipients hospitalized for community-acquired infections and evaluated clinical characteristics to predict bacteremia. Methods: This retrospective study included 136 febrile cases in 97 kidney transplant recipients admitted to our hospital for whom blood cultures were performed between February 2001 and March 2013. Results: Among the 136 cases, blood cultures were positive, contaminated, and negative in seven (5.1%) cases, 12 (8.8%) cases, and 117 cases (86.1%), respectively. All bacteria detected in the seven cases were sensitive to the initial empirical antibiotics. Antibiotic treatment was changed based on the blood culture results only in one case for which the coverage was narrowed. The white blood cell count and C-reactive protein level were significantly higher in the patients with bacteremia. The predictive model based on these two factors successfully identified the high-risk group with a sensitivity and specificity of 86% and 91%, respectively. Conclusion: Among the outpatient kidney transplant recipients, positive blood cultures were uncommon and scarcely affected antibiotic therapy, especially in patients with upper respiratory tract or urinary tract infections. Therefore, it may be reasonable to perform blood cultures only for patients with marked leukocytosis and high C-reactive protein level, even among transplant recipients

Brexpiprazole I: In Vitro and in Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl) piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (K i \u3c 1 nM) to human serotonin 1A (h5-HT 1A )-, h5-HT 2A -, long form of human D 2 (hD 2L )-, hα 1B -, and hα 2C -adrenergic receptors. It displayed partial agonism at h5-HT 1A and hD 2 receptors in cloned receptor systems and potent antagonism of h5-HT 2A receptors and hα 1B/2C -adrenoceptors. Brexpiprazole also had affinity (K i \u3c 5 nM) for hD 3- , h5-HT 2B -, h5-HT 7 -, hα 1A -, and hα 1D -adrenergic receptors, moderate affinity for hH 1 (K i = 19 nM), and low affinity for hM 1 receptors (K i \u3e 1000 nM). Brexpiprazole potently bound to rat 5-HT 2A and D 2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT 1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT 2A antagonism. Furthermore, in vivo D 2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D 2 partial agonist activity. In particular, based on a lower intrinsic activity at D 2 receptors and higher binding affinities for 5-HT 1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D 2 receptor agonist-and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders

Behavioral measurements of epilepsy following induction.

<p><b>A.</b> Distribution of weekly seizure frequency as observed during video monitoring (n = 10) <b>B.</b> Mean daily seizure frequency of animals during the recording period, data are expressed as mean ± SEM (n = 10). <b>C.</b> The percentage of animals meeting PSBB criteria at various weeks post-induction (n = 31). <b>D.</b> Touch x pickup and <b>E.</b> time bin pickup PSBB scores of animals having undergone <i>status</i> epilepticus induction (n = 37) and age-matched controls (criteria met/seizure observed, n = 13; criteria met/no seizure observed, n = 18; criteria not met/no seizure observed, n = 6; control, n = 12).</p

Spontaneous network activity in CA3 during the latent period.

<p><b>A.</b> Raw data from CA3 recorded during the latent period and in controls. Scale bar 200 ms x 50 μV. <b>B.</b> Power spectral density plots of the activity shown in A. <b>C.</b> Example Morlet-wavelet spectra and power spectral density plots of the same traces, white dotted lines on spectra indicate 20–60 Hz pseudo-frequency band. <b>C.</b> Pooled power and frequency plots for control and latent period.</p

Spontaneous network activity in CA3 following establishment of SRS.

<p><b>A.</b> Raw data from CA3 recorded 90 days post-induction and in controls. Scale bar 200 ms x 50 μV. <b>B.</b> Power spectral density plots of the activity shown in A. <b>C.</b> Example Morlet-wavelet spectra and power spectral density plots of the same traces, white dotted lines on spectra indicate 20–60 Hz pseudo-frequency band. <b>C.</b> Pooled power and frequency plots for control and PSE 90d.</p

Summary of <i>in vitro</i> network and behavioural observations at different stages of the RISE model.

<p>Summary of <i>in vitro</i> network and behavioural observations at different stages of the RISE model.</p