The presence of smear layer affects the antimicrobial action of root canal sealers.

AIM: To assess the chemical and microstructural characteristics of dentine after the use of two irrigation protocols and correlate this with the antimicrobial properties of hydraulic calcium silicate cement (HCSC) sealers and changes to the dentine structure/chemistry after sealer placement. METHODOLOGY: Two irrigation protocols - Protocol A using 2% NaOCl used 5 mL/5 min and Protocol B with 2% NaOCl (5 mL/5 min) followed by 17% EDTA (5 mL/3 min) - were used to prepare dentine. The chemical and microstructural changes following irrigation were assessed by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and Fourier transform infrared (FT-IR) spectroscopy (n = 5) on dentine obtained from the mid-root and coronal parts of extracted human teeth. Four sealers (AH Plus, BioRoot, MTA Fillapex, TotalFill) were characterized by SEM/EDS (n = 3). The ability of the sealers to eradicate intratubular Enterococcus faecalis biofilms was assessed by live/dead dye and confocal laser scanning microscopy to measure the percentage of living cells. The effect of combined irrigation and root filling on dentine was assessed by SEM and EDS analysis (n = 5). Statistical analysis was undertaken using one-way anova and a number of post hoc tests to detect intergroup differences. The F-test was used for comparison of variances in the microbiology testing. RESULTS: The use of NaOCl alone left the smear layer intact, with traces of chlorine remaining on dentine. The use of BioRoot sealer restored the calcium levels of dentine which had been depleted by the irrigation with EDTA. BioRoot exhibited antimicrobial properties against intratubular bacteria even in the presence of smear layer (Protocol A). Smear layer removal improved the bactericidal effect of all sealers and Ca2+ leaching. The use of a chelating agent was important for the intratubular sealer penetration for AH Plus but not the other sealers. CONCLUSION: The removal of smear layer was necessary for penetration of AH Plus into the dentinal tubules. BioRoot was a more effective sealer in reducing the bacterial load in the dentinal tubules than the other materials tested and the presence of smear layer did not affect its activity.

A role for D-aspartate oxidase in schizophrenia and in schizophrenia-related symptoms induced by phencyclidine in mice.

Increasing evidence points to a role for dysfunctional glutamate N-methyl-D-aspartate receptor (NMDAR) neurotransmission in schizophrenia. D-aspartate is an atypical amino acid that activates NMDARs through binding to the glutamate site on GluN2 subunits. D-aspartate is present in high amounts in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-aspartate oxidase (DDO). The agonistic activity exerted by D-aspartate on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for some of the NMDAR-related alterations observed in schizophrenia. Consistently, substantial reductions of D-aspartate and NMDA were recently observed in the postmortem prefrontal cortex of schizophrenic patients. Here we show that DDO mRNA expression is increased in prefrontal samples of schizophrenic patients, thus suggesting a plausible molecular event responsible for the D-aspartate imbalance previously described. To investigate whether altered D-aspartate levels can modulate schizophrenia-relevant circuits and behaviors, we also measured the psychotomimetic effects produced by the NMDAR antagonist, phencyclidine, in Ddo knockout mice (Ddo(-)(/-)), an animal model characterized by tonically increased D-aspartate levels since perinatal life. We show that Ddo(-/-) mice display a significant reduction in motor hyperactivity and prepulse inhibition deficit induced by phencyclidine, compared with controls. Furthermore, we reveal that increased levels of D-aspartate in Ddo(-/-) animals can significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in schizophrenia. Collectively, the present results suggest that altered D-aspartate levels can influence neurodevelopmental brain processes relevant to schizophrenia.

Dysfunctional dopaminergic neurotransmission in asocial BTBR mice.

Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by pronounced social and communication deficits and stereotyped behaviours. Recent psychosocial and neuroimaging studies have highlighted reward-processing deficits and reduced dopamine (DA) mesolimbic circuit reactivity in ASD patients. However, the neurobiological and molecular determinants of these deficits remain undetermined. Mouse models recapitulating ASD-like phenotypes could help generate hypotheses about the origin and neurophysiological underpinnings of clinically relevant traits. Here we used functional magnetic resonance imaging (fMRI), behavioural and molecular readouts to probe dopamine neurotransmission responsivity in BTBR T(+) Itpr3(tf)/J mice (BTBR), an inbred mouse line widely used to model ASD-like symptoms owing to its robust social and communication deficits, and high level of repetitive stereotyped behaviours. C57BL/6J (B6) mice were used as normosocial reference comparators. DA reuptake inhibition with GBR 12909 produced significant striatal DA release in both strains, but failed to elicit fMRI activation in widespread forebrain areas of BTBR mice, including mesolimbic reward and striatal terminals. In addition, BTBR mice exhibited no appreciable motor responses to GBR 12909. DA D1 receptor-dependent behavioural and signalling responses were found to be unaltered in BTBR mice, whereas dramatic reductions in pre- and postsynaptic DA D2 and adenosine A2A receptor function was observed in these animals. Overall these results document profoundly compromised DA D2-mediated neurotransmission in BTBR mice, a finding that is likely to have a role in the distinctive social and behavioural deficits exhibited by these mice. Our results call for a deeper investigation of the role of dopaminergic dysfunction in mouse lines exhibiting ASD-like phenotypes, and possibly in ASD patient populations.

Haemorrhagic cystitis in haematopoietic stem cell transplantation (HSCT): a prospective observational study of incidence and management in HSCT centres within the GITMO network (Gruppo Italiano Trapianto Midollo Osseo).

UNLABELLED: Haemorrhagic cystitis (HC) is a recognised complication in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT). This study evaluates the incidence and severity of HC in patients undergoing allogeneic HSCT during hospitalisation and within the first 100 days following transplant, looking at the use of prophylaxis, management of HC, outcomes at 100 days post transplant, and to identify any correlations between development of HC and the different conditioning regimens for transplant or HC prevention methods used. RESULTS: Four hundred and fifty patients (412 adult and 38 paediatric) were enrolled in this prospective, multicentre, and observational study. HC was observed in 55 patients (12.2%) of which 8/38 were paediatric (21% of total paediatric sample) and 47/412 adults (11.4% of total adult sample). HC was observed primarily in the non-related HSCT group (45/55; 81.8%, p= 0.001) compared to sibling and myeloablative transplant protocols (48/55; 87.3%; p= 0.008) and with respect to reduced intensity conditioning regimens (7/55;12.7%). In 33 patients with HC (60%), BK virus was isolated in urine samples, a potential co-factor in the pathogenesis of HC. The median day of HC presentation was 23 days post HSCT infusion, with a mean duration of 20 days. The most frequent therapeutic treatments were placement of a bladder catheter (31/55; 56%) and continuous bladder irrigation (40/55; 73%). The range of variables in terms of conditioning regimens and so on, makes analysis difficult. CONCLUSIONS: This multi-centre national study reported similar incidence rates of HC to those in the literature. Evidence-based guidelines for prophylaxis and management are required in transplant centres. Further research is required to look at both prophylactic and therapeutic interventions, which also consider toxicity of newer conditioning regimens.

Bimodal effect of D-aspartate on brain aging processes: insights from animal models.

Nowadays it is widely recognized that D-amino acids are present in bacteria as well as in eukaryotes, including mammals. In particular, free D-serine and D-aspartate are found in the brain of mammals. Notably, D-aspartate occurs at substantial levels in the embryo brain to then consistently decrease at post-natal phases. Temporal regulation of D-aspartate content depends on the post-natal onset of D-aspartate oxidase expression, the only known enzyme able to catabolize this D-amino acid. Pharmacological evidence indicates that D-aspartate binds and activates NMDA receptors (NMDARs). To decipher the physiological function of D-aspartate in mammals, in the last years, genetic and pharmacological mouse models with abnormally higher levels of this D-amino acid have been generated. Overall, these animal models have pointed out a significant neuromodulatory role for D-aspartate in the regulation of NMDAR-dependent functions. Indeed, increased content of D-aspartate are able to increase hippocampal NMDAR-dependent long-term potentiation (LTP) and spatial memory of adult mice. However, if exposure to elevated levels of D-Asp lasts for the entire lifetime of mice, enhancement of synaptic plasticity turns into a dramatic worsening, thus triggering an acceleration of the NMDAR-dependent aging processes in the hippocampus. Nonetheless, administration of D-Asp to old mice can restore the physiological age-related decay of hippocampal NMDA-related LTP. Besides its effect on hippocampus-dependent processes in mouse models, different points of evidence are indicating, today, a potential role for D-Asp in neurologic and psychiatric disorders associated with aberrant signalling of NMDARs.

Warm fish with cold hearts: thermal plasticity of excitation-contraction coupling in bluefin tuna.

Bluefin tuna have a unique physiology. Elevated metabolic rates coupled with heat exchangers enable bluefin tunas to conserve heat in their locomotory muscle, viscera, eyes and brain, yet their hearts operate at ambient water temperature. This arrangement of a warm fish with a cold heart is unique among vertebrates and can result in a reduction in cardiac function in the cold despite the elevated metabolic demands of endothermic tissues. In this study, we used laser scanning confocal microscopy and electron microscopy to investigate how acute and chronic temperature change affects tuna cardiac function. We examined the temporal and spatial properties of the intracellular Ca2+ transient (Δ[Ca2+]i) in Pacific bluefin tuna (Thunnus orientalis) ventricular myocytes at the acclimation temperatures of 14°C and 24°C and at a common test temperature of 19°C. Acute (less than 5 min) warming and cooling accelerated and slowed the kinetics of Δ[Ca2+]i, indicating that temperature change limits cardiac myocyte performance. Importantly, we show that thermal acclimation offered partial compensation for these direct effects of temperature. Prolonged cold exposure (more than four weeks) increased the amplitude and kinetics of Δ[Ca2+]i by increasing intracellular Ca2+ cycling through the sarcoplasmic reticulum (SR). These functional findings are supported by electron microscopy, which revealed a greater volume fraction of ventricular SR in cold-acclimated tuna myocytes. The results indicate that SR function is crucial to the performance of the bluefin tuna heart in the cold. We suggest that SR Ca2+ cycling is the malleable unit of cellular Ca2+ flux, offering a mechanism for thermal plasticity in fish hearts. These findings have implications beyond endothermic fish and may help to delineate the key steps required to protect vertebrate cardiac function in the cold.

Elevated forebrain excitatory L-glutamate, L-aspartate and D-aspartate in the Naples high-excitability rats.

The Naples high-excitability (NHE) rats are thought to model the mesocortical variant of attention-deficit hyperactivity disorder (ADHD). The aim of this study was to investigate forebrain level of L-glutamate, L-aspartate and D-aspartate, in NHE vs. Naples random bred (NRB) control rats. Thus, prepuberal NHE and NRB rats were daily handled in the 5th and 6th week of postnatal life. Then rats were exposed to two spatial novelties i.e. a Làt and a Olton maze for 10 min. Amino acids were detected by HPLC in the prefrontal cortex (PFC), striatum (STR), hippocampus (HPC) and hypothalamus (HYP). Results indicate that all amino acids were higher in NHE than in NRB rats. This, in turn, may explain the behavioural hyperactivity and attention deficit of this animal model of ADHD.

Spontaneous insulin fluctuations and the preabsorptive insulin response to food ingestion in humans.

Insulin secretion occurs in response to cephalic stimulation by foods; in humans, the response is quite variable and its importance in meal situations is difficult to assess. Insulinemia also varies spontaneously in the absence of food stimulation. In the present work, a comparative study of spontaneous and food-associated insulinemia changes was performed. Spontaneous preprandial fluctuations of glycemia and insulinemia were recorded and the presence of significant oscillations or trends was investigated. Premeal changes in insulinemia then served as a basis for evaluating the preabsorptive insulin response (PIR) during food ingestion. A sinewave fitted to preprandial insulin oscillations did not appear satisfactory as a basis for the assessment of the PIR. Significant PIRs were then defined in terms of deviation from a confidence interval (mean of the preprandial values +/- 2 SD). Significant PIRs were more frequent when the food presented was more palatable. Individual differences in responsiveness appeared. The physiological significance of a PIR over a background of spontaneous fluctuations is discussed.

The Soviet Union and population: theory, problems, and population policy.

PIP: Until the important public dialog on 3rd World population issues began in the Soviet Uuion in 1965, ideological limitations and bureaucratic interests prevented policy makers from recognizing the existence of a world of national "population problem." Since then, freer discussions of the Soviet Union's surprising decline in birthrate and labor shortages have led to serious policy questions. Conflicting policy goals, however, have resulted in only modest pronatalist policies. The Soviet population problem is a result of interregional disparities in population growth rates between the highly urbanized Soviet European populations with low birth rates and the least urbanized Central Asians with dramatically higher birth rates. As a result, these essentially Muslim people will provide the only major increases in labor resources and an increasing percentage of Soviet armed forces recruits. Policy planners are thus faced with difficult options. Current policies stressing technological transfers from the west and greater labor productivity, however, are unlikely to solve further labor shortages and regional imbalances. Ultimately, nonEuropana regions will be in an improved bargaining position for more favorable nationwide economic policies and for a greater role in policy planning.^ieng