A novel form of low-frequency hippocampal mossy fiber plasticity induced by bimodal mGlu1 receptor signaling

Mossy fiber synapses act as the critical mediators of highly dynamic communication between hippocampal granule cells in the dentate gyrus and CA3 pyramidal neurons. Excitatory synaptic strength at mossy fiber to CA3 pyramidal cell synapses is potentiated rapidly and reversibly by brief trains of low-frequency stimulation of mossy fiber axons. We show that slight modifications to the pattern of stimulation convert this short-term potentiation into prolonged synaptic strengthening lasting tens of minutes in rodent hippocampal slices. This low-frequency potentiation of mossy fiber EPSCs requires postsynaptic mGlu1 receptors for induction but is expressed presynaptically as an increased release probability and therefore impacts both AMPA and NMDA components of the mossy fiber EPSC. A nonconventional signaling pathway initiated by mGlu1 receptors contributes to induction of plasticity, because EPSC potentiation was prevented by a tyrosine kinase inhibitor and only partially reduced by guanosine 5'-O-(2-thiodiphosphate). A slowly reversible state of enhanced synaptic efficacy could serve as a mechanism for altering the integrative properties of this synapse within a relatively broad temporal window.     

Bayesian adaptive non-inferiority with safety assessment: retrospective case study to highlight potential benefits and limitations of the approach

Adaptive trial design applied to randomized clinical trials of psychiatric medicines offers the potential to make clinical trials more efficient. In the current analysis, we retrospectively applied Bayesian adaptive allocation methods to a case study in agitated patients with schizophrenia and related diseases. The original study used a randomized, double-blind, parallel design. The objective of this analysis was to demonstrate the potential benefits of Bayesian adaptive designs by shortening the study duration and therefore limiting patient exposure to ineffective placebo or an active comparator with a known side effect. Bayesian methods allowed us to fully leverage historical data along with data observed as the study was ongoing to calculate predictive probabilities of patient response to treatment without experiencing a specified side effect. Using the Bayesian adaptive approach would have required less than half the number of patients as the original study to draw the same conclusion. Sample size was reduced from 311 to 156 patients, thereby decreasing the number of patients exposed to placebo from 54 to 30 and the number exposed to the active control with a known side effect from 126 to 60.     

Differential regional decline in dopamine receptor availability across adulthood: Linear and nonlinear effects of age

Theories of adult brain development, based on neuropsychological test results and structural neuroimaging, suggest differential rates of age‐related change in function across cortical and subcortical sub‐regions. However, it remains unclear if these trends also extend to the aging dopamine system. Here we examined cross‐sectional adult age differences in estimates of D2‐like receptor binding potential across several cortical and subcortical brain regions using PET imaging and the radiotracer [¹⁸F]Fallypride in two samples of healthy human adults (combined N = 132). After accounting for regional differences in overall radioligand binding, estimated percent difference in receptor binding potential by decade (linear effects) were highest in most temporal and frontal cortical regions (~6–16% per decade), moderate in parahippocampal gyrus, pregenual frontal cortex, fusiform gyrus, caudate, putamen, thalamus, and amygdala (~3–5%), and weakest in subcallosal frontal cortex, ventral striatum, pallidum, and hippocampus (~0–2%). Some regions showed linear effects of age while many showed curvilinear effects such that binding potential declined from young adulthood to middle age and then was relatively stable until old age. Overall, these data indicate that the rate and pattern of decline in D2 receptor availability is regionally heterogeneous. However, the differences across regions were challenging to organize within existing theories of brain development and did not show the same pattern of regional change that has been observed in gray matter volume, white matter integrity, or cognitive performance. This variation suggests that existing theories of adult brain development may need to be modified to better account for the spatial dynamics of dopaminergic system aging.     

Serum copper levels in carcinoma of ovary and cervix

The role of serum copper level (SCL) as a diagnostic and prognostic tool in genital tract malignancies was evaluated. SCL was employed as a marker for response to treatment (surgical/radiotherapy). 129 women attending gynaecology outpatient department or admitted in the gynecology ward were studied. Of these 77 patients in the disease (study) group were proven cases of genital tract malignancies and 52 served as controls. Outcome measures studied were: SCL levels estimated before initiation of any treatment i.e. surgery/radiotherapy; thereafter, at two weeks after completion of treatment. Follow up of the study subjects was done between 4-8 weeks and 8-10 weeks, when the patients were evaluated for any recurrence of disease and SCLs were also estimated. Kruskal-Wallis one-way analysis of variance determined whether values varied significantly among the different groups studied. Mean SCLs were found to be significantly elevated in cases of Ca ovary (n = 15), early CaCx (n = 14) and late CaCx (n = 48), as compared to the control group, comprising of women with no signs and symptoms of malignancy (n = 52). SCLs decreases significantly (P < 0.001) after treatment of Ca ovary and CaCx. These results indicate a possible clinical usefulness of estimating serum copper levels in women with genital tract cancer and suggest a role for SCL in the evaluation of the disease activity and as a prognostic tool in the management of genital malignancies.     

Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients.

PURPOSE: To assess the Aspergillus galactomannan enzyme-linked immunosorbent assay (ELISA) in the diagnosis of invasive aspergillosis (IA) in adult and pediatric oncohematologic patients. PATIENTS AND METHODS: The study was conducted in four patient groups: those with fever of unknown origin (FUO) during neutropenia, suspected pulmonary infection (PI), or nonpulmonary aspergillosis (NPA) and those undergoing surveillance (S) after hematopoietic stem-cell transplantation (HSCT). IA was classified as definite, probable, or possible, according to European Organization for Research and Treatment of Cancer/Mycosis Study Group definitions. RESULTS: A total of 3,294 serum samples were collected during 797 episodes (FUO, 261; PI, 297; NPA, 28; and surveillance, 211), and 153 episodes of IA were diagnosed (31 definite, 67 probable, and 55 possible). Three episodes were first suspected from galactomannan ELISA; the remaining 150 cases were diagnosed from clinical or radiologic evidence. Sensitivity of the ELISA was 64.5%, 16.4%, and 25.5% in definite, probable, and possible episodes of IA, respectively, and was lower in patients positive for anti-Aspergillus antibodies than in antibody-negative patients. Most false-positive results occurred in children and in allogeneic HSCT (allo-HSCT) patients. Overall specificity of the ELISA was 94.8%. It was lower in children compared with adults (P <.0001) and in allo-HSCT patients compared with non-allo-HSCT adults (P =.0002). Lowering the ELISA cutoff value from 1.500 to 0.700 seemed more relevant for non-allo-HSCT adults (sensitivity, 73.1%, 44.3%, and 44.7% in definite, probable, and possible IA, respectively; specificity, 94%). CONCLUSION: Galactomannan ELISA seems less sensitive than previously described, and sensitivity can be further reduced by the presence of anti-Aspergillus antibodies. A new cutoff value for the ELISA of 0.700 is proposed for non-allo-HSCT adults.     

Fluoride treatment and microhardness of dentin.

Effects of various fluoride treatments on the microhardness of human dentin were determined. Treatment with acidulated phosphate-fluoride at pH 3.0 induced a significant (p less than .05) softening when compared to treatment with water. APF at pH 4.0 did not bring about a significant change. Response to treatment with 0.4% SnF2 did not differ significantly from water treatment. Sequential treatment with APF (pH 4.0) followed by SnF2 produced significant (p less than .05) hardening of dentin. This hardening with APF-SnF2 differed at a high level of significance (p less than .001) from the softening produced by the pH 3.0 APF. A similarly significant difference was found between this single APF treatment and the single SnF2 treatment. When hardening of exposed dentin surfaces is desired, the sequential treatment method should be employed.