Sexually dimorphic behavioral effects of maternal separation in anorexic rats

Exposure to negative events during the neonatal period is one of the leading factors contributing to the development of psychiatric disorders, including anorexia nervosa. In this study, we investigated the effects of maternal separation (MS) on the development of anorexia in rodents using the mild-stress form of the activity-based anorexia (ABA) model (2 hr of free access to a running wheel and a 1-hr feeding test) in both male and female rats. We assessed anxiety-like and locomotor behavior and hyperactivity with the open field and elevated plus maze tests. Our results showed that ABA rats of both sexes displayed hyperactive behavior associated with reduced anxiety-like behavior when compared to controls. However, a sexually dimorphic effect of MS emerged in anorexic rats: while the females exposed to MS + ABA were hyperactive with diminished anxiety-related behaviors compared to females of the ABA group, MS in males attenuated or did not alter the effects of the ABA protocol. In conclusion, our data reveal that the synergistic effects of MS and ABA on physical activity and anxiety-like behavior act in opposite directions in the two sexes.     

The relationship between the diameter of chemically-functionalized multi-walled carbon nanotubes and their organ biodistribution profiles in vivo

Carbon nanotubes (CNTs) exhibit unique properties which have led to their applications in the biomedical field as novel delivery systems for diagnosis and therapy purposes. We have previously reported that the degree of functionalization of CNTs is a key factor determining their biological behaviour. The present study broadens the spectrum by investigating the impact of the diameter of CNTs using two series of multi-walled CNTs (MWNTs) with distinct differences in their diameters. Both MWNTs were doubly functionalized by 1,3-dipolar cycloaddition and amidation reactions, allowing the appended functional groups to be further conjugated with radionuclide chelating moieties and antibodies or antibody fragments. All constructs possessed comparable degree of functionalization and were characterized by thermogravimetric analysis, transmission electron microscopy, gel electrophoresis and surface plasmon resonance. The MWNT conjugates were radio-labelled with indium-111, which thereby enabled in vivo single photon emission computed tomography/computed tomography (SPECT/CT) imaging and organ biodistribution study using γ-scintigraphy. The narrow MWNTs (average diameter: 9.2 nm) demonstrated enhanced tissue affinity including non-reticular endothelial tissues compared to the wider MWNTs (average diameter: 39.5 nm). The results indicate that the higher aspect ratio of narrow MWNTs may be beneficial for their future biological applications due to higher tissue accumulation.     

Linking novelty seeking and harm avoidance personality traits to basal ganglia: volumetry and mean diffusivity

Novelty Seeking (NS) and Harm Avoidance (HA) temperamental traits are related to approaching or avoiding motivational circuits relying on the integrity and functionality of distributed brain areas implicated in arousal and action. The present study verified whether and how macro- and micro-structural variations of basal ganglia are correlated with scores obtained in the NS and HA temperamental scales of the Temperament and Character Inventory by Cloninger. To this aim, 125 healthy adults aged 18–67 years of both sexes completed the Temperament and Character Inventory and underwent a high-resolution T1-weighted magnetic resonance imaging and a diffusion tensor imaging using a 3T scanner. The scores obtained in the temperamental scales were associated with volumes, mean diffusivity and fractional anisotropy measures of basal ganglia of both hemispheres separately, by using linear regression analyses. We found increased bilateral caudate and pallidum volumes associated with higher NS scores, as well as increased mean diffusivity in the bilateral putamen associated with higher HA scores. Macro- and micro-structural variations of basal ganglia regions contribute to explain the biological variance associated with NS or HA personality phenotype. The present findings evidencing some brain-temperament relationships highlight the importance of obtaining macro- and micro-structural measures in relation to individual differences.     

Translocation mechanisms of chemically functionalised carbon nanotubes across plasma membranes

Understanding the mechanisms responsible for carbon nanotube (CNT) internalisation into live cells is considered critical both from a fundamental point of view and for further engineering of CNT-based delivery systems to intracellular targets. While several studies are focused on the development of such CNT-based delivery systems, attempts to systematically elucidate the cellular uptake mechanisms of CNTs are still rather limited. The aim of the present study is to evaluate the cellular internalisation of chemically functionalised multi-walled carbon nanotubes (f-MWCNTs) in the presence of different well-known cellular uptake inhibitors. Our data reveal how f-MWCNTs are able to translocate across cell membranes of both phagocytic and non-phagocytic cell lines. We have evidenced that at least 30-50% of f-MWCNTs are taken up by cells through an energy-independent mechanism. This characteristic makes nanotubes loaded with therapeutic or diagnostic cargos extremely interesting as the release of active molecules directly into the cytoplasm increase their biological activity and therapeutic efficacy.     

Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency

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Defective Processing of Contextual Information May Be Involved in the Poor Performance of DBA/2 Mice in Spatial Tasks

These experiments examine the influence of context manipulations on radial maze performance in C57BL/6 (C57) and DBA/2 (DBA) mice. Animals from each strain were trained in two distinct contexts—poor cuing vs rich cuing—that were sucessively switched. The results first show that C57 performed better when trained under rich cuing conditions than under poor ones, whereas DBA performed poorly under both conditions. In addition, contextual manipulations were found to produce more drastic effects in C57 than in DBA mice. That is, C57 showed a strong performance decrement following each context shift, whereas DBA mice did not. In particular, the fact that DBA mice performed similarly under rich and poor cuing conditions and also reacted mildly—or did not react—to context shifts suggests a deficit in processing contextual information, which places important constraints on their capability to form spatial representations.     

5-Lipoxygenase is Coexpressed with Cox-2 in Sporadic Colorectal Cancer: A Correlation with Advanced Stage

Purpose It has been extensively documented that the cyclooxygenase inducible form and 15-lipoxygenase are implicated in colorectal carcinogenesis. Nonetheless, the role of other enzymes involved in the arachidonic acid metabolism, such as 5-lipoxygenase, in colorectal neoplasms has not been fully ascertained. This study was designed to evaluate 5-lipoxygenase expression in sporadic colorectal adenocarcinomas by using immunohistochemistry and to analyze its potential correlations with clinicopathologic parameters and with cyclooxygenase-2 expression. Methods Expression of 5-lipoxygenase and cyclooxygenase-2 were evaluated by immunohistochemistry in 50 surgically resected sporadic colorectal adenocarcinomas (28 male and 22 female patients age range, 47–88 (mean age, 69 ± 8) years). The chi-squared and Spearman correlation tests were used to analyze correlations with clinicopathologic characteristics and to evaluate any relationships between expression of the two enzymes. P values <0.05 were considered statistically significant. Results 5-Lipooxygenase and cyclooxygenase-2 immunostaining was found in the cytoplasm of neoplastic cells in 41 (82 percent) and in 43 cases (86 percent), respectively. Spearman correlation test demonstrated a positive correlation in the expression of the two enzymes. A statistically significant correlation also was observed between 5-lipoxygenase expression and tumor stage and lymph node metastasis, whereas no significant correlations emerged regarding cyclooxygenase-2 expression and clinicopathologic parameters. Conclusions Our study demonstrates that 5-lipoxygenase is expressed in colorectal adenocarcinomas in association with cyclooxygenase-2 expression. Moreover, an elevated expression of this enzyme seems to be significantly correlated with tumor aggressiveness. Further studies would clarify the need for target therapies inhibiting both metabolic pathways in such tumors. Supported by the grants from the University of Messina, Messina, Italy. Presented at the meeting of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology (SIAPEC), Venice, Italy, October 4 to 5, 2006.     

Imeglimin population pharmacokinetics and dose adjustment predictions for renal impairment in Japanese and Western patients with type 2 diabetes

Imeglimin is an orally administered first‐in‐class drug to treat type 2 diabetes mellitus (T2DM) and is mainly excreted unchanged by the kidneys. The present study aimed to define the pharmacokinetic (PK) characteristics of imeglimin using population PK analysis and to determine the optimal dosing regimen for Japanese patients with T2DM and chronic kidney disease (CKD). Imeglimin plasma concentrations in Japanese and Western healthy volunteers, and patients with T2DM, including patients with mild to severe CKD with an estimated glomerular filtration rate (eGFR) greater than 14 ml/min/1.73 m² were included in a population PK analysis. PK simulations were conducted using a population PK model, and the area under concentration‐time curve (AUC) was extrapolated with power regression analysis to lower eGFR. The influence of eGFR, weight, and age on apparent clearance and of dose on relative bioavailability were quantified by population PK analysis. Simulations and extrapolation revealed that the recommended dosing regimen based on the AUC was 500 mg twice daily (b.i.d.) for patients with eGFR 15–45 ml/min/1.73 m², and 500 mg with a longer dosing interval was suggested for those with eGFR less than 15. Simulations revealed that differences in plasma AUCs between Japanese and Western patients at the same dose were mainly driven by a difference in the eGFR and that the plasma AUC after 1000 and 1500 mg b.i.d. in Japanese and Western patients, respectively, was comparable in the phase IIb studies. These results indicate suitable dosages of imeglimin in the clinical setting of T2DM with renal impairment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Imeglimin is a first‐in‐class oral agent for the treatment of type 2 diabetes (T2DM) and is excreted unchanged into urine. A Japanese phase IIb study found that 1000 mg b.i.d. was optimal in Japanese population, and phase III studies confirmed significant glucose lowering effect. A Western phase IIb study found an optimal dose of 1500 mg b.i.d.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed the key determinants of imeglimin pharmacokinetics (PKs), recommended doses for patients with renal impairment, and what drives the different optimal doses between Japanese and Western patients with T2DM.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Renal function significantly impacts imeglimin PKs. Recommended doses for patients with renal impairment have been proposed for exposure matching. Differences in estimated glomerular filtration rate (eGFR) comprised the key driver for different optimal doses at which estimated exposures were similar between Japanese and Western patients.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Doses of imeglimin could be reduced based on eGFR. Exposure responses seemed similar between Japanese and Western patients.