Neuroprotective Effect of Physical Exercise in a Mouse Model of Alzheimer’s Disease Induced by β-Amyloid1–40 Peptide

This study was designed to investigate the potential neuroprotective effect of exercise in a mouse model of Alzheimer’s disease (AD) induced by intracerebroventricular (i.c.v.) injection of beta-amyloid_1–40 (Aβ_1–40) peptide. For this aim, male Swiss Albino mice were submitted to swimming training (ST) with progressive increase in intensity and duration for 8 weeks before Aβ_1–40 administration (400 pmol/animal; 3 μl/site, i.c.v. route). The cognitive behavioral, oxidative stress, and neuroinflammatory markers in hippocampus and prefrontal cortex of mice were assessed 7 days after Aβ_1–40 administration. Our results demonstrated that ST was effective in preventing impairment in short- and long-term memories in the object recognition test. ST attenuated the increased levels of reactive species and decreased non-protein thiol levels in hippocampus and prefrontal cortex induced by Aβ_1–40. Also, Aβ_1–40 inhibited superoxide dismutase activity and increased glutathione peroxidase, glutathione reductase, and glutathione S-transferase activities in hippocampus and prefrontal cortex—alterations that were mitigated by ST. In addition, ST was effective against the increase of tumor necrosis factor-alpha and interleukin-1 beta levels and the decrease of interleukin-10 levels in hippocampus and prefrontal cortex. This study confirmed the hypothesis that exercise is able to protect against some mechanisms of Aβ_1–40-induced neurotoxicity. In conclusion, we suggest that exercise can prevent the cognitive decline, oxidative stress, and neuroinflammation induced by Aβ_1–40 in mice supporting the hypothesis that exercise can be used as a non-pharmacological tool to reduce the symptoms of AD.     

Diferencias en la tasa de atrofia global y regional y del volumen lesional entre género en esclerosis múltiple

Introduction

Previous studies showed gender-associated clinical and MRI differences in multiple sclerosis (MS) evolution. However, only few studies were done with non conventional MRI techniques and no one was done in a South American MS population. The aim of this study was to investigate gender differences according to nonconventional MRI measures in patients with MS from Buenos Aires, Argentina.

Methods

Relapsing-remitting MS patients (RRMS) with at least 6 years of follow up and an MRI at onset and at 6 years were included. Patients were assessed using nonconventional MRI measures: total brain volume (TBV), neocortical grey brain volume (GBV), white brain volume (WBV), lesion load (LL), % of brain volume change between onset and year 6 (% BVC) and regional brain volume change. Gender-related MRI differences were investigated using general linear model analysis.

Results

The 45 patients were included (25 female). Mean follow up time was 7.3±0.2 years. No differences in age, EDSS at onset, DMD treatment, TBV, GBV, WBV neither LL were found between gender at baseline. Six years later, males showed a decrease in TBV (P=.002) and GBV (P≤0.001) and an increase in LL (P=.02) and % BVC (P<.001) vs. females. Female patients showed a decrease in the volume of frontal subcortical region.

Discussion

This is the first study showing differences in brain volume changes between gender in MS patients from South America. Future studies will confirm our initial findings.     

Chimeric antigen receptor-modified human regulatory T cells that constitutively express IL-10 maintain their phenotype and are potently suppressive

Clinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA-A2 CAR-Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL-10) and an imaging reporter as additional payloads. Cells were engineered to express combinations of these domains and assessed for phenotype and function. Cells expressing the full construct maintained a stable phenotype after transduction, were specifically activated by HLA-A2, and suppressed alloresponses potently. The addition of IL-10 provided an additional advantage to suppressive capacity. This study therefore provides an important proof-of-principle for this cell engineering approach for next-generation Treg therapy in transplantation.     

Radioautographic visualization of collagen metabolism in the periodontal tissues of the mouse

The time sequence of collagen formation in periodontal structures of mice was studied by radioautography after injection of tritium-labelled proline or glycine. For comparison, some animals were injected with leucine-H³ or methionine-H³. The structures studied were periodontal membrane, cementum, and alveolar bone of molar teeth. Grains were counted in each component of the periodontium at the levels of root apex, root sides and alveolar crest.

Results showed that in all structures radioactivity appeared first in cells (fibro-,osteo-, and cementoblasts) and later in intercellular spaces. The fact that glycine-H³ or proline-H³ (the most abundant amino acids in collagen) labelled these collagen secreting cells far more strongly than any other cell type was taken as evidence that the label was mainly in collagen.

In the periodontal membrane, collagen formation proceeds at a rapid rate which is much more pronounced than in dense connective tissue elsewhere (tendons, ligaments, gingiva). Periodontal membrane around the root apex (apical ligament) or at the level of alveolar crest (crest ligament) incorporates more glycine-H³ than at other sites (horizontal and oblique ligaments).

In cementum only small areas were labelled, indicating that not all cementoblasts are actively secreting collagen at a given time. The label migrated from the cells to the pre-cementum and later to calcified cementum, with a small decrease in total radioactivity.

Alveolar bone showed labelled osteoblasts at 30 min after injection. Later the radioactivity was found in pre-bone and in bone proper. The radioactivity stayed a shorter time in pre-bone than in pre-cementum, before appearing in the calcified structures. This means that calcification proceeds faster in alveolar bone than in cementum. In bone the number of radioactive areas decreased with time, but the number of silver grains per unit area in regions of persisting radioactivity decreased only slightly or not at all.

The radioautographic evidence presented in this paper, showing that the periodontium is characterized by a constant renewal of collagen, may explain why this structure is sensitive to metabolic disturbances and food deficiencies.     

Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant

BackgroundDiffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.MethodsImmunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.ResultsGD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.ConclusionOur study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.     

Tridimensional personality questionnaire factors in major depressive disorder: relationship to anxiety disorder comorbidity and age of onset

OBJECTIVE: We used the Tridimensional Personality Questionnaire (TPQ) to study the relationship between temperamental traits and comorbid anxiety disorders as well as age of onset of major depressive disorder (MDD) in 263 patients with MDD. METHODS: Patients recruited for a large clinical study on MDD underwent a Structured Clinical Interview for DSM-III-R assessment and were administered the self-rated TPQ [mean age = 39.5 +/- 10.5 years, women = 138 (53%), initial 17-item Hamilton Rating Scale for Depression (HAM-D-17) score = 19.6 +/- 3.4]. The TPQ was scored for three previously identified factors -- harm avoidance (HA), novelty seeking (NS), and reward dependence (RD). Multiple linear regression methods were used to evaluate the relationship between TPQ factors and each comorbid anxiety disorder as well as between early-- vs. late-onset MDD, after controlling for age, gender and initial HAM-D-17 score (when these were related to the dependent variable in simple regressions). RESULTS: Social anxiety disorder in MDD was strongly associated with higher scores on HA and lower scores on NS and RD (t = 5.4, p < 0.0001; t = 2.6, p = 0.009; t = 2.2, p = 0.028, respectively). A diagnosis of generalized anxiety disorder in MDD was significantly related to higher HA scores (t = 2.8, p = 0.006). The presence of comorbid obsessive-compulsive disorder was associated with lower NS scores (t = 2.3, p = 0.023) as was that of comorbid panic disorder (t = 2.0, p = 0.051). Finally, the presence of simple phobias was associated with lower scores on RD (t = 2.4, p = 0.016). HA scores were higher in patients with early onset of MDD (adjusted p = 0.05). Early versus late onset of MDD was not significantly related to NS or RD scores. LIMITATIONS: Since our sample consisted of moderately depressed outpatients, our ability to generalize our findings to other populations is limited. CONCLUSIONS: Features of temperament are related to patterns of anxiety disorder comorbidity and age of onset among patients with MDD. Higher levels of HA and lower levels of RD and NS were associated with an increased risk of anxiety disorder comorbidity in our sample. HA may also be related to early onset of depression.     

Right Cerebral Activation in REM Sleep: Evidence from a Unilateral Tactile Recognition Test

Several authors have advanced the hypothesis that the right cerebral hemisphere predominates during REM sleep. This hypothesis was tested by giving a newly-devised unilateral tactile recognition test to 16 right-handed male subjects during waking and upon awakenings from REM and NREM sleep. A two-way analysis of variance revealed both a main effect for hand (the left hand being superior to the right) and a condition (waking-REM-NREM) X hand interaction. Consistent with the hypothesis of right-hemisphere activation during REM, left-hand superiority upon awakenings from REM was greater than that during waking; in the NREM condition, no between-hand difference was observed. The latter result, as well as previous findings by Gordon, Frooman, and Lavie (1982), seems to point to the presence of left-hemisphere activation during NREM and, more generally, to the link between hemispheric functional alternation and the REM-NREM cycle.     

Depression and anxiety associated with secondary amenorrhea

Secondary amenorrhea, when an organic etiology has been ruled out, is a considerable challenge to gynecologists and family physicians. Five of 18 patients suffering from amenorrhea were found to have major depressive disorder and four others generalized anxiety disorder. The dexamethasone suppression test corroborated clinical findings in three of the five depressed patients, but otherwise yielded low specificity. Since antidepressants may potentially reverse amenorrhea when a severe depressive state is present, the findings should alert the physician to include clinical and biologic criteria for depression in the diagnostic work-up for amenorrhea.