Diffusion MRI detects early brain microstructure abnormalities in 2‐month‐old 3×Tg‐AD mice

The 3×Tg‐AD mouse is one of the most studied animal models of Alzheimer's disease (AD), and develops both amyloid beta deposits and neurofibrillary tangles in a temporal and spatial pattern that is similar to human AD pathology. Additionally, abnormal myelination patterns with changes in oligodendrocyte and myelin marker expression are reported to be an early pathological feature in this model. Only few diffusion MRI (dMRI) studies have investigated white matter abnormalities in 3×Tg‐AD mice, with inconsistent results. Thus, the goal of this study was to investigate the sensitivity of dMRI to capture brain microstructural alterations in 2‐month‐old 3×Tg‐AD mice. In the fimbria, the fractional anisotropy (FA), kurtosis fractional anisotropy (KFA), and radial kurtosis (K_┴) were found to be significantly lower in 3×Tg‐AD mice than in controls, while the mean diffusivity (MD) and radial diffusivity (D_┴) were found to be elevated. In the fornix, K_┴ was lower for 3×Tg‐AD mice; in the dorsal hippocampus MD and D_┴ were elevated, as were FA, MD, and D_┴ in the ventral hippocampus. These results indicate, for the first time, dMRI changes associated with myelin abnormalities in young 3×Tg‐AD mice, before they develop AD pathology. Morphological quantification of myelin basic protein immunoreactivity in the fimbria was significantly lower in the 3×Tg‐AD mice compared with the age‐matched controls. Our results demonstrate that dMRI is able to detect widespread, significant early brain morphological abnormalities in 2‐month‐old 3×Tg‐AD mice.     

Estrogen receptor alpha as a key target of organochlorines to promote angiogenesis

Epidemiological studies report that exposure to pesticides like chlordecone and lindane increases risk of cancer. They may act as endocrine disruptors via the activation of estrogen receptor α (ERα). Carcinogenesis involved angiogenesis and no available data regarding these organochlorines have been reported. The present study aimed at investigating the effects of lindane and chlordecone on cellular processes leading to angiogenesis through an involvement of ERα. Angiogenesis has been analyzed both in vitro, on human endothelial cells, and in vivo by quantifying neovascularization with the use of ECMgel^? plug in mice. Both pesticides increased endothelial cell proliferation, migration and MMP2 activity. These toxics potentiated cell adhesion by enhancing FAK phosphorylation and stress fibers. The two organochlorines increased nitric oxide production via an enhancement of eNOS activity without modification of oxidative stress. Evidence has been provided that the two toxins increased in vivo neovascularization. Most interestingly, all the above processes were either partially or completely prevented after silencing of ERα. Altogether, these data highlight that organochlorines modulate cellular angiogenic processes through activation of ERα. This study further reinforces the harmful effects of these pesticides in carcinogenesis, particularly in the modulation of angiogenesis, a critical step in tumor promotion, through ERα.     

Maternal citrulline supplementation enhances placental function and fetal growth in a rat model of IUGR: involvement of insulin-like growth factor 2 and angiogenic factors

Objective: To determine the effects of maternal citrulline supplementation on fetal growth and placental efficiency in a rat model of intrauterine growth restriction (IUGR) induced by maternal protein restriction.

Methods: Pregnant Sprague–Dawley rats were randomly assigned to three groups: NP (receiving a control 20% protein diet), LP (a 4% protein diet), or LP-CIT (an LP diet along with L-citrulline, 2?g/kg/d in drinking water). On the 15th and 21st day of gestation (GD15 and GD21, respectively), dams underwent a C-section, by which fetuses and placentas were extracted. The expression of genes involved in placental growth and angiogenesis was studied by quantitative RT-PCR.

Results: Maternal citrulline supplementation increased fetal weight at GD21, and fetal weight/placental weight ratio, an index of placental efficiency, from mid gestation (p?Igf2-P0, a placenta-specific variant of insulin-like growth factor 2 (Igf2) gene, and Vegf and Flt-1, involved in angiogenic pathways, was enhanced in the LP-CIT group (versus NP, p?p?p?Igf2-P0, Vegf, and Flt-1, respectively).

Conclusions: In a model of IUGR induced by protein deprivation, citrulline enhances fetal growth, placental efficiency, and the expression of genes involved in angiogenesis. The relevance of such effect in human pregnancies complicated by IUGR warrants further study.     

Dose reduction of epoetin-alpha in the prevention of chemotherapy-induced anaemia

Introduction  

Anaemia during chemotherapy is often left untreated. Erythropoiesis-stimulating agents are frequently used to treat overt anaemia. Their prophylactic use, however, remains controversial and raises concerns about cost-effectiveness. Therefore, we assessed the efficacy of a dose-reduction schedule in anaemia prophylaxis.     

Effects of interleukin-2 therapy combined with highly active antiretroviral therapy on immune restoration in HIV-1 infection: a randomized controlled trial

BACKGROUND: Intermittent interleukin-2 (IL-2) therapy leads to a sustained increase of CD4 T cells in HIV-1-infected patients. METHODS: Symptom-free HIV-1-infected patients who were naive to all antiretroviral drugs (n = 68) and/or to protease inhibitors (n = 50) and had a CD4 cell count of 200-550 x 10(6) cells/l were randomly assigned to start lamivudine/stavudine/indinavir alone (controls) or combined from week 4 with subcutaneous IL-2 (5 x 10(6) IU twice daily for 5 days: every 4 weeks for three cycles, then every 8 weeks for seven cycles). Immunological and virological results were monitored until week 74. RESULTS: CD4 T cell counts increased more in the IL-2 group than in the controls (median increases 865 and 262 x 10(6) cells/l, respectively; P < 0.0001); an 80% increase in CD4 T cells was achieving by 89% of the IL-2 group and by 47% of the controls (P < 0.0001). Decrease of plasma viral loads was similar in both groups. Compared with controls, IL-2 induced a greater increase of naive and memory CD4 T cells, lymphocyte expression of CD28 and CD25 (P < 0.0001) and natural killer cells (P < 0.001). In a logistic regression analysis, odds of being responders to recall antigens was 8.5-fold higher in IL-2 recipients (P = 0.002) than in controls. The former experienced a higher level of antibody response to tetanus vaccination at week 64 than controls (32 and 8 haemagglutinating units/ml, respectively; P = 0.01). CONCLUSIONS: The combination of antiviral drugs and IL-2 induced a greater expansion and function of CD4 T cells than antiretroviral drugs alone.