Behavioral impairments of the aging rat

Several disturbances occurring during aging of humans and rodents alike stem from changes in sensory and motor functions. Using a battery of behavioral tests we have studied alterations in performance with advancing age in female and male rats of some frequently used strains. In parallel, we collected survival and body weight data. The median survival age was similar for female and male Sprague-Dawley rats, inbred female Lewis and outbred male Wistar rats (29-30 months). In contrast, male Fisher 344 had a significantly shorter median life span. During aging there is a gradual decline in locomotor activity and explorative behavior while disturbances of coordination and balance first became evident at more advanced age. In old age, also weight carrying capacity, limb movement and temperature threshold were impaired. While whole body weight continues to increase over the better part of a rats' life span, the behavioral changes in old age associated with a decrease in both total body weight and muscle mass. Dietary restriction increases median life span expectancy; retards the pace of behavioral aging and impedes sarcopenia. Housing in enriched environment did not improve the scoring in the behavioral tests but tended to increase median life span. Finally, there was an agreement between behavioral data collected from longitudinal age-cohorts and those obtained from multiple age-cohorts.     

Peroxide bond-dependent antiplasmodial specificity of artemisinin and OZ277 (RBx11160)

Using nonperoxidic analogs of artemisinin and OZ277 (RBx11160), the strong in vitro antiplasmodial activities of the latter two compounds were shown to be peroxide bond dependent. In contrast, the weak activities of artemisinin and OZ277 against six other protozoan parasites were peroxide bond independent. These data support the iron-dependent artemisinin alkylation hypothesis.     

Metabolic training: new paradigms of exercise training for metabolic diseases with exercise calorimetry targeting individuals.

For patients with metabolic diseases, as with other diseases, exercise training is a fully recognized therapy. Such training helps obese patients stabilize weight after slimming. For patients with type 2 diabetics, it is both a prevention and a glucose-lowering treatment and reduces health care costs. We propose a targeted training for individuals at the level of maximal lipid oxidation (LIPOXmax) with a protocol of exercise calorimetry (four 6-min workloads) based on Brooks and Mercier's crossover concept. Calorimetric interpretation of gas exchange at the fifth and sixth minutes of each stage shows a bell-shaped curve for lipid oxidation that peaks at LIPOXmax, a point that varies considerably among individuals. As well, glucose oxidation is a linear function of power (carbohydrate cost of the watt). Such a calculation predicts fairly actual lipid oxidation over 45 min at the same level. Other protocols, with 3-min workloads used in sports medicine, are not reliable for patients with metabolic diseases. For obese adults and teenagers, as well as those with type 2 diabetes, 2 months' training at the LIPOXmax (three sessions at 45 min per week) results in a net loss of fat mass, with preserved fat-free mass, and increased ability to oxidize lipids. At the end of this period, training can be "re-targeted" to be more effective and, possibly, associated with other strategies with stronger exercise intensities. Therefore, metabolic training is a viable option for patients with metabolic diseases, but the full concept is still evolving. However, the major challenge remains to transform inactive individuals into active ones.     

PDGF Receptor Signaling in Osteoblast Lineage Cells Controls Bone Resorption Through Upregulation of Csf1 Expression

The physiological functions of platelet-derived growth factor receptors (PDGFRs) α and β in osteoblast biology and bone metabolism remain to be established. Here, we show that PDGFRA and PDGFRB genes are expressed by osteoblast-lineage canopy and reversal cells in close proximity to PDGFB-expressing osteoclasts within human trabecular bone remodeling units. We also report that, although removal of only one of the two PDGFRs in Osterix-positive cells does not affect bone phenotype, suppression of both PDGFRs in those osteoblast lineage cells increases trabecular bone volume in male mice as well as in female gonad-intact and ovariectomized mice. Furthermore, osteoblast lineage-specific suppression of PDGFRs reduces Csf1 expression, bone marrow level of macrophage colony-stimulating factor (M-CSF), number of osteoclasts, and, therefore, bone resorption, but does not change bone formation. Finally, abrogation of PDGFR signaling in osteoblasts blocks PDGF-induced ERK1/2-mediated Csf1 expression and M-CSF secretion in osteoblast cultures and calcitriol-mediated osteoclastogenesis in co-cultures. In conclusion, our results indicate that PDGFR signaling in osteoblast lineage cells controls bone resorption through ERK1/2-mediated Csf1 expression. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Survival Benefit of Hyperthermic Intraperitoneal Chemotherapy for Recurrent Ovarian Cancer: A Multi-institutional Case Control Study

Background

Hyperthermic intraperitoneal chemotherapy (HIPEC) and complete surgical removal of the tumor, in relapsing patients may provide a clinical benefit. There is no consensus considering the place of HIPEC for patients who had first ovarian cancer relapse. To assess for possible efficacy of HIPEC on overall survival (OS) rates in this situation, we performed a multi-institutional study.

Methods

The current study was a retrospective case control multi-institutional study comparing a group of patients treated with HIPEC to a group of patients treated without HIPEC. Inclusion criteria were first relapse of a serous ovarian carcinoma and >6 months after the end of initial treatment. Exclusion criteria were another pathological subtype of ovarian cancer, a relapse at <6 months after initial treatment, and a second relapse or more. We aimed to assess OS, morbidity, and mortality rates and prognostic factors.

Results

From June 1997–July 2011, 42 patients were included, 23 in the HIPEC group and 19 in the control group. Each patient from the two groups had a complete secondary surgery at the time of the first relapse. At 4 years OS was 75.6 % in the HIPEC group and 19.4 % in the control group (p = 0.013). In a multivariate analysis, HIPEC and interval-free before the end of initial treatment were both independent prognostic factors.

Conclusion

When compared to the control group, complete secondary surgery and HIPEC appear to afford a better OS rate than complete secondary surgery alone, in case of first ovarian cancer relapse. Further randomized trials are warranted to confirm these results.     

Gene transfer improves erythroid development in ribosomal protein S19-deficient Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Forty percent of the patients are blood transfusion-dependent. Recent reports show that the ribosomal protein S19 (RPS19) gene is mutated in 25% of all patients with DBA. We constructed oncoretroviral vectors containing the RPS19 gene to develop gene therapy for RPS19-deficient DBA. These vectors were used to introduce the RPS19 gene into CD34(+) bone marrow (BM) cells from 4 patients with DBA with RPS19 gene mutations. Overexpression of the RPS19 transgene increased the number of erythroid colonies by almost 3-fold. High expression levels of the RPS19 transgene improved erythroid colony-forming ability substantially whereas low expression levels had no effect. Overexpression of RPS19 had no detrimental effect on granulocyte-macrophage colony formation. Therefore, these findings suggest that gene therapy for RPS19-deficient patients with DBA using viral vectors that express the RPS19 gene is feasible.     

Hemorheological aspects of the metabolic syndrome: markers of insulin resistance, obesity or hyperinsulinemia?

The metabolic syndrome is a major health problem in western countries, due to the deleterious metabolic consequences of sedentarity and rich diet in the large part of the population who exhibits the so-called "thrifty phenotype". This syndrome, which is at high risk for diabetes and atherothrombosis is associated with hemorheologic abnormalities. Initially, insulin resistance was considered as the core of the syndrome. However, it becomes clear that the syndrome is a cluster in which the combined effects of obesity, insulin resistance, and hyperinsulinemia can be inconstantly associated. Thus, we investigated in 157 nondiabetic subjects (53 males and 104 females, age 35.6+/-1.1 yr, mean BMI 29.2+/-0.6 kg/m2) the respective importance of each of these factors. Subjects were divided in 6 groups according to BMI (cut-off point 25 kg/m2) and insulin sensitivity (SI) measured with the minimal model (lowest quartile SI<1.1 min(-1)/(microU/ml) x 10(-4), highest quartile SI>9.5, middle zone between 1.1 and 9.5). Results show that whole blood viscosity at high shear rate is higher in obese subjects (p<0.01). Plasma viscosity is also higher in obese subjects 1.41+/-0.02 vs 1.34+/-0.012 (p<0.01), and, in addition, in lean subjects, is lower when SI is in the upper quartile. RBC rigidity index "Tk" is higher in obese subjects. A worsening effect of insulin resistance (SI<1.1) on Tk is found only in obese subjects. The aggregability index "M1" is increased when SI<1.1 in both obese and nonobese subjects. No clear effect of either SI or obesity on hematocrit is observed. On the whole, obesity and insulin resistance both impair blood rheology by acting on red cell rigidity and plasma viscosity. Whole blood viscosity at high shear rate reflects rather obesity than insulin resistance. Myrenne "M1" aggregation is rather a marker of hyperinsulinemia. Thus, the hemorheologic picture of the metabolic syndrome is far to be only a reflect of insulin resistance alone.     

Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C

BACKGROUND/AIMS: Our aims were to investigate the host and viral specific factors associated with diabetes mellitus (DM) and insulin resistance in chronic hepatitis C patients. METHODS: One hundred and three hepatitis C virus (HCV)-infected were studied to assess the effects of HCV genotype, hepatic iron content, steatosis, hepatic fibrosis, body mass index (BMI) and family history of DM on the occurrence of DM. Insulin resistance (HOMA IR) was studied in 81 non-diabetic patients to determine the mechanism associated with insulin resistance in this subgroup. RESULTS: Sixteen of the 123 were diabetic (13.0%). The variables predictive of DM were METAVIR fibrosis score 4 (OR, 13.16; P = 0.012), family history of diabetes (OR, 16.2; P = 0.0023), BMI (OR, 1.37; P = 0.017) and age (OR, 1.09; P = 0.002). In non-diabetic HCV-infected patients, HOMA-IR of METAVIR fibrosis score 0 and 1 patients were significantly different than score 2 and score 3/4 patients. CONCLUSIONS: Our findings indicate that older age, obesity, severe liver fibrosis and family history of diabetes help identify those HCV patients who might have potential risk factors for development of DM. We observed that insulin resistance in non-diabetic HCV-infected patients was related to grading of liver fibrosis, and occurs already at an early stage in the course of HCV infection.