Effects of chronic antidepressant treatments in a putative genetic model of vulnerability (Roman low-avoidance rats) and resistance (Roman high-avoidance rats) to stress-induced depression

Introduction

The Roman low- (RLA) and high-avoidance (RHA) rats were selectively bred for, respectively, poor versus rapid acquisition of active avoidance in a shuttle box and, under aversive conditions, display reactive (RLA) versus proactive (RHA) coping behaviors. In the forced swim test (FST), RLA rats exhibit a depression-like behavior characterized by greater immobility and fewer climbing counts when compared with their RHA counterparts. Furthermore, subacute treatments with clinically effective antidepressant drugs decrease immobility and increase climbing or swimming in RLA rats but do not modify the performance of RHA rats.

Objective and methods

Because chronic treatment with antidepressants is usually required to produce clinical effects, the present study was designed to compare the behaviors of RLA and RHA rats in the FST after subacute (1 day) and chronic (15 days) administration of desipramine, fluoxetine, and chlorimipramine.

Results

In RLA rats, subacute treatments with low doses of desipramine, fluoxetine, and chlorimipramine (2.5–5 mg/kg) were ineffective whereas chronic treatments with the same doses of all three antidepressants decreased immobility and also increased climbing (desipramine) or swimming (fluoxetine). By contrast, neither subacute nor chronic treatments with these antidepressants induced significant changes in the behavior of RHA rats in the FST.

Conclusions

RLA and RHA rats represent two divergent phenotypes, respectively susceptible and resistant to develop depression-like behavior under aversive environmental conditions that may be used to identify genetically determined neural substrates and mechanisms underlying vulnerability and resistance to stress-induced depression.     

Multidrug regimens for treatment of older patients with metastatic pancreatic cancer

Background and AimsOlder patients with metastatic pancreatic adenocarcinoma (MPDAC) are under-represented in clinical trials.MethodsOur single-center, retrospective study enrolled MPDAC patients ≥ 70 treated with chemotherapyResults105 patients were divided in groups based on the received treatments: 44 gemcitabine or capecitabine monotherapy (A), 34 nabpaclitaxel-gemcitabine (B) 27 4-drugs combinations (gemcitabine, cisplatin, capecitabine plus either nab-paclitaxel or epirubicin or docetaxel) (C). Group A: median age was 78 (70–87) and Karnofsky performance status (KPS) ≥80 was found in 84% of patients; Group B: median age 77 (71–84) and KPS ≥ 80 in 88% of patients; Group C: median age 73 (70–78) and KPS ≥ 80 in 93% of patients. Median OS was 7.9, 11.7 and 14.2 months in group A, B and C respectively; 1 and 2-year OS were 27% and 8% in group A; 44% and 5% in group B; 52% and 22% in group C. When lung metastatic only patients were excluded, patients <75 and ≥ 75 had similar OS in group A (6.4 vs 5.6 months) and in group B (12.3 vs 11.1 months). In group B grade 3 thrombocytopenia, fatigue and peripheral neuropathy were more frequent in patients ≥ 75.ConclusionsIn older patients, combination chemotherapy shows acceptable feasibility and promising efficacy.     

Interaction between Hb Hasharon and alpha-thalassemia: an approach to the problem of the number of human alpha loci

We report the case of an Italian infant girl from Polesine (Po delta region in northern Italy) who was heterozygous for Hb Hasharon and alpha-thalassemia, did not synthesize any normal HbA, and had 3% HbH on electrophoresis. Hematologic and biosynthetic studies on Hb Hasharon carriers of the propositus' family suggest the possibility that the Hb Hasharon gene is linked to an alpha-thalassemia gene. On the other hand, in the Askenazy carriers of Hb Hasharon, Hb Harsharon is probably linked to a normal alpha gene. In comparing Hb Hasharon's behavior with that of other alpha variants, particularly HbG Philadelphia, frequent recombinations between alpha structural genes were suggested. The possible identity between the single alpha locus and the alpha2- thalassemia genotype is discussed.     

Engineered secreted T-cell receptor alpha beta heterodimers.

We have produced a soluble form of a mouse alpha beta T-cell antigen receptor (TCR) by shuffling its variable (V) and constant (C) domains to the C region of an immunoglobulin kappa light chain. These chimeric molecules composed of V alpha C alpha C kappa and V beta C beta C kappa chains were efficiently secreted (up to 1 micrograms/ml) by transfected myeloma cells as noncovalent heterodimers of about 95-kDa molecular mass. In the absence of direct binding measurement, we have refined the epitopic analysis of the soluble V alpha C alpha C kappa-V beta C beta C kappa dimers and shown that they react with an anti-clonotypic antibody and two antibodies directed to the C domain of the TCR alpha and beta chains. Conversely, we have raised three distinct monoclonal antibodies against the soluble TCR heterodimers and shown that they recognize surface-expressed TCRs. Two of these antibodies were found to react specifically with the products of the V alpha 2 (V delta 8) and V beta 2 gene segments, respectively. When considered together, these data suggest that these soluble TCR molecules are folded in a conformation indistinguishable from that which they assume at the cell surface.     

Angiogenesis inhibition and depression in older men

Background

Cardiovascular diseases have been associated with depression in later life, and a potential mechanism is inhibition of angiogenesis. We designed this study to determine if depression is associated with higher serum concentration of endostatin, an endogenous angiogenesis inhibitor.

Methods

We performed a cross-sectional examination of a random sample of men aged 69–86 years. Those who scored 7 or higher on the 15-item Geriatric Depression Scale were deemed depressed. We determined the concentration of serum endostatin using a reproducible assay. Other measures included age, education, body mass index, smoking, history of depression, use of antidepressants, hypertension, diabetes, coronary heart disease and stroke, high sensitivity C-reactive protein, plasma homocysteine, triglycerides and cholesterol. We used logistic regression to investigate the association between endostatin and depression, and adjusted the analyses for confounding factors.

Results

Our sample included 1109 men. Sixty-three (5.7%) men were depressed. Their serum endostatin was higher than that of nondepressed participants (p = 0.021). Men in the highest decile of endostatin had greater adjusted odds of depression (odds ratio [OR] 1.78, 95% confidence interval [CI] 1.03–3.06). A doubling of endostatin doubled the odds of depression (OR 1.93, 95% CI 1.31–2.84). The probability of depression increased with the concentration of endostatin in a log-linear fashion up to a maximum of about 20%–25%.

Limitations

The cross-sectional design limits the study’s ability to ascribe causality to the association between high endostatin and depression.

Conclusion

Serum endostatin is associated with depression in older men. It remains to be established whether correction of this imbalance is feasible and could decrease the prevalence of depression in later life.