The effect of aging on insulin signalling pathway is tissue dependent: Central role of adipose tissue in the insulin resistance of aging

Insulin resistance progressively increases with age, resulting in excessively high incidence of T2D in the elderly population. To investigate the molecular mechanisms underlying insulin resistance of aging, we carried out a comparative study of insulin signalling cascade in adipose tissue, liver and skeletal muscle. We measured the protein levels in different subcellular compartments and the phosphorylation status of key components of the insulin signalling pathway in response to in vivo insulin infusion. White adipose tissue (WAT) from old rats shows altered subcellular distribution of insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) and a marked reduction in the insulin-stimulated IR tyrosine phosphorylation. Furthermore, activation of Akt, as well as GLUT4 translocation to the plasma membrane, is impaired. Quadriceps muscle from old rats also has a defect in GLUT4 trafficking but, in contrast to WAT, insulin signalling at the level of IR and Akt is increased. In liver, we found no major differences in the ability of insulin to induce autophosphorylation of the IR or activation of Akt between adult and old animals. These data, therefore, show at the molecular level that insulin resistance in adipose tissue precedes the development of liver and muscle insulin resistance in aged rats.     

Ovarian structure and hormonal status of the UChA and UChB adult rats in response to ethanol

Objectives

In females, chronic alcoholism has a current and dangerous incidence to fertility. This work had the goal of elucidating the alterations on the ovary of UChA and UChB adult rats (ethanol 10% (v/v) voluntary drinkers).

Study design

After the treatment period, 42 female rats divided into three experimental groups (UChA, UChB and Wistar) suffered decapitation and their ovaries were removed and processed to further analysis on light and electron microscopy. The ovary was entirely sliced and stained by hematoxylin–eosin, toluidine blue, periodic acid Schiff (PAS) and Masson's tricromic. Thereby, the enzymatic reaction to acid and alkaline phosphatase, estral cyclicity, reproductive hormonal status and frequency in oestrous-related ovarian structures were assigned.

Results

The UChB rats showed an increase in body mass gain index and the ovaries relative weight was significantly lower comparing to the other groups. UCh rats presented the longest estral cycle durations and also persistent oestrous phasis, with uninterrupted cycles. Advanced follicular atresia was common in UCh animals, and degenerating intracellular fragments could be observed through acid phosphatase and electron microscopy techniques.

Conclusions

There were some estral cyclicity irregularities caused by chronic ethanol intake in the UCh groups which were consequently reflected as morphologic injury in the ovary structure.     

Patient–clinician information engagement increases treatment decision satisfaction among cancer patients through feeling of being informed

Objective

Examine how patient–clinician information engagement (PCIE) may operate through feeling informed to influence patients’ treatment decision satisfaction (TDS).

Methods

Randomly drawn sample (N = 2013) from Pennsylvania Cancer Registry, comprised of breast, prostate and colon cancer patients completed mail surveys in the Fall of 2006 (response rate = 64%) and Fall of 2007. Of 2013 baseline respondents, 85% agreed to participate in follow-up survey (N = 1703). Of those who agreed, 76% (N = 1293) completed follow-up surveys. The sample was split between males and females. The majority of participants were White, over the age of 50, married, and with a high school degree. Most reported having been diagnosed with in situ and local cancer.

Results

PCIE was related to concurrent TDS (β = .06) and feeling informed (β = .15), after confounder adjustments. A mediation analysis was consistent with PCIE affecting TDS through feeling informed. Baseline PCIE predicted feeling informed (β = .04) measured 1 year later, after adjustments for baseline feeling informed and other confounders. Feeling informed was related to concurrent TDS (β = .35) after confounder adjustment and follow-up TDS (β = .13) after baseline TDS and confounder adjustment.

Conclusion

Results suggest PCIE affects TDS in part through patients’ feeling informed.

Practice implications

PCIE may be important in determining patients’ level of feeling informed and TDS.     

Investigation of Different Group A Immunoassays following One Dose of Meningococcal Group A Conjugate Vaccine or A/C Polysaccharide Vaccine in Adults

A double-blind, randomized, controlled phase I study to assess the safety, immunogenicity, and antibody persistence of a new group A conjugate vaccine (PsA-TT) in volunteers aged 18 to 35 years was previously performed. Subjects received one dose of either the PsA-TT conjugate vaccine, meningococcal A/C polysaccharide vaccine (PsA/C), or tetanus toxoid vaccine. The conjugate vaccine was shown to be safe and immunogenic as demonstrated by a standardized group A-specific immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) and by a serum bactericidal antibody (SBA) assay using rabbit complement (rSBA). This report details further analysis of the sera using four additional immunologic assays to investigate the relationship between the different immunoassays. The immunoassays used were an SBA assay that used human complement (hSBA), a group A-specific IgG multiplexed bead assay, and two opsonophagocytic antibody (OPA) assays which used two different methodologies. For each vaccine group, geometric mean concentrations or geometric mean titers were determined for all assays before and 4, 24, and 48 weeks after vaccination. Pearson''s correlation coefficients were used to assess the relationship between the six assays using data from all available visits. An excellent correlation was observed between the group A-specific IgG concentrations obtained by ELISA and those obtained by the multiplexed bead assay. hSBA and rSBA titers correlated moderately, although proportions of subjects with putatively protective titers and those demonstrating a ≥4-fold rise were similar. The two OPA methods correlated weakly and achieved only a low correlation with the other immunoassays. The correlation between hSBA and group A-specific IgG was higher for the PsA-TT group than for the PsA/C group.Within the African meningitis belt, unpredictable epidemics of meningococcal disease continue to occur every 5 to 15 years. To prevent these epidemics, a novel serogroup A conjugate meningococcal vaccine was developed. The Meningitis Vaccine Project, a partnership between the World Health Organization (WHO) and PATH (Seattle, WA) with core funding from the Bill and Melinda Gates Foundation, was created in 2001 with the goal of eliminating meningococcal epidemics in sub-Saharan Africa through the development, testing and licensure, and widespread use of serogroup A meningococcal conjugate vaccines (11) (http://www.meningvax.org).A group A meningococcal conjugate vaccine using tetanus toxoid as a carrier protein (PsA-TT) was developed at the Serum Institute of India Ltd., using a new licensed conjugation technique from the Center for Biologics Evaluation and Research/Food and Drug Administration (CBER/FDA, Bethesda, MD) (15). The results from a double-blind, randomized, controlled phase I study to assess safety, immunogenicity, and antibody persistence in healthy volunteers aged 18 to 35 years have been reported elsewhere (13). Subjects received either the PsA-TT vaccine, meningococcal A/C polysaccharide vaccine (PsA/C), or the tetanus toxoid vaccine. Blood samples were taken on the day of immunization and 4, 24, and 48 weeks later. Assessment by standardized enzyme-linked immunosorbent assay (ELISA) for group A-specific immunoglobulin G (IgG) and serum bactericidal antibody (SBA) assay using rabbit complement (rSBA) showed the vaccine to be immunogenic and able to elicit persistent functional antibody titers (13). Sera from this study were analyzed by additional immunologic assays, data from which have been used to investigate the relationship between different group A immunologic assays. Previously, knowledge of the relationship between group A immunoassays has been limited, with the majority of studies comparing only two assays; therefore, the goal of this study was to investigate the relationship between six different group A immunoassays, knowledge of which may aid our understanding of the immune response to this and other vaccines.     

The Role of Invasive Therapies in Elderly Patients with Acute Myocardial Infarction

INTRODUCTION:

In elderly patients with acute myocardial infarction, very little is known about the role of surgical myocardial revascularization and percutaneous coronary intervention (invasive therapies - IT), especially in the context of long-term outcomes after hospital discharge.

METHODS:

We analyzed 1588 patients with MI who had been included prospectively in a databank and followed for up to 7.5 years. In this population, 548 patients were ≥70 years old (elderly group - EG), and 1040 were <70 years of age (younger group - YG); 1088 underwent IT during hospitalization, and the remaining 500 were treated medically (conservative therapy - CT). Patients were monitored either by visit or by phone at least once a year. A standard questionnaire was administered to all patients. The impact of IT was analyzed with both non-adjusted and adjusted models.

RESULTS:

By the end of the follow-up period, the survival rates for the IT and CT groups were, respectively, 71.9% versus 47.2% in the global population (hazard ratio=0.55, P<0.001), 81.5% versus 66.6% in the YG (hazard ratio=0.68, P=0.018) and 48.8% versus 20.3% in the EG (hazard ratio=0.58, P<0.001). In the adjusted models, the hazard ratios were 0.62 (P<0.001) in the global population, 0.74 in the YG (P=0.073) and 0.64 (P=0.001) in the EG.

CONCLUSION:

Long-term follow-up of patients with myocardial infarction revealed that IT during the in-hospital phase was at least as effective in elderly patients as in younger patients.     

Liposome‐bound APO2L/TRAIL is an effective treatment in a rabbit model of rheumatoid arthritis

Objective

We previously observed that T lymphocytes present in synovial fluid (SF) from patients with rheumatoid arthritis (RA) were sensitive to APO2L/TRAIL. In addition, there was a drastic decrease in the amount of bioactive APO2L/TRAIL associated with exosomes in SF from RA patients. This study was undertaken to evaluate the effectiveness of bioactive APO2L/TRAIL conjugated with artificial lipid vesicles resembling natural exosomes as a treatment in a rabbit model of antigen‐induced arthritis (AIA).

Methods

We used a novel Ni²⁺‐(N‐5‐amino‐1‐carboxypentyl)‐iminodiacetic acid)–containing liposomal system. APO2L/TRAIL bound to liposomes was intraarticularly injected into the knees of animals with AIA. One week after treatment, rabbits were killed, and arthritic synovial tissue was analyzed.

Results

Tethering APO2L/TRAIL to the liposome membrane increased its bioactivity and resulted in more effective treatment of AIA compared with soluble, unconjugated APO2L/TRAIL, with substantially reduced synovial hyperplasia and inflammation in rabbit knee joints. The results of biophysical studies suggested that the increased bioactivity of APO2L/TRAIL associated with liposomes was due to the increase in the local concentration of the recombinant protein, augmenting its receptor crosslinking potential, and not to conformational changes in the protein. In spite of this increase in bioactivity, the treatment lacked systemic toxicity and was not hepatotoxic.

Conclusion

Our findings indicate that binding APO2L/TRAIL to the liposome membrane increases its bioactivity and results in effective treatment of AIA.