The short-term effects of high-dose testosterone on sleep,breathing, and function in older men

Androgen therapy may precipitate obstructive sleep apnea in men. Despite increasing androgen use in older men, few studies have examined sleep and breathing. Randomized, double-blind, placebo-controlled studies examining effects of testosterone simultaneously on sleep, breathing, and function in older men are not available. Seventeen community-dwelling healthy men over the age of 60 yr were randomized to receive three injections of im testosterone esters at weekly intervals (500 mg, 250 mg, and 250 mg) or matching oil-based placebo and then crossed over to the other treatment after 8 wk of washout. Polysomnography, anthropometry, and physical, mental, and metabolic function were assessed at baseline and after each treatment period. Testosterone treatment reduced total time slept ( approximately 1 h), increased the duration of hypoxemia ( approximately 5 min/night), and disrupted breathing during sleep (total and non-rapid eye movement respiratory disturbance indices both increased by approximately seven events per hour) (all P < 0.05). Despite expected effects on body composition (increase in total and lean mass, reduction in fat mass, P < 0.05, bioimpedance method), upper airway dimensions did not change (acoustic reflectometry). Driving ability (computer simulation), physical activity (accelerometry, Physical Activity Scale in the Elderly), quality of life (SF36, Functional Outcomes of Sleep Questionnaire), mood (Profile of Mood States Questionnaire), sleepiness (Epworth, Stanford scales), and insulin resistance (homeostasis model) also were not changed by treatment. Short-term administration of high-dose testosterone shortens sleep and worsens sleep apnea in older men but did not alter physical, mental, or metabolic function. These changes did not appear to be due to upper airway narrowing. Further study of longer-term lower-dose androgen therapy on sleep and breathing is needed to evaluate its safety in older men.     

Genetics and autoantibodies

Autoimmune diseases (ADs) are chronic conditions initiated by the loss of immunological tolerance to self-antigens. The pathogenic hypothesis comprises a complex interaction between genetic, environmental and hormonal factors that interact with an individual over time generating a dysregulation of the immune system leading to disease development. Several polymorphic genes contribute to the development of ADs. Furthermore, age and gender play a major role by influencing hormone levels that can represent the fulcrum unbalancing from susceptibility to protection. Evidences suggest that while all these steps occur, the susceptible individual develops autoantibodies over a long time lapse. Such autoantibody production is genetically determined and finally, their presence seems to determine the clinical presentation of ADs. The genetic predisposition to the developments of autoantibodies and toward the disease process may overlap. The unveiling of these mechanisms could allow not only to treat but also to prevent the development of autoimmune diseases.     

Toxoplasma gondii: bystander or cofactor in rheumatoid arthritis

Parasitic infections may induce variable immunomodulatory effects and control of autoimmune disease. Toxoplasma gondii (T. gondii) is a ubiquitous intracellular protozoan that was recently associated with autoimmunity. This study was undertaken to investigate the seroprevalence and clinical correlation of anti-T. gondii antibodies in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We evaluated sera from European patients with RA (n = 125) and SLE (n = 164) for the prevalence of anti-T. gondii IgG antibodies (ATXAb), as well as other common infections such as Cytomegalovirus, Epstein-Barr, and Rubella virus. The rates of seropositivity were determined utilizing the LIAISON chemiluminescent immunoassays (DiaSorin, Italy). Our results showed a higher seroprevalence of ATXAb in RA patients, as compared with SLE patients [63 vs. 36 %, respectively (p = 0.01)]. The rates of seropositivity of IgG against other infectious agents were comparable between RA and SLE patients. ATXAb-seropositivity was associated with older age of RA patients, although it did not correlate with RA disease activity and other manifestations of the disease. In conclusion, our data suggest a possible link between exposure to T. gondii infection and RA.     

Infections and SLE

Viral and bacterial infections may serve as an environmental trigger for the development or exacerbation of systemic lupus erythematosus (SLE) in the genetically predetermined individual. In addition, SLE patients are more prone to develop common (pneumonia, urinary tract infection, cellulitis, sepsis), chronic (tuberculosis), and opportunistic infections possibly due to inherit genetic and immunologic defects (complement deficiencies, mannose-binding lectin [MBL] polymorphisms, elevated Fcgamma III and GM-CSF levels, osteopontion polymorphism), but also due to the broad spectrum immunosuppressive agents that are part of therapy for severe manifestations of the disease. Hence, SLE patients are considered a high-risk population, where identification and treatment of chronic infections such as tuberculosis, hepatitis B or human immunodeficiency virus, are important prior to the institution of immunosuppression so as to prevent reactivation or exacerbation of the infection. Infections in SLE patients remain a source of morbidity and mortality. A caveat often encountered is to distinguish between a lupus flare and an acute infection; in such cases parameters including elevated CRP (and adhesion molecules) may aid in the diagnosis of infection. Recent research has provided convincing evidence that EBV infection may play a major role not only in molecular mimicry but also in aberrations of B cells and apoptosis leading to a state of perpetual heightened immune response in SLE.     

The Clinical and Diagnostic Significance of Anti-myosin Autoantibodies in Cardiac Disease

Autoimmunity is influenced by genetic, immune, hormonal, and environmental factors. Viral infections may trigger autoimmunity. It has been established that autoimmunity may be a contributing factor in the pathogenesis of heart disease. Anti-heart autoantibodies have been identified in the sera of patients with heart diseases, as well as in low titers in certain healthy individuals. Nevertheless, the role of humoral immunity in the development of autoimmune heart disease has not been fully established. Anti-myosin autoantibodies appear in several heart diseases such as myocarditis, dilated cardiomyopathy, Chagas' heart disease, Kawasaki disease, rheumatic fever, and ischemic myocardium. The pathogenic role of anti-myosin autoantibodies in heart disease is not fully understood. Moreover, little is known concerning the clinical implications of anti-myosin autoantibodies in heart disease and its prognostic significance. Anti-cardiac myosin autoantibodies were found to cross-react with the β-adrenergic receptor. Studies have reported the effective use of the anti-myosin directed immune-modulating approach in animals with heart disease, although no specific anti-myosin autoantibody therapeutic approach has been attempted in humans. Herein, we review the current knowledge of anti-myosin autoantibodies and the use of targeted immune-modulating therapy in different heart diseases.     

Engineering of NIR fluorescent PEGylated poly(RGD) proteinoid polymers and nanoparticles for drug delivery applications in chicken embryo and mouse models

Proteinoids are non-toxic biodegradable polymers based on thermal step-growth polymerization of natural or synthetic amino acids. Hollow proteinoid nanoparticles (NPs) may then be formed via a self-assembly process of the proteinoid polymers in an aqueous solution. In the present article polymers and NPs based on d-arginine, glycine and l-aspartic acid, poly(R^DGD), were synthesized for tumor targeting, particularly due to the high affinity of the RGD motif to areas of angiogenesis. Near IR fluorescent P(R^DGD) NPs were prepared by encapsulating the fluorescent NIR dye indocyanine green (ICG) within the formed P(R^DGD) NPs. Here, we investigate the effect of the covalent conjugation of polyethylene glycol (PEG), with different molecular weights, to the surface of the near IR encapsulated P(R^DGD) NPs on the release of the dye to human serum due to bio-degradation of the proteinoid NPs and on the uptake by tumors. This work illustrates that the release of the encapsulated ICG from the non-PEGylated NPs is significantly faster than for that observed for the PEGylated NPs, and that the higher molecular weight is the bound PEG spacer the slower is the dye release profile. In addition, in a chicken embryo model, the non-PEGylated ICG-encapsulated P(R^DGD) NPs exhibited a higher uptake in the tumor region in comparison to the PEGylated ICG-encapsulated P(R^DGD) NPs. However, in a tumor xenograft mouse model, which enables a prolonged experiment, the importance of the PEG is clearly noticeable, when a high concentration of PEGylated P(R^DGD) NPs was accumulated in the area of the tumor compared to the non-PEGylated P(R^DGD). Moreover, the length of the PEG chain plays a major role in the ability to target the tumor. Hence, we can conclude that selectivity towards the tumor area of non-PEGylated and the PEGylated ICG-encapsulated P(R^DGD) NPs can be utilized for targeting to areas of angiogenesis, such as in the cases of tumors, wounds or cuts, etc.

Synthesis of NIR/ICG PEGylated poly(R^DGD) proteinoid NPs and their drug delivery towards mCherry-labeled 4T1 tumor.     

Vaccines, viruses, and voodoo.

Vaccinations are invaluable in protection from a wide variety of diseases that can cause substantial morbidity and mortality. Although a rare complication of vaccination, autoimmune disorders represent one of these morbidities. Recently, widespread public concern has arisen from case reports suggesting that--similar to what has been observed after natural viral infections--there might be an association between specific immunizations and autoimmune diseases. Herein we address the biological plausibility of such a connection, focusing particularly on the examples of hepatitis B, rubella, and measles-mumps-rubella (MMR) vaccinations, and the autoimmune diseases they are potentially associated with. Our review of the available data suggests that, for the general population, the risk: benefit ratio is overwhelmingly in favor of vaccinations. However, the possibility cannot be ruled out that, in genetically susceptible individuals, vaccination can result in the unmasking of an autoimmune disease triggered by the immunization. We also critically examine the existing data suggesting a link between immunization against MMR and autism, and briefly discuss the controversial evidence pointing to a possible relationship between mercury exposure from vaccines and autistic disorders. There is a continued urgent need for rigorously designed and executed studies addressing these potential associations, although the use of vaccinations remains a critical public health tool for protection against infectious disease.     

Impact of left ventricular filling properties on the benefit of exercise training in patients with advanced chronic heart failure secondary to ischemic or nonischemic cardiomyopathy

This study examined left ventricular (LV) filling properties and exercise hemodynamics noninvasively before and after an exercise training program in patients with chronic heart failure (HF). Although exercise training did not improve LV filling properties in patients with advanced HF, LV filling properties determined the hemodynamic benefit attainable from exercise in this patient group.     

Contraceptive efficacy of a depot progestin and androgen combination in men

WHO studies provided proof of concept for hormonal male contraception using a prototype androgen-alone regimen. Combined testosterone plus progestin regimens offer more practical promise, but no contraceptive efficacy studies have been completed. The objective of this study was to establish the proof of principle for depot hormonal androgen/progestin combination as a male contraceptive. We performed a contraceptive efficacy study of 55 healthy men in stable fertile relationships seeking a change in contraceptive method. Testosterone (four 200-mg implants, every 4 or 6 months) and 300 mg depot medroxyprogesterone acetate, im, every 3 months were administered. Once sperm output was suppressed (<1 million/ml for 2 consecutive months), men entered a 12-month contraceptive efficacy period, ceasing other contraception. The main outcome measure was contraceptive failure (pregnancy) rate. No pregnancies occurred in 426 person-months (35.5 person-years; 95% confidence limits for contraceptive failure rate, 0-8%/annum), superior to the first year failure rate of condoms, the only reversible male method. Sperm density fell rapidly, so 94% of men entered the efficacy phase by 3 months, with only 2 of 55 (3.6%) men not sufficiently suppressed to enter efficacy. A few men treated with testosterone implants at 6-month intervals demonstrated androgen deficiency symptoms and/or escape of gonadotropin and spermatogenic suppression between months 5 and 6; after a protocol amendment, all men receiving testosterone implants at 4-month intervals avoided androgen deficiency or loss of gonadotropin and sperm output suppression. Recovery was complete (median, 3.6 months to sperm reappearance and 5.0 months to 20 million sperm/ml) in all but one man with an incidental testicular disorder. Discontinuations were for protocol-related reasons (n = 15) or altered personal circumstances (n = 12), but there were no serious adverse effects related to drug exposure. The first male contraceptive efficacy study using a prototype depot androgen/progestin combination demonstrates high contraceptive efficacy with satisfactory short-term safety and recovery of spermatogenesis. Further studies of purpose-developed products are required to extend the overall safety and efficacy experience with depot androgen/progestin combinations, the most promising approach to hormonal male contraception.