Triiodothyronine Increases Contractility Independent of beta-Adrenergic Receptors or Stimulation of Cyclic-3',5'-Adenosine Monophosphate

Background: Triiodothyronine regulates cardiac contractility; however, the mechanisms by which it produces its acute contractile effects remains unknown. We compared the acute effects of thyroid hormones (triiodothyronine [T3] and thyroxine [T4]) and of isoproterenol on the contractility of isolated rat hearts. In addition, we sought to determine whether the acute inotropic effects of thyroid hormones were mediated by beta-adrenergic receptors or by increased production of cyclic-3',5'-adenosine monophosphate (cAMP).

Methods: A Langendorff heart preparation harvested from euthyroid male Sprague-Dawley rats was used. Drugs were administered through an aortic perfusion catheter. A pressure-transduced left-ventricular balloon catheter measured pressure and heart rate changes. Changes in the maximum positive rate of change in pressure (dP/dT) and maximum negative dP/dT were determined. Responses to varying doses of T3, T sub 4, and isoproterenol were assessed in the presence and absence of beta-adrenergic receptor blockade with propranolol, cAMP production, measured by radioimmunoassay, was determined in myocardial cell suspensions after incubation with T3 or isoproterenol.

Results: T3 0.74 nmol rapidly and significantly increased maximum dP/dT by 335 plus/minus 38 mmHg/s within 30 s after bolus injection; however, contractility was unchanged after as much as 12.9 nmol T4. The maximal increase in dP/dT after 0.8 nmol isoproterenol was comparable to that produced by T3. However, the cardiotonic actions of isoproterenol were significantly slower to develop (peaking at 60 vs. 15 s) and lasted longer than those of T3. Pretreatment with propranolol 1 micro mol diminished the contractile effects of isoproterenol but had no effect on those of T3. Concentrations of isoproterenol that increase contractility also significantly increased cAMP production in isolated rat myocardial cells. However, T3 failed to increase cAMP production.     

C‐terminal agrin fragment is inversely related to neuromuscular fatigue in older men

Introduction: The aim of this study was to examine the relationship between serum C‐terminal agrin fragment (CAF) concentrations and neuromuscular fatigue in older adults. Methods: Twenty‐two healthy older men and women volunteered for this study. Resting fasted blood samples were collected and prepared for measurement of serum CAF concentration by a commercially available ELISA kit. The onset of neuromuscular fatigue was measured by monitoring electromyographic fatigue curves from the vastus lateralis muscle using the physical working capacity at fatigue threshold (PWC_FT) test. Results: A significant inverse correlation for men was observed between CAF and PWC_FT (r = ?0.602; P = 0.05), but not for women (r = 0.208; P = 0.54). After controlling for age and body mass index, significant correlations (r = ?0.69; P = 0.042) remained for men, but not for women (r = 0.12; P = 0.76). Conclusions: These data suggest that serum CAF concentrations were significantly related to the onset of neuromuscular fatigue independent of age and BMI in men only. Muscle Nerve 51 : 132–133, 2015     

Impact of Detergent on Biophysical Properties and Immune Response of the IpaDB Fusion Protein,a Candidate Subunit Vaccine against Shigella Species

Shigella spp. are causative agents of bacillary dysentery, a human illness with high global morbidity levels, particularly among elderly and infant populations. Shigella infects via the fecal-oral route, and its virulence is dependent upon a type III secretion system (T3SS). Two components of the exposed needle tip complex of the Shigella T3SS, invasion plasmid antigen D (IpaD) and IpaB, have been identified as broadly protective antigens in the mouse lethal pneumonia model. A recombinant fusion protein (DB fusion) was created by joining the coding sequences of IpaD and IpaB. The DB fusion is coexpressed with IpaB''s cognate chaperone, IpgC, for proper recombinant expression. The chaperone can then be removed by using the mild detergents octyl oligooxyethelene (OPOE) or N,N-dimethyldodecylamine N-oxide (LDAO). The DB fusion in OPOE or LDAO was used for biophysical characterization and subsequent construction of an empirical phase diagram (EPD). The EPD showed that the DB fusion in OPOE is most stable at neutral pH below 55°C. In contrast, the DB fusion in LDAO exhibited remarkable thermal plasticity, since this detergent prevents the loss of secondary and tertiary structures after thermal unfolding at 90°C, as well as preventing thermally induced aggregation. Moreover, the DB fusion in LDAO induced higher interleukin-17 secretion and provided a higher protective efficacy in a mouse challenge model than did the DB fusion in OPOE. These data indicate that LDAO might introduce plasticity to the protein, promoting thermal resilience and enhanced protective efficacy, which may be important in its use as a subunit vaccine.     

Air Pollution Particulate Matter Alters Antimycobacterial Respiratory Epithelium Innate Immunity

Inhalation exposure to indoor air pollutants and cigarette smoke increases the risk of developing tuberculosis (TB). Whether exposure to ambient air pollution particulate matter (PM) alters protective human host immune responses against Mycobacterium tuberculosis has been little studied. Here, we examined the effect of PM from Iztapalapa, a municipality of Mexico City, with aerodynamic diameters below 2.5 μm (PM_2.5) and 10 μm (PM₁₀) on innate antimycobacterial immune responses in human alveolar type II epithelial cells of the A549 cell line. Exposure to PM_2.5 or PM₁₀ deregulated the ability of the A549 cells to express the antimicrobial peptides human β-defensin 2 (HBD-2) and HBD-3 upon infection with M. tuberculosis and increased intracellular M. tuberculosis growth (as measured by CFU count). The observed modulation of antibacterial responsiveness by PM exposure was associated with the induction of senescence in PM-exposed A549 cells and was unrelated to PM-mediated loss of cell viability. Thus, the induction of senescence and downregulation of HBD-2 and HBD-3 expression in respiratory PM-exposed epithelial cells leading to enhanced M. tuberculosis growth represent mechanisms by which exposure to air pollution PM may increase the risk of M. tuberculosis infection and the development of TB.     

The predictive value of serum myeloperoxidase for vasospasm in patients with aneurysmal subarachnoid hemorrhage

Vasospasm is a major contributor to morbidity and mortality in aneurysmal subarachnoid hemorrhage (SAH), with inflammation playing a key role in its pathophysiology. Myeloperoxidase (MPO), an inflammatory marker, was examined as a potential marker of vasospasm in patients with SAH. Daily serum samples from patients with aneurysmal SAH were assayed for MPO, and transcranial Doppler (TCDs) and neurological exams were assessed to determine vasospasm. Suspected vasospasm was confirmed by angiography. Peak MPO levels were then compared with timing of onset of vasospasm, based on clinical exams, TCDs and cerebral angiography. Patients with vasospasm had a mean MPO level of 115.5?ng/ml, compared to 59.4?ng/ml in those without vasospasm, 42.0?ng/ml in those with unruptured aneurysms, and 4.3?ng/ml in normal controls. In patients who experienced vasospasm, MPO was elevated above the threshold on the day of, or at any point prior to, vasospasm in 10 of 15 events (66.7%), and on the day of, or within 2?days prior to, vasospasm in 8 of 15 events (53.3%). Elevated serum MPO correlates with clinically evident vasospasm following aneurysmal SAH. The potential utility of MPO as a marker of vasospasm is discussed.