Conversion from vagal to sympathetic predominance with strenuous training in high-performance world class athletes.

BACKGROUND: Benefits of moderate endurance training include increases in parasympathetic activity and baroreflex sensitivity (BRS) and a relative decrease in sympathetic tone. However, the effect of very intensive training load on neural cardiovascular regulation is not known. We tested the hypothesis that strenuous endurance training, like in high-performance athletes, would enhance sympathetic activation and reduce vagal inhibition. METHODS AND RESULTS: We studied the entire Italian junior national team of rowing (n=7) at increasing training loads up to 75% and 100% of maximum, the latter approximately 20 days before the Rowing World Championship. Autoregressive power spectral analysis was used to investigate RR interval and blood pressure (BP) variabilities. BRS was assessed by the sequences method. Increasing training load up to 75% of maximum was associated with a progressive resting bradycardia and increased indexes of cardiac vagal modulation and BRS. However, at 100% training load these effects were reversed, with increases in resting heart rate, diastolic BP, low-frequency RR interval, and BP variabilities and decreases in high-frequency RR variability and BRS. Three athletes later won medals in the World Championship. CONCLUSIONS: This study indicates that very intensive endurance training shifted the cardiovascular autonomic modulation from a parasympathetic toward a sympathetic predominance. This finding should be interpreted within the context of the substantial role played by the sympathetic nervous system in increasing cardiovascular performance at peak training. Whether the altered BP and autonomic function shown in this study might be in time hazardous to human cardiovascular system remains to be established.

Getting an Insight into the Complexity of Major Chronic Inflammatory and Degenerative Diseases: A Potential New Systemic Approach to Their Treatment.

As the modern society is troubled by multi-factorial diseases, research has been conducted on complex realities including chronic inflammation, cancer, obesity, HIV infection, metabolic syndrome and its detrimental cardiovascular complications as well as depression and other brain disorders. Deterioration of crucial homeostatic mechanisms in such diseases invariably results in activation of inflammatory mediators, chronic inflammation, loss in immunological function, increased susceptibility to diseases, alteration of metabolism, decrease of energy production and neuro-cognitive decline. Regulation of genes expression by epigenetic code is the dominant mechanism for the transduction of environmental inputs, such as stress and inflammation to lasting physiological changes. Acute and chronic stress determines DNA methylation and histone modifications in brain regions which may contribute to neuro-degenerative disorders. Nuclear glucocorticoids receptor interacts with the epigenoma resulting in a cortisol resistance status associated with a deterioration of the metabolic and immune functions. Gonadal steroids receptors have a similar capacity to produce epigenomic reorganization of chromatine structure. Epigenomic-induced reduction in immune cells telomeres length has been observed in many degenerative diseases, including all types of cancer. The final result of these epigenetic alterations is a serious damage to the neuro-endocrine-immune-metabolic adaptive systems. In this study, we propose a treatment with stem cells differentiation stage factors taken from zebrafish embryos which are able to regulate the genes expression of normal and pathological stem cells in a different specific way.

Cytokine production in women with antiretroviral treatment-associated breast fat accumulation and limb wasting.

OBJECTIVE: To test the cytokine production of peripheral blood mononuclear cells in a group of HIV-infected women with breast enlargement and lower limb wasting while receiving antiretroviral therapy (ART) including a protease inhibitor. DESIGN: Case-control study including 20 women with fat tissue alterations and 20 matched controls treated with comparable ART. METHODS: Adipose tissue alterations (ATA) were defined by increased breast size (> or = 2 bra sizes) accompanied by lower limb fat wasting. A randomly selected subset of patients underwent analyses including: dual energy X-ray absorptiometry, metabolic and endocrine assays, in vitro cytokine production testing [interferon-gamma, interleukin (IL)-2, IL-4, IL-10, IL-12, tumor necrosis factor-alpha (TNF-alpha)] after appropriate stimulation; T-cell phenotyping, T-helper function after stimulation with either tetanus toxoid, influenza antigen, allogeneic peripheral blood lymphocytes, and phytohemagglutinin. Endocrinological study included the determination of plasma concentrations of prolactin, growth hormone, testosterone, adrenocorticotropic hormone, cortisol and C-peptide. RESULTS: In vitro production of IL-12 was higher (P = 0.0001), and TNF-alpha (P = 0.0093) and IL-10 (P < 0.0001) production were lower in stimulated peripheral blood mononuclear cells of ATA-positive women compared with ATA-negative women. ATA-positive women also showed a better response to tetanus toxoid (P = 0.021) and a lower median fluorescence intensity of CD14/DR (P=0.033). Plasma C-peptide values were higher in ATA-positive women compared with ATA-negative women (P = 0.033), even if in the normal range (< 4 ng/ml) in all but one of the ATA-positive patients. CONCLUSION: HIV-1-infected women who developed breast enlargement and lower limb fat wasting while receiving ART had a favorable immunological profile with efficient IL-12 production and T-helper function, and with TNF-a production in the range of a HIV-negative reference population. These findings suggest that the rescue of some immune functions under ART may be involved in the pathogenesis of this particular adipose tissue disorder.

Type I collagen N-telopeptide variation in adolescents receiving oral isotretinoin for severe acne.

The prolonged use of retinoids has been reported to be associated with changes of bone biochemical markers and toxic skeletal effects. Among collagen markers, type I collagen N-telopeptide (NTx) is present in all tissues that contain type I collagen, mostly in bone and in cutaneous tissue. It is a reliable indicator of bone resorption in metabolic bone disease, but has not previously been investigated in dermatological diseases during retinoid therapy. Isotretinoin, a synthetic 13-cis-retinoic acid, is highly effective in the treatment of severe acne vulgaris. We evaluated the effect of low-dose short-term oral isotretinoin treatment on bone remodeling markers in 10 adolescents (mean age 17.8 years) affected by severe acne. We measured urinary NTx as a marker of bone resorption, alkaline phosphatase (ALP) and osteocalcin (OC) as markers of bone formation, parathyroid hormone (PTH) and metabolites of vitamin D (25OH-D3 and 1,25(OH)2D3). Clinical and laboratory tests were performed before and after three months of isotretinoin treatment at the dosage of 0.5 mg/kg/day. All patients showed a good clinical response to the treatment (7/10 marked improvement, 3/10 mild improvement). No changes were detected in serum PTH, 25OH-D3, 1,25(OH)2D3, OC and ALP, while urinary NTx concentrations were significantly reduced (p < 0.05). In conclusion, the lack of change in PTH, OC, ALP and vitamin D metabolites and the absence of increase of NTx suggest no bone effect of the isotretinoin treatment. The decrease of urinary NTx could be due to the effect of isotretinoin on the cutaneous component of type I collagen. Severe acne in the active inflammatory phase could change the levels of this marker. Thus, short-term low-dose oral isotretinoin is an effective and safe treatment for severe acne.

Endocrine, metabolic, and immunologic components of HIV infection.

It is generally accepted that the progression of HIV infection is the consequence of increased HIV virus load and defective CD4(+) T cell-mediated immunity. Previous studies have shown that T helper-directed cellular immunity is suppressed in hypercortisolemic HIV patients, while it is activated in cortisol-resistant HIV patients. This is suggestive of a cytokine system intimately linked with cortisol and its receptors. Highly active antiretroviral therapy is an important advance in the treatment of HIV infection, but the suppression of viral replication is not associated with reconstitution of the immune function. This would account for reduced control of inflammation and the activation of 11ß-hydroxysteroid dehydrogenase type 1(11ß-HSD1) and increases in glucocorticoid and mineralocorticoid production in peripheral tissues. Such hormonal activation may cause insulin resistance and cardiometabolic complications. Therapeutic approaches with 11ß-HSD1 inhibitors, aldosterone antagonists, type 1 angiotensin receptor blockers, or renin inhibitors are suggested.

Hemodynamic and autonomic adjustments to real life stress conditions in humans.

Psychological stress represents a risk factor for hypertension, but mechanisms are not known in detail. In this investigation we tested the hypothesis that real-life stress conditions produce changes in autonomic cardiac and vascular regulation that might differ in magnitude. University students, a well-established model of mild real-life stress, were examined shortly before a university examination, and a second time 3 months afterward, during holiday. Autonomic cardiovascular regulation was assessed by a noninvasive approach, based on autoregressive analysis of RR interval variability (V) and of systolic arterial pressure (SAP) V. The overall level of stress in the two sessions was gauged from the elevated salivary cortisol (5.6+/-0.5 versus 2.4+/-0.2 ng/mL, P<0.05) and altered cytokine profile (P<0.05). During the stress day, the RR interval was reduced and arterial pressure increased significantly; simultaneously, the normalized low frequency component of RRV (a marker of sympathetic modulation of the sinoatrial node) was increased and the index alpha (a measure of baroreflex gain) reduced. Concomitantly, the autonomic response to the sympathetic excitation produced by standing was altered: cardiac response was impaired and vascular responsiveness increased. Markers of autonomic regulation of the sinoatrial node correlated significantly with cortisol levels, both at rest and also considering standing induced changes, suggesting a gradual range of effects. The data support the concept that mild real-life stress increases arterial pressure and impairs cardiovascular homeostasis. These changes, assessable with spectral analysis of cardiovascular variability, might contribute, in susceptible individuals, to the link between psychological stress and increased cardiovascular risk of hypertension.

Comparative measurement of N-terminal pro-brain natriuretic peptide and brain natriuretic peptide in ambulatory patients with heart failure.

It is not clear whether brain natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) is superior as a diagnostic and prognostic indicator in cardiac diseases. Here, we compare the clinical correlations of both peptides in a population of 92 ambulatory patients with heart failure, using a well-established immunoradiometric assay (IRMA) for BNP and an automated electrochemiluminescence immunoassay for NT-proBNP. The analytical correlation between the two peptides was satisfactory over a wide range of concentrations (1-686 pM for BNP) with the equation: NT-proBNP = 3.48 x BNP -19 and a correlation coefficient r2=0.94. In addition, the concentration of both peptides increased in a similar fashion according to the severity of the disease New York Heart Association (NYHA) functional class, left ventricular ejection fraction, etiology) and age; for instance, the ratios between median levels measured in NYHA class III vs. class II patients were comparable for BNP (383 vs. 16 pM, ratio 24) and NT-proBNP (1306 vs. 57 pM, ratio 23). We conclude that N-terminal proBNP, as assayed in the present study, correlates equally to BNP with clinical variables in patients with heart failure.