Effect of homeostatic T-cell proliferation in the vaccine responsiveness against influenza in elderly people.

BACKGROUND: Seasonal influenza virus infection is a significant cause of morbimortality in the elderly. However, there is poor vaccine efficacy in this population due to immunosenescence. We aimed to explore several homeostatic parameters in the elderly that could impact influenza vaccine responsiveness. METHODS: Subjects (> 60 years old) who were vaccinated against influenza virus were included, and the vaccine response was measured by a haemagglutination inhibition (HAI) test. At baseline, peripheral CD4 and CD8 T-cells were phenotypically characterized. Thymic function and the levels of different inflammation-related biomarkers, including Lipopolysaccharide Binding Protein (LBP) and anti-cytomegalovirus (CMV) IgG antibodies, were also measured. RESULTS: Influenza vaccine non-responders showed a tendency of higher frequency of regulatory T-cells (Tregs) before vaccination than responders (1.49 [1.08-1.85] vs. 1.12 [0.94-1.63], respectively, p = 0.061), as well as higher expression of the proliferation marker Ki67 in Tregs and different CD4 and CD8 T-cell maturational subsets. The levels of inflammation-related biomarkers correlated with the frequencies of different proliferating T-cell subsets and with thymic function (e.g., thymic function with D-dimers, r = - 0.442, p = 0.001). CONCLUSIONS: Age-related homeostatic dysregulation involving the proliferation of CD4 and CD8 T-cell subsets, including Tregs, was related to a limited responsiveness to influenza vaccination and a higher inflammatory status in a cohort of elderly people.

Urotensinergic system genes in experimental subarachnoid hemorrhage.

OBJECTIVE: Cerebral vasospasm, one of the main complications of subarachnoid hemorrhage (SAH), is characterized by arterial constriction and mainly occurs from day 4 until the second week after the event. Urotensin-II (U-II) has been described as the most potent vasoconstrictor peptide in mammals. An analysis is made of the serum U-II concentrations and mRNA expression levels of U-II, urotensin related peptide (URP) and urotensin receptor (UT) genes in an experimental murine model of SAH. DESIGN: An experimental study was carried out. SETTING: Experimental operating room of the Biomedicine Institute of Seville (IBiS), Virgen del Rocío University Hospital (Seville, Spain). PARTICIPANTS: 96 Wistar rats: 74 SAH and 22 sham intervention animals. INTERVENTIONS: Day 1: blood sampling, followed by the percutaneous injection of 100µl saline (sham) or blood (SAH) into the subarachnoid space. Day 5: blood sampling, followed by sacrifice of the animals. MAIN VARIABLES OF INTEREST: Weight, early mortality, serum U-II levels, mRNA values for U-II, URP and UT. RESULTS: Serum U-II levels increased in the SAH group from day 1 (0.62pg/mL [IQR 0.36-1.08]) to day 5 (0.74pg/mL [IQR 0.39-1.43]) (p<0.05), though not in the sham group (0.56pg/mL [IQR 0.06-0.83] day 1; 0.37pg/mL [IQR 0.23-0.62] day 5; p=0.959). Between-group differences were found on day 5 (p<0.05). The ROC analysis showed that the day 5 serum U-II levels (AUC=0.691), URP mRNA (AUC=0.706) and UT mRNA (AUC=0.713) could discriminate between sham and SAH rats. The normal serum U-II concentration range in rats was 0.56pg/mL (IQR 0.06-0.83). CONCLUSION: The urotensinergic system is upregulated on day 5 in an experimental model of SAH.

TNF-α levels in HIV-infected patients after long-term suppressive cART persist as high as in elderly, HIV-uninfected subjects.

BACKGROUND: Chronic and systemic inflammatory alterations occur in HIV-infected patients and elderly uninfected subjects and in both scenarios these alterations are associated with the development of chronic morbidities and mortality. However, whether the levels of inflammatory alterations in untreated HIV-infected patients and elderly individuals are similar is unknown. Moreover, whether long-term antiretroviral therapy normalizes inflammatory alterations compared with HIV-uninfected persons of different age is not known. METHODS: We analysed soluble inflammatory levels [high-sensitivity C-reactive protein, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8 and IL-17] in a cohort of viraemic HIV-infected patients compared with (i) age-matched, (ii) elderly and (iii) non-survivor elderly, uninfected healthy controls. We longitudinally analysed the effect of long-term 48 and 96 week suppressive combined antiretroviral therapy (cART) on the soluble inflammatory levels compared with those found in control subjects. RESULTS: Baseline IL-6 and IL-8 levels were at similar or lower concentrations in untreated patients compared with healthy elderly individuals. However, TNF-α and IFN-γ levels broadly exceeded those found in survivors and non-survivor elderly individuals. Long-term suppressive cART normalized most of the inflammatory markers, with the exception of TNF-α levels, which persisted as high as those in elderly non-survivor controls. CONCLUSIONS: Chronic inflammatory alterations associated with HIV infection are maintained at a different level from those of ageing. The persistent alteration of TNF-α levels in HIV-infected patients might cause tissue damage and have implications for developing non-AIDS-defining illnesses, even when HIV replication is long-term controlled by cART.

Incidence and prevalence of multiple sclerosis in China and other Asian countries.

The prevalence of multiple sclerosis (MS) in Asian countries is thought to be lower than in Western countries, with Asian populations presenting 80% less risk of MS than white populations. Incidence and prevalence rates in Asian countries are therefore not well defined and their association with rates in neighboring countries, as well as with ethnic, environmental, and socioeconomic factors, are not well understood. We performed a comprehensive literature review of epidemiological data from China and neighbouring countries to study the frequency of the disease, focusing on prevalence, and the progression over time and the influence of sex-related, environmental, dietary, and sociocultural factors. Prevalence rates in China range between 0.88 cases/100,000 population in 1986 and 5.2 cases/100,000 population in 2013, with a non-significant upwards trend (p = .08). The increase observed in Japan, where figures ranged between 8.1 and 18.6 cases/100,000 population was highly significant (p < .001). Prevalence rates in countries with predominantly white populations are considerably higher and have increased over time, reaching 115 cases/100,000 population in 2015 (r2 = 0.79, p < .0001). In conclusion, the prevalence of MS in China appears to have risen in recent years, although Asian populations (including Chinese and Japanese populations, among others) appear to present less risk than other populations. Within Asia, geographical latitude appears not to be a determining factor for developing MS.

CYFRA 21-1 as a tool for distant metastasis detection in lung cancer.

BACKGROUND: A study to analyse tumor markers (CEA, CA125, CA15.3, CA19.9, CYFRA 21-1, and NSE) for metastasis detection in lung cancer patients. METHODS: Serum tumor markers from 73 lung cancer patients were measured before they were diagnosed. After lung cancer diagnosis, tumor markers were analyzed for the detection of distant metastases. RESULTS: In NSCLC patients CYFRA 21-1 and NSE showed differences between stage IV and any of the other stages, p < 0.05. The accuracy for metastasis detection was AUC = 81.5 % for CYFRA 21-1 and AUC = 78.6 % for < 0.05) were independent predictors for metastasis presence. No tumor marker showed significant differences according to stages in SCLC patients. CONCLUSIONS: CYFRA 21-1 could be used as a screening tool for metastasis detection in lung cancer patients without symptoms of metastasis as well as CYFRA 21-1 and NSE in NSCLC patients.

A novel interplay between membrane and nuclear melatonin receptors in human lymphocytes: significance in IL-2 production.

Human lymphocyte melatonin, through membrane and nuclear receptors binding, acts as an activator in IL-2 production. Antagonism of membrane melatonin receptors using luzindole exacerbates the drop of the IL-2 production induced by PGE(2) in peripheral blood mononuclear and Jurkat cells. This paper studies the melatonin membrane and nuclear receptors interplay in PGE(2)-diminished IL-2 production. The decrease in IL-2 production after PGE(2) and/or luzindole administration correlated with downregulation in the nuclear receptor RORalpha. We also highlighted a role of cAMP in the pathway, because forskolin mimicked the effects of luzindole and/or PGE(2) in the RORalpha expression. Finally, a significant RORalpha downregulation was observed in T cells permanently transfected with inducible MT(1) antisense. In conclusion, we show a novel connection between melatonin membrane receptor signalling and RORalpha expression, opening a new way to understand melatonin regulation in lymphocyte physiology.

Incidence and prevalence of multiple sclerosis in China and other Asian countries. / Incidencia y prevalencia de la esclerosis múltiple en China y países asiáticos.

The prevalence of multiple sclerosis (MS) in Asian countries is thought to be lower than in Western countries, with Asian populations presenting 80% less risk of MS than white populations. Incidence and prevalence rates in Asian countries are therefore not well defined and their association with rates in neighboring countries, as well as with ethnic, environmental, and socioeconomic factors, are not well understood. We performed a comprehensive literature review of epidemiological data from China and neighbouring countries to study the frequency of the disease, focusing on prevalence, and the progression over time and the influence of sex-related, environmental, dietary, and sociocultural factors. Prevalence rates in China range between 0.88 cases/100,000 population in 1986 and 5.2 cases/100,000 population in 2013, with a non-significant upwards trend (p = .08). The increase observed in Japan, where figures ranged between 8.1 and 18.6 cases/100,000 population was highly significant (p < .001). Prevalence rates in countries with predominantly white populations are considerably higher and have increased over time, reaching 115 cases/100,000 population in 2015 (r2 = 0.79, p < .0001). In conclusion, the prevalence of MS in China appears to have risen in recent years, although Asian populations (including Chinese and Japanese populations, among others) appear to present less risk than other populations. Within Asia, geographical latitude appears not to be a determining factor for developing MS.

Thyrotropin-releasing hormone receptor expression in thyroid follicular cells: a new paracrine role of C-cells?

Thyrotropin-releasing hormone (TRH) synthesized in the hypothalamus has the capability of inducing the release of thyroid-stimulating hormone (TSH) from the anterior pituitary, which in turn stimulates the production of thyroid hormones in the thyroid gland. Immunoreactivity for TRH and TRH-like peptides has been found in some tissues outside the nervous system, including thyroid. It has been demonstrated that thyroid C-cells express authentic TRH, affecting thyroid hormone secretion by follicular cells. Therefore, C-cells could have a paracrine role in thyroid homeostasis. If this hypothesis is true, follicular cells should express TRH receptors (TRH-Rs) for the paracrine modulation carried out by C-cells. In order to elucidate whether or not C-cell TRH production could act over follicular cells modulating thyroid function, we studied TRH-Rs expression in PC C13 follicular cells from rat thyroid, by means of immunofluorescence technique and RT-PCR analysis. We also investigated the possibility that C-cells present TRH-Rs for the autocrine control of its own TRH production. Our results showed consistent expression for both receptors, TRH-R1 and TRH-R2, in 6-23 C-cells, and only for TRH-R2 in PC C13 follicular cells. Our data provide new evidence for a novel intrathyroidal regulatory pathway of thyroid hormone secretion via paracrine/autocrine TRH signaling.

Melatonin in the thyroid gland: regulation by thyroid-stimulating hormone and role in thyroglobulin gene expression.

Melatonin is an indoleamine with multiple functions in both plant and animal species. In addition to data in literature describing many other important roles for melatonin, such as antioxidant, circadian rhythm controlling, anti-aging, antiproliferative or immunomodulatory activities, our group recently reported that thyroid C-cells synthesize melatonin and suggested a paracrine role for this molecule in the regulation of thyroid activity. To discern the role played by melatonin at thyroid level and its involvement in the hypothalamic-pituitary-thyroid axis, in the present study we have analyzed the effect of thyrotropin in the regulation of the enzymatic machinery for melatonin biosynthesis in C cells as well as the effect of melatonin in the regulation of thyroid hormone biosynthesis in thyrocytes. Our results show that the key enzymes for melatonin biosynthesis (AANAT and ASMT) are regulated by thyroid-stimulating hormone. Furthermore, exogenous melatonin increases thyroglobulin expression at mRNA and protein levels on cultured thyrocytes and this effect is not strictly mediated by the upregulation of TTF1 or, noteworthy, PAX8 transcription factors. The present data show that thyroid C-cells synthesize melatonin under thyroid-stimulating hormone control and, consistently with previous data, support the hypothesis of a paracrine role for C-cell-synthesised melatonin within the thyroid gland. Additionally, in the present study we show evidence for the involvement of melatonin in thyroid function by directly-regulating thyroglobulin gene expression in follicular cells.

Melatonin activates Th1 lymphocytes by increasing IL-12 production.

Melatonin could act on immune system by regulating cytokine production of immunocompetent cells. The hormone enhances IL-2, IFN-gamma and IL-6 production by cultured human mononuclear cells. As enhancement of IL-6 production is related to monocyte activation by melatonin, the hormone acts on human lymphoid cells causing a Th1-type response. This paper shows that melatonin seems to promote a Th1-response by increasing IL-12 production. The hormone enhances IL-12 production by cultured monocytes under suboptimal stimulation in a dose-dependent way. The effect of the hormone increases when PBMCs are incubated with melatonin before monocyte isolation. Enhanced IL-12 production by melatonin can also be shown in cultured human mononuclear cells.

Melatonin and glucose metabolism: clinical relevance.

The role of melatonin in glucose homeostasis is an active area of investigation. There is a growing body of evidence suggesting a link between disturbances in melatonin production and impaired insulin, glucose, lipid metabolism, and antioxidant capacity. Furthermore, melatonin has been found to influence insulin secretion both in vivo and in vitro, and night-time melatonin levels are related to night-time insulin concentrations in patients with diabetes. In several recent studies, a single nucleotide polymorphism of the human melatonin receptor 1B has been described as being causally linked to an increased risk of developing type 2 diabetes. Taken together, these data suggest that endogenous as well as exogenous melatonin may play a role in diabetes and associated metabolic disturbances not only by regulating insulin secretion but also by providing protection against reactive oxygen species, considering pancreatic ß-cells are particularly susceptible to oxidative stress because they possess only low-antioxidative capacity.

Melatonin biosynthesis in the thymus of humans and rats.

Melatonin is an indoleamine widely distributed in the evolution that shows a great functional versatility, playing an important role as a transmitter of photoperiodic information and exhibiting antioxidant, oncostatic, anti-aging and immunomodulatory properties. In vertebrates, this molecule is produced by the pineal gland and other extrapineal sites. The present study was carried out to investigate the presence of melatonin in thymus and the possibility of an endogenous melatonin synthesis in this organ, in which T cells are matured. In this work, we demonstrate in humans and rats that thymus contains melatonin, expresses the mRNAs encoding N-acetyltransferase and hydroxyindol-O-methyltransferase, the two key enzymes of the melatonin synthesis, and has this biosynthetic machinery activated. In addition, rat thymocytes cultured for 24 h exhibited high levels of melatonin. The results presented here suggest that human and rat thymuses are able to synthesize melatonin, which could have intracrine, autocrine and paracrine functions.

The pineal secretory product melatonin reduces hydrogen peroxide-induced DNA damage in U-937 cells.

Melatonin, the chief secretory product of the pineal gland, is a potent and efficient endogenous radical scavenger. Thus, melatonin was shown to protect different biomolecules, such as DNA, membrane lipids, and cytosolic proteins, from oxidative damage induced by oxygen-derived free radicals. In order to study the protective role of melatonin in hydrogen peroxide (H2O2)-induced DNA damage, U-937 cells were treated with different concentrations of H2O2, either in the presence or absence of melatonin, and DNA damage was assessed using the cytokinesis-block micronucleus technique. Melatonin diminished H2O2-induced micronuclei production both in short and long treatments. Additionally, melatonin concentrations higher than 1 microM were capable of protecting cells from spontaneous micronuclei production. These data suggest that melatonin, an endogenous antioxidant and nontoxic compound, may have an important role in protecting cells from genetic damage due to free radicals, supporting the idea of this hormone as a possible therapeutic agent in preventing aging and age-related diseases.

Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system.

The neurohormone melatonin plays a fundamental role in neuroimmunomodulation of several mammalian species, including mice. This effect is supported by the existence of specific melatonin-binding sites in murine immunocompetent organs. Moreover, using melatonin receptor analogues, several effects of the neurohormone on mice physiology through its membrane and nuclear receptors have been described. The expression of these receptors has never been studied, despite indirect evidence showing the presence of melatonin receptor in the murine immune system. At present, the MT1 and MT2 membrane receptors, and nuclear receptors belonging to the RZR/ROR family have been related to the immunomodulator effect of melatonin. Here, we show the presence of membrane and nuclear melatonin-binding sites in mouse thymus and spleen, using the specific melatonin membrane (S 20098) and nuclear (CGP 52608) receptor agonist. To confirm the presence of melatonin receptors, we analyzed the presence of membrane and nuclear receptor mRNA and protein by RT-PCR, Southern blot, and Western blot. Thus, we show that MT1 and RORalpha receptor mRNA and protein are expressed in both thymus and spleen, while MT2 receptor mRNA is only detected in the thymus. This expression of melatonin receptors strongly supports the idea of an immunomodulatory role of melatonin through its receptors.