Qualitative mucin disorders in patients with primary Sjögren's syndrome: a literature review.

BACKGROUND: It is a common opinion that Primary Sjögren Syndrome (pSS) damages the exocrine glands and determines the reduction of secreted saliva, some studies show that there are qualitative anomalies of the mucins produced in saliva, including MUC7, MUC5B, MUC1. The purpose of this study is to trace all the information useful to establish whether there is a qualitative or quantitative defect of the mucins in the pSS. MATERIAL AND METHODS: We reviewed the literature by looking for publications relevant to the topic in electronic databases. Sixteen articles met the search criteria. The studies were divided into two categories, those that studied the rheological characteristics of the saliva and those that studied the structural and / or metabolism modifications of the muciparous cells in the salivary glands. RESULTS: in Patients with pSS, xerostomia and the reduction of salivary spinnbarkeit are only partially related to the reduction of the unstimulated salivary flow. In pSS, pathological alterations of mucins' chemical-physical properties prevail as a cause of the clinical characteristics. Moreover, in pSS there are structural and metabolism changes in salivary glands' muciparous cells. CONCLUSIONS: There is much evidence that supports the presence of qualitative alterations in the saliva's rheological properties in Patients with pSS, and these are the main cause, more than the reduction of the unstimulated salivary flow, of the disease clinical characteristics - dry mouth and complications in the oral cavity. Therefore we propose to add to the classification criteria of pSS also a qualitative test of salivary glycoproteins.

Neuropeptide Y reduces the expression of PLCB2, PLCD1 and selected PLC genes in cultured human endothelial cells.

Endothelial cells (EC) are the first elements exposed to mediators circulating in the bloodstream, and react to stimulation with finely tuned responses mediated by different signal transduction pathways, leading the endothelium to adapt. Neuropeptide Y (NPY), the most abundant peptide in heart and brain, is mainly involved in the neuroendocrine regulation of the stress response. The regulatory roles of NPY depend on many factors, including its enzymatic processing, receptor subtypes and related signal transduction systems, including the phosphoinositide (PI) pathway and related phospholipase C (PI-PLC) family of enzymes. The panel of expression of PI-PLC enzymes differs comparing quiescent versus differently stimulated human EC. Growing evidences indicate that the regulation of the expression of PLC genes, which codify for PI-PLC enzymes, might act as an additional mechanism of control of the PI signal transduction pathway. NPY was described to potentiate the activation of PI-PLC enzymes in different cell types, including EC. In the present experiments, we stimulated human umbilical vein EC using different doses of NPY in order to investigate a possible role upon the expression PLC genes. NPY reduced the overall transcription of PLC genes, excepting for PLCE. The most significant effects were observed for PLCB2 and PLCD1, both isoforms recruited by means of G-proteins and G-protein-coupled receptors. NPY behavior was comparable with other PI-PLC interacting molecules that, beside the stimulation of phospholipase activity, also affect the upcoming enzymes' production acting upon gene expression. That might represent a mode to regulate the activity of PI-PLC enzymes after activation.

Transcritpional effects of S100B on neuroblastoma cells: perturbation of cholesterol homeostasis and interference on the cell cycle.

S100B is a Ca2+ binding protein mainly secreted by astrocytes in the vertebrate brain that is considered a multifunctional cytokine and/or a damage-associated molecular pattern (DAMP) protein and a marker of brain injury and neurodegeneration when measured in different body fluids. It has been widely shown that this protein can exert diverse effects in neural cultures depending on its concentration, having detrimental effects at micromolar concentrations. The molecular mechanisms underlying this effect are still largely unknown. This study attempts to delineate the genome-wide gene expression analysis of the events associated with exposure to micromolar concentration of S100B in a human neuroblastoma cell line. In this experimental condition cells undergo a severe perturbation of lipid homeostasis along with cell cycle arrest. These mechanisms might reasonably mediate some aspects of the S100B-related detrimental effects of S100B, although obvious differences between mature neurons and neuroblastoma cells have to be considered.

Relationship between proinflammatory cytokines (Il-1beta, Il-18) and leukocyte telomere length in mild cognitive impairment and Alzheimer's disease.

Inflammation plays a crucial role in Alzheimer's disease (AD). AD neurodegeneration and concurrent involvement of the peripheral immune system may promote leukocyte division and telomere shortening. We examined genotypes and plasma levels of two proinflammatory cytokines, IL-1beta and IL-18, and leukocyte telomere length (LTL) in patients with mild cognitive impairment (MCI) and AD. We wanted to determine whether changes in plasma IL-1beta and IL-18 levels, together with LTL shortening, could be diagnostic for disease progression from MCI to AD. Median plasma IL-1beta levels were in the order MCI patients (2.2 pg/ml) < AD patients (4.0 pg/ml), both of which differed significantly from the controls (0.0 pg/ml). In the AD patients, the lowest IL-1beta levels were associated with the presence of the C allele of IL-1beta rs16944 SNP. Median plasma IL-18 levels were in the order MCI patients (116.3 pg/ml) > AD patients (85.8 pg/ml), both of which were significantly higher than in the controls (17.6 pg/ml). Analysis of LTL showed a progressive reduction in the order controls > MCI > AD patients (p < 0.0001). Overall LTL reduction was correlated with increased plasma IL-1beta levels, substantiating the hypothesis that inflammatory processes secondary to neuroinflammation may trigger telomere attrition. Changes in plasma IL-1beta and Il-18 levels, and LTL seem to reflect shifts in AD stage; they may have potential use as blood biomarkers to monitor disease onset and progression from MCI to AD.

Modulation of Inflammation as a Way of Delaying Alzheimer's Disease Progression: The Diet's Role.

BACKGROUND: Most of the recent reports suggest that inflammatory mediators play a central role in the etiopathogenesis of Alzheimer's disease (AD) and that the conditions leading to a chronic low-grade inflammation, such as stress, depression, obesity and metabolic syndrome, increase the odds of developing Mild Cognitive Impairment (MCI) and AD. Microglia cells are the main actors in the AD process: stimuli from the microenvironment may induce microglia cells to switch to a classically activated inflammatory phenotype M1, or, on the contrary to an alternatively activated M2 phenotype characterized by the secretion of different types of cytokines. Many attempts are currently being made in order to delay the progression of AD by reducing inflammatory mechanisms underlying the disease. Several studies support a relationship among neuroinflammation and nutrients, foods or dietary patterns, taking into account the synergistic or antagonistic biochemical interactions among nutrients as well as the different food sources of the same nutrient. Natural antioxidant and anti-inflammatory compounds found in plant foods, such as fruits, particularly berries (such as strawberry, blueberry, blackcurrant, blackberry, blueberry and mulberry) have been shown to exert neuroprotective activity. It is still unclear whether the dietary bioactive compounds enter the Blood Brain Barrier (BBB) playing a direct antiinflammatory or pro-inflammatory effect on microglia and/or other Central Nervous System (CNS) cells. Another hypothesis is that they may trigger a peripheral reaction that induce indirectly a CNS' response. The subsequent synthesis of cytokines may drive microglia polarization by different ways. So, via an indirect route microglia detects and responds to immune-to-brain signaling. CONCLUSION: This review summarizes current evidence about the potential mechanisms of the interaction among diet, neuroinflammation and AD.

Protection of mice against syngeneic C1300 neuroblastoma challenge by immunization with membranes of C1300 neuroblastoma cells.

Male A/J mice 2-3 months old were inoculated sc with membranes from syngeneic C1300 neuroblastoma cells (clone NB6R) in complete Freund's adjuvant. Significant immunoprophylaxis was noted in the sensitized mice upon sc challenge with viable NB6R cells. During the experiment (60 days from viable cell challenge), each control mouse developed a palpable tumor and died within 50 days. Complete protection was obtained with a program of 4 inoculations of NB6R cell membranes. Each mouse given only 1 inoculation of NB6R cell membranes developed a palpable tumor, but afer 60 days only 1 mouse in 7 had died, which indicated a significant degree of protection. With in vitro tests of lymphocyte proliferation, rosette formation, and complement fixation, it was shown that these mice had mounted both cellular and humoral immune response against the tumor cells.

Cognitive disability in alzheimer's disease and its management.

Cognitive disability linked to neurodegenerative diseases and in particular to Alzheimer's disease, remains an increasing cause for concern through a dramatic prevalence increment and associated socio-economic burdens. Initially Alzheimer's disease develops asymptomatically with primary clinical signs, such as memory impairment, decline of spatial and perceptual abilities, occurring at a later stage. This delay implies the possibility of promoting early interventions during the pre-symptomatic stage of the disease. Different strategies have been applied in order to prevent/delay onset of Alzheimer's disease or at least to improve quality of life and health conditions of Alzheimer's disease patients and their caregivers, especially in the absence of current viable therapies. Multidomain interventions, aimed at affecting several risk factors simultaneously, offer a versatility that may attain improved outcomes in comparison with single-domain prevention trials. These multidomain interventions involve diet, physical exercise, cognitive training and social activities, while music therapy, improving self-consciousness and reducing neurofibrils, may contribute to deceleration/delay onset of Alzheimer's disease progression. Information and Communication Technology (ICT) provides broad applications to improve quality of life and well-being of Alzheimer's disease patients and caregivers, suffering from psychological distress, as well as reducing additional public health costs.

Qualitative mucin disorders in patients with primary Sjögren's syndrome: a literature review

BACKGROUND: It is a common opinion that Primary Sjögren Syndrome (pSS) damages the exocrine glands and determines the reduction of secreted saliva, some studies show that there are qualitative anomalies of the mucins produced in saliva, including MUC7, MUC5B, MUC1. The purpose of this study is to trace all the information useful to establish whether there is a qualitative or quantitative defect of the mucins in the pSS. MATERIAL AND METHODS: We reviewed the literature by looking for publications relevant to the topic in electronic databases. Sixteen articles met the search criteria. The studies were divided into two categories, those that studied the rheological characteristics of the saliva and those that studied the structural and / or metabolism modifications of the muciparous cells in the salivary glands. RESULTS: in Patients with pSS, xerostomia and the reduction of salivary spinnbarkeit are only partially related to the reduction of the unstimulated salivary flow. In pSS, pathological alterations of mucins' chemical-physical properties prevail as a cause of the clinical characteristics. Moreover, in pSS there are structural and metabolism changes in salivary glands' muciparous cells. CONCLUSIONS: There is much evidence that supports the presence of qualitative alterations in the saliva's rheological properties in Patients with pSS, and these are the main cause, more than the reduction of the unstimulated salivary flow, of the disease clinical characteristics - dry mouth and complications in the oral cavity. Therefore we propose to add to the classification criteria of pSS also a qualitative test of salivary glycoproteins

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Modulation of the alpha 2 macroglobulin receptor/low density lipoprotein receptor related protein by interferon-gamma in human astroglial cells.

Alpha 2 macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2 Mr/LRP) is a multi-functional cell surface receptor that has been implicated in important processes, such as atherogenesis, cellular migration, immune response and degenerative diseases. Its expression increases in human brain during Alzheimer's disease, tissue injury and neoplastic transformation. In the present paper we studied the regulation of alpha 2 Mr expression by interferon-gamma (IFN gamma) in human astrocytoma cell lines and in fetal astrocytes. Western blots demonstrated an increase of the alpha 2 Mr expression after 24 h of IFN gamma treatment. This effect paralleled the up-regulation of alpha 2 Mr mRNA, as detected by PCR. By prolonging incubation with IFN gamma, we observed a decrement of alpha 2 Mr in IFN gamma treated cells, both by western blot and cytometric analysis. Since in the same cells IFN gamma also up-regulates alpha 2 macroglobulin, this effect may be due to an augmented degradation of the receptor during its recycling.

Interferon gamma up-regulates alpha 2 macroglobulin expression in human astrocytoma cells.

An established human astrocytoma cell line (T67) was shown to constitutively produce the proteinase inhibitor alpha 2 macroglobulin (alpha 2M). Interferon gamma (IFN gamma), a potent immunoregulatory lymphokine, was able to increase the synthesis of alpha 2M by these cells, as measured by ELISA on cell supernatants. The alpha 2M induction was also observed in other human glioma cell lines (T70 and ADF) and in human fetal astrocyte cultures following IFN gamma treatment. In T67 cells this effect was dose-dependent and the maximum (2.7-fold increase) was obtained with 2000 U/ml of IFN gamma. A corresponding enhanced alpha 2M mRNA accumulation was demonstrated by PCR and Northern blot techniques. Our results suggest an important role of alpha 2M during inflammatory and immune processes in the CNS. An increased release of alpha 2M following IFN gamma stimulation may allow the removal of the bulk of proteases released at the site of inflammation, strengthening at the same time the antigen presentation processes.

Prevalence and clinical correlates of microalbuminuria in stage I hypertension. Results from the Hypertension and Ambulatory Recording Venetia Study (HARVEST Study).

The objective of the present study was to examine the association between albumin excretion rate (AER) and office and ambulatory blood pressures (BP), and other recognized cardiovascular risk factors in stage I hypertension. The study was carried out in 870 never-treated 18- to 45-year-old hypertensives (628 men, 242 women). Office and ambulatory BP, 24-h urinary collection for AER assessment, and echocardiographic left ventricular mass (n = 587) were obtained. AER was similar in men and women (12.3 v 12.5 mg/24 h) and was unrelated to age and body mass index. In 85.2% of the subjects, AER was < 16 mg/24 h, in 8.3% it was between 16 and 29 mg/24 h (borderline microalbuminuria), and in 6.1% it was >or= 30 mg/24 h (overt microalbuminuria). Office systolic BP was not different in the three groups, whereas 24-h systolic BP was higher in the subjects with microalbuminuria than in those with normal AER (P < .0001) and was similar in the two microalbuminuric groups. Office and 24-h diastolic BPs were higher in the subjects with overt microalbuminuria than in those with normal AER. Left ventricular mass was correlated to systolic (P < .0001) and diastolic (P = .01) 24-h BP, but was unrelated to AER. Family history for hypertension, smoking, coffee and alcohol intake, and physical activity habits did not influence AER. In a logistic regression analysis, 24-h systolic BP emerged as the only determinant of microalbuminuria (P < .0001). In conclusion, these results indicate that borderline levels of microalbuminuria may also be clinically relevant in stage I hypertension. Overweight and lifestyle factors do not appear to influence AER in these patients. Finally, the lack of correlation between AER and left ventricular mass suggests that renal and cardiac involvement do not occur in a parallel fashion in the initial phase of hypertension.

Receptor-mediated endocytosis of alpha 2 macroglobulin by a glioma cell line.

Previous experiments have shown that human neoplastic and embryonic glial cell lines synthesize and secrete in culture, alpha 2 macroglobulin (alpha 2M), a broad spectrum proteinase inhibitor present in serum and extracellular fluids. The present study was aimed to investigate the presence of alpha 2M receptors on glial cell membrane, since several non-neural cell types producing alpha 2M also express alpha 2M receptors. By flow cytometric analysis, immunofluorescence and immunoelectronmicroscopy techniques we demonstrate an alpha 2M receptor-related immunoreactivity on the plasma membrane of a human glioma cell line. Ultrastructural experiments reveal a close colocalization of immunoreactivities for alpha 2M and its receptor in clathrin-coated pits and vesicles, structures typically involved in receptor-mediated endocytic pathways.

The expression of the LDL receptor-related protein (LRP) correlates with the differentiation of human neuroblastoma cells.

The low density lipoprotein receptor-related protein (LRP) has been localized in human brain at the level of neurons, astrocytes and along capillary membranes. It is a multifunctional receptor responsible for binding and internalization of lipoproteins enriched with apoliprotein E, lipoprotein lipase, protease-alpha 2 macroglobulin complexes and plasminogen activator-inhibitor complexes. LRP expression is observed in cells involved in Alzheimer's disease, neoplastic transformation and tissue repair. Moreover, its synthesis is modulated during brain development. In this study we used the SK-N-AS human neuroblastoma cell line as a model system to study LRP expression during cellular differentiation induced by phorbol esters, retinoic acid and interferon gamma. Since LRP plays a major role in the regulation of lipid metabolism, the decreased levels of LRP measured by immunofluorescence, western blot and PCR on differentiated neuroblastoma cells may be the consequence of the lower requirements of cholesterol and lipids of differentiated cells in relation to their reduced mitotic index.

[Effect of physical exercise training on the arterial pressure in normotensive subjects]. / Effetto dell'allenamento all'esercizio fisico sulla pressione arteriosa in soggetti normotesi.

To determine the effect of exercise training on blood pressure at rest and during maximal exercise 15 adolescent and 15 adult normotensive cyclists were studied after a period of detraining and of physical activity. In the lying position resting blood pressure did not change with training, while a slight but significant decrease in blood pressure (p less than 0.05) was observed on standing up. At the same absolute work rate, after training exertional blood pressure was lower than before training, but at peak exercise the same blood pressure levels were achieved before and after training. These results indicate that, contrary to what has been reported in the sedentary subject, resuming exercise training after a period of detraining brings about in the normotensive athlete only minor changes in blood pressure.

Inverse relationship between spontaneous interleukin-1 production and mitogen-driven proliferation in patients with pulmonary tuberculosis.

The blastogenic response to mitogens of peripheral blood mononuclear cells (PBMC) obtained from healthy volunteers and patients with chronic or acute tuberculosis (TB) was evaluated. Cells derived from TB patients showed a reduced proliferative capacity compared to that of healthy individuals. Three possible causes of such an impairment were investigated, namely: 1) a change in the proportion of lymphocyte subpopulations; 2) an altered ratio between monocytes and lymphocytes and 3) a reduction in the state of monocyte-macrophage activation, with an impaired production of interleukin-1 (IL-1). We observed no significant modification of lymphocyte subsets from TB patients and normal individuals. However, the relative number of monocytes in the patients was always higher than the controls. Furthermore, circulating monocytes from the patients with TB exhibited a decreased phagocytosis of latex beads, a normal expression of DR antigens, and an increased spontaneous production of IL-1. The possibility that the hyperactivation of macrophages may be responsible for the observed low blastogenic response is discussed.

[Investigation on a group of autistic children: risk factors and medical social considerations]. / Indagine su un gruppo di bambini autistici: possibili fattori di rischio e considerazioni medico sociali.

AIMS: The aim of this work is to study the association between autism in a group of autistic children and risk factors for specific familiar diseases and developmental disease in the early years of life, through a medical social investigation. MATERIALS AND METHODS: For this study, we have submitted an anamnestic questionnaire to 29 autistic children and their families in a South Italy region (Basilicata), collecting data about children and their parents. RESULTS: The results show that many children have a family history of autoimmune diseases (psoriasis, rheumatoid arthritis, celiac disease, Takayasu's arteritis), allergies and food intolerances, suggesting a putative involvement of the immune system in autism etiopathogenesis. Analyzing residences areas of patients, Potenza and Matera, with their environmental factors (radioactive waste repositories, incinerators, intensive farming), we demonstrate that the particular territorial characteristics don't affect autism. CONCLUSIONS: Autistic disorder is a spectrum of neurologic disorders complex both in etiopathogenesis and healthcare. So we aim to continue the study already undertaken on cytokines of autistic subjects serum and to extend it through biomolecular approaches assessing the presence of specific genetic polymorphisms in order to identify the physiopathogenetic mechanisms underlying the disease and to evaluate the predictive risk with the aim to improve care interventions.

Plaque-infiltrating T lymphocytes in patients with carotid atherosclerosis: an insight into the cellular mechanisms associated to plaque destabilization.

AIM: Inflammation plays a crucial role in the progression of atherosclerotic plaques. The aim of the present study was to investigate phenotypic and functional characteristics of plaque-infiltrating T lymphocytes associated with a complicated phenotype of carotid atherosclerotic lesions. METHODS: Atherosclerotic plaques were obtained from 17 patients undergoing carotid endarterectomy and cultured to isolate infiltrating T lymphocytes. Blood samples were obtained from patients and from 20 sex- and age-matched healthy subjects. The presence of lymphocytes (CD3+ cells) within atherosclerotic plaques was determined by immunohistochemistry. Phenotypic characteristics and intracellular cytokine expression of plaque-infiltrating and circulating T lymphocytes were determined by flow cytometry. Cytokine levels in supernatants from infiltrating T cell cultures were evaluated by enzyme-linked immunosorbent assay. RESULTS: A higher number of CD3+ cells was detected in complicated than in uncomplicated plaques. Complicated plaques had higher percentages of tumor necrosis factor (TNF)-α- and interferon (IFN)-γ- positive cells than uncomplicated ones, especially in CD4+ subpopulation. In patients the percentages of TNF-α-positive cells were higher in infiltrating than in circulating lymphocyte samples. Intracellular TNF-α, IFN-γ, interleukin (IL)-4 and IL-10 expression resulted higher in circulating lymphocyte samples from patients than in those from healthy subjects. Supernatants of infiltrating T cell cultures from complicated plaques showed higher levels of TNF-α and lower levels of IL-4 than those from uncomplicated plaques. CONCLUSION: Our data provide new information on the presence of increased percentages of pro-inflammatory T lymphocytes in complicated plaques with respect to uncomplicated ones and support the concept of the key role played by activated T cells in the progression of atherosclerotic lesions.

Lypopolysaccharide downregulates the expression of selected phospholipase C genes in cultured endothelial cells.

The signaling system of phosphoinositides (PI) is involved in a variety of cell and tissue functions, including membrane trafficking, ion channel activity, cell cycle, apoptosis, differentiation, and cell and tissue polarity. Recently, PI and related molecules, such as the phosphoinositide-specific phospholipases C (PI-PLCs), main players in PI signaling were supposed to be involved in inflammation. Besides the control of calcium levels, PI-PLCs contribute to the regulation of phosphatydil-inositol bisphosphate metabolism, crucial in cytoskeletal organization. The expression of PI-PLCs is strictly tissue specific and evidences suggest that it varies under different conditions, such as tumor progression or cell activation. In a previous study, we obtained a complete panel of expression of PI-PLC isoforms in human umbilical vein endothelial cells (HUVEC), a widely used experimental model for endothelial cells. In the present study, we analyzed the mRNA concentration of PI-PLCs in lipopolysaccharide (LPS)-treated HUVEC by using the multiliquid bioanalyzer methodology after 3, 6, 24, 48, and 72 h from LPS administration. Marked differences in the expression of most PI-PLC codifying genes were evident.

Altered cytokine and BDNF levels in autism spectrum disorder.

The contribution of neuroimmune functioning and brain-derived neurotrophic factor (BDNF) to functional dysregulation in autism spectrum disorder was assessed in 29 patients under treatment in two specialized centers of Basilicata (Chiaromonte and Matera), Southern Italy, through analysis of serum levels of cytokines and BDNF. Elevated levels of the pro-inflammatory cytokine, including interleukin-1, interleukin-6, interleukin-12, interleukin-23, tumor necrosis factor-α and BDNF were observed, regardless of age and gender. Comparisons were made with age- and gender-related healthy controls. The present findings reinforce current notions regarding immunoexcitotoxic mechanisms contributing to the pathophysiology of autistic disorder.

Expression of phosphoinositide-specific phospholipase C isoforms in human umbilical vein endothelial cells.

AIMS: The signalling system of phosphoinositides (PIs) is involved in a number of cell and tissue functions including membrane trafficking, ion channel activity, cell cycle, apoptosis, differentiation and cell and tissue polarity. Recently, a role in cell migration was hypothesised for PI and related molecules including the phosphoinositide-specific phospholipases C (PI-PLCs), main players in PI signalling. The expression of PI-PLCs is tissue-specific and evidence suggests that it varies under different conditions such as tumour progression or cell activation. In order to obtain a complete picture, the expression of all PI-PLC isoforms was analysed in human endothelial cells (EC). METHODS: Using molecular biology methods (RT-PCR), the expression of PI-PLC isoforms was analysed in human umbilical vein endothelial cells (HUVEC), a widely used experimental model for human EC. RESULTS: All the PI-PLC isoforms except PI-PLC ß1, PI-PLC ε and PI-PLC ζ were expressed in HUVEC. CONCLUSIONS: The growing interest in the complex cascade of events occurring in angiogenesis will provide useful insights for therapeutic strategies. The expression of PI-PLC isoforms in HUVEC is a useful tool for further studies directed to understanding their role in angiogenesis. However, although HUVEC represent a widely used experimental model for human macrovascular EC, limitations remain in that they cannot fully represent the metabolic properties and interactions of the EC distributed in the entire organism.