bluuebunny/crossref_metadata_2025 huggingface dataset:
Benign intracranial hypertension associated to blood coagulation derangements
Authors: De Lucia Domenico , Napolitano Marisanta , Di Micco Pierpaolo , Niglio Alferio , Fontanella Andrea , Di lorio Giuseppe
Published: December 2006

Background

Benign Intracranial Hypertension (BIH) may be caused, at least in part, by intracranial sinus thrombosis. Thrombosis is normally due to derangements in blood coagulation cascade which may predispose to abnormal clotting activation or deficiency in natural inhibitors' control. The aim of the study is to examine the strength of the association between risk factors for thrombosis and BIH.

Patients and methods

The incidence of prothrombotic abnormalities among a randomly investigated cohort of 17 patients with BIH, was compared with 51 healthy subjects matched for sex, age, body mass index, height and social background.

Results

The number of subjects with protein C deficiency was significantly higher in patients than in controls (3 vs 1, p < .001; Fisher Exact Test). Moderate to high titers of anticardiolipin antibodies (β2-Glycoprotein type I) were found in 8 out of 17 patients.

Increased plasma levels of prothrombin fragment 1+2, fibrinopeptide A (FPA), and PAI-1 were demonstrated in patients group (5.7 ± 1.15 nM vs 0.45 ± 0.35 nM; 8.7 ± 2.5 ng/mL vs 2.2 ± 1.25 ng/mL; 45.7 ± 12.5 ng/mL vs 8.5 ± 6.7 ng/mL, respectively; p < .001; Fisher Exact Test). Gene polymorphisms for factor V Leiden mutation, prothrombin mutation 20210 A/G, MTHFR 677 C/T, PAI-1 4G/5G, ACE I/D were detected in 13 patients.

Discussion

In agreement with other authors our data suggest a state of hypercoagulability in BIH associated with gene polymorphisms. Our findings also showed that mutations in cardiovascular genes significantly discriminate subjects with a BIH history. The association between coagulation and gene derangements, usually regarded to as cryptogenic, may suggest a possible pathogenetic mechanism in BIH. So, a prothrombotic tendency may exist that would, at least in part, explain some cases of BIH.

Although based on a small population, these findings raise the exciting possibility of using these haemostatic factors as markers for selecting high-risk subjects in BIH disease.
Consequences of infertility in developing countries: results of a questionnaire and interview survey in the South of Vietnam
Authors: Wiersema Nicole J , Drukker Anouck J , Dung Mai Ba Tien , Nhu Giang Huynh , Nhu Nguyen Thanh , Lambalk Cornelis B
Published: December 2006

Background

This study explores the psychological, socio-cultural and economic consequences of infertility on couples' life. The purpose of this research is to improve knowledge about the potentially serious implications of infertility in the South of Vietnam.

Methods

This study included 118 infertile couples who filled in questionnaires and 28 men and women who were interviewed.

Results

Data of the questionnaire show men and women do not differ in their responses and attitudes towards infertility. Almost one-third of the participants require psychological support. Interviewees experience secrecy, social pressure and economic hardship.

Conclusion

Offspring are very important to Vietnamese couples. Their future depends on children. Family plays an important role in the experiences of the infertile couple. Economic consequences are a particular distressing factor. There is a need for psychological counselling in the treatment of infertile couples in the South of Vietnam. It should be realised that in developing countries, despite overpopulation, unwanted childlessness is an important social and economical burden that needs attention.
Up-regulation of HLA class-I antigen expression and antigen-specific CTL response in cervical cancer cells by the demethylating agent hydralazine and the histone deacetylase inhibitor valproic acid
Authors: Mora-García María de Lourdes , Duenas-González Alfonso , Hernández-Montes Jorge , De la Cruz-Hernández Erick , Pérez-Cárdenas Enrique , Weiss-Steider Benny , Santiago-Osorio Edelmiro , Ortíz-Navarrete Vianney Francisco , Rosales Víctor Hugo , Cantú David , Lizano-Soberón Marcela , Rojo-Aguilar Martha Patricia , Monroy-García Alberto
Published: December 2006

Background

DNA hypermethylation and histone deacetylation are epigenetic events that contribute to the absence or downregulated expression of different components of the tumor recognition complex. These events affect the processing and presentation of antigenic peptides to CTLs by HLA class-I molecules. In this work evaluated the effect of the DNA hypomethylating agent hydralazine and the histone deacetylase inhibitor valproic acid, on the expression of HLA class-I molecules and on the antigen-specific immune recognition of cervical cancer cells.

Methods

Cell lines C33A (HPV-), CaSki (HPV-16+) and MS751 (HPV-18+) were treated with hydralazine and valproic acid to assess the expression of HLA class-I molecules by flow cytometry and RT-PCR. Promoter methylation of HLA class-I -A, -B and C, was also evaluated by Methylation-Specific PCR. Primary cervical tumors of four HLA-A*0201 allele patients were typed for HPV and their CTL's stimulated in vitro with the T2 cell line previously loaded with 50 μM of the HPV peptides. Cytotoxicity of stimulated CTL's was assayed against Caski and MS751 cells pre-treated with hydralazine and valproic acid.

Results

Valproic acid and hydralazine/valproic acid up-regulated the constitutive HLA class-I expression as evaluated by flow cytometry and RT-PCR despite constitutive promoter demethylation at these loci. Hydralazine and valproic acid in combination but no IFN-gamma hyperacetylated histone H4 as evaluated by ChiP assay. The antigenic immune recognition of CaSki and MS751 cells by CTLs specific to HPV-16/18 E6 and E7-derived epitopes, was increased by VA and H/VA and the combination of H/VA/IFN-gamma.

Conclusion

These results support the potential use of hydralazine and valproic acid as an adjuvant for immune intervention in cervical cancer patients whenever clinical protocols based on tumor antigen recognition is desirable, like in those cases where the application of E6 and E7 based therapeutic vaccines is used.
Adrenocortical Tumorigenesis
Authors: BEUSCHLEIN FELIX , REINCKE MARTIN
Published: December 2006

Abstract:  Through the widespread use of imaging techniques with great sensitivity adrenal tumors are often diagnosed as an incidental finding. Although the majority of these adrenal lesions are benign and without evidence of endocrine activity or malignancy, hormone hypersecretion needs to be ruled out by specific tests. In addition to the classical forms of overt adrenocortical hypersecretion, it has become evident over the recent years that modest adrenocortical steroid autonomy as present in normokalemic primary aldosteronism and subclinical Cushing's syndrome is also associated with a significant morbidity. However, detection and differential diagnosis of these subtle changes in adrenal steroidogenesis can pose a diagnostic challenge to the clinician and is dependent on tests with reliable sensitivity and specificity. Regulation of adrenocortical development and growth, which results in clinical symptoms if disrupted, is dependent upon the distinct spatiotemporal expression of a variety of transcription factors as well as stimulation by extra‐adrenal peptide hormones. Contributions to the elucidation of growth regulation of the adrenal cortex come from rare familiar syndromes associated with adrenocortical tumors, expression studies of adrenal tumor samples, in vitro studies on adrenocortical tumor cell lines, and mouse models displaying adrenal growth defects. In this review, we will summarize the important molecular aspects of adrenal tumorigenesis and highlight some prospects for clinical applications.
Annexin 1, Glucocorticoids, and the Neuroendocrine–Immune Interface
Authors: BUCKINGHAM JULIA C. , JOHN CHRISTOPHER D. , SOLITO EGLE , TIERNEY TANYA , FLOWER RODERICK J. , CHRISTIAN HELEN , MORRIS JOHN
Published: December 2006

Abstract:  Annexin 1 (ANXA1) was originally identified as a mediator of the anti‐inflammatory actions of glucocorticoids (GCs) in the host defense system. Subsequent work confirmed and extended these findings and also showed that the protein fulfills a wider brief and serves as a signaling intermediate in a number of systems. ANXA1 thus contributes to the regulation of processes as diverse as cell migration, cell growth and differentiation, apoptosis, vesicle fusion, lipid metabolism, and cytokine expression. Here we consider the role of ANXA1 in the neuroendocrine system, particularly the hypothalamo‐pituitary‐adrenocortical (HPA) axis. Evidence is presented that ANXA1 plays a critical role in effecting the negative feedback effects of GCs on the release of corticotrophin (ACTH) and its hypothalamic‐releasing hormones and that it is particularly pertinent to the early‐onset actions of the steroids that are mediated via a nongenomic mechanism. The paracrine/juxtacrine mode of ANXA1 action is discussed in detail, with particular reference to the significance of the secondary processing of ANXA1, the processes that control the intracellular and transmembrane trafficking of the protein of the molecule and the mechanism of ANXA1 action on its target cells. In addition, the role of ANXA1 in the perinatal programming of the HPA axis is discussed.
Neurosteroids as Endogenous Inhibitors of Neuronal Cell Apoptosis in Aging
Authors: CHARALAMPOPOULOS IOANNIS , ALEXAKI VASSILIKI‐ISMINI , TSATSANIS CHRISTOS , MINAS VASSILIS , DERMITZAKI ERENE , LASARIDIS IAKOVOS , VARDOULI LINA , STOURNARAS CHRISTOS , MARGIORIS ANDREW N. , CASTANAS ELIAS , GRAVANIS ACHILLE
Published: December 2006

Abstract: The neuroactive steroids dehydroepiandrosterone (DHEA), its sulfate ester DHEAS, and allopregnanolone (Allo) are produced in the adrenals and the brain. Their production rate and levels in serum, brain, and adrenals decrease gradually with advancing age. The decline of their levels was associated with age‐related neuronal dysfunction and degeneration, most probably because these steroids protect central nervous system (CNS) neurons against noxious agents. Indeed, DHEA(S) protects rat hippocampal neurons against NMDA‐induced excitotoxicity, whereas Allo ameliorates NMDA‐induced excitotoxicity in human neurons. These steroids exert also a protective role on the sympathetic nervous system. Indeed, DHEA, DHEAS, and Allo protect chromaffin cells and the sympathoadrenal PC12 cells (an established model for the study of neuronal cell apoptosis and survival) against serum deprivation–induced apoptosis. Their effects are time‐ and dose‐dependent with EC501.8, 1.1, and 1.5 nM, respectively. The prosurvival effect of DHEA(S) appears to be NMDA‐, GABAA‐ sigma1‐, or estrogen receptor‐independent, and is mediated by G‐protein‐coupled‐specific membrane binding sites. It involves the antiapoptotic Bcl‐2 proteins, and the activation of prosurvival transcription factors CREB and NF‐κB, upstream effectors of the antiapoptotic Bcl‐2 protein expression, as well as prosurvival kinase PKCα/β, a posttranslational activator of Bcl‐2. Furthermore, they directly stimulate biosynthesis and release of neuroprotective catecholamines, exerting a direct transcriptional effect on tyrosine hydroxylase, and regulating actin depolymerization and submembrane actin filament disassembly, a fast‐response cellular system regulating trafficking of catecholamine vesicles. These findings suggest that neurosteroids may act as endogenous neuroprotective factors. The decline of neurosteroid levels during aging may leave the brain unprotected against neurotoxic challenges.
Regulation of Dendritic Cell Differentiation by Vasoactive Intestinal Peptide
Authors: CHORNY ALEJO , GONZALEZ‐REY ELENA , DELGADO MARIO
Published: December 2006

Abstract:  Dendritic cells (DCs) are the most potent antigen‐presenting cells (APCs) involved in the defense of the body and in the maintenance of the immune tolerance. The regulation of their maturation, migration, and expression of stimulatory and costimulatory molecules has major consequences on the immune response. The endogenous factors that regulate DC function are poorly known. Vasoactive intestinal peptide (VIP) is a neuropeptide with potent anti‐inflammatory actions. This anti‐inflammatory profile is maintained partially through effects on DC differentiation/function. Thus, VIP has differential effects on DCs, depending on the differentiation and stimulatory states. Immature DCs treated with VIP exhibit increased CD86 expression and induce CD4+ T cell proliferation. In addition, the CD4+ T cells activated in vitro or in vivo by VIP‐treated iDCs exhibit a Th2 phenotype. In contrast, VIP reduces both CD86 and CD80 expression on lipopolysaccharide (LPS)‐stimulated DCs, and inhibits the capacity of DCs to induce in vitro or in vivo T cell proliferation. However, addition of VIP in the early states of DC differentiation results in the generation of DCs that cannot mature following inflammatory stimuli that exhibit a tolerogenic phenotype, characterized by low expression of costimulatory molecules (CD40, CD80, and CD86), low production of proinflammatory cytokines, increased production of IL‐10, and capacity to induce regulatory T cells with suppressive actions. The effect of VIP on the DC‐Treg axis represents an additional mechanism for their general anti‐inflammatory role, particularly relevant in autoimmunity and transplantation.
Immunoneuroendocrine Interactions in Chagas Disease
Authors: CORRÊA‐DE‐SANTANA ELIANE , PINTO‐MARIZ FERNANDA , SAVINO WILSON
Published: December 2006

Abstract:  We investigated immunoneuroendocrine interactions in vivo and in vitro following infection by Trypanosoma cruzi, the causative agent of Chagas disease. In a first set of experiments, we studied the hypothalamus–pituitary–adrenal axis. Nests of parasites were seen in the adrenal gland, whereas T. cruzi–specific PCR gene amplification product was found in both the adrenal and pituitary glands of infected mice. These endocrine glands also revealed alterations including vascular stasis, increase in the deposition of extracellular matrix (ECM), as well as T cell and macrophage infiltration. Functionally, we found a decrease in corticotrophin‐releasing hormone and an increase in corticosterone contents, in hypothalamus and serum, respectively, whereas no significant changes were seen in serum adrenocortricotropic hormone of infected animals. Nevertheless, the serum levels of interleukin‐6 (known to directly stimulate glucocorticoid secretion) were increased, as compared to controls. Considering the presence of T cells within the nervous tissue of chagasic animals, we performed a number of in vitro experiments co‐culturing spleen‐derived T cells from control or infected mice, with neuronal cells (being or not being directly infected in vitro). In particular, we looked for ECM‐mediated interactions, known to affect T cell migration. We found an increase in ECM deposition in infected cultures, as compared to controls. Moreover, adhesion of T cells was enhanced when neuronal cells were infected in vitro, or when T cells were derived from T. cruzi–infected mice, events that could be abrogated with anti‐ECM antibodies. Together, the data summarized above clearly reveal that neuroendocrine axes are altered in experimental Chagas disease.
Molecular Understanding of Cytokine–Steroid Hormone Dialogue
Authors: DRUKER JIMENA , LIBERMAN ANA C. , ACUÑA MATÍAS , GIACOMINI DAMIANA , REFOJO DAMIÁN , SILBERSTEIN SUSANA , PAEZ PEREDA MARCELO , STALLA GÜNTER K. , HOLSBOER FLORIAN , ARZT EDUARDO
Published: December 2006

Abstract:  Highly sophisticated mechanisms confer upon the immune system the capacity to respond with a certain degree of autonomy. However, the final outcome of an adaptative immune response depends on the interaction with other systems of the organism. The immune–neuroendocrine systems have an intimate cross‐communication, making possible a satisfactory response to environmental changes. Part of this interaction occurs through cytokines and steroid hormones. The last step of this crosstalk is at the molecular level. In this article we will focus on the physical and functional interrelationship between cytokine signaling pathway–activated transcription factors (TFs) and steroid receptors in different cell models, where the signals triggered by cytokines and steroid hormones have major roles: (1) the ligand‐dependent‐activated glucocorticoid receptor (GR) influence the genetic program that specifies lineage commitment in T helper (Th) cell differentiation. How posttranslational modifications of several TFs as well as nuclear hormone receptors could be implicated in the molecular crosstalk between the immune–neuroendocrine messengers is discussed. (2) glucocorticoid (GC) antagonism on the TCR‐induced T cell apoptosis. (3) estrogen receptor/TGF‐β family proteins molecular interaction implicated on pituitary prolactinomas pathogenesis. The functional crosstalk at the molecular level between immune and steroids signals is essential to determine an integrative response to both mediators (which in the last instance results in a new gene activation/repression profile) and constitutes the ultimate integrative level of interaction between the immune and neuroendocrine systems.
Participation of the Endocannabinoid System in the Effect of TNF‐α on Hypothalamic Release of Gonadotropin‐Releasing Hormone
Authors: FERNANDEZ‐SOLARI JAVIER , PRESTIFILIPPO JUAN P. , BORNSTEIN STEFAN R. , McCANN SAMUEL M. , RETTORI VALERIA
Published: December 2006

Abstract:  It is known that Δ9‐tetrahydrocannabinol (THC), the major active ingredient of marijuana, can suppress reproductive function. Also, we reported previously that the endocannabinoid, anandamide (AEA), inhibited gonadotropin‐releasing hormone (LHRH) release from medial basal hypothalamus (MBH) of male rats incubated in vitro as well as reduced plasma LH levels after i.c.v. AEA injections into the cerebral lateral ventricle. On the other hand, it is known that during endotoxemia the hypothalamic gonadotropin axis is inhibited. Therefore, the aim of the present study was to determine whether the effect of TNF‐α, a proinflammatory cytokine induced by lipopolysaccharide (LPS) that inhibits LHRH release, is mediated by the activation of the endocannabinoid system. The intraperitoneal injection of LPS (5 mg/kg) as well as the i.c.v. injection of tumor necrosis factor‐α (TNF‐α) (100 ng/rat) increased significantly the AEA synthesis measured ex vivo in MBHs removed 3 h after the treatments. To examine the possibility that TNF‐α also acted by increasing the synthesis of AEA that was released and activated the CB1‐r followed by inhibition of LHRH release, we measured the effect of TNF‐α on the AEA synthase activity in MBHs incubated in vitro. As expected, we found that TNF‐α (2.9 × 10−9 M) increased the AEA synthesis. Second, we showed that TNF‐α reduced significantly the forskolin‐stimulated LHRH release and that the CB1‐r antagonist AM251 (10−5 M) blocked that inhibition, supporting the hypothesis that TNF‐α inhibits LHRH release, acting at least in part by activating the endocannabinoid system. Therefore, our data demonstrate a key role for the endocannabinoid system in the response of the reproductive system to inflammatory signals.
Thymus‐Dependent T Cell Tolerance of Neuroendocrine Functions
Authors: GEENEN VINCENT
Published: December 2006

Abstract:  Under the evolutionary pressure exerted by the emergence of adaptive immunity and its inherent risk of horror autotoxicus, the thymus appeared some 500 million years ago as a novel lymphoid structure able to prevent autoimmunity and to orchestrate self‐tolerance as a cornerstone in the physiology of the immune system. Also, the thymus plays a prominent role in T cell education to neuroendocrine principles. Some self‐antigens (oxytocin, neurotensin, insulin‐like growth factor 2 [IGF‐2]) have been selected to be predominantly expressed in thymic epithelium and to be presented to thymus T cells for educating them to tolerate other antigens related to them. In the insulin family, IGF2 is dominantly transcribed in cortical (c) and medullary (m) thymic epithelial cells (TECs), whereas the insulin gene (INS) is expressed at low level by only a few subsets of mTECs. Intrathymic transcription of both IGF2 and INS is under the control of the autoimmune regulator (Aire) gene. The highest concentrations of IGF‐2 in the thymus explain why this peptide is much more tolerated than insulin, and why tolerance to IGF‐2 is so difficult to break by active immunization. The high level of tolerance to IGF‐2 is correlated to the development of a tolerogenic/regulatory profile when the sequence B11‐25 of IGF‐2 (homologous to the autoantigen insulin B9‐23) is presented to DQ8+ type 1 diabetic patients. Since subcutaneous and oral insulin does not exert any tolerogenic properties, IGF‐2 and other thymus self‐antigens related to type 1 diabetes (T1D) should be preferred to insulin for the design of novel specific antigen‐based preventive approaches against T1D.
Chronology of Advances in Neuroendocrine Immunomodulationa
Authors: McCANN SAMUEL M. , DE LAURENTIIS ANDREA , RETTORI VALERIA
Published: December 2006

Abstract:  This review documents the remarkable progress over the last 50 years of our knowledge of the control of anterior pituitary hormone release and synthesis by a family of peptidic releasing and inhibiting hormones, synthesized in hypothalamic neurons and released into the hypophysial portal vessels. These vessels transport them to the anterior pituitary, where they stimulate release and synthesis of pituitary hormones or inhibit these processes. In general, there are at least two hypothalamic hormones for each pituitary hormone–vasopressin and corticotrophin‐releasing hormone (CRH) for adrenocorticotropin hormone (ACTH) and growth hormone–releasing hormone (GHRH) and growth hormone–inhibiting hormone (GIH) for growth hormone (GH). Some of these hormones have extrapituitary action: for example, luteinizing hormone–releasing hormone (LHRH) stimulates mating behavior. High doses of LHRH have an inhibitory action on the growth of prostate cancer. Proinflammatory and anti‐inflammatory cytokines act not only in the brain, but also on the pituitary and peripheral tissues. All of these transmitters are controlled by neuronal transmitters. We anticipate further rapid progress and clinical application of these transmitters and the discovery of new ones.
Roles of Glia‐Derived Cytokines on Neuronal Degeneration and Regeneration
Authors: SUZUMURA AKIO , TAKEUCHI HIDEYUKI , ZHANG GUIQIN , KUNO REIKO , MIZUNO TETSUYA
Published: December 2006

Abstract:  Accumulation of activated microglia and reactive astrocytes is observed around degenerating neurons in various inflammatory or degenerative disorders in the central nervous system. These reactive glial cells may play either neurotoxic or neuroprotective roles. In this study, we examined the effects of glia‐derived cytokines on neuronal degeneration and regeneration. Neuron‐rich cultures were stimulated with supernatant of microglia and astrocytes stimulated with LPS, or a various concentrations of recombinant cytokines. Neurotoxicity was evaluated by an MTS assay. Neuronal damage was also evaluated by a frequency of dendritic beading, which was found to be an early feature of neuronal damage toward cell death. Effects of the cytokines on production of neurotrophic factors by astrocytes were also examined by RT‐PCR for the expression of mRNA. Supernatant of LPS‐stimulated microglia induced neuronal cell death. However, all the recombinant cytokines examined did not induce cell death, while IFNγ and TNFα induced dendrite beading, an early feature of neuronal damage. IL‐1β and TNFα enhanced the production of neurotrophic factors by astrocytes. These observations suggest that glial cell–derived cytokines may synergistically function in neuronal degeneration with other toxic factors produced by activated microglia, and that some of them may also function in regeneration by inducing neurotrophic factors.
PPARγ, a Lipid‐Activated Transcription Factor as a Regulator of Dendritic Cell Function
Authors: SZATMARI ISTVAN , RAJNAVOLGYI EVA , NAGY LASZLO
Published: December 2006

Abstract:  In recent years it became apparent that PPARγ, besides being a key component of adipose tissue development and a target of insulin‐sensitizing drugs, also has a role in immune cell differentiation and function. This receptor has been identified by us and others as a conductor of lipid handling in macrophages, and has roles also in inflammation control. Here we review recent advances on the role of this nuclear receptor in another key cell type of myeloid origin, dendritic cells (DCs). DCs are professional antigen‐presenting cells having essential roles in antigen‐uptake processing and presentation and in initiation of various forms of immune responses. It appears that PPARγ is expressed and is active in myeloid DCs and likely to be a regulator of DC function by altering antigen uptake, maturation, activation, migration, cytokine production, and lipid antigen presentation. Thus PPARγ is at the crossroads of lipid metabolism and innate immune response, and by studying its functions one has a unique opportunity to discern how these two seemingly distant fields (lipid metabolism and immune response) are interrelated. It is also possible that this receptor is a relevant target for pharmacological intervention in immune diseases such as chronic inflammation and autoimmune conditions.
The Role of Stress in the Clinical Expression of Thyroid Autoimmunity
Authors: TSATSOULIS AGATHOCLES
Published: December 2006

Abstract:  During stress, activation of the hypothalamic‐pituitary‐adrenal axis and the sympathoadrenal system leads to increased secretion of glucocorticoids and catecholamines, respectively, in order to maintain homeostasis. Recent evidence suggests that stress hormones, acting on antigen‐presenting immune cells, may influence the differentiation of bipotential T helper (Th) cells away from Th1 and toward a Th2 phenotype. This results in suppression of cellular immunity and potentiation of humoral immunity. Thyroid autoimmunity is clinically expressed as Hashimoto's thyroiditis (HT) and its variants (sporadic or postpartum thyroiditis) or as Grave's disease (GD). The different phenotypic expression of thyroid autoimmunity is largely dependent on the balance of Th1 versus Th2 immune response. A predominantly Th1‐mediated immune activity may promote apoptotic pathways on thyroid follicular cells leading to thyroid cell destruction and HT. Conversely, predominance of Th2‐mediated immune response may induce antigen‐specific B lymphocytes to produce anti‐TSH receptor (TSHr) antibodies causing GD. The weight of evidence from epidemiological and case–control studies supports an association between stress and GD. On the other hand, there is little information available on the effect of stress on HT, but there is evidence for an increase in postpartum thyroiditis, following the cellular immune suppressive effect of pregnancy. Whether stress has a causative effect on GD remains elusive. Circumstantial evidence supports the hypothesis that stress may influence the clinical expression of thyroid autoimmunity in susceptible individuals favoring the development of GD by shifting the Th1–Th2 balance away for Th1 and toward Th2. Conversely, recovery from stress or the immune suppressive effect of pregnancy may induce a Th2 to Th1 “return shift” leading to autoimmune (sporadic) or postpartum thyroiditis, respectively.
Therapeutic Management of Chronic Neuropathic Pain
Authors: VADALOUCA ATHINA , SIAFAKA IOANNA , ARGYRA ERIPHYLLI , VRACHNOU EVI , MOKA ELENI
Published: December 2006

Abstract:  Neuropathic pain is defined as pain caused by a lesion in the nervous system and is common in clinical practice. Diagnosis can be difficult. Recommendations for first‐line pharmacologic treatments are based on positive results from multiple, randomized, controlled trials, and recommendations for second‐line pharmacologic treatments are based on the positive result of a single, randomized, controlled trial or inconsistent results of multiple, randomized, controlled trials. The results of published trials and clinical experience provide the foundation for specific recommendations for first‐line treatments, which include gabapentin, 5% lidocaine patch, opioid analgesics, tramadol hydrochloride, and tricyclic antidepressants (TCAs). Gabapentin (up to 3,600 mg/day) significantly reduced pain compared with placebo; improvements in sleep, mood, and quality of life were also demonstrated. Adverse effects of gababentin include somnolence and dizziness, and, less commonly, gastrointestinal symptoms and mild peripheral edema. Thus, monitoring and dosage adjustment are required, without discontinuation of the drug. Gabapentin combined with morphine achieved better analgesia at lower doses of each drug than each drug alone, with only mild adverse effects. The first medication that proved effective for neuropathic pain in placebo‐controlled trials was TCAs. Treatment decisions for patients with neuropathic pain can be difficult. Interest in the mechanisms and treatment of chronic neuropathic pain has increased during the past years, resulting in significant treatment advances in the future. In this article all recent knowledge on therapeutic management of chronic neuropathic pain is presented.
Alpha 2‐Adrenergic Receptors Decrease DNA Replication and Cell Proliferation and Induce Neurite Outgrowth in Transfected Rat Pheochromocytoma Cells
Authors: KARKOULIAS G. , MASTROGIANNI O. , ILIAS I. , LYMPEROPOULOS A. , TARAVIRAS S. , TSOPANOGLOU N. , SITARAS N. , FLORDELLIS C.S.
Published: December 2006

Abstract: Alpha 2‐adrenergic receptors (α2‐ARs) have a widespread distribution in the central nervous system (CNS) and affect a number of biochemical and behavioral functions, including stimulation of prefrontal cortex (PFC) and cognitive function. In addition to its role as a classical neurotransmitter, norepinephrine (NE) has been recently shown to exert an important influence on the plasticity in areas of the brain where neurogenesis persists in the adult, notably the subgranular zone (SGZ) within the dentate gyrus of the hippocampus and the olfactory bulb (OB). In regulating adult neurogenesis, the noradrenergic system is functionally integrated with chronic stress and depression. Chronic stress, depression, or depletion of NEin vivosuppress, and antidepressant treatments induce hippocampal neurogenesis by down‐ or upregulating, respectively, cell proliferation. In the present study we show that α2‐AR subtypes promote the differentiation rather than cell proliferation of PC12 cells. It is conceivable that α2‐ARs might contribute neurotrophic actionsin vivosynergistically or in permutation with other neurotrophic factors.
Hypothalamic‐Pituitary‐Adrenal Axis Function in Sjögren's Syndrome
Authors: JOHNSON ELIZABETH O. , KOSTANDI MARIA , MOUTSOPOULOS HARALAMPOS M.
Published: December 2006

Abstract:  To date, evidence suggests that rheumatic diseases are associated with hypofunctioning of the hypothalamic‐pituitary‐adrenal (HPA) axis. Sjögren's syndrome (SS), the second most common autoimmune disorder, is characterized by diminished lacrimal and salivary gland secretion. To examine HPA axis activity in SS patients, the adrenocorticotropin (ACTH) response to ovine corticotropin‐releasing factor (oCRH) was used as a direct measure of corticotrophic function, and the plasma cortisol response to the ACTH released during oCRH stimulation as an indirect measure of adrenal function. Significantly lower basal ACTH and cortisol levels were found in patients with SS and were associated with a blunted pituitary and adrenal response to oCRH compared to normal controls. Fibromyalgia (FM) patients demonstrated elevated evening basal ACTH and cortisol levels and a somewhat exaggerated peak, delta, and net integrated ACTH response to oCRH. A subgroup of SS patients also met the diagnostic criteria for FM and demonstrated a pituitary‐adrenal response that was intermediate to SS and FM. These findings suggest not only adrenal axis hypoactivity in SS and FM patients, but also that varying patterns of adrenal and thyroid axes dysfunction may exist in patients with different rheumatic diseases.
The Mitochondrion as a Primary Site of Action of Regulatory Agents Involved in Neuroimmunomodulation
Authors: PSARRA A.M.G. , SOLAKIDI S. , SEKERIS C.E.
Published: December 2006

Abstract:  A major system of neuroimmunomodulation is the hypothalamic‐pituitary‐adrenocortical (HPA) axis, acting through glucocorticoids and their intracellular signaling components, exerting both stimulatory and inhibitory effects on the immune reaction. Glucocorticoids inhibit the production of proinflammatory cytokines by interacting with nuclear transcription factors (nuclear factor [NF]‐κB, activated protein [AP]‐1) and induce the production of several anti‐inflammatory cytokines by gene activation. In some cells and/or in extreme stress conditions, apoptosis is evoked. In most processes related to neuroimmunomodulation a prominent role is emerging for mitochondria. These organelles generate more than 90% of the cell's energy requirements through oxidative phosphorylation (OXPHOS), which is regulated by several agents, including steroid and thyroid hormones. These hormones are inducers of nuclear and mitochondrial OXPHOS gene transcription and they exert a primary action not only on nuclear but also on mitochondrial genes by way of cognate receptors. Recently, additional nuclear transcription factors involved in neuroimmunomodulation have been detected in mitochondria (NF‐κB, AP‐1, p53, calcium/cAMP response element binding protein [CREB]), and binding sites of these and putative binding sites of other nuclear transcription factors have been identified in the mitochondrial genome. The interaction of these factors with mitochondrial regulatory proteins, with receptors and with the genome has been shown and, in some cases, modulation of mitochondrial transcription was observed with possible effects on energy yield. The mitochondria store a host of critical apoptotic activators and inhibitors in their intermembrane space and the release of these factors could be another possible mode of action of the mitochondrially translocated regulatory agents and receptors.
Brain Cytokines and the 5‐HT System during Poly I:C‐Induced Fatigue
Authors: KATAFUCHI TOSHIHIKO , KONDO TETSUYA , TAKE SACHIKO , YOSHIMURA MEGUMU
Published: December 2006

Abstract:  Fatigue is evoked not only by peripheral factors, such as muscle fatigue, but also by the central nervous system (CNS). For example, it is generally known that the feeling of fatigue is greatly influenced by psychological aspects, such as motivation. However, little is known about the central mechanisms of fatigue. The clinical symptoms of chronic fatigue syndrome (CFS) are shown to include disorders in neuroendocrine, autonomic, and immune systems. On the other hand, it has been demonstrated that cytokines produced in the brain play significant roles in neural–immune interactions through their various central actions, including hypothalamo‐pituitary and sympathetic activation, as well as immunosuppression. In this article, using the immunologically induced fatigue model, which was achieved by intraperitoneal (i.p.) injection of synthetic double‐stranded RNAs, polyriboinosinic: polyribocytidylic acid (poly I:C) in rats, we show an involvement of brain interferon‐α (IFN‐α) and serotonin (5‐HT) transporter (5‐HTT) in the central mechanisms of fatigue. In the poly I:C‐induced fatigue rats, expression of IFN‐α and 5‐HTT increased, while extracellular concentration of 5‐HT in the medial prefrontal cortex decreased, probably on account of the enhanced expression of 5‐HTT. Since the poly I:C‐induced reduction of the running wheel activity was attenuated by a 5‐HT1A receptor agonist, but not by 5‐HT2, 5‐HT3, or dopamine D3 receptor agonists, it is suggested that the decrease in 5‐HT actions on 5‐HT1A receptors may at least partly contribute to the poly I:C‐induced fatigue.
Interleukin‐6
Authors: MASTORAKOS GEORGE , ILIAS IOANNIS
Published: December 2006

Abstract:  The hypothalamic‐pituitary‐adrenal (HPA) axis and the proinflammatory cytokines (and interleukin‐6 [IL‐6] in particular) are enmeshed in the response to somatic stress, either in health or in acute or chronic disease. Usually IL‐6 is elevated in states of septic (such as sepsis) or aseptic inflammation (such as rheumatoid arthritis). Exercise is a form of somatic stress. Local tissue IL‐6 elevation is noted during shorter and less intense exercise, whereas brief peripheral IL‐6 “bursts” are observed with longer and more intense exercise. Therapeutic interventions that target IL‐6 or its soluble receptor are currently assessed, with an emphasis on autoimmune diseases and inflammatory conditions.
Pheochromocytoma
Authors: ZAPANTI EVANGELIA , ILIAS IOANNIS
Published: December 2006

Abstract:  Pheochromocytoma (PHEO) is a chromaffin cell tumor embryologically arising from the neural crest tissue. The dominant secretory products of PHEO are catecholamines: noradrenaline (norepinephrine), adrenaline (epinephrine), and to a lesser extent dopamine. In addition to catecholamines, PHEO cells also elaborate and release several neuropeptides and inflammatory cytokines which can exert intra‐adrenal and extra‐adrenal systemic effects and cause characteristic clinical syndromes. In a concise review we present the intra‐adrenal and extra‐adrenal pathophysiologic implications of PHEO and the nuclear medicine modalities that permit functional imaging of physiological processes and help localize these tumors. The specific pathways of synthesis, metabolism, and inactivation of catecholamines (of PHEOs and paragangliomas) can be used as means to develop suitable tracers for positron emission tomography (PET) ligands. In this review we focus on imaging with PET using [18F]‐fluorodopamine, [18F]‐fluorohydroxyphenylalanine, [11C]‐epinephrine, or [11C]‐hydroxyephedrine and examine how functional imaging can often complement traditional anatomical imaging modalities and other scintigraphic techniques.
The Role of Stress in Asthma
Authors: VIG RATTANJEET S. , FORSYTHE PAUL , VLIAGOFTIS HARISSIOS
Published: December 2006

Abstract:  Asthma, a chronic inflammatory disease of the airways, is greatly influenced by psychosocial factors and stress. This review looks at clinical studies that have shown strong associations between psychological stress and asthma to identify potential mechanisms for these interactions. Furthermore, we review animal studies involving stress and airway inflammation or airway hyperresponsiveness, and discuss possible mechanisms of stress action in asthma. In conclusion, further research, both in humans and in animal models, into the mechanisms of stress‐induced changes in asthma exacerbation are required to help better understand the complex makeup of asthma and assist in the development of therapies directed at the interplay between the nervous system and airway inflammation.
Immunomodulatory Properties of Substance P
Authors: KOON HON WAI , POTHOULAKIS CHARALABOS
Published: December 2006

Abstract:  Communication between nerves and immune and inflammatory cells of the small and large intestine plays a major role in the modulation of several intestinal functions, including intestinal motility, ion transport, and mucosal permeability. Neuroimmune interactions at intestinal sites have been associated with the pathophysiology of infectious and enterotoxin‐mediated diarrhea and intestinal inflammation, including inflammatory bowel disease (IBD). During the past 20 years the neuropeptide substance P (SP) has been identified as an important mediator in the development and progress of intestinal inflammation by binding to its high‐affinity neurokinin‐1 receptor (NK‐1R). This peptide, released from enteric nerves, sensory neurons, and inflammatory cells of the lamina propria during intestinal inflammation, participates in gut inflammation by interacting, directly or indirectly, with NK‐1R expressed on nerves, epithelial cells, and immune and inflammatory cells, such as mast cells, macrophages, and T cells. SP‐dependent activation of these cells leads to the release of cytokines and chemokines as well as other neuropeptides that modulate diarrhea, inflammation, and motility associated with the pathophysiology of several intestinal disease states. The recent development of specific nonpeptide NK‐1R antagonists and NK‐1R‐deficient mice helped us understand the functional importance of the SP‐NK‐1R system in mediating intestinal neuroimmune interactions and to identify the particular cells and signaling pathways involved in this response. This review summarizes our understanding on the immunomodulatory properties of SP and its receptor in the intestinal tract with particular focus on their involvement in intestinal physiology as well as in the pathophysiology of several intestinal disease states at the in vivo and cell signaling level.
The Critical Role of Mast Cells in Allergy and Inflammation
Authors: THEOHARIDES THEOHARIS C. , KALOGEROMITROS DIMITRIOS
Published: December 2006

Abstract: Mast cells are well known for their involvement in allergic and anaphylactic reactions, but recent findings implicate them in a variety of inflammatory diseases affecting different organs, including the heart, joints, lungs, and skin. In these cases, mast cells appear to be activated by triggers other than aggregation of their IgE receptors (FcɛRI), such as anaphylatoxins, immunoglobulin‐free light chains, superantigens, neuropeptides, and cytokines leading to selective release of mediators without degranulation. These findings could explain inflammatory diseases, such as asthma, atopic dermatitis, coronary inflammation, and inflammatory arthritis, all of which worsen by stress. It is proposed that the pathogenesis of these diseases involve mast cell activation by local release of corticotropin‐releasing hormone (CRH) or related peptides. Combination of CRH receptor antagonists and mast cell inhibitors may present novel therapeutic interventions.
Neural Correlates of IgE‐Mediated Allergy
Authors: COSTA‐PINTO FREDERICO AZEVEDO , BASSO ALEXANDRE SALGADO , DE SÁ‐ROCHA LUIZ CARLOS , BRITTO LUIZ ROBERTO GIORGETTI , RUSSO MOMTCHILO , PALERMO‐NETO JOÃO
Published: December 2006

Abstract:  Although many authors have considered a direct interaction between allergic reactions and behavioral changes, supporting evidence has been elusive. In this series of studies we show that after oral or nasal ovalbumin (OVA) challenge, allergic mice present increased Fos expression in the paraventricular nucleus of the hypothalamus (PVN) and in the central nucleus of the amygdala (CeA). Mice with food allergy display higher levels of anxiety and increased serum corticosterone levels, and allergy‐activated neurons express corticotropin‐releasing factor (CRF) in the PVN and CeA. OVA‐allergic mice develop aversion to an antigen‐containing solution, and also avoid a dark compartment previously associated with nebulized OVA. Results on brain Fos expression and behavioral data seem compatible with adaptive responses. Removal of IgE by either antibody depletion or the development of oral tolerance precluded all responses analyzed here. C‐sensitive fiber destruction by neonatal capsaicin inhibited the activation in the PVN, but not in the CeA, and decreased the magnitude of food aversion. Cromolyn, a mast cell stabilizer, completely blocked Fos expression in the PVN and CeA, and precluded the development of aversion to the dark compartment associated with nebulized OVA. Employing mice that do not develop an important inflammatory infiltrate following nasal OVA challenge, we found that inflammatory cells are not required at the site of challenge in order to trigger neural or behavioral correlates of murine experimental asthma. Altogether, we have built a solid foundation for understanding neuroimmune interactions during allergic responses that may contribute to the comprehension of psychological disorders associated with allergy.
The Role of Chaperone Proteins in Autoimmunity
Authors: ROUTSIAS JOHN G. , TZIOUFAS ATHANASIOS G.
Published: December 2006

Abstract:  Heat‐shock or stress proteins (HSPs) are intracellular molecules that are expressed under cellular stress and have housekeeping and cytoprotective functions. Many of them act also as molecular chaperones, assisting the correct folding, stabilization, and translocation of proteins. In pathological situations, such as necrotic cell death, they can be released into the extracellular environment complexed with intact or fragmented cellular proteins. Evidence is now accumulating to indicate that, under certain circumstances, these complexes can contribute to induction of autoimmunity by receptor‐mediated activation of the innate immune response (signaling the “danger”) and by participation in the presentation of autoantigens for the adaptive immune response (acting as natural adjuvants). In addition, the conservation of HSPs through prokaryotes and eukaryotes, together with the increased production of host and microbial HSPs at the site of infection, has led to the proposition that these proteins may provide a link between infection and autoimmunity. This review outlines the mechanisms for the potential involvement of chaperones in the induction of autoimmune disease.
Low‐Grade Inflammation in Chronic Infectious Diseases
Authors: MOUTSOPOULOS NIKI M. , MADIANOS PHOEBUS N.
Published: December 2006

Abstract:  Increasing evidence implicates periodontitis, a chronic inflammatory disease of the tooth‐supporting structures, as a potential risk factor for increased morbidity or mortality for several systemic conditions including cardiovascular disease (atherosclerosis, heart attack, and stroke), pregnancy complications (spontaneous preterm birth [SPB]), and diabetes mellitus. Cross‐sectional, case–control, and cohort studies indicate that periodontitis may confer two‐ and up to sevenfold increase in the risk for cardiovascular disease and premature birth, respectively. Given the recently acquired knowledge that systemic inflammation may contribute in the pathogenesis of atherosclerosis and may predispose to premature birth, research in the field of periodontics has focused on the potential of this chronic low‐grade inflammatory condition to contribute to the generation of a systemic inflammatory phenotype. Consistent with this hypothesis clinical studies demonstrate that periodontitis patients have elevated markers of systemic inflammation, such as C‐reactive protein (CRP), interleukin 6 (IL‐6), haptoglobin, and fibrinogen. These are higher in periodontal patients with acute myocardial infarction (AMI) than in patients with AMI alone, supporting the notion that periodontal disease is an independent contributor to systemic inflammation. In the case of adverse pregnancy outcomes, studies on fetal cord blood from SBP babies indicate a strong in utero IgM antibody response specific to several oral periodontal pathogens, which induces an inflammatory response at the fetal–placental unit, leading to prematurity. The importance of periodontal infections to systemic health is further strengthened by pilot intervention trials indicating that periodontal therapy may improve surrogate cardiovascular outcomes, such as endothelial function, and may reduce four‐ to fivefold the incidence of premature birth. Nevertheless, further research is needed to fully discern the underlying mechanisms by which local chronic infections can have an impact on systemic health, and in this endeavor periodontal disease may serve as an ideal disease model.