Migraine, daily chronic headache and fibromyalgia in the same patient: an evolutive "continuum" of non organic chronic pain? About 100 clinical cases.

Aim of this study is to evaluate if migraine, daily chronic headache and fibromyalgia in the same patient can be considered as an evolutive continuum of non organic chronic pain. Therefore, migraine, daily chronic headache and fibromyalgia should be considered the expression of chronic antinociceptive system alteration.

The immunocompromised host: immune alterations in splenectomized patients and clinical implications.

The spleen plays a paramount role in the host protection against invading microorganisms. In support of the above concept, in splenectomized patients there is increasing evidence of overwhelming postsplenectomy infections (OPSI). OPSI are caused by Streptococcus pneumoniae in about 80% of cases, but also Gram-negative bacteria are implicated in a certain number of cases. Therapeutically, penicillin and pneumococcal vaccines represent valid therapeutic approaches in Gram-positive OPSI. However, the effectiveness of polyvalent polysaccharide pneumococcal vaccines is still debated and, thus, other therapeutic strategies should be validated for combating OPSI. According to our personal data, a deficit of phagocytic activities and of T helper (h)-1 cells is very frequent in splenectomized patients. In sera, we found reduced levels of both Interferon-gamma and Interleukin (IL)-4. These data are in accordance with the recent observation on the protective role of T cells against S. pneumoniae. In fact, patients deficient in IL-12 develop severe pneumococcal infections and undergo apoptosis of Th(1) cells.

Modifications of the immune responsiveness in patients with autoimmune thyroiditis: evidence for a systemic immune alteration.

Hashimoto's thyroiditis, the most common form of autoimmune thyroid disease, is characterised by lymphocytic infiltration of the thyroid gland, gradual destruction of the organ and production of thyroid specific auto antibodies (antithyroid peroxidase and antithyroglobulin antibodies). There are evidences that cast doubt on the pathogenetic role of these antibodies in thyroid autoimmunity. It is very likely that cellular destruction is mediated by other cellular mechanisms, such as auto reactive T-lymphocytes, natural killer and cytokines. However, other studies performed in animal models have led to the conclusion that organ specific autoimmune thyroiditis should be regarded as a polygenic disease with a penetrance that is strongly influenced by environmental factors. According to our recent results, patients affected by autoimmune thyroiditis exhibited a decreased percentage of NK and CD25 + bearing cells significantly in comparison to normal controls. Altogether these data indicated that in the patients with autoimmune thyroid disease a certain degree of peripheral immune deficiency was present.

Immunological aspects in migraine: increase of IL-10 plasma levels during attack.

In the present study, 23 patients with migraine without aura were monitored during a migraine attack. Plasma levels of interleukin (IL)-4, IL-5, IL-10, and interferon-gamma were measured by enzyme-linked immunosorbent assay techniques. Interestingly, we observed low to undetectable IL-5 and IL-4 levels, whereas high IL-10 levels were seen in 52.2% of the patients. Interferon-gamma plasma levels were undetectable in all patients. After treatment with sumatriptan, 10 patients showed a subsequent decrease in IL-10 and an increase in both IL-4 and IL-5 plasma levels. Although these findings are derived from a limited number of patients, the apparent return to the IL-4 and IL-5 cytokine profile observed during the interictal period leads us to speculate that a preferential enhancement of TH2-type cytokine production may contribute to the pathogenesis of migraine.

A syndrome characterized by psychiatric disorders, recurrent mucosal infections and natural immunity deficits: clinical approach.

The authors summarize their own previous work on the identification of a subset of patients characterized by psychiatric disorders, recurrency of mucosal infections and impaired natural immunity. The diagnostic approach to these patients based on the close collaboration between infectivologists, immunologists and psychiatrists is described with the aim to find out combined treatments for the amelioration of clinical manifestations.

Evaluation of nonspecific immunity and plasma levels of interferon-gamma, interleukin-6 and tumor necrosis factor-alpha in preeclampsia.

In this study we evaluated the maternal cell-mediated immune aspects of preeclampsia in terms of phagocytosis and killing of monocytes and polymorphonuclear cells. To evaluate the contribution of cytokines (Cks) in the pathophysiology of preeclampsia, we investigated the plasma levels of interferon-gamma (IFN-gamma), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), respectively, by an enzyme-linked immunosorbent assay. Data showed that phagocytic and killing activities of monocytes were depressed in preeclamptic and normal pregnancies. At the same time, IFN-gamma plasma levels were undectable in both groups. Conversely, we detected significant levels of TNF-alpha in plasma from preeclamptic and normal pregnancies. Moreover, since in three preeclamptic patients the onset of severe preeclampsia was associated with a sharp increased of TNF-alpha plasma levels, we suggest that an increased production of this CK may be implicated in the pathophysiology of preeclampsia.

Spontaneous and induced release of prostaglandins, interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha by placental tissue from normal and preeclamptic pregnancies.

PROBLEM: The objective of this study was to clarify the role of the main proinflammatory cytokines (interleukin [IL]-1, IL-6, tumor necrosis factor [TNF]-alpha) in the pathogenesis of preeclampsia and how these cytokines affect one another and the production of prostaglandins (PGs). METHOD OF STUDY: The concentrations of cytokines and PGs in supernatants of placental tissue from preeclamptic and normal women were determined by enzyme-linked immunosorbent assay. RESULTS: The concentrations of the PGs from unstimulated preeclamptic placental tissue were significantly higher compared to the concentrations of PGs from normal unstimulated placental tissue. Significant levels of IL-1beta were observed only in the supernatants of preeclamptic placental tissue. Of interest, an increase in TNF-alpha production was detected in the supernatants of IL-1-stimulated preeclamptic placental tissue. CONCLUSIONS: The overproduction of TNF-alpha may be related not only to the effect of a stimulant like IL-1beta, but mainly to the lack of mechanisms down-regulating the production of TNF-alpha.

Evaluation of hypothalamic-pituitary-adrenocortical hormones and inflammatory cytokines in patients with persistent vegetative state.

Hypothalamic-pituitary-adrenocortical hormones, i.e. prolactin (PRL), human growth hormone (hGH), thyroid stimulating hormone (TSH), and Cortisol and plasma levels of cytokines, i.e. tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and interleukin-6 (IL-6), were assessed in 27 patients with persistent vegetative state (PVS) and in 16 outcome patients. In comparison with normal parameters, plasma levels of TSH were not significantly altered, while elevated basal hGH concentrations in 48.1% of PVS subjects and depressed cortisol levels in all PVS individuals and in patients who emerged from coma (outcome patients), respectively, were observed. In addition, higher TNF-alpha plasma levels in PVS subjects than in outcome patients and in healthy donors were found, while IL-1 beta plasma levels were elevated in both groups of patients in comparison with healthy controls. Of interest, in 55% PVS male patients hyperprolactinemia was observed, whereas in outcome patients more than six months these values were within normal range. In four patients, who emerged from coma in the course of this study, prolactin plasma levels were followed-up and increased basal values progressively fell to normal range within six months.

Cytokines and migraine: increase of IL-5 and IL-4 plasma levels.

Thirty-two patients suffering from migraine without aura were assessed during in interictal period to evaluate the contribution of cytokines to the pathophysiology of migraine. To this end, plasma levels of IFN-gamma, IL-4, IL-5, and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA) techniques. Plasma levels of both IFN-gamma and IL-10 were not increased in the patients and did not differ significantly from healthy controls. Of interest, we observed a strong increase of IL-5 levels in 84.3% as well as increased IL-4 levels in 37.5% of patients with migraine without aura. These results suggests a preferential enhancement of some Th2-type cytokines, and may support the growing arguments of an immunoallergic mechanism in the pathophysiology of migraine.

Impairment of non-specific immunity in patients in persistent vegetative state.

In fourteen patients in persistent vegetative state (PVS) immune responsiveness was investigated. In particular, we studied the relationship between brain lesions following traumatic injury and immune system. In this respect, phagocytosis and killing of Candida albicans by polymorphonuclear cells (PMN) and monocytes were tested. In addition serum levels of Interferon-gamma (IFN-gamma) were evaluated. The patients come out from PVS by 3-4 month were used as control group. Data shown a profound impairement of phagocytosis and killing of monocytes and low serum levels of IFN gamma when compared with normal values. Taken together, these findings suggest that brain lesions, may affect non-specific immune response.

The influence of stress intrusion on immunodepression in generalized anxiety disorder patients and controls.

Previous work from our group has examined the relationship between stress and immunodepression in medical students taking National Boards, Part I, and has described a relationship between stress intrusion scores (SIS) and immunodepression. We have also shown that a high proportion of individuals with generalized anxiety disorders (GAD) and panic disorders (PD) exhibit enhanced stress intrusion (SI) and are more prone to upper respiratory infections (URI). In the present preliminary study, we sought to establish a model to evaluate further the role of SI level on the extent of immunodepression. This would serve to assess in further studies the mechanism(s) of stress-induced immunodepression, its relationship to morbidity, and the role of therapeutic interventions. In 14 GAD patients and 14 controls, we correlated the expression of interleukin-2 receptors (CD25) on T lymphocytes stimulated with anti-CD3 in short term cultures and the frequency of URI and the SIS to assess the relationships among these parameters. A decreased expression of CD25 correlates linearly with increasing SIS and with a higher number of sick days with URI. These results support our previous observations that GAD patients are more susceptible to URI. Moreover, they suggest that there may be a direct relationship between immunodepression and morbidity and between SIS and immunodepression.

Immunomodulatory effects of alpha interferon and thymostimulin in patients with neoplasias.

In this report, we have evaluated the immunological effects following administration of alpha interferon (IFN-alpha) in combination with thymostimulin (TP-1), as well as of IFN-alpha and TP-1 alone in patients with neoplasias who underwent surgery and were subsequently treated with conventional chemotherapy. Data suggest that the combination of IFN-alpha and TP-1 is the most effective in the up-regulation of some immune parameters such as the CD4(+)-CD8+ cell-dependent antibacterial activity. Since this immune function plays an important role in the host protection against different targets such as invading microorganisms and/or neoplastic cells, the administration of TP-1-IFN-alpha is advisable for patients with neoplasias under chemotherapy.

In vivo administration of propranolol decreases exaggerated amounts of serum TNF-alpha in patients with migraine without aura. Possible mechanism of action.

Patients with migraine without aura (MWA) display elevated amounts of Tumor Necrosis Factor (TNF)-alpha in their sera. In this study in 18 patients with MWA the in vivo effect of propranolol, a beta blocker agent, was evaluated with regard to the TNF serum levels before and after treatment. Results show that in 9 out 11 patients exaggerated serum concentrations of TNF reverted to normality after three months of therapy. Some hypotheses on the mechanisms of action of propranolol in terms of modulation of the immune response are formulated.

Neurological damage mediated by cytokines.

Our results suggest that CKs, in particular Interleukin-1 and Tumor Necrosis Factor (TNF)-alpha, are involved in the pathogenesis of some neurological disorders and HIV infection. Infact, we observed an exaggerated spontaneous release of TNF-alpha in patients with migraine without aura. Furthermore, in a broad spectrum of patients with HIV-infection we have also found increased amounts of serum TNF-alfa and IL-1. Interestingly, a strict correlation between plasma lipopolysaccharide (LPS) and IL-1 or TNF-alpha levels seems to exist in both group of patients, thus indicating that LPS could account for the production of CKs in the course of the above diseases.

Interleukin-1 beta and beta-endorphin circadian rhythms are inversely related in normal and stress-altered sleep.

Normal sleep is associated to physiological nocturnal rises in Interleukin 1 beta (IL 1 beta) secretion. The 24 h pattern of IL 1 beta, beta-Endorphin (beta-EPH), ACTH and cortisol (F) production was evaluated in four male healthy volunteers. Two subjects were unable to sleep, due to the stress of the experiment; in these cases, no detectable plasma IL 1 beta secretion, both diurnal and nocturnal, was present, beta-EPH plasma levels were significantly higher (p < 0.01) than in the subjects who slept regularly and, in one case, increased F plasma levels were also reported. A strong negative correlation between IL 1 beta and beta-EPH plasma levels was present in all the cases. In conclusion, stress-induced sleep alterations might deeply affect both diurnal and nocturnal IL 1 beta plasma secretion, probably due to the hypothalamus-pituitary-adrenal axis (HPAA) activation, and beta-EPH might be the reliable marker of the stress-induced HPAA activation level.

On the physiological significance of tumor necrosis factor-alpha in the human amniotic fluid.

Tumor Necrosis Factor (TNF)-alpha and Interleukin (IL)-1 beta levels have been measured in 16 weeks gestation amniotic fluids and mother's sera. Detectable levels of TNF-alpha were found in amniotic fluids, while IL-1 beta was absent. No cytokines were detected in mother's sera. The possible role of TNF-alpha as growth factor for fetal hematopoietic cells is discussed.

Influence of ST 789 on interleukin-1, interleukin-2 and interferon-gamma production from normal human peripheral blood mononuclear cells.

ST 789, previously named PCF 39, is a synthetic hypoxanthine derivative endowed with immunomodulating properties. However, the mode of action of this compound on immunocompetent cells has not yet been elucidated and, in particular, no evidence has been provided on its ability to trigger monokine (MK) and lymphokine (LK) release. In this framework, here we have evaluated the influence of ST 789 on interleukin (IL)-1, IL-2 and interferon (IFN)-gamma production from normal human peripheral blood mononuclear cells (PBMC). Results will show that following stimulation of PBMC with lipopolysaccharides (LPS) or lectins [phytohemagglutinin (PHA) and concanavalin A (Con A)] in the presence of increasing concentrations of ST 789 no modification of cytokine release is obtained, in comparison with cultures activated with LPS or lectins. In addition, this hypoxanthine is not able per se to induce release of MKs and LKs. The overall results suggest that ST 789 acts on the immune system through mechanisms which are not dependent on the release of ILs and IFN-gamma.

Somnogenic cytokines with special reference to interleukin-1.

Cytokines (CKs) are involved in the mechanisms of sleep induction, and, in particular, interleukin-1 (IL-1) and tumor necrosis factor-alpha seem to play an important role in the slow-wave sleep. Here are reported two cases of normal sleep and altered sleep in which plasma levels of IL-1 beta have been determined. In the subject with a normal sleep a dramatic increase of this CK has been observed, while beta-endorphin levels were reduced. In the light of these findings, the role of sleep in the host protection is discussed.