The burden and epidemiology of community-acquired central nervous system infections: a multinational study.

Risk assessment of central nervous system (CNS) infection patients is of key importance in predicting likely pathogens. However, data are lacking on the epidemiology globally. We performed a multicenter study to understand the burden of community-acquired CNS (CA-CNS) infections between 2012 and 2014. A total of 2583 patients with CA-CNS infections were included from 37 referral centers in 20 countries. Of these, 477 (18.5%) patients survived with sequelae and 227 (8.8%) died, and 1879 (72.7%) patients were discharged with complete cure. The most frequent infecting pathogens in this study were Streptococcus pneumoniae (n = 206, 8%) and Mycobacterium tuberculosis (n = 152, 5.9%). Varicella zoster virus and Listeria were other common pathogens in the elderly. Although staphylococci and Listeria resulted in frequent infections in immunocompromised patients, cryptococci were leading pathogens in human immunodeficiency virus (HIV)-positive individuals. Among the patients with any proven etiology, 96 (8.9%) patients presented with clinical features of a chronic CNS disease. Neurosyphilis, neurobrucellosis, neuroborreliosis, and CNS tuberculosis had a predilection to present chronic courses. Listeria monocytogenes, Staphylococcus aureus, M. tuberculosis, and S. pneumoniae were the most fatal forms, while sequelae were significantly higher for herpes simplex virus type 1 (p < 0.05 for all). Tackling the high burden of CNS infections globally can only be achieved with effective pneumococcal immunization and strategies to eliminate tuberculosis, and more must be done to improve diagnostic capacity.

Tissue leptin levels in patients with breast cancer.

PURPOSE: High leptin serum levels, overexpression of leptin and its two main receptor isoforms, OBR-L and OBR-S, have been documented in breast cancer patients. In the present study, the relationship between tissue leptin levels and breast cancer was evaluated. METHODS: Thirty-three normal breast tissue samples and 33 breast cancer tissue samples from 33 patients with breast cancer were evaluated. The association of tissue leptin levels and important prognostic factors related to breast cancer was analyzed. RESULTS: Mean tissue leptin levels in breast cancer tissue samples (5.02 + or - 1.06 pg/ml) were significantly higher than those found in normal breast tissue (2.02 + or - 0.83 pg/ml; p=0.01). No correlation was found in tissue leptin levels and menopausal status, hormone receptor and HER-2/neu status, lymph node involvement, and histopathologic features. CONCLUSION: High leptin levels were significantly higher in breast cancer tissue compared with normal tissue. No special correlation was found between tissue leptin levels and different clinicopathological characteristics.

Pronounced interferon-alpha production from plasmacytoid dendritic cells in patients with Behçet's disease following CpG D ODN stimulation.

OBJECTIVE: Several lines of evidence point to a polarized T-helper-1 (Th1) immune response in Behçet's disease (BD). Interferon (IFN)-alpha which has an ability to promote strong Th1 type immune response has been shown to increase in patients with BD. In order to clarify if plasmacytoid dendritic cells (pDCs) abnormally respond to a stimulus in patients with BD, we investigated the levels of intracellular IFN-alpha and beta in pDCs with or without CpG D ODN stimulation. METHODS: The study population consisted of 8 patients with clinically active BD, 8 ankylosing spondilitis (AS) patients having active disease and 11 healthy volunteers. pDC subsets in peripheral blood mononuclear cells (PBMCs) cultures were analysed by flow cytometry. RESULTS: The percentage of IFN-alpha+ pDCs in unstimulated PBMCs cultures from patients BD was significantly higher (p=0.036) than in AS and HC. But this difference disappeared in stimulated PBMCs cultures (p=0.167). The mean fluorescence intensity (MFI) of IFN-alpha+ pDCs in stimulated PBMCs cultures of BD patients was significantly higher than those from patients with AS and HC. The percentage of IFN-beta+ pDCs in unstimulated PBMCs cultures from patients with BD and AS was significantly higher (p=0.004) than in HC. But this difference was not significant in stimulated PBMCs cultures (p=0.694). When compared to healthy subjects, the MFI of IFN-beta + pDCs in unstimulated and stimulated PBMCs cultures from patients with BD and AS was not different (p=0.287, p=0.152, respectively). In patients with BD, the percentage and MFI of IFN-alpha+ pDCs were higher (p=0.012 for all) in stimulated PBMCs cultures as compared to unstimulated ones. CONCLUSION: We suggest that increased frequency of IFN-alpha+ pDC in BD patients and the higher sensitiveness of these cells to CpG D ODN stimulus contribute to high serum IFN-alpha levels found in these patients which eventually resulted in Th1 type immune response.

Human cytomegalovirus in peripheral giant cell granuloma.

BACKGROUND: The peripheral giant cell granuloma is a relatively common non-neoplastic inflammatory lesion of gingiva, but the etiopathogeny remains unknown. This study aimed to evaluate the importance of human cytomegalovirus and Epstein-Barr virus in a peripheral giant cell granuloma of a 47-year-old female. METHODS: The lesion was studied clinically, histopathologically, immunologically and virologically using established procedures. RESULTS: The gingival growth was located at the mesial surface of the maxillary left canine having a vital pulp. The mass was 12 x 21 mm in size and exhibited a smooth surface with no evidence of fluctuation on palpation. An excisional biopsy revealed giant cells in a fibrohistiocytic stroma with areas of haemorrhage. Serum protein levels and lymphocyte subsets were within normal limits, except CD3(+) and CD4(+) cells were below normal ranges. Polymorphonuclear leukocytes expressed p150,95 (CD11c/CD18) and CXCR-2 receptors within normal ranges, but the CXCR1 receptor showed decreased density, and CD15 were below normal range. A virological sample of the tooth surface adjacent to the gingival swelling yielded 7.6 x 10(3) copy-counts of cytomegalovirus and 4.3 x 10(3) copy-counts of Epstein-Barr virus. CONCLUSIONS: The clinical and histological findings were consistent with the diagnosis of peripheral giant cell granuloma. Cytomegalovirus has the potential to induce multinucleated giant cells, and the possibility that the virus contribute to the development of peripheral giant cell granuloma merits further study.

Synovial lymphoid neogenetic factors in Behçet's synovitis: do they play a role in self-limiting and subacute course of arthritis?

OBJECTIVE: Lymphoid neogenesis seems to play an important role in the persistence of chronic inflammation and has been shown in various disorders characterized by chronic inflammation including rheumatoid arthritis. Arthritis of Behçet's disease is characterized by non-erosive arthritis in which the disease course is considered to be subacute and self limiting. However, molecular mechanisms underlying those features of Behçet's arthritis have not been defined yet. In order to determine the contribution of lymphoid neogenesis in the disease course of Behçet's arthritis, we investigated the synovial fluid (SF) levels of CXCL 12, CXCL 13, CCL 21 homeostatic chemokines and the percentage of SF naive lymphocytes expressing their receptors such as CXCR4+ and CCR7+. We further measured the SF TGF-Beta and INF-Beta levels which are known to contribute lymphoid neogenesis via leading persistent expression of CXCR4 on T cells and inhibiting T cell apoptosis, respectively. METHODS: Fifty-one [15 BD, 17 RA, and 19 osteoarthritis (OA)] patients with at least one- sided knee arthritis were enrolled in the study. Patients with BD constituted the study group, and RA, OA patients were used as positive and negative control groups, respectively. The SF levels of CXCL 12, CXCL 13, CCL 21, TGF-Beta and INF-Beta were measured by ELISA. CXCR4, CCR7 chemokine receptors on SF lymphocytes were tested by Flow- cytometry. Kruskal-Wallis test and Mann-Whitney U test were used for statistical analysis where appropriate. RESULTS: Synovial fluid CCL 21 levels were found to be increased in RA patients as compared to BD and OA patients (p = 0.003, and p = 0.013, respectively). No significant difference was detected between BD and OA patients with respect to CCL 21 levels. Both CXCL 12 and CXCL 13 SF levels were found to be higher in RA and BD patients as compared to OA patients (CXCL-12; p = 0.012, and p = 0.024), (CXCL 13; p < 0.001, and p = 0.007). However, no difference with regard to SF levels of both CXCL 12 and CXCL 13 were found between RA and BD patients. Percentages of both CD3+CXCR4+ lymphocytes and CD3+CCR7+ lymphocytes in the SF of RA patients were detected to be increased as compared to those of BD and OA patients (CD3+CXCR4+; p = 0.019, p = 0.048, respectively), (CD3+CCR7+; p = 0.023, p = 0.001, respectively). However, no differences with respect to the percentages of SF lymphocytes expressing CD3+CXCR4+ or CD3+CCR7+ were found between BD and OA patients. Both TGF-Beta and INF-Beta SF levels were found to be higher in RA patients as compared to BD and OA patients (TGF-Beta; p = 0.041, and p = 0.003), (INF-Beta; p = 0.012, and p = 0.016). However, no differences with regard to SF levels of both TGF-Beta and INF-Beta were found between BD and OA patients. CONCLUSION: Considering the subacute, self limiting and non-erosive course of arthritis observed in BD, our finding of detection of lower levels of CCL21 and TGF-Beta1 and IFN-Beta in BD patients, seems to prevent the development of LN and chronic inflammation in Behçet's synovitis. In support of this view, percentages of SF naïve T lymphocytes were found to be lower in BD patients comparing with those of the RA. Absence of tertiary lymphoid structures in BD patients, may explain the spontaneous resolution of Behçet's arthritis in most of the cases.

Dendritic cell subsets and type I interferon system in Behçet's disease: does functional abnormality in plasmacytoid dendritic cells contribute to Th1 polarization?

OBJECTIVE: Several lines of evidence point to a polarized T-helper-1 (Th1) immune response in Behçet's disease (BD). However, it is not yet clear which factors are involved in the proposed Th1 mediated pathogenesis of BD. Dendritic cells (DCs) are antigen presenting cells which play a crucial role in the polarization of immune response. No previous study has examined the possible role of DCs in the pathogenesis of BD. We conducted both quantitative and functional analysis of the peripheral blood DC subsets in BD patients with different clinical presentations. METHODS: Thirty-eight patients with BD, 12 healthy controls (HC), and 12 patients with undifferentiated spondylarthritis (uSpA) were enrolled in the study. Peripheral blood DC subsets were analysed by flow cytometry and were further characterized for maturation with CCR7. Serum levels of interferon (IFN)-alpha and IFN-b were measured by ELISA. RESULTS: BD patients had a decreased percentage of plasmacytoid DCs (pDCs) compared to HC (p = 0.036). IFN-alpha levels were found to be increased in BD patients as compared to HC and uSPA (p < 0.001, p = 0.005, respectively). BD patients had decreased levels of IFN-Beta as compared to HC and uSpA (p = 0.013, p = 0.004, respectively). No difference was found between HC and patients with uSpA regarding IFN-Beta levels. Subgroup analysis of BD patients disclosed normalization of percentage of pDCs and the level of IFN-Beta in patients receiving IFN-alpha-2b. CONCLUSION: We suggest abnormalities in pDCs and type I IFNs appear to be a master switch leading to the pathogenicity in BD by directing immune response towards Th1.

Serum MMP-2 and MMP-9 in patients with Behçet's disease: do their higher levels correlate to vasculo-Behçet's disease associated with aneurysm formation?

OBJECTIVES: Basic and clinical studies have revealed a strong correlation between matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, and the formation of abdominal aortic aneurysms. In addition, previous studies have clearly shown that MMP-2 and MMP-9 play an important role in the pathogenesis of vasculitis characterized by aneurysm formation such as Kawasaki disease, temporal arteritis and Takayasu arteritis. Depending on those findings, we hypothesized that circulating MMP-2 and MMP-9 could be useful markers to demonstrate vascular aneurysmatic involvement in patients with Behçet's disease (BD). METHODS: Fifty-eight patients with BD, and 20 healthy controls were enrolled in the study. We assessed the disease activity of patients according to the Leeds activity score system. We compared the Leeds activity scores of patients with their serum levels of MMP2 and MMP-9. Patients with BD were categorized as active (total activity score > or = 5) or inactive (total activity score < 5). Patients were further categorized with respect to their extent of involvement as muco-cutaneous or systemic. Patients with systemic involvement were subdivided into ocular or vascular involvement. Patients with vascular involvement were subgrouped as thrombotic or aneurysmatic involvement. The levels of MMP-2 and MMP-9 were measured by ELISA. RESULTS: Serum MMP-9 but not MMP-2 levels were significantly higher both in patients with active and inactive disease as compared to healthy controls (p = 0.008 and 0.013 respectively). We found positive correlation between Leeds activity score and serum MMP-2 levels in patients with vascular involvement (p = 0.035 and r = 0.485), and serum MMP-9 levels in active BD patients (p = 0.003 and r = 0.599). The serum levels of MMP-2 and MMP-9 in patients with systemic involvement were higher than those of healthy controls but not patients with mucocutaneous involvement (p = 0.046 and 0.002 respectively). The serum levels of MMP-2 in patients with vascular involvement were found to be higher than those of healthy controls and patients with mucocutaneous involvement (p = 0.001 and 0.003, respectively) but not different in those with ocular involvement. The serum levels of MMP-9 in patients with vascular involvement were found to be higher than those of healthy controls and ocular disease (p = 0.001 and 0.033 respectively) but not different in those with mucocutaneous involvement. The serum levels of MMP-2 in patients with aneurysmatic involvement were found to be higher than those of healthy controls, mucocutaneous and ocular involvement (p = 0.004, 0.008 and 0.004 respectively). The serum levels of MMP-2 in patients with thrombotic involvement were found to be higher than those of healthy controls and mucocutaneous (p = 0.018 and 0.033 respectively) but not ocular involvement. The serum levels of MMP-9 in patients with aneurysmatic involvement were found to be higher than those of healthy controls, mucocutaneous and ocular involvement (p = 0.001, 0.048 and 0.007 respectively). The serum levels of MMP-9 in patients with thrombotic involvement were found to be higher than those of healthy controls but not mucocutaneous and ocular involvement (p = 0.046). CONCLUSIONS: We concluded that serum MMP-2 and MMP-9 levels can be used as an activity indicator for vasculo-Behçet's or active Behçet's patients, respectively. But they can not be used as a marker reflecting the systemic involvement of patients with BD. The systemic expressions of MMP-2 and MMP-9 were strongly associated with vasculo-Behçet's disease, particularly aneurysmatic involvement, suggesting their pathogenetic roles in vasculo-Behçet's disease complicated with aneurysm formation.

Effect of modern surgical treatment on the inflammatory/anti-inflammatory balance in patients with obstructive sleep apnoea.

OBJECTIVE: To investigate the inflammatory/anti-inflammatory cytokine balance - T helper 1/T helper 2 ratios - in obstructive sleep apnoea patients, before and after treatment. METHODS: Twenty-eight patients received continuous positive airway pressure treatment and 29 patients who could not tolerate continuous positive airway pressure were scheduled for surgery. Serum levels of interleukins 2, 4 and 10, tumour necrosis factor-alpha, and interferon gamma were analysed by enzyme-linked immunosorbent assays before and three months after treatment. RESULTS: The success rate of surgical treatment was 65.5 per cent. Mean compliance for the continuous positive airway pressure group was 40.9 per cent. The apnoea/hypopnoea index significantly decreased in both groups after treatment (p < 0.001). The interferon gamma/interleukin-4 ratio decreased following surgical treatment (p = 0.014), and the interleukin-2/interleukin-4 ratio decreased after treatment in 57 patients in the overall cohort (p = 0.032). CONCLUSION: After treatment for obstructive sleep apnoea, some ratios reflecting T helper 1/T helper 2 cytokine balance favoured the T helper 2 direction, suggesting a shift to an anti-inflammatory state. Successful surgery and better continuous positive airway pressure compliance can help ameliorate inflammation in obstructive sleep apnoea patients, which may reduce associated morbidities.

Gonadotropin treatment increases homocysteine levels in idiopathic hypogonadotropic hypogonadism: an indirect effect mediated by changes in body composition.

The main objective of the present study was to examine the alterations in plasma total homocysteine (tHcy) concentrations during a testosterone-deficient state and after gonadotropin treatment for 6 Months in patients with idiopathic hypogonadotropic hypogonadism (IHH). Thirty-five newly diagnosed male patients with IHH (mean age 21.34+/-1.53 years) and 29 age- and body mass index-matched healthy males (mean age 21.52+/-1.77 years) were recruited into the study. Pretreatment levels of free testosterone (1.51+/-0.66 pg/ml), estradiol (21.37+/- 4.37 pg/ml), FSH (0.91+/-0.24 IU/l) and LH (1.25+/- 0.53 IU/l) were lower than controls (25.17+/-3.06 pg/ml, 31.00+/-4.96 pg/ml, 3.14+/-1.62 IU/l and 4.83+/-1.65 IU/l respectively) (P<0.001). They increased significantly after treatment (18.18+/-1.59 pg/ml, 27.97+/- 4.25 pg/ml, 2.41+/-0.27 IU/l and 2.79+/-0.19 IU/l respectively) (P<0.001). Patients with IHH had lower tHcy levels than controls (10.14+/-1.34 and 12.58+/- 2.29 micro mol/l respectively) (P<0.001). Plasma tHcy concentrations increased significantly (12.63+/-1.44 micromol/l) after 6 months of treatment (P<0.001). As compared with the controls, pretreatment levels of serum creatinine (63.54+/-13.01 vs 82.84+/-16.69 micromol/l), hemoglobin (12.98+/-0.56 vs 13.83+/-0.71 g/dl) and hematocrit (39.29+/-2.01 vs 41.38+/-1.95%) were significantly lower (P<0.001), and they increased significantly following treatment (80.24+/-11.93 micromol/l, 13.75+/-0.49 g/dl and 41.26+/-1.78% respectively) (P<0.001). The pretreatment folic acid and vitamin B(12) levels were significantly higher in patients when compared with controls (14.87+/-5.68 vs 12.52+/-4.98 nmol/l, P=0.034 and 289.75+/-92.34 vs 237.59+/-108.17 pmol/l, P=0.002 respectively). They decreased significantly after treatment (11.29+/-3.31 nmol/l and 228.51+/-54.33 pmol/l respectively) (P<0.001). The univariate and multivariate regression analysis results showed that only changes in creatinine, creatinine clearance, vitamin B12 and folic acid were independently associated with changes in tHcy levels in patients with IHH. In conclusion, the increase in plasma tHcy concentrations following gonadotropin treatment seems to be largely independent of changes in androgen levels.

Serum interleukin-18 levels in patients with Behçet's disease. Is its expression associated with disease activity or clinical presentations?

Interleukin (IL)-18 is a proinflammatory cytokine which plays a crucial role in T helper (Th)1 type immune response. The aim of this study is to investigate the relationship of serum levels of IL-18 with disease activity and clinical presentations in patients with Behcet's disease (BD). Sixty patients with BD and 20 healthy controls were included in the study. Patients were grouped as having active or inactive disease according to the Leeds activity score. They were also separated as a systemic involvement or mucocutaneous symptoms only. Patients with systemic involvement were further grouped according to the presence of ocular, articular and vascular involvement. IL-18 levels were significantly higher in all patient subgroups as compared to healthy controls and found to be correlated with the activity score in patients having active disease. In conclusion, this cytokine participates in the pathogenesis of BD and its levels are correlated with the disease activity. Detection of increased levels of IL-18 in patients with inactive disease implies that Th1 activation and subclinical inflammation persist during the inactive period of the disease.

Leptin, soluble interleukin-6 receptor, C-reactive protein and soluble vascular cell adhesion molecule-1 levels in human coronary atherosclerotic plaque.

The aim of the present study was to explore the relationship between tissue levels of leptin, soluble interleukin-6 receptor (sIL-6R), high-sensitive-C-reactive protein (hs-CRP) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in atherosclerotic plaques, and traditional risk factors. Coronary artery specimens were obtained from 35 consecutive patients (26 men and nine women) who underwent coronary artery bypass grafting procedure. The mean tissue levels of leptin, hs-CRP and sIL-6R were significantly higher in patients with diabetes mellitus than without diabetes mellitus. When patients were classified according to the smoking status, the mean tissue levels of leptin, hs-CRP and sIL-6R were significantly higher in current smokers than both former smokers and non-smokers. In addition, the mean tissue levels of leptin and sIL-6R were significantly higher in former smokers than non-smokers. There was a positive association between leptin and hs-CRP, sIL-6R and plasma glucose in all patients. Plasma HDL levels were associated negatively with atherosclerotic tissue levels of leptin. Tissue levels of sIL-6R were associated significantly in a positive manner with leptin, hs-CRP and plasma glucose, while tissue levels of hs-CRP were associated with both leptin and sIL-6R. In conclusion, it is attractive to speculate that hs-CRP, sIL-6R and leptin could act synergistically in course of local inflammatory activity and those molecules may not be just markers of inflammation and cardiovascular risk but are also likely to play a pathogenic role in atheromatous plaque. In addition, atherosclerotic tissue levels of CRP, sIL-6R and leptin were significantly higher in current smokers and patients with diabetes.

Chimerical anti-TNF-alpha, infliximab, inhibits neutrophil chemotaxis and production of reactive oxygen species by blocking the priming effect of mononuclear cells on neutrophils.

Clinical experience with anti-tumor necrosis factor alpha (anti-TNF-alpha) agents implies that these agents can cause a rapid onset amelioration of the symptoms and laboratory parameters in some inflammatory diseases. Precise explanation of this fast antiinflammatory action is not known. The aim of our study is to investigate the direct and indirect effects of anti-TNF agents on the chemotaxis and reactive oxygen species (ROS) production of neutrophils. For this purpose, isolated neutrophil cultures (INCs) and mixed leukocyte cultures were prepared from the venous blood of healthy subjects. Those cultures were separated to different groups according to the presence of anti-TNF or the stimulation of phytohemagglutinin (PHA). In this study, anti-TNF treatment did not change the migration ability of neutrophils in INCs. However, we established that chimerical anti-TNF-alpha, infliximab, inhibits neutrophil chemotaxis and production of ROS by blocking the priming effect of PHA-stimulated circulating mononuclear cells. These results may explain, at least partly, the rapid onset antiinflammatory actions of these agents observed in clinical practice.

A case of Addison's disease associated with the Lambert-Eaton myasthenic syndrome.

Nonneoplastic Lambert-Eaton Myasthenic Syndrome (LEMS) is rare. A 27-year-old man as initially having the diagnosis of Addison's disease was admitted to the hospital because of fatigue, dry-mouthness and proximal limb weakness for 1 year. A diagnosis of LEMS was made from electrophysiological studies. Clinical and laboratory studies revealed no malignancy. We report the first case of Addison's disease associated with non-neoplastic LEMS. It is possible that subclinical LEMS might be present in patients with Addison's disease more frequently than currently believed, since the prominent symptoms of LEMS may be confused with symptoms of Addison's disease.

Does immune activation continue during an attack-free period in familial Mediterranean fever?

Although some information is available regarding immune activation in familial Mediterranean fever (FMF), little is known about either peripheral blood T cell activation marker expression or the T cell proliferative response to phytohaemagglutinin (PHA). In the present study, we aimed to investigate the percentages of peripheral blood lymphocyte subsets, T cell expression of cellular activation markers (CD25, CD69, HLA-DR), the T cell response to PHA and serum levels of soluble interleukin-2 receptor (sIL-2R) and interleukin (IL)-10 in patients with FMF. Forty patients with FMF were enrolled into the study. Control groups were sex- and age-matched and consisted of 20 healthy blood donors and 15 patients with inactive Behcet's disease. The patients with FMF in an attack period had higher levels of sIL-2R than those in an attack-free period, and also in comparison with both control groups. The levels of sIL-2R were also found to be higher in patients with FMF in an attack-free period than those in both control groups. The mean levels of IL-10 were found to be lower in patients with FMF in an attack-free period than those in an attack period and were also lower than those in the healthy controls. In an acute attack period, the absolute counts of CD3+HLA-DR+, CD4+CD69+, CD8+CD25+ and CD8+CD69+ T cells in peripheral blood samples were also higher than those in both control groups. Both the percentages and absolute counts of CD4+CD69+ T cells in peripheral blood samples of patients with FMF in an attack-free period were slightly but significantly higher than those in the healthy controls. In conclusion, our study indicates that the T cell system is abnormally activated in patients with FMF in both the attack and attack-free period and that decreased IL-10 levels may create a tendency to perpetuate subclinical immune activation in the attack-free period.

Gonadotropin treatment restores in vitro interleukin-1beta and tumour necrosis factor-alpha production by stimulated peripheral blood mononuclear cells from patients with idiopathic hypogonadotropic hypogonadism.

In the present study, we aimed to investigate the effects of testosterone deficiency and gonadotropin therapy on the in vitro production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) by peripheral blood mononuclear cells (PBMCs) from patients with idiopathic hypogonadotropic hypogonadism (IHH) in order to elucidate the modulatory role of androgen in cytokine production. Fifteen male patients with untreated IHH and 15 age-matched healthy male subjects were enrolled in the study. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), free testosterone (FT), sex hormone binding globulin (SHBG), prolactin, and IL-2 and IL-4 levels were also measured. In unstimulated cultures, IL-1beta and TNF-alpha secretion were not significantly different between patient and control groups. However, after stimulation with lipopolysaccharide (LPS), secretion of IL-1beta and TNF-alpha was significantly higher in cultures from untreated patients with IHH than in control subjects. Mean FSH, LH and FT levels were significantly lower, whereas SHBG, IL-2 and IL-4 levels were significantly higher in patients with IHH compared than in controls. In patients with IHH, FT negatively affected the serum levels of IL-4 and in vitro secretion of IL-1beta and TNF-alpha. In addition, IL-2 and IL-4 affected the in vitro secretion of IL-1beta in a positive manner. Gonadotropin therapy decreased both TNF-alpha and IL-1beta in PBMCs from patients with IHH. The levels of serum IL-2 and IL-4 were also decreased by therapy. In conclusion, in the present study, gonadotropin treatment restored the in vitro production of IL-1beta and TNF-alpha by PBMCs from patients with IHH, suggesting that androgen modulates proinflammatory cytokine production, at least directly through its effects on PBMCs. It seems probable that this effect plays an important role in the immunosuppressive action of androgens.