Associations of OSAHS complicated by cerebral infarction with intestinal flora, inflammatory factors, homocysteine and adiponectin expression.

OBJECTIVE: The aim of this study was to investigate the associations between obstructive sleep apnea hypopnea syndrome (OSAHS) complicated by cerebral infarction and intestinal flora, inflammatory factors, homocysteine, and adiponectin expression. PATIENTS AND METHODS: A total of 30 healthy volunteers (control group), 28 patients with simple cerebral infarction (cerebral infarction group) and 28 patients with OSAHS complicated by cerebral infarction (OSAHS + cerebral infarction group) were enrolled as research objects. The fecal bacterial DNA of research objects was extracted and subject to 16S ribosomal ribonucleic acid sequencing. Furthermore, the levels of inflammatory factors, homocysteine and adiponectin in the peripheral blood were detected. RESULTS: Compared with control group, cerebral infarction group exhibited significantly higher levels of interleukin-4 (IL-4), tumor necrosis factor-beta (TNF-ß), IL-1ß and C-reactive protein (CRP) (p<0.05). However, the levels of TNF-ß, IL-1ß and CRP in OSAHS + cerebral infarction group were notably higher than those in cerebral infarction group (p<0.05). The levels of myeloperoxidase (MPO) and malondialdehyde (MDA) were remarkably higher in cerebral infarction group than those in the control group (p<0.05). However, they were significantly higher in OSAHS + cerebral infarction group than cerebral infarction group (p<0.05). Compared with control group, cerebral infarction group exerted a noticeably higher level of homocysteine (p<0.05). However, homocysteine level was markedly higher in OSAHS + cerebral infarction group than that in cerebral infarction group (p<0.05). Adiponectin level was significantly lower in cerebral infarction group than that in the control group (p<0.05). Meanwhile, it was evidently lower in OSAHS + cerebral infarction group than that in the cerebral infarction group (p<0.05). Control group had the highest abundance of Actinobacteria, and cerebral infarction group exhibited the highest abundance of Coriobacteriales, Vagococcus, Sphingobacteriales and Adlercreutzia. However, OSAHS + cerebral infarction group exhibited the highest abundance of Bifidobacterium, Parascardovia, Metascardovia and Anaerostipes caccae. There was a strong positive correlation between Proteobacterium and Ruminococcus (r=0.9, p=0.000) and between Firmicutes and Bacteroidetes (r=0.72, p=0.004). However, there was a significant negative correlation between Firmicutes and Enterobacteriales (r=-0.45, p=0.009). CONCLUSIONS: OSAHS complicated by cerebral infarction is significantly associated with intestinal flora, inflammatory factors, homocysteine and adiponectin expression.

Candesartan inhibits inflammation through an angiotensin II type 1 receptor independent way in human embryonic kidney epithelial cells.

Besides stimulating vasoconstriction, Angiotensin II is also well known in inducing reactive oxygen species and promoting inflammatory phenotype switch via its type 1 receptor. In clinic, Angiotensin II type 1 (AT1) receptor blocker like candesartan has been widely applied as an antihypertensive medication. We previous have demonstrated that a higher dose of candesartan plays a protective role after kidney injury. However, whether candesartan could exhibit anti-inflammatory effects remains unclear. Here, by stimulating isolated human embryonic kidney epithelial cells with tumor necrosis factor-α (TNF-α), we observed the anti-inflammation capacity of candesartan ex vivo. It was found that pre-treat with candesartan significantly suppressed transforming growth factor-ß (TGF-ß) and interleukin-6 (IL-6) expression after incubation with TNF-α. Surprisingly, silence of angiotensin II type 1 receptor has little effects on reducing TGF-ß or IL-6 products. Furthermore, candesartan inhibited TNF-α-induced oxidative stress in the primary cultured tubular epithelial cells. Overall, our data indicates that candesartan suppresses TNF-α-induced inflammatory cytokine production by inhibiting oxidative stress, rather than block AT1 receptor activity.

The lymphotoxin ß receptor is a potential therapeutic target in renal inflammation.

Accumulation of inflammatory cells in different renal compartments is a hallmark of progressive kidney diseases including glomerulonephritis (GN). Lymphotoxin ß receptor (LTßR) signaling is crucial for the formation of lymphoid tissue, and inhibition of LTßR signaling has ameliorated several non-renal inflammatory models. Therefore, we tested whether LTßR signaling could also have a role in renal injury. Renal biopsies from patients with GN were found to express both LTα and LTß ligands, as well as LTßR. The LTßR protein and mRNA were localized to tubular epithelial cells, parietal epithelial cells, crescents, and cells of the glomerular tuft, whereas LTß was found on lymphocytes and tubular epithelial cells. Human tubular epithelial cells, mesangial cells, and mouse parietal epithelial cells expressed both LTα and LTß mRNA upon stimulation with TNF in vitro. Several chemokine mRNAs and proteins were expressed in response to LTßR signaling. Importantly, in a murine lupus model, LTßR blockade improved renal function without the reduction of serum autoantibody titers or glomerular immune complex deposition. Thus, a preclinical mouse model and human studies strongly suggest that LTßR signaling is involved in renal injury and may be a suitable therapeutic target in renal diseases.

Distribution of furin, TNF-α, and TGF-ß2 in the endometrium of missed abortion and voluntary first trimester termination cases.

OBJECTIVE: To identify the role of furin, TNF-α, and TGF-ß2 in human missed abortion pathogenesis. STUDY DESIGN: Decidual materials were collected from patients diagnosed with a missed abortion (n = 10) (missed abortion group) and from legal voluntary termination cases at < 10 gestational weeks (n = 10) (normal pregnancy group). Tissue samples were collected from each group by dilation and curettage under mask anesthesia. For all tissue samples,furin, TNF-α, and TGF-ß2 primary antibodies were performed by immunohistochemical staining. The number of stained cells was evaluated by using the H-score technique. RESULTS: In immunohistochemical examination, the immunoreactivities of furin, TNF-α, and TGF-ß2 were found to be higher in syncytiotrophoblastic cells in the missed abortion group than in the normal pregnancy group (p < 0.005). Additionally, high immunoreactivity of TNF-α and TGF-ß2 molecules was established only in cytotrophoblastic cells of missed abortions (p < 0.005) in examination at decidual cells of the missed abortion group; furin immunoreactivities were detected higher in the missed abortion group than in the control group, but TNF-α and TGF-ß2 immunoreactivity were increased in number in the normal pregnancy group (p < 0.005). CONCLUSION: It is considered that high levels offurin and the 2 furin-related proteins (TNF-α and TGF-ß2), which play important roles in proliferation, invasion, migration, differentiation, and survival of cells, may be the reason of proceeding decidualization, placentation, and prevention from abortion, in spite of terminating thefetal life.

A possible complementary tool for diagnosing tuberculosis: a feasibility test of immunohistochemical markers.

Differentiation of tuberculous granuloma (TG) from non-tuberculous granuloma (NG) is histopathologically difficult. We evaluated the usefulness of selected immunohistochemical markers to differentiate tuberculous granuloma (TG) and non-tuberculous granuloma (NG). We selected six biomarkers (FoxP3, TNF-beta, E-selectin [ESEL], indoleamine 2,3-dioxygenase [IDO], lactoferrin [LACT], and tartrate-resistant acid phosphatase [TRAP]) and immunohistochemically analyzed their expression in the presence of two types of granulomatous tissue samples, TG (n = 36) and NG (n = 31), using a microarray format. Three of those six biomarkers (LACT, IDO, and TNF-beta) were moderately accurate in discriminating TG from NG, individually and in combination, according to ROC analysis (AUC = 0.7-0.89, sensitivity = 55.6-77.8%, specificity = 71.0-100%). Our data indicate that selected immunohistochemical markers (LACT, IDO, and TNF-beta) can be used in ancillary tests to differentiate TG from NG in tissue samples. Further large-scale studies are required to validate our results.

Implications of cytokine genes in allergic asthma

Asthma is a complex disease involving numerous mediator molecules and effector cells, in combination with a range of environmental determining factors. Cytokines play a key role in the physiopathological mechanisms of asthma; the study of the structure, regulation and variations of the genes that encode for these molecules is therefore crucial. Cytokines have extremely diverse roles, and exert effects both as activators and inhibitors of the innate and adaptive immune response. Certain modifications in the expression or structure of these molecules, resulting from the presence of polymorphisms, may give rise to deregulation of the mentioned effects, and therefore to a predisposition to develop concrete asthma phenotypes

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Influence of allergy on clinical, immunological and histological characteristics of nasal polyposis.

OBJECTIVES: Although polyps seem to be a manifestation of the chronic inflammation of nasal/paranasal sinuses mucosa in both allergic and non-allergic subjects, the pathogenesis of nasal polyposis remains unknown. The aim of this prospective study was to compare the clinical characteristics of nasal polyposis in non-allergic and allergic patients, to compare the cytokine levels in nasal secretions in atopic and non-atopic nasal polyp patients and to correlate these levels with eosinophil counts in nasal polyp tissue specimens. METHODS: This study included thirty patients with nasal polyposis (13 atopic and 17 non-atopic) requiring surgical treatment. Nasal secretion samples were collected from the nasal cavities of all 30 subjects a few days before the surgical treatment. The levels of tumour necrosis factor-alpha (TNF-alpha), tumour necrosis factor-beta (TNF-beta), interleukin (IL)-1beta, IL-2, IL-12, interferon-gamma (IFN-gamma), IL-4, IL-5, IL-6, IL-10, and IL-8 were measured using the flow cytometric method. Each of the 30 patients was staged clinically according to nasal symptom score, endoscopic score and Lund-Mackay computed tomography (CT) score. All these patients had undergone sinus surgery. Eosinophils were counted in hematoxylin- and eosin-stained sections of all nasal polyp samples. RESULTS: Our results showed that allergy does not modify the symptoms, or the endoscopic and CT findings, of nasal polyposis. We found significantly higher concentrations of IL-4 (p < 0.01), IL-5 (p < 0.05), IL-6 (p < 0.05) and TNF-beta (p < 0.05) in nasal secretions of allergic nasal polyp patients than in non-allergic ones. Eosinophil counts were significantly higher in tissues of atopic patients' polyps than in non-atopic subjects (p < 0.01). No correlation was observed between cytokine levels and eosinophil counts. CONCLUSION: Non-atopic and atopic patients' polyps have different immunological patterns. Our results showed that the presence of Th2 cytokines was a more significant feature in allergic patients with nasal polyposis than in non-allergic patients.

Does cytokine profiling of aspirate from jaw cysts and tumors have a role in diagnosis?

PURPOSE: The objective of the present study was twofold: first, to assess aspirates for use in cytokine profiling and second, to initiate pilot analyses to determine whether the cytokine profiling can serve as an aid in the diagnosis of jaw lesions. MATERIALS AND METHODS: The aspirates from 12 benign odontogenic cysts and tumors of the jaw were collected and randomized, and a formal incisional biopsy was performed to establish the tissue diagnosis. The biopsies revealed keratocystic odontogenic tumor, ameloblastoma, and dentigerous cyst. The cystic aspirate was analyzed using the Q-Plex Human Cytokine Screen to detect cytokine expression and determine the level of expression for each pathologic entity. An array of 16 cytokines was investigated, including interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IL-23, interferon-γ, tumor necrosis factor (TNF)-α, and TNF-ß. Tables were developed to determine the ratio of expression for the candidate cytokine pairs that were differentially expressed among the 3 pathologic entities encountered. One-way analysis of variance was used to search for significant differences in the ratio of expression of the candidate pairs among the 3 entities. RESULTS: Cytokines expressed by the 3 distinct jaw lesions were detected in the aspirate without the need for tissue biopsy. Cytokine profiling of these entities is possible owing to differential expression of the various cytokines studied. The ratio of expression was significant (P < .05) for 15 pairs of cytokines: IL-5/IL-1α, IL-4/IL-2, IL-8/IL-4, TNF-ß/IL-6, IL-23/IL-6, TNF-α/IL-23, TNF-α/TNF-ß, TNF-α/IL-8, TNF-ß/IL-5, TNF-ß/TNF-α, TNF-ß/IL-13, IL-12/IL-23, IL-13/IL-15, IL-15/IL-2, and IL-6/IL-2. A comparison of the mean values indicated a "high/low" expression value for each lesion type for the 15 cytokine pairs. CONCLUSIONS: Cytokines, expressed by the 3 groups of jaw lesions, can be detected in the cystic aspirate, and a comparison of the ratio of the expression of the aspirates demonstrated a differential expression pattern of cytokines among the 3 groups. These ratios could assist in establishing a prompt and accurate diagnosis of lesions that might be difficult to discern clinically and radiographically. The use of a simple, minimally invasive aspiration procedure can help to establish an accurate diagnosis.

Reduced production of IFN-γ and LT-α is associated with successful prednisone therapy in patients with acquired hemophilia A: a pilot study.

Glucocorticoids (GC) are a standard treatment for acquired hemophilia A (AH). Although the optimal treatment regimen and duration of GC's is unknown, measurement of sub-clinical immune responses may help direct therapeutic decision making. To study the helpfulness of this approach, three male patients diagnosed with AH were treated with prednisone. The therapy resulted in inhibitor elimination in two out of the three individuals. During the treatment, peripheral mononuclear cells were isolated at different time points and stimulated in vitro. The expression of IFN-γ and LT-α were monitored at both the protein and the mRNA levels. The amount of IFN-γ and LT-α were markedly reduced by the time of inhibitor disappearance in the patients responding to GC therapy but remained high in the non-responder until cyclophosphamide was added. This study suggests that the secretion level of IFN-γ and/or LT-α could be a predictive marker of prednisone responsiveness.

Different effects of commonly prescribed statins on abdominal aortic aneurysm wall biology.

BACKGROUND: Pharmaceutical stabilisation of the abdominal aortic aneurysm (AAA) wall can delay surgery and improve outcome. Observational studies indicate statins can be used to reduce AAA growth but mechanistic data are scarce. In this study, our aim was to determine the pleiotropic effects of different statins on AAA wall composition. METHODS: We included 216 patients undergoing open AAA repair, of which 60 used simvastatin, 52 atorvastatin and 23 pravastatin. The AAA wall histology and protein expression (IL 1beta,2,4,5,6,8,10,12, interferon-gamma (IFNgamma), tumour necrosis factor (TNF)alpha,beta, matrix metalloproteinase (MMP)2 and 9 activities, total MMP8,9 and cathepsin A and B levels) between statin users and non-users were compared as also among the use of different statins. RESULTS: As far as histological inflammation goes, the AAA walls of statin users did not differ from those not using them. After multivariate adjustment for risk factors, pravastatin use was associated with tendencies of increased MMP8 (p = 0.022), active MMP9 (p = 0.040) and higher cathepsin B (p = 0.056) levels. The AAA walls of simvastatin and atorvastatin users showed no differences in proteases or cytokines in multivariate analyses. CONCLUSIONS: The use of statins was not associated with a decrease in protease levels or inflammation. The trends of elevated protease levels associated with pravastatin use suggest pleiotropic differences among the various statins, supporting the need for further research to target pharmaceutical AAA treatment.

Mycobacterial antigen-induced T helper type 1 (Th1) and Th2 reactivity of peripheral blood mononuclear cells from diabetic and non-diabetic tuberculosis patients and Mycobacterium bovis bacilli Calmette-Guérin (BCG)-vaccinated healthy subjects.

Patients with diabetes mellitus are more susceptible to tuberculosis (TB), and the clinical conditions of diabetic TB patients deteriorate faster than non-diabetic TB patients, but the immunological basis for this phenomenon is not understood clearly. Given the role of cell-mediated immunity (CMI) in providing protection against TB, we investigated whether CMI responses in diabetic TB patients are compromised. Peripheral blood mononuclear cells (PBMC) obtained from diabetic TB patients, non-diabetic TB patients and Mycobacterium bovis bacilli Calmette-Guérin (BCG)-vaccinated healthy subjects were cultured in the presence of complex mycobacterial antigens and pools of M. tuberculosis regions of difference (RD)1, RD4, RD6 and RD10 peptides. The PBMC were assessed for antigen-induced cell proliferation and secretion of T helper 1 (Th1) [interferon (IFN)-gamma, interleukin (IL)-2, tumour necrosis factor (TNF)-beta], and Th2 (IL-4, IL-5, IL-10) cytokines as CMI parameters. All the complex mycobacterial antigens and RD1(pool) stimulated strong proliferation of PBMC of all groups, except moderate responses to RD1(pool) in healthy subjects. In response to complex mycobacterial antigens, both IFN-gamma and TNF-beta were secreted by PBMC of all groups whereas diabetic TB patients secreted IL-10 with concentrations higher than the other two groups. Furthermore, in response to RD peptides, IFN-gamma and IL-10 were secreted by PBMC of diabetic TB patients only. The analyses of data in relation to relative cytokine concentrations showed that diabetic TB patients had lower Th1 : Th2 cytokines ratios, and a higher Th2 bias. The results demonstrate a shift towards Th2 bias in diabetic TB patients which may explain, at least in part, a faster deterioration in their clinical conditions.

Differential cytokine expression by human dendritic cells in response to different Porphyromonas gingivalis capsular serotypes.

AIM: Capsular polysaccharides play an important role in the virulence of Gram-positive and Gram-negative bacteria. In Porphyromonas gingivalis, six serotypes have been described based on capsular antigenicity and its pathogenicity has been correlated both in vitro and in animal models. This study aimed to investigate the differential response of human dendritic cells (DCs) when stimulated with different P. gingivalis capsular serotypes. MATERIALS AND METHODS: Using different multiplicity of infection (MOI) of the encapsulated strains K1-K6 and the non-encapsulated K(-) strain of P. gingivalis, the mRNA expression levels for interleukin (IL)-1beta, IL-2, IL-5, IL-6, IL-10, IL-12, IL-13, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, and TNF-beta in stimulated DCs were quantified by real-time reverse transcription-polymerase chain reaction. RESULTS: All P. gingivalis capsular serotypes induced a T-helper type 1 (Th1) pattern of cytokine expression. K1- and K2-stimulated DCs expressed higher levels of IL-1beta, IL-6, IL-12p35, IL-12p40, and IFN-gamma and at lower MOI than DCs stimulated with the other strains. CONCLUSIONS: These results demonstrate a differential potential of P. gingivalis capsular serotypes to induce DC responses and a higher capacity of strains K1 W83 and K2 HG184 than other K serotypes to trigger cytokine expression.

Over-expression of forkhead box P3 and its association with receptor activator of nuclear factor-kappa B ligand, interleukin (IL) -17, IL-10 and transforming growth factor-beta during the progression of chronic periodontitis.

AIM: T regulatory (Treg) cells have been detected in periodontitis lesions, and forkhead box P3 (Foxp3) expression has been negatively correlated to receptor activator of nuclear factor-kappa B ligand (RANKL). The aim of this study was to correlate T-helper type 1 (Th1), Th2, Th17 and Treg transcription factor expressions, in gingival tissues from patients undergoing active periodontal tissue destruction, with bone loss-associated cytokines. MATERIALS AND METHODS: In 10 chronic periodontitis patients undergoing disease progression, the mRNA expressions of T-bet, GATA-3, Foxp3, RORC2, interleukin (IL)-1beta, IL-10, IL-17, RANKL, interferon (IFN)-gamma and transforming growth factor (TGF)-beta1 were quantified using real-time reverse transcription-polymerase chain reaction. The levels of these markers were compared between active and inactive periodontal lesions. RESULTS: In active periodontal lesions, Foxp3, T-bet, RANKL, IL-17, IL-1beta and IFN-gamma were significantly over-expressed compared with inactive lesions. The expression of IFN-gamma was the highest within the active periodontal lesions, similar to that of TGF-beta1 within the inactive ones. There was a positive correlation between RANKL and IL-17. Additionally, RANKL and IL-17 were positively correlated with RORC2, but no correlation was detected with Foxp3. CONCLUSIONS: These results lead us to speculate that Foxp3(+) cells that do not have a regulatory function might have a role in the pathogenesis of active periodontal lesions by down-regulating TGF-beta1 and IL-10 synthesis that lead to the over-expression of Th17-associated cytokines RANKL and IL-17.

TWEAK, el facilitador del daño renal agudo / No disponible

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Three-dimensional ultrasonographic application for analyzing synovial hypertrophy of the knee in patients with osteoarthritis.

OBJECTIVE: The purpose of this study was to evaluate 3-dimensional (3D) ultrasonography for the visualization of intra-articular synovial hypertrophy in patients with osteoarthritis. METHODS: Knee joints of 22 patients with osteoarthritis were examined by 3D ultrasonography, and their synovial fluids were analyzed. Ultrasonographic image patterns, vascular endothelial growth factor and transforming growth factor beta concentrations in synovial fluid, and serum inflammatory markers were analyzed. RESULTS: It was possible to visualize the intra-articular structure by 3D ultrasonography. Three-dimensional ultrasonography revealed various interesting stereoscopic views of the synovial structures, and the patterns of synovial proliferation ranged from simple proliferations to complex shrubby structures. Patients with a more complex and proliferative pattern in the synovium tended to have higher C-reactive protein concentrations, but this difference was not significant (P = .09). The concentrations of vascular endothelial growth factor and transforming growth factor beta in synovial fluid were significantly higher in patients with complex hypertrophy (P < .05). CONCLUSIONS: Three-dimensional technology was useful in delineating the shape of the synovium. It may have a possible impact on future imaging in rheumatology.

Etanercept attenuates the development of cerulein-induced acute pancreatitis in mice: a comparison with TNF-alpha genetic deletion.

TNF-alpha plays a pivotal role in the pathogenesis of acute pancreatitis. Recent studies have shown that TNF-alpha inhibition significantly ameliorates the course of experimental acute pancreatitis, but in this context, the effects of Etanercept, a novel anti-TNF-alpha agent, have not been investigated so far. The aims of the present study are (i) to assess the effects of pharmacological inhibition of TNF-alpha by means of Etanercept on the inflammatory response and apoptosis in a murine model of necrotizing acute pancreatitis and (ii) to compare the results to those observed in TNF-alpha receptor 1 knockout (TNFR1-KO) mice. Necrotizing acute pancreatitis was induced in TNF-alpha wild type for TNFR1 (WT) and TNFR1-KO mice by intraperitoneal injection of cerulein (hourly x5, 50 microg/kg). In another group of WT mice, Etanercept was administered (5 or 10 mg/kg, s.c.) at 1 h after first cerulein injection. Control groups received saline treatment. After 24 h, biochemical, histological, and immunohistochemical evidences of acute pancreatitis developed in all cerulein-treated mice; apoptosis was also present in the pancreas. Contrarily, pancreatitis histological features, amylase and lipase levels, pancreas water content, and myeloperoxidase activity were reduced in a similar degree in Etanercept-treated and TNFR1-KO mice. Likewise, in these two groups, immunohistochemical stainings and terminal deoxynucleotidyltransferase-mediated UTP nick-end labeling assay were found negative. TNF-alpha receptor 1 gene deletion and Etanercept administration ameliorate the course of experimental acute pancreatitis in a similar degree. Future studies on clinical applications of Etanercept in pancreatitis seem promising.

A case-control investigation of immune function gene polymorphisms and risk of testicular germ cell tumors.

There is reason to suspect that testicular germ cell tumor (TGCT) development may be influenced by cytokines, secreted proteins that modulate tumor immune surveillance activity as well as a variety of processes in the testis. To address this hypothesis, we conducted a case-control analysis (508 cases, 608 controls) of 32 putatively functional single-nucleotide polymorphisms (SNP) in 16 immune function genes among non-Hispanic Caucasian participants in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study. The TGFB1 Ex5-73C>T variant was positively associated with TGCT (CT/TT versus CC: odds ratio, 1.73; 95% confidence interval, 1.01-2.95; P(trend) = 0.05); additionally, haplotypes of the assessed TGFB1 SNPs (-509C>T, 327C>T, Ex1-282C>G, and Ex5-73C>T) differed in frequency between cases and controls (all TGCT, P 0.07; seminoma, P 0.04; nonseminoma, P 0.11). We also observed excess frequencies among TGCT cases versus controls of LTA 252G (P(trend) = 0.08) and of the TNF variants -1042C (P(trend) = 0.06), -1036T (P(trend) = 0.07), and -238G (P(trend) = 0.09). Analyses of haplotypes for LTA-TNF SNPs (LTA -91C>A, LTA 252A>G, TNF -863C>A, TNF -857C>T, TNF -308G>A, and -238G>A) were similarly suggestive of an association with TGCT (P = 0.06) and nonseminoma (P = 0.04), but not seminoma (P = 0.21). Polymorphisms in other genes were found to be associated only with seminoma (IL2) or nonseminoma (IFNGR2 and IL10). However, none of the associations remained noteworthy after applying the false discovery rate method to control for multiple testing. In conclusion, our findings suggest that polymorphisms in TGFB1 and LTA/TNF, and possibly other immune function genes, may influence susceptibility to TGCT.

A transcription inhibitor, actinomycin D, enhances HIV-1 replication through an interleukin-6-dependent pathway.

We previously demonstrated that Actinomycin D (ActD) enhanced HIV-1 replication in the MT-2 cell, a human T-cell leukemia virus type-1-infected cell line. The MT-2 cell is known to produce multiple cytokines spontaneously. In this study, we investigated the impact of ActD on the cytokine production from MT-2 cells and HIV-1 replication in a latently infected cell line, U1. MT-2 cells were pulse-treated with 0 or 200 nM of ActD, and culture supernatants were collected 3 days after incubation. Supernatants from untreated cells (Sup0) induced HIV-1 replication by 150-fold in U1 cells. Culture supernatants from ActD-treated cells (Sup200) enhanced HIV-1 replication by 1200-fold. A combination of a sequential chromatographic approach and mass spectrometric analysis identified that the HIV-inducing factors in Sup200 were interleukin (IL)-6 and tumor necrosis factor (TNF)-beta. Quantitative analysis revealed that ActD treatment increased the concentration of IL-6 in Sup200 by 600% compared with that in Sup0 but decreased the amount of TNFbeta in Sup200 by 85%. Northern blot analysis showed that ActD treatment increased IL-6 transcripts; however, no change was seen in TNFbeta transcripts. These results suggest that ActD induces replication of HIV-1 through modulation of cytokine production.

Transforming growth factor beta and connective tissue growth factor are involved in the evolution of nevus of Nanta.

We report a 59-year-old Japanese male with nevus of Nanta on the face. Histological examination revealed a nest of nevus cells in the dermis and ossification beneath the nevus. Positive staining for transforming growth factor-beta and connective tissue growth factor suggested the involvement of these growth factors in the ossification of nevus of Nanta.