Clinical relevance of Küttner tumour and IgG4-related dacryoadenitis and sialoadenitis.

OBJECTIVES: Küttner tumour (KT), so-called chronic sclerosing sialoadenitis, is characterised by concomitant swelling of the submandibular glands secondary to strong lymphocytic infiltration and fibrosis independent of sialolith formation. However, recent studies have indicated that some patients with KT develop high serum levels of IgG4 and infiltration of IgG4-positive plasma cells, namely IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease. The aim of this study was to clarify the clinical and pathological associations between KT and IgG4-DS. MATERIALS AND METHODS: Fifty-four patients pathologically diagnosed with KT or chronic sialoadenitis were divided into two groups according to the presence or absence of sialolith (KT-S (+) or KT-S (-), respectively). RESULTS: There were no significant differences in the clinical findings, including the mean age, sex and disease duration, between the two groups. All patients in the KT-S (+) group showed unilateral swelling without infiltration of IgG4-positive plasma cells or a history of other IgG4-related diseases (IgG4-RD), while those in the KT-S (-) group showed bilateral swelling (37.5%), strong infiltration of IgG4-positive plasma cells (87.5%) and a history of other IgG4-RD (12.5%). CONCLUSIONS: These results suggest an association between the pathogeneses of KT-S (-) and IgG4-DS, but not KT-S (+).

Overexpression of inducible nitric oxide synthase and accumulation of 8-OHdG in nasopharyngeal carcinoma.

AIMS: Nitric oxide (NO), produced by inducible NO synthase (iNOS), has been suggested to cause oxidative stress, leading to 8-hydroxydeoxyguanosine (8-OHdG) accumulation and subsequent transversion mutation of DNA. The aim was to evaluate iNOS expression and the status of oxidative stress in nasopharyngeal carcinoma (NPC). METHODS AND RESULTS: Seventy-three cases of NPC were investigated to examine the immunohistochemical expression of iNOS, 8-OHdG and latent membrane protein-1 (LMP-1) and Epstein-Barr virus-encoded small RNA (EBER) expression using in situ hybridization. iNOS mRNA expression and p53 gene mutations were also assessed. Overexpression of iNOS, LMP-1 and EBER was observed in 62 (84.9%), 28 (38.4%) and 53 (72.6%) cases respectively. p53 gene mutation was found in 10 of 73 (13.7%) cases. Immunohistochemical iNOS expression was associated with the 8-OHdG labelling index, iNOS mRNA expression and p53 gene alteration (P < 0.0001, P = 0.016 and 0.0082 respectively). CONCLUSIONS: Our present findings suggest that the expression of iNOS induces oxidative stress in NPC. Although the presence of p53 mutation was associated with iNOS overexpression, the type of acid-base change of p53 was transition, but not transversion, which suggests that the p53 gene is not the direct target of DNA damage by 8-OHdG accumulation.

Modulation of the effector function of human monocytes for Mycobacterium avium by human immunodeficiency virus-1 envelope glycoprotein gp120.

Disseminated Mycobacterium avium infection in AIDS is associated with high tissue burdens (10(9)-10(10) mycobacteria/g tissue) of organism. The basis for the extraordinary susceptibility of AIDS to M. avium infection is unclear. HIV or its constituents may alter mononuclear phagocyte functions resulting in enhanced intracellular M. avium growth. The effects of an envelope glycoprotein (gp120), a transmembrane protein (p121), and core proteins of HIV-1 on M. avium infection of human monocytes were examined. Preculturing monocytes with gp120 inhibited M. avium phagocytosis and consistently enhanced intracellular growth of six M. avium strains. Pretreatment with p121, gag5, or p24 did not inhibit phagocytosis nor enhance intracellular growth of M. avium. Incubation of gp120 with soluble CD4 before addition to monocyte cultures or pretreatment of monocytes with OKT4A abrogated gp120 effects on M. avium phagocytosis and intracellular growth. gp120 also augmented cytokine production by infected monocytes. These results suggest that gp120, but not p121 or core proteins, modulate monocyte phagocytosis and enhance intracellular growth of M. avium at least in part through monocyte CD4 receptors. Direct effects of HIV-1 products may, therefore, contribute to the diathesis of AIDS to develop disseminated M. avium infection and to the extensive replication of the organisms within tissue macrophages.

Ultraviolet-irradiated monocytes efficiently inhibit the intracellular replication of Mycobacterium avium intracellulare.

The purpose of this study was to evaluate the effect of ultraviolet (UV) radiation on the antimicrobial activities of monocytes for the intracellular pathogen Mycobacterium avium intracellulare (MAI). UV radiation augmented monocyte antimicrobial activity for MAI in a dose-dependent fashion. UVB doses of greater than or equal to 25 J/m2 resulted in a 50-100-fold reduction in MAI growth 7 d after initiation of culture. The increased monocyte antibacterial effect could be blocked by a plate glass filter, indicating that wavelengths within the UVB were responsible for the effect. UV radiation did not stimulate monocyte phagocytosis, and enhanced inhibition of MAI growth was observed in populations of adherent mononuclear cells that were devoid of T cells. This suggested that UV radiation acted directly to augment intrinsic monocyte antimicrobial activities. The administration of 8-methoxypsoralen plus UVA radiation to monocytes also augmented their antimicrobial activities against MAI. UV radiation thus may serve as a unique agent by which to evaluate the mechanisms by which mononuclear phagocytes control the growth of MAI.

Sarcoidosis of the tongue: a case report.

A case of sarcoidosis involving the tongue is described in a 48-year-old Japanese man. A definite diagnosis of sarcoidosis was made for the clinical lesion and pathological examinations. Sarcoidosis is a multisystem granulomatous disease that may affect any organ. Sarcoidosis of the tongue is particularly rare.

Macrophages, mycobacteria and HIV: the role of cytokines in determining mycobacterial virulence and regulating viral replication.

The marriage of two scourges, one old (mycobacterial disease) and one new (HIV), has presented an enormous challenge to the medical and public health communities, and has stirred renewed interest in mechanisms for immune control of mycobacterial infection. Virulence of both M. avium and M. tuberculosis appears to be inversely related to the capacity of the microorganisms to induce production of protective cytokines in infected hosts. TNF alpha and IFN gamma are central to this process, and mycobacterial polysaccharides may be their main determinant. Despite these similarities, M. tuberculosis and M. avium cause illnesses at the polar extremes of HIV disease. Tuberculosis, occurring early in the course of HIV disease, may promote HIV replication in otherwise latently infected cells via induction of cytokines. As such, the potential exists for accelerated progression to AIDS due to the mutual synergy of these pathogens.

Increased circulating activated T-cells in lung cancer.

T-cell activation (Tac) antigens, which are closely associated with the receptors for interleukin 2 (IL 2) and expressed on activated human T-lymphocytes, are found on a small percentage of normal peripheral T-cells. Elevated levels of Tac antigen-positive (Tac+) cells were observed in a high proportion of patients with untreated primary lung cancer assessed by using monoclonal anti-Tac antibody. The mean percentage of Tac+ cells in peripheral blood lymphocytes was 13.1 +/- 6.4 percent in patients with primary lung cancer (n = 67), as compared with 4.3 +/- 1.9 percent in normal controls (n = 30) (p less than 0.001). No significant differences were observed among the cell types of lung cancer examined (adenocarcinoma and squamous and small cell carcinoma). The stages of the disease also showed no significant differences in the development of Tac+ cells. Our results suggest that T-cell-mediated active immune mechanisms against malignant cancer cells are operative in patients with lung cancer, resulting in an increase in activated T-cells in the peripheral blood, although it remains to be elucidated whether these activated T-cells exert a favorable or unfavorable effect on their host.

An analysis of in vitro T cell responsiveness in nontuberculous mycobacterial infection.

In vitro cell-mediated immunity was examined in patients infected with nontuberculous mycobacteria, Mycobacterium avium-intracellulare complex in Japan. Peripheral blood lymphocytes of patients, as compared with those of tuberculous patients or tuberculin-positive healthy donors, showed depressed in vitro blastogenic responses to purified protein derivative of tuberculin (PPD), not only to PPDs of Mycobacterium tuberculosis but also to PPD-B and PPD-Y of M intracellulare and M kansasii, respectively. Nonspecific lymphocyte blastogenic responses to concanavalin A, phytohemagglutinin and pokeweed mitogen were normal. Analysis of defective in vitro PPD-induced lymphocyte blastogenic responses in these patients revealed that PPD-induced interleukin 2 (IL-2) production was impaired whereas PPD-induced IL-2 responsiveness was normally developed after PPD stimulation. Therefore, addition of exogenous recombinant human IL 2 substantially recovered the in vitro depressed PPD-induced blastogenic responses in these patients with nontuberculous mycobacterial infection.

Mutations of the p53 gene in malignant rhabdoid tumors of soft tissue and the kidney: immunohistochemical and DNA direct sequencing analysis.

Malignant rhabdoid tumor (MRT) is characterized by the presence of intracytoplasmic eosinophilic inclusions composed of whorls of intermediate filaments. This tumor was originally described as an entity of the abortive type of Wilms' tumor in childhood. Recently, it has been proved that these rhabdoid cells can be observed in various types of malignant tumors, including soft tissue sarcoma or carcinoma. To investigate the oncogenesis of this tumor, we examined the p53 gene alteration by means of immunohistochemical analysis and DNA direct sequencing in three cases of malignant rhabdoid tumor (MRT) of the soft tissue and three cases of MRT of the kidney. All the cases of MRT of the soft tissue and two of the cases of MRT of the kidney showed immunopositivity for p53 protein. Among them, one of the cases of MRT of the soft tissue and two of the cases of MRT of the kidney showed missense mutations of the p53 gene. These results strongly suggest that p53 gene alterations may have an important role to play in the aggressive biological behavior and poor prognosis of this tumor.

Cytokeratin subunits of inclusion bodies in rhabdoid cells: immunohistochemical and clinicopathological study of malignant rhabdoid tumor and epithelioid sarcoma.

Extrarenal malignant rhabdoid tumor (MRT), which is recognized as being histologically similar to renal MRT, is characterized by the presence of "rhabdoid cell" (RC) and a highly aggressive biological behavior. Recently it has been proposed that "proximal variant" of epithelioid sarcoma (ES), whose morphology is similar to that of MRT, actually has a more aggressive clinical course than classical type ES. Detailed immunohistochemical analysis of cytokeratin (CK) subunits was performed in 3 cases of extrarenal MRT, 3 cases of renal MRT, and 11 cases of ES comprising 2 "proximal variants" and 9 classical types. Renal and extrarenal MRTs showed positive immunoreactivity for both CK8 and CK18. Classical type ESs were diffusely positive, not only for CK8 and CK18, but also for other cytokeratin subunits including CK4, 6, 10, 13, 16, 17, and "high-molecular-weight" CKs (CK1, 5, 10, and 14). On the other hand, proximal ES revealed limited immunohistochemical reactivity for cytokeratins, compared with classical ES. In conclusion, the inclusion bodies of RCs show immunoreactivity confined to CK8, CK18, and vimentin. Furthermore, ES has additional CK expressions, while proximal ES possesses characteristics intermediate between those of classical ES and those of external MRT.

Serial water changes in human skeletal muscles on exercise studied with proton magnetic resonance spectroscopy and imaging.

In vivo 1H-magnetic resonance imaging (MRI) enabled us to study the distribution of water in living tissues and to document changes in human skeletal muscles during physical exercise. The purpose of the present study was to determine the total muscle water changes after exercise using water in 1H-MR spectroscopy and to compare these changes to the signal intensity change on T2*-weighted images and/or to the T2 value change. Seven young male volunteers were positioned in a 1.5 T Philips MR imaging system. They were then asked to dorsiflex their ankle joint against a 2 kg weight once every 2 seconds for 2 minutes. The peak height of water declined according to the clearance curve after exercise in all seven cases with the 1H-MRS similar to the signal intensity. The increasing rate at peak height of total muscle water exceeded both the signal intensity and the T2 value because the water peak height on the 1H-MRS included the extracellular water. In addition, we measured the changes in signal intensity in both calf muscles after walking race exercise. The time intensity curves were used to draw a clearance curve for each muscle group after exercise. It was possible to discern which muscle was used most from the T2*-weighted image that was obtained once after exercise.

Criteria for preserving posterior cruciate ligament depending on intra-operative gap measurement in total knee replacement.

OBJECTIVES: Because posterior cruciate ligament (PCL) resection makes flexion gaps wider in total knee replacement (TKR), preserving or sacrificing a PCL affects the gap equivalence; however, there are no criteria for the PCL resection that consider gap situations of each knee. This study aims to investigate gap characteristics of knees and to consider the criteria for PCL resection. METHODS: The extension and flexion gaps were measured, first with the PCL preserved and subsequently with the PCL removed (in cases in which posterior substitute components were selected). The PCL preservation or sacrifice was solely determined by the gap measurement results, without considering other functions of the PCL such as 'roll back.' RESULTS: Wide variations were observed in the extension and flexion gaps. The flexion gaps were significantly larger than the extension gaps. Cases with 18 mm or more flexion gap and with larger flexion than extension gap were implanted with cruciate retaining component. A posterior substitute component was implanted with the other cases. CONCLUSIONS: In order to make adequate gaps, it is important to decide whether to preserve the PCL based on the intra-operative gap measurements made with the PCL intact. Cite this article: Bone Joint Res 2014;3:95-100.

Tuberculin purified protein derivative-reactive T cells in cord blood lymphocytes.

Lymphocytes obtained from cord blood of newborn babies who were born of healthy mothers were studied in vitro for their responsiveness to purified protein derivative (PPD) of tuberculin. Cord blood lymphocytes proliferated in vitro by stimulation with PPD, despite wide variations in the results. Studies with fractionated lymphocytes revealed that PPD-responding cells belonged to E-rosetting, nylon wool-nonadherent T lymphocytes. Non-E-rosetting B lymphocytes alone did not proliferate at all after stimulation with PPD. In addition, bromodeoxyuridine and light treatment of in vitro PPD-stimulated lymphocytes eliminated the responsiveness to PPD. These results suggest that T lymphocytes do exist in cord blood and respond in vitro to stimulation with PPD. A possible role for PPD-reactive T lymphocytes in cell-mediated protective immunity in newborns is discussed.

Analysis of T cell subsets by monoclonal antibodies in patients with tuberculosis after in vitro stimulation with purified protein derivative of tuberculin.

By using OKT monoclonal antibodies; OKT3(pan T), OKT4(inducer/helper), OKT8 (suppressor/cytotoxic) and OKIa1, T lymphocyte subsets were examined in lymphocytes of patients with tuberculosis both before and after in vitro stimulation with purified protein derivative of tuberculin (PPD). In freshly obtained lymphocytes samples before culture, a significantly high T4/T8 ratio in pleural fluid lymphocytes (PFL) from patients with tuberculous pleurisy was observed as compared with either their PBL, or the PBL from healthy controls. In addition, PFL from patients with tuberculous pleurisy showed increased numbers of E rosetting (E-RFC), OKT3+ and OKT4+ cells as compared with their PBL. A low T4/T8 ratio was also observed in PBL of patients with advanced, refractory tuberculosis. After stimulation with PPD in vitro, the T4/T8 ratio increased further in PFL as well as in PBL from patients with newly diagnosed, fresh tuberculosis. Investigation of fractionated T lymphocyte subsets revealed that PPD-induced proliferating lymphocytes belonged to T4+ and not T8+ lymphocytes. Ia antigen bearing T lymphocytes (Ia-T) were increased in all lymphocyte groups studied after in vitro stimulation with PPD. In particular, a remarkable increase was observed when PFL were stimulated in vitro with PPD. Our results suggest that the clinical features of tuberculosis reflect the immunological activity of T lymphocyte subsets in this disease.

T-lymphocyte subsets in primary lung cancer.

T-cell subsets in the peripheral blood of 63 primary lung cancer patients (23 with adenocarcinoma, 23 with squamous cell carcinoma and 17 with small cell carcinoma) and 24 normal healthy controls were determined by indirect immunofluorescence, using the monoclonal antibody reagents OKT3, OKT4 and OKT8. Correlations between T-lymphocyte subset values and stages or cell types of disease were sought. Total lymphocytes in the patient group were decreased. However, no significant difference from controls was seen in the percentage of OKT3-positive cells (Pan T-cells) in the cancer patients. The percentage of OKT8-positive cells (cytotoxic/suppressor) was increased in the early stage of disease whereas the percentage of OKT4 positive cells (inducer/helper) remained at the control level throughout all stages. The ratio of OKT4-positive to OKT8-positive T-cells (OKT4/OKT8), reflecting the balance of immunoregulatory T-cells, was, therefore, significantly decreased in patients with stage I-II lung cancer (P less than 0.05), especially in squamous cell lung cancer (P less than 0.05), whereas in stages III or IV, this T4/T8 ratio returned to the control level. In small cell carcinoma, the T4/T8 ratio was significantly decreased in stage III (P less than 0.01) and returned to the control level in stage IV.

Recombinant human interleukin-2 reverses in vitro-deficient cell-mediated immune responses to tuberculin purified protein derivative by lymphocytes of tuberculous patients.

In vitro lymphocyte proliferative response to purified protein derivative of tuberculin (PPD) was investigated in patients with tuberculosis. Peripheral blood lymphocytes (PBL) from patients with advanced, refractory tuberculosis showed a significantly depressed response compared with the response of PBL from patients with newly diagnosed tuberculosis (P less than 0.01). A further characterization of this low responsiveness to PPD revealed that PBL from these advanced tuberculous patients failed to generate interleukin-2 (IL-2) in response to PPD stimulation. IL-2 receptor (Tac antigen) expression on the surface of T cells after PPD stimulation was also impaired, although to a lesser extent, in the patients with advanced, refractory tuberculosis. We attempted to overcome the depressed in vitro response observed in PBL from patients with advanced, refractory tuberculosis and found that the addition of exogenous, recombinant IL-2 returned the depressed PPD-induced PBL proliferation in these patients to the level of response observed in PBL from patients with newly diagnosed tuberculosis. The addition of recombinant IL-2 also had a restorative effect (up regulation) in vitro on the partly impaired PPD-induced IL-2 receptor expression by PBL from the patients with advanced, refractory tuberculosis. Our results suggest that recombinant IL-2 may offer a novel approach to the therapy of advanced, drug-resistant tuberculosis.

Increase in rosette-forming T cells with autologous human erythrocytes in lymphocytes of patients with tuberculosis by in vitro stimulation with purified protein derivative.

Lymphocytes of tuberculous patients activated in vitro with purified protein derivative of tuberculin (PPD) were examined for rosette formation with human autologous erythrocytes. The percentage of the rosette-forming cell (auto-RFC) was increased when pleural fluid lymphocytes of patients with tuberculous pleurisy and peripheral blood lymphocytes (PBL) from patients with tuberculosis or from tuberculin skin test positive healthy individuals were stimulated with PPD in vitro, whereas no increase of auto-RFC was observed in PBL from tuberculin skin test negative donors. Increased numbers of auto-RFC were shown to form rosettes with sheep erythrocytes but have no IgG Fc receptors on their surfaces. It was also shown that adherent cells were required for the PPD-induced increase of auto-RFC. Depletion of PPD-induced auto-RFC by the density gradient sedimentation technique led to a significant decrease in the degree of the proliferative response to gradient sedimentation technique let to a significant decrease in the degree of the proliferative response to PPD and the number of the auto-RFC after stimulation with PPD. These findings strongly suggest that PPD-induced auto-RFC represents the consequence of an immunological interaction between sensitized T lymphocytes and relevant antigen PPD, and reflects the PPD responsiveness of tuberculosis at the T cell level.

Expression of IL-18 by Mycobacterium avium-infected human monocytes; association with M. avium virulence.

Disseminated Mycobacterium avium infection is the most frequent bacterial infection in patients with advanced AIDS and also associated with interferon-gamma (IFN-gamma) or IL-12 receptor deficiency. IFN-gamma is a key cytokine in host defence against M. avium infection. Expression of IL-18, a potent IFN-gamma inducer, and IFN-gamma by human monocytes after infection with M. avium was examined. Monocytes were co-cultured with isogenic smooth-transparent (SmT: virulent) or smooth-domed (SmD: avirulent) M. avium strains (10 organisms per monocyte). Infection with the SmD strain induced significantly higher concentration of IL-18 and IFN-gamma in culture supernatants than did the SmT strain. IFN-gamma production in response to M. avium was partially inhibited by anti-human IL-18 MoAb. Both recombinant human IL-12 (77 +/- 42 pg/ml, control versus 1492 +/- 141 pg/ml, cultures with IL-12 1 ng/ml) and IL-18 (126 +/- 37 pg/ml, control versus 2683 +/- 864 pg/ml, cultures with IL-18 10 ng/ml) augmented M. avium-induced IFN-gamma production. Freshly isolated uninfected monocytes expressed constitutive levels of IL-18. Following infection with M. avium, enhancement of IL-18 mRNA expression peaked at 3-6 h. IL-18 protein was detected in monocyte lysates as early as 1 h after infection with both SmT and SmD M. avium strains by Western blotting. Higher IL-18 expression by monocytes infected with the avirulent strain may result in more IFN-gamma production, thus modulating its pathogenicity. Local induction of IL-18 may be important both for M. avium pathogenicity and host defence and become a potential candidate for immunotherapy.