Changes in penile length after radical prostatectomy: effect of neoadjuvant androgen deprivation therapy.

Although reports have shown evidence for penile length (PL) shortening after radical prostatectomy (RP), the association between neoadjuvant androgen deprivation therapy (NADT) and PL after RP has yet to be determined. This study evaluates chronological changes in PL after NADT and RP. Stretched PLs (SPLs) of 143 patients, 41 of whom had undergone NADT, were measured before, 10 days after, and 1, 3, 6, 9, 12, 18, and 24 months after RP. Chronological erectile function and testosterone levels were then evaluated. SPL was shortest 10 days after RP in both the NADT (-) and NADT (+) groups and gradually recovered in length thereafter. SPL in the NADT (-) group was significantly longer than that in the NADT (+) group before RP. However, no significant differences in SPLs were found between both groups 6 months after RP. Although all subjects in the NADT (+) group had testosterone levels of <50 ng/dL before RP, such levels increased after RP. Before RP, the NADT (-) group was found to have significantly better erectile function than the NADT (+) group. However, differences in erectile function between the NADT (-) and NADT (+) groups after RP were not significant. This report is the first to show that among patients with prostate cancer, those who underwent NADT had greater PL recovery after RP than those who did not. Data regarding PL recovery after NADT and RP obtained in this study could be useful for patients with prostate cancer who plan to undergo such procedures.

Effects of testosterone replacement therapy on metabolic syndrome among Japanese hypogonadal men: A subanalysis of a prospective randomised controlled trial (EARTH study).

We investigated the effects of testosterone replacement therapy (TRT) on metabolic factors among hypogonadal men with a metabolic syndrome. From the study population of the EARTH study, which was a randomised controlled study in Japan, 65 hypogonadal patients with a metabolic syndrome, comprising the TRT group (n = 32) and controls (n = 33), were included in this study analysis. The TRT group was administered 250 mg of testosterone enanthate as an intramuscular injection every 4 weeks for 12 months. Waist circumference, body mass index, body fat volume and blood pressure were measured in all patients at baseline and at 12 months. In addition, blood biochemical data, including total cholesterol, triglyceride (TG), HDL cholesterol, fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) levels, were also evaluated. Changes in these categories from baseline to 12 months were compared between the TRT and control groups, with significant differences observed in waist circumference, body fat percentage, FPG, TG and HbA1c levels. No significant differences were observed in other parameters. TRT for 1 year was associated with improvements in some metabolic factors among Japanese men with hypogonadism and metabolic syndrome.

Effects of bethanechol chloride and distigmine bromide on postvoiding residual volume in patients with underactive bladder.

AIM: The efficacy of cholinergic drugs for reduction of post-voiding residual volume (PVR) in patients with underactive bladder is still controversial. This study was performed to examine whether cholinergic drugs have such an effect on PVR. METHODS: Patients with underactive bladder treated for more than two months with cholinergic drugs, which were later discontinued, were extracted retrospectively based on their charts. The changes in PVR, cholinesterase activity (ChE), renal function, and voiding function before and after discontinuation of cholinergic drugs were reviewed and analyzed. RESULTS: Twenty-nine patients were included in this study. In multiple linear regression analysis, the discontinuation of distigmine bromide (DB) was indicated as a significant covariate for PVR increase and ChE increase, while bethanechol chloride (BC) was not a significant covariate. The increase in ChE was significantly correlated with both PVR and voided volume after discontinuation of cholinergic drugs. CONCLUSION: DB could reduce PVR via a decrease in ChE. However, BC at doses up to 60 mg did not reduce PVR. DB may be recommended for the reduction of PVR in patients with underactive bladder.

Increased circulating interleukin-12 (IL-12) p40 in pulmonary sarcoidosis.

In sarcoidosis, a T helper 1 (Th1) response is an essential event and the up-regulation of interleukin-12 (IL-12) has been detected in affected disease sites. In order to investigate the clinical usefulness of circulating IL-12, we measured the serum concentrations of IL-12 by ELISA and performed immunohistochemistry using specific MoAbs for IL-12 in the lungs and scalene lymph nodes of patients with sarcoidosis. The serum concentration of IL-12 p40 was detectable in all 45 patients with pulmonary sarcoidosis and 18 normal controls, whereas that of IL-12 p70 was undetectable. The serum concentrations of IL-12 p40 in pulmonary sarcoidosis were significantly higher than those of the normal controls, especially in cases with abnormal intrathoracic findings detected by chest roentogenogram. The serum concentrations of interferon-gamma (IFN-gamma) also increased compared with those of normal controls and there was a significant positive correlation between the serum concentrations of IL-12 p40 and IFN-gamma. Furthermore, serum angiotensin-converting enzyme (ACE) and lysozyme, which are known to be useful markers for disease activity in sarcoidosis, correlated well with the serum concentrations of IL-12 p40. The positive 67Ga scan group (for lung field) had significantly elevated serum IL-12 p40 levels compared with those of the negative group. No bioactivity of IL-12 p70 was detected in three sarcoid cases sera by using the IL-12 responsive cell line. Finally, the immunohistochemical approach revealed that IL-12 p40 was expressed in the epithelioid cells and macrophages of sarcoid lungs and lymph nodes. We concluded that the production of IL-12 p40 was far greater in the sera and we have demonstrated this to be a useful clinical marker for disease activity and the Th1 response in pulmonary sarcoidosis.

IL-12 and IL-18 are increased and stimulate IFN-gamma production in sarcoid lungs.

Sarcoidosis is a systemic chronic granulomatous disease of unknown cause. Recent investigations revealed that the cytokine profile in inflamed lesions of sarcoidosis is Th1 dominant. To obtain better immunopathologic understanding of sarcoidosis, we examined the expression of IL-12 and IL-18 and their roles in IFN-gamma production in pulmonary sarcoidosis. Sarcoid cases had significantly elevated levels of IL-12 (p40 and p70) and IL-18 in bronchoalveolar lavage (BAL) fluids compared with healthy subjects. IL-12 p70 and IL-18 were immunohistochemically expressed in the epithelioid cells and giant cells of sarcoid granulomas. Significant induction of IFN-gamma, IL-12 p70, and IL-18 was observed from sarcoid BAL fluid cells with LPS stimulation, whereas LPS tended to induce only IL-12 p70 in BAL fluid cells from healthy subjects. Sarcoid cases had significantly greater IFN-gamma induction with LPS stimulation than healthy subjects did. IL-18 mRNA expression was observed in freshly isolated sarcoid BAL fluid cells as well as in LPS-stimulated sarcoid BAL fluid cells, but IFN-gamma and IL-12 mRNA expression was observed only in LPS-stimulated BAL fluid cells. Treatment with anti-IL-12- and anti-IL-18-neutralizing Abs significantly inhibited IFN-gamma production from LPS-stimulated BAL fluid cells of sarcoid cases. Coadministration of rIL-12 or rIL-18 induced greater IFN-gamma production in sarcoid BAL fluid cells than in normal BAL fluid cells. We concluded that bioactive IL-12 and IL-18 were produced in sarcoid BAL fluid cells and synergistically induced IFN-gamma production, indicating important cytokines in the Th1 response of sarcoidosis.

Increased levels of interleukin-18 in patients with pulmonary sarcoidosis.

Interleukin-18 (IL-18) has recently been identified as an interferon-gamma (IFN-gamma)-inducing factor, and it plays an important role in T helper 1 (Th1) response. We measured the serum levels of IL-18 and IFN- gamma in 37 patients with pulmonary sarcoidosis and 25 healthy control subjects. We also measured the levels of IL-18 and IFN-gamma in 10-fold concentrated bronchoalveolar lavage (BAL) fluids of 19 patients with pulmonary sarcoidosis and 9 healthy control subjects (all lifelong nonsmokers). The levels of serum IL-18 and IFN-gamma were significantly increased in patients with sarcoidosis. The levels of BAL fluid IL-18 were significantly elevated in patients with sarcoidosis, however, the IFN-gamma levels of the patients and control subjects were all below sensitivity. Serum IL-18 levels significantly correlated with serum IFN-gamma levels and lysozyme activity. The patients positive for gallium-67 ((67)Ga) scan had significantly elevated serum IL-18 levels as compared with those of the negative patients. BAL fluid IL-18 levels significantly correlated with serum IL-18 levels in patients with sarcoidosis, and there was a significant correlation between IL-18 levels and lymphocyte proportions in sarcoid BAL fluids. In patients with sarcoidosis, IL-18 seems to induce IFN-gamma production and IL-18 levels in sera may reflect disease activity of sarcoidosis.

Association of Clara cell 10-kDa protein, spontaneous regression and sarcoidosis.

Sarcoidosis is a systemic granulomatous disorder with a high rate of spontaneous regression. Clara cell 10-kDa protein (CC10), the predominant product of nonciliated bronchiolar epithelial cells, is a potent immunoregulatory and anti-inflammatory agent. CC10 levels were measured in sera and bronchoalveolar lavage (BAL) fluids from 31 sarcoidosis patients (nine progressive disease and 22 regressive disease) and their relevance to spontaneous regression investigated. The inhibitory effects of recombinant CC10 on interferon gamma (IFN-gamma) production were examined using lipopolysaccharide (LPS)-stimulated sarcoid BAL fluid cells, and the blocking effects of monoclonal antibody TY-5, directed against CC10, on CC10 function were also tested. Serum and BAL fluid CC10 levels in the regressive disease group were significantly higher than those in the progressive disease group (serum, p<0.05; BAL fluid, p<0.005) and healthy subjects (serum, p<0.0001; BAL fluid, p<0.005). CC10 inhibited, in part, IFN-gamma production from LPS-stimulated sarcoid BAL fluid cells (CC10 inhibition: 1,000 ng x mL(-1), 30%; 100 ng x mL(-1), 14%). TY-5 restored IFN-gamma production by blocking CC10 function. Sarcoidosis patients with regressive disease showed increased Clara cell 10-kDa protein levels in their sera and bronchoalveolar lavage fluids. Clara cell 10-kDa protein may be a regulator of the inflammatory process in sarcoidosis.

Enhanced mRNA expression of Th1 cytokines and IL-12 in active pulmonary sarcoidosis.

BACKGROUND AND AIM OF THE WORK: Active sarcoidosis is considered to be a Th1 dominant condition. We examined whether Th1 cytokines are highly expressed at inflammed lesions of Japanese patients with sarcoidosis. METHODS: To investigate the mRNA expression of Th1 cytokines and IL-12 in sarcoid BAL cells, we used semiquantitative reverse transcription--polymerase chain reaction method. RESULTS: The mRNA expressions of Th1 cytokines (IFN-gamma and IL-2) in active sarcoid BAL cells were significantly elevated as compared with those in healthy volunteers. The proportion of positive IL-4 mRNA expression in sarcoid BAL cells was not significantly higher than that in healthy volunteers. Further, there was no significant difference in IFN-gamma mRNA levels between the groups positive and negative for IL-4 mRNA expression. Although the proportion of positive expression of IL-12 mRNA in active sarcoid BAL cells was not significantly higher than that in healthy volunteers, the group positive for IL-12 mRNA expression had significantly elevated levels of IFN-gamma mRNA than did the negative group. CONCLUSIONS: These results may indicate that IL-12 induces IFN-gamma expression and subsequent Th1 dominant condition in Japanese patients with sarcoidosis.

Increased levels of circulating interleukin-18 in patients with advanced tuberculosis.

Interleukin-18 (IL-18) has recently been identified as an interferon- gamma-inducing factor and it plays an important role in the Th1 response. We measured serum levels of IL-18 and interferon-gamma (IFN-gamma) in 43 patients with pulmonary tuberculosis and 25 healthy control subjects. Significantly increased levels of circulating IL-18 and IFN-gamma were found in pulmonary tuberculosis as compared with those in healthy control subjects. Circulating IL-18 and IFN-gamma correlated with the extent of disease in pulmonary tuberculosis. We found significantly increased levels of circulating IL-18 and IFN-gamma in the patients with high-grade fever. Circulating IL-18 significantly correlated with circulating IFN-gamma. IL-18 may play an important role in immune response to human infection with Mycobacterium tuberculosis.

[Intrathoracic neurofibroma originating in the left vagus nerve].

A 20-year-old man was admitted because of an abnormal mass shadow on chest X-ray film. Computed tomography (CT) and magnetic resonance imaging (MRI) disclosed a mass lesion in the superior portion of the left mediastinum. CT scans showed a well-defined mass with low density. Axial MRI rendered the mass lesion with intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images. The preoperative diagnosis was bronchogenic cyst. Video-assisted thoracic surgery revealed that the tumor originated in the truncus of the left vagus nerve. The resected tumor was 90 x 24 x 18 mm in size. The postoperative course was uneventful and hoarseness did not develop. The pathologic diagnosis was benign mediastinal neurofibroma without von Recklinghausen's disease. Such cases are extremely rare in the Japanese literature.

Immunolocalization of extracellular matrix proteins and integrins in sarcoid lymph nodes.

To improve our understanding of the role of extracellular matrix (ECM) proteins and integrins during the processes of granuloma formation in sarcoidosis, we examined the distribution of ECM proteins and the expression of integrins in sarcoid lymph nodes by immunohistochemical methods. We also examined the expression of transforming growth factor-beta1 (TGF-beta1), which is one of major regulators for synthesis of ECM proteins. Most ECM proteins were detected in the periphery of the granulomas in a concentric pattern, and fibronectin was diffusely detected from an early to a regressive stage. Compared with normal lymph nodes, most beta1-integrin subfamilies (alpha1, alpha4, alpha5 and alpha6) were more strongly expressed on lymphocytes around the granulomas. Epithelioid cells exhibited strong expression of the alpha5 molecule. Fibroblasts exhibited the expression of the alpha2 and alpha5 molecules surrounding ECM proteins. The alpha5beta1 molecule had a distribution similar to that of fibronectin. TGF-beta1 was detected in epithelioid cells throughout the various evolutional stages and its expression was especially marked in mature granulomas. Interaction of fibronectin and the alpha5beta1 molecule may have an important role in the process of formation of sarcoid granuloma. The expression of TGF-beta1 may be involved in the regression of sarcoid granuloma by initiating fibrosis and atrophy of epithelioid cells.

Circulating soluble intercellular adhesion molecule-1 (sICAM-1) in patients with sarcoidosis.

sICAM-1 has been elevated in sera of specific inflammatory diseases, and circulating sICAM-1 concentrations reflect disease activity in these diseases. We measured circulating sICAM-1 concentrations and serum angiotensin-converting enzyme (SACE) activity in patients with sarcoidosis. Patients with sarcoidosis had significantly increased circulating sICAM-1 concentrations (62.8 +/- 33.5 U/ml) and SACE activity (23.7 +/- 7.4 U/l) compared with controls (circulating sICAM-1 50.9 +/- 12.1 U/ml, and SACE 13.5 +/- 3.8 U/l). Successive measurements showed that circulating sICAM-1 values changed in parallel with disease activity in sarcoidosis. In the progressive disease group (progressed or without change for 2 years or more), circulating sICAM-1 values (102.2 +/- 35.3 U/ml) at the time of diagnosis were significantly increased compared with those in the regressive disease group (disappeared or regressed within 2 years) 46.4 +/- 12.6 U/ml). However, there was no significant difference in SACE activity of the regressive and progressive disease groups. Fifteen patients with a high value of circulating sICAM-1 (> 75 U/ml, mean of controls + 2 s.d.) all had progressive disease, while only 15 of 44 patients with a high value of SACE had progressive disease. Circulating sICAM-1 will be a useful blood marker to predict outcome and to monitor disease activity in sarcoidosis.

Cranial defect and decrease in cerebral blood flow resulting from deep contact burn of the scalp in the neonatal period.

A case of cranial defect in the anterior fontanelle region is reported. The patient suffered a deep contact burn on the right parietofrontal region in the neonatal period. At age 3 years, a bone defect of 30 x 20 mm was observed in the right parietofrontal region, including the anterior fontanelle, and the pulsation of the brain was palpable. Moreover, scintigraphy of cerebral blood flow using SPECT with 99mTc-HMPAO demonstrated extensive decrease in blood flow in the right parietosquamosal region. Cranioplasty was performed at 3 years and 4 months using split ribs grafts and at age 5 years and 4 months using split-thickness calvarial bone grafts. After the cranioplasty, there was no bony defect and no region of reduced blood flow. The child is developing well.

Lactic dehydrogenase-immunoglobulin G kappa complex in a patient with idiopathic interstitial pneumonia.

A female patient with idiopathic interstitial pneumonia (IIP) was admitted again 40 months after the diagnosis due to progression of clinical findings and increased activity of serum lactic dehydrogenase (LDH). Analysis of LDH isoenzyme disclosed a broad band between LDH4 and LDH5. Gel filtration and immunoelectrophoresis showed that immunoglobulin (Ig) G (kappa type) bound the LDH. With prednisolone and azathioprine, her symptoms and radiological findings improved concomitant with a decrease in the serum LDH activity. The LDH-IgG kappa complex disappeared in the circulation 14 months after initiation of the therapy. We report circulating LDH-Ig complex in a patient with IIP, which may be related to the disease progression of IIP.

Soluble intercellular adhesion molecule-1 (ICAM-1) in sera and bronchoalveolar lavage (BAL) fluids of extrinsic allergic alveolitis.

ICAM-1 plays an important role in inflammatory diseases. We analysed ICAM-1 expression on BAL fluid cells and measured soluble ICAM-1 (sICAM-1) concentrations in sera and BAL fluids from patients with extrinsic allergic alveolitis (EAA). We found significantly increased cellular ICAM-1 expression on BAL fluid lymphocytes and alveolar macrophages, and significantly increased values of circulating and BAL fluid sICAM-1 in EAA patients compared with controls. Successive measurement showed prompt decrease of both sICAM-1 values in EAA patients during periods when antigen exposure was prevented. In BAL fluids from EAA patients, sICAM-1 values significantly correlated to neutrophil and ICAM-1+ lymphocyte counts. In EAA patients, circulating and BAL fluid sICAM-1 values has significant negative correlations to values of carbon monoxide diffusing capacity and to time intervals between last episode and sample collection. However, these values had significant positive correlation to values of alveolar-arterial oxygen pressure difference. In EAA, antigen exposure appears to induce cellular ICAM-1 expression on BAL fluid cells, and also appears to up-regulate shedding of ICAM-1 in the alveolar lining fluid and in the circulation. The sICAM values appear to reflect disease activity of EAA.

Pulmonary cryptococcal infection in an untreated patient with sarcoidosis.

A 36-year-old housewife was referred to our hospital in March, 1993. Her chest X ray films showed mediastinal and bilateral hilar lymphadenopathy. She was confirmed to have pulmonary sarcoidosis. We did not administer any medications for her. Four months after the diagnosis of sarcoidosis, opacities with cavitation appeared on the chest X ray. Histologic findings of lung biopsy specimens revealed granulomas with the existence of encapsulated Cryptococci. We administered an antifungal drug, itraconazole. The opacities were greatly improved by the medication. We report focal pulmonary cryptococcal infection in an untreated patient with sarcoidosis.

Circulating gamma delta-T-cell-receptor-positive lymphocytes in sarcoidosis.

We investigated phenotypic surface markers of peripheral blood lymphocytes including expression of gamma delta T cell receptor (TCR gamma delta) in 185 patients with sarcoidosis and 42 normal subjects. The proportion of TCR gamma delta+ lymphocytes in peripheral blood of patients with sarcoidosis (5.5 +/- 5.4%) was significantly higher than in normal subjects (3.6 +/- 2.2%; p < 0.05). A number of patients with sarcoidosis had prominently increased levels of circulating TCR gamma delta+ lymphocytes. Successive measurements of circulating TCR gamma delta+ lymphocytes demonstrated the persistence of increased levels of circulating TCR gamma delta+ lymphocytes. We divided the patients with sarcoidosis into two groups, one with high, the other with low TCR gamma delta+ expression. Compared with the low-value group, the high-value group had significantly decreased levels of circulating CD4+ lymphocytes, decreased incidence of a positive tuberculin reaction, and higher levels of serum angiotensin-converting enzyme and lysozyme, suggesting that these two groups may differ in their immunological response and disease activity of sarcoidosis. Measurement of TCR gamma delta+ expression in the circulation seems to be useful for estimating the disease activity of sarcoidosis.

Eosinophilic cationic protein in chronic eosinophilic pneumonia and eosinophilic granuloma.

We measured eosinophilic cationic protein (ECP) concentrations in the circulation and bronchoalveolar lavage (BAL) fluids from patients with chronic eosinophilic pneumonia, patients with eosinophilic granuloma, and normal control subjects. Significantly increased ECP concentrations were found in the circulation of patients with chronic eosinophilic pneumonia and with eosinophilic granuloma compared with those found in control subjects. The ECP concentrations were well correlated to eosinophil counts in the circulation of patients with chronic eosinophilic pneumonia, while they were not in patients with eosinophilic granuloma. Chronic eosinophilic pneumonia patients had prominently increased ECP concentrations in BAL fluids compared with those found in control subjects, while eosinophilic granuloma patients did not. Those concentrations in chronic eosinophilic pneumonia patients were well correlated to eosinophil counts in the BAL fluid. Corticosteroid therapy remarkably decreased circulating ECP concentrations in three patients with chronic eosinophilic pneumonia, but it had no significant effects in two patients with eosinophilic granuloma. Measurement of ECP concentrations seems to be useful to evaluate the disease activity of chronic eosinophilic pneumonia.

[Expression of integrin molecules in sarcoid lesions].

In order to assess the role of adhesion molecules in sarcoid lesions, we examined the expression of integrin families and extracellular matrix proteins by immunohistochemical techniques in sarcoid lymph nodes. Epithelioid cells exhibited intensive expression of ICAM-1, the alpha 5 and the beta 2 molecules. Lymphocytes exhibited intensive expression of ICAM-1, the alpha 4, the alpha 5 and beta 2 molecules. Laminin and type IV collagen were detected at basement membranes in vessels. Fibronectin was distributed within granulomas with a concentric pattern and around granulomas with a fibrillar pattern. Its distribution was well correspondence with the alpha 5 expression. These data suggest that integrin families might play an important role in granuloma formation and migration of lymphocytes into inflamed sarcoid lesions.

Increased level of circulating gamma/delta T cells in a patient with eosinophilic granuloma.

A patient with eosinophilic granuloma, histologically confirmed from open lung biopsy specimen, had a history of scarlet fever and a prominently high level of circulating gamma/delta T cells (25 percent) in comparison with normal levels (< 10 percent). Despite steroid therapy, the levels were persistently high. To our knowledge, this is the first report of an increased level of circulating gamma/delta T cells in a patient with eosinophilic granuloma.